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 to treat conditions, diseases, or disorders that would benefit from modulation of TYK2 activity.

Description

[0001] Cross-references to related applications This application claims the benefits of U.S. Provisional Application No. 63 / 604,080, filed November 29, 2023, and U.S. Provisional Application No. 63 / 717,459, filed November 7, 2024, which are incorporated herein by reference in their entirety. Background Technology

[0002] This disclosure relates to compounds that bind to the pseudokinase domain (JH2) of non-receptor tyrosine protein kinase 2 (TYK2). The compounds of this disclosure can inhibit several cytokine signaling pathways, such as IL-12, IL-23, and IFNα signaling. Further aspects of this disclosure include pharmaceutical compositions comprising the compounds described herein, methods of treating certain diseases using said compounds, and intermediates and methods for synthesizing said compounds.

[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins (including TYK2) are components of cytokine signaling. TYK2 is associated with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines associated with TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitins)) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncosin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). The activated TYK2 then continues to phosphorylate other signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. Summary of the Invention

[0004] The compounds described herein are regulators of the JAK kinase family. More specifically, the compounds disclosed herein are inhibitors of TYK2. In some embodiments, the compounds exhibit higher selectivity for TYK2 than for other JAKs. For example, the compounds may specifically bind to the pseudokinase domain (JH2) of TYK2, thereby enhancing selectivity for TYK2 relative to other JAK family members. In some embodiments, the compounds disclosed herein may be allosteric regulators or non-competitive inhibitors of TYK2. In other embodiments, the compounds described herein may be used to treat TYK2-mediated diseases or conditions. In some embodiments, the compounds disclosed herein cross the blood-brain barrier and interact with the central nervous system.

[0005] In one respect, this disclosure provides compounds of formula (I): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X 2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ;; R 12a and R 12bEach of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is a group of the following formula: ; in: Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R15 or -C(=O)OR 14 ; R 14 It consists of unsubstituted or substituted bicyclic carbon rings and unsubstituted or substituted bicyclic heterocycles; R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The functional groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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 can be 0, 1, 2 or 3.

[0006] In some embodiments, the compound of formula (I) is further defined as a compound of formula (IA): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0007] In some embodiments, the compound of formula (IA) is further defined as a compound of formula (IB): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0008] On the other hand, this disclosure provides compounds of formula (II): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 Is it CF or N, X 2 It is CH or CF, and X 3 It is N; or X 1 It is N, X 2 It is CH or CF, and X 3 Is it CH or CF? B 1 Is it N or CR?12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, wherein ring B is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; Or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is when X 1 It is N, X 2 It is CH, and X 3 When it is N, then no .

[0009] In some embodiments, the compound of formula (II) is further defined as a compound of formula (II-A): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0010] In some embodiments, the compound of formula (II-A) is further defined as a compound of formula (II-B): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0011] In yet another aspect, this disclosure provides compounds of formula (III): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X 2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; Or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R sThe groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is that when m is 1, then no .

[0012] In some embodiments, the compound of formula (III) is further defined as a compound of formula (III-A): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0013] In some embodiments, the compound of formula (III-A) is further defined as a compound of formula (III-B): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0014] This document considers any combination of groups described above for various variables. Throughout the specification, groups and substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0015] This document also describes pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts, tautomers, or solvates thereof, and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical compositions are formulated for administration to mammals via intravenous, subcutaneous, oral, inhalation, nasal, skin, or intraocular administration. In some embodiments, the pharmaceutical compositions are formulated for oral administration to mammals. In some embodiments, the pharmaceutical compositions are in the form of tablets, pills, capsules, liquids, suspensions, gels, dispersants, solutions, emulsions, ointments, or lotions. In some embodiments, the pharmaceutical compositions are in the form of tablets, pills, or capsules.

[0016] This document describes compounds of formulas (I)-(III), or pharmaceutically acceptable salts, tautomers, or solvates thereof, for the treatment of TYK2-mediated conditions. This document also describes compounds of formulas (I)-(III), or pharmaceutically acceptable salts, tautomers, or solvates thereof, for the treatment of inflammatory or autoimmune diseases. In some embodiments, the diseases are 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 neuromyelitis optica spectrum disorders, such as neuromyelitis optica.

[0017] In any of the foregoing aspects, including additional embodiments, an effective amount of a compound of formula (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, is administered to the mammal by: (a) systemic administration; and / or (b) oral administration to the mammal; and / or (c) intravenous administration to the mammal; and / or (d) administration by inhalation; and / or (e) administration by nasal administration; or and / or (f) administration by injection to the mammal; and / or (g) topical administration to the mammal; and / or (h) administration by intraocular administration; and / or (i) rectal administration to the mammal; and / or (j) non-systemic or non-local administration to the mammal.

[0018] In any of the foregoing aspects, additional embodiments are included that comprise a single administration of an effective amount of the compound, and further embodiments are included that the compound is administered to the mammal once daily, or that the compound is administered to the mammal multiple times throughout a day. In some embodiments, the compound is administered according to a continuous dosing regimen. In some embodiments, the compound is administered according to a continuous daily dosing regimen.

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

[0020] In some implementations, the compounds provided herein are administered orally to humans.

[0021] Articles are provided comprising packaging material, a compound described herein or a pharmaceutically acceptable salt thereof within the packaging material, and a label indicating the compound or composition, or a pharmaceutically acceptable salt thereof, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, the articles being used to modulate TYK2 or to treat, prevent, or improve one or more symptoms of a disease or condition that would benefit from modulating TYK2.

[0022] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of example only, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art based on this detailed description. Detailed Implementation

[0023] TYK2 activation is associated with many diseases and conditions, including inflammatory diseases and conditions, autoimmune diseases and conditions, respiratory diseases and conditions, and cancer.

[0024] Specifically, 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 a downstream effector of IL-23, TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Bechtel disease. TYK2 is also associated with skin diseases and conditions such as psoriasis, vitiligo, atopic dermatitis, and scleroderma; or eye diseases and conditions such as Sjögren'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 proliferation (GCH) and excessive mucus secretion are mediated by activation of the IL-13-induced 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 mutations in TYK2 lead to reduced neuronal demyelination and increased myelin regeneration, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders. Various type I IFN signaling pathways dependent on TYK2 signaling have implied the role of TYK2 in SLE and other autoimmune diseases and conditions.

[0027] TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Reduced TYK2 activity leads to protection of joints from collagen antibody-induced arthritis (a human model of rheumatoid arthritis).

[0028] TYK2 has also been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibit impaired cytotoxic T cell responses and accelerated tumor development. These effects are primarily due to the effective suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for treating autoimmune diseases or transplant rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 is a superior target because it is involved in fewer and more closely related signaling pathways, resulting in fewer off-target effects. However, studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL maintains cancer cell survival via TYK2 / STAT1 signaling in a highly IL-10-dependent manner by upregulating the anti-apoptotic protein BCL2. Knockdown of TYK2, rather than other JAK family members, reduces cell growth. Therefore, selective inhibition of TYK2 has been considered a suitable target for patients with IL-10 and / or BCL2-addictive tumors, such as those accounting for 70% of adult T-cell leukemia cases.

[0029] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptide. Reduced TYK2 phosphorylation of STAT3 following Aβ administration leads to reduced neuronal cell death, and increased STAT3 phosphorylation has been observed in the post-mortem brains of Alzheimer's disease patients.

[0030] Inhibition of the JAK-STAT signaling pathway is also involved in the reversal of hair growth and alopecia areata-related hair loss.

[0031] There is a persistent need for novel inhibitors with more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased migration across the blood-brain barrier, or compounds with increased activity or selectivity, which is higher than that for other JAK kinases, particularly JAK2. In some embodiments, this disclosure provides inhibitors of TYK2 that exhibit increased migration across the blood-brain barrier. In some embodiments, TYK2 inhibitors exhibit selectivity higher than that for JAK1, JAK2, and / or JAK3. In some embodiments, compounds with such selectivity (especially higher than that for JAK2) deliver a pharmacological response that advantageously treats one or more of the diseases or conditions described herein without the side effects associated with JAK2 inhibition. For example, compounds with increased activity or selectivity, which is higher than that for other JAK kinases, particularly JAK2. This disclosure relates to compounds that bind to the pseudokinase domain (JH2) of non-receptor tyrosine protein kinase 2 (TYK2) and inhibit certain cytokine signaling (especially IL-23 and IFNα signaling), to pharmaceutical compositions comprising these compounds, to methods of using these compounds to treat certain autoimmune diseases, multiple sclerosis (MS), lupus and systemic lupus erythematosus (SLE), and other CNS demyelinating diseases, and to intermediates and methods for synthesizing these compounds.

[0032] In some implementations, the TYK2 inhibitors described herein are used to treat diseases or conditions in mammals.

[0033] The compounds disclosed herein The compounds described herein, including their pharmaceutically acceptable salts, tautomers, and solvates, are inhibitors of TYK2. In some embodiments, the compounds described herein exhibit higher selectivity for TYK2 than for other JAKs. In some embodiments, the compounds described herein selectively / specifically bind to the pseudokinase domain (JH2) of TYK2. In some embodiments, the compounds described herein bind to the allosteric site of TYK2. In other embodiments, the compounds described herein can be used to treat TYK2-mediated diseases or conditions. In some embodiments, the compounds described herein exhibit improved blood-brain barrier penetration relative to previously disclosed TYK2 inhibitors.

[0034] In one respect, this disclosure provides compounds of formula (I): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is a group of the following formula: ; in: Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It consists of unsubstituted or substituted bicyclic carbon rings and unsubstituted or substituted bicyclic heterocycles; R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms to which they are attached, they form substituted or unsubstituted N-containing heterocycles; and; Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The functional groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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 can be 0, 1, 2 or 3.

[0035] On the other hand, this disclosure provides compounds of formula (II): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2--; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 Is it CF or N, X 2 It is CH or CF, and X 3 It is N; or X 1 It is N, X 2 It is CH or CF, and X 3 Is it CH or CF? B 1 Is it N or CR?12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; Or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms to which they are attached, they form substituted or unsubstituted N-containing heterocycles; and; Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The functional groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is when X 1 It is N, X 2 It is CH, and X 3 When it is N, then no .

[0036] In yet another aspect, this disclosure provides compounds of formula (III): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X 2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16)2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. Or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; Or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; Or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 16Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is that when m is 1, then no .

[0037] In some implementation schemes, R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is a C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is a C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is a C1-C4 alkyl, C1-C6 heteroalkyl, C1-C4 deuterated alkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is a C1-C4 alkyl, C1-C4 deuterated alkyl, or C3-C6 cycloalkyl. In some embodiments, R 4 It is a C1-C4 alkyl, C1-C6 heteroalkyl, or C1-C4 deuterated alkyl. In some embodiments, R 4 It is a C1-C4 alkyl or a C1-C4 deuterated alkyl. In some embodiments, R 4 It is a C1-C4 deuterated alkyl group. In some embodiments, R 4 It is 2,2,2-trideuterated ethyl-1-yl.

[0038] In some implementation schemes, R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 1It is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 1 It is hydrogen or a C1-C6 alkyl group. In some embodiments, R 1 It is hydrogen or a C1-C4 alkyl group. In some embodiments, R 1 It is hydrogen.

[0039] In some implementation schemes, R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic. In some embodiments, R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl. In some embodiments, R 5 It is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or C3-C4 cycloalkyl. In some embodiments, R 5 It is hydrogen or a C1-C4 alkyl group. In some embodiments, R 5 It is hydrogen.

[0040] In some implementation schemes, B 1 It is CR 12a And B 2 It is CR 12b ; or B 1 It is N and B 2 It is CR 12b ; or B 1 It is CR 12a And B 2 It is N; or B 1 It is N and B 2 It is N. In some implementations, B 1 It is CR 12a And B 2 It is CR 12b In some implementations, B 1 It is N; and B 2 It is CR 12b In some implementations, B 1 It is CR 12a And B 2 It is N.

[0041] In some implementation schemes, R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2.

[0042] In some implementation schemes, R 12a and R 12b Each of these can be independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, or -OR. 17 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-SO2R 17 or -SO2N(R) 16 )2. In some implementation schemes, R 12a and R 12b Each of these can be independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, or -OR. 17 -C(=O)N(R) 16 )2、-N(R 16 )2 or -SO2N(R 16 )2. In some implementation schemes, R 12a and R 12b Each of these can be independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, or -OR. 17 -N(R) 16 )2. In some implementation schemes, R 12a and R 12b Each of these can be independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, or -OR. 17 or -N(R) 16 )2. In some implementation schemes, R 12a and R 12b Each is independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 12a and R 12b Each is independently hydrogen, halogen, or -CN. In some implementations, R 12a and R 12b Each is independently either hydrogen or halogen. In some implementations, R 12a and R12b Each is hydrogen.

[0043] In some implementation schemes, B 1 It is CH. In some implementations, B 2 It is CH. In some implementations, B 1 and B 2 Each is CH.

[0044] In some implementations, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-. In some implementations, Z is -NR. 10 -, -O-, -S-, or -SO2-. In some implementations, Z is -NR. 10 -, -O-, or -SO2-. In some implementations, Z is -NR. 10 -, -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 -NR. 10 - or -O-. In some implementations, Z is -NR. 10 -

[0045] In some implementation schemes, R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl. In some embodiments, R 10 It is a C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a 4- to 6-membered heterocyclic alkyl. In some embodiments, R 10 It is hydrogen, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or a four-membered heterocyclic alkyl. In some embodiments, R 10 It is a C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or a four-membered heterocyclic alkyl. In some embodiments, R 10 It is hydrogen, C1-C4 alkyl, or C1-C4 deuterated alkyl. In some embodiments, R 10 It is a C1-C4 alkyl or a C1-C4 deuterated alkyl. In some embodiments, R 10 It is a C1-C6 alkyl group. In some embodiments, R 10 It is a C1-C4 alkyl group. In some embodiments, R 10 It is a methyl group.

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

[0047] In some embodiments, the compound of formula (I) is further defined as the compound of formula (IA): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0048] In some embodiments, the compound of formula (II) is further defined as the compound of formula (II-A): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0049] In some embodiments, compounds of formula (III) are further defined as compounds of formula (III-A): , Or its pharmaceutically acceptable salts, tautomers or solvates.

[0050] In some embodiments, ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C, where if ring A is replaced, then ring A is replaced by p R. 8 Examples of substitution. In another embodiment, ring A is an unsubstituted or substituted phenyl group, wherein if ring A is substituted, ring A is replaced by p R groups. 8 The instance is replaced.

[0051] In some embodiments, ring A is an unsubstituted or substituted 5- or 6-membered heterocycle, wherein A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 The instance is replaced.

[0052] In some embodiments, ring A is an unsubstituted or substituted 5- or 6-membered heterocyclic alkyl ring, wherein A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted 5-membered heterocyclic alkyl ring, wherein A... 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted 6-membered heterocyclic alkyl ring, wherein A... 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 The instance is replaced.

[0053] In some embodiments, ring A is an unsubstituted or substituted triazolone, an unsubstituted or substituted pyridinone, an unsubstituted or substituted pyridazinone, an unsubstituted or substituted imidazolidinone, or an unsubstituted or substituted oxazolidinone, wherein if ring A is substituted, then ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted triazolone, an unsubstituted or substituted pyridinone, or an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted triazolone or an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, ring A is replaced by one R 8 Substitution. In some embodiments, ring A is an unsubstituted or substituted triazolone, wherein if ring A is substituted, ring A is replaced by one R. 8 Substitution. In some embodiments, ring A is an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, ring A is replaced by one R. 8 replace.

[0054] In some embodiments, ring A is an unsubstituted or substituted triazolone, an unsubstituted or substituted pyridinone, an unsubstituted or substituted imidazolidinone, or an unsubstituted or substituted oxazolone, wherein if ring A is substituted, then ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted triazolone or an unsubstituted or substituted pyridinone, wherein if ring A is substituted, ring A is replaced by p R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted triazolone, wherein if ring A is substituted, ring A is replaced by one R. 8 replace.

[0055] In some implementation schemes, yes , , , or In some implementation schemes, yes or In some implementation schemes, yes In some implementation schemes, yes .

[0056] In some implementation schemes, yes , , or .

[0057] In some embodiments, ring A is an unsubstituted or substituted 5- or 6-membered heteroaryl ring, wherein A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 The instance is replaced.

[0058] In some embodiments, ring A is an unsubstituted or substituted 5-membered heteroaryl ring, wherein A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrrole, an unsubstituted or substituted furan, an unsubstituted or substituted thiophene, an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted oxazole, an unsubstituted or substituted isoxazole, an unsubstituted or substituted thiazole, an unsubstituted or substituted isothiazole, an unsubstituted or substituted triazole, an unsubstituted or substituted oxadiazole, an unsubstituted or substituted thiadiazole, an unsubstituted or substituted tetraazole, an unsubstituted or substituted triadimefon, an unsubstituted or substituted pyridazine, or an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, then ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted oxazole, an unsubstituted or substituted thiazole, an unsubstituted or substituted triazole, an unsubstituted or substituted tetraazole, an unsubstituted or substituted triadimefon, an unsubstituted or substituted pyridazine, or an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, then ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted thiazole, an unsubstituted or substituted triazole, an unsubstituted or substituted triadimefon, an unsubstituted or substituted pyridazine, or an unsubstituted or substituted pyridazinone, wherein if ring A is substituted, then ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted thiazole, an unsubstituted or substituted triazole, or an unsubstituted or substituted pyridazine, wherein if ring A is substituted, then ring A is p-R 8Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted thiazole, or an unsubstituted or substituted triazole, wherein if ring A is substituted, ring A is p-R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, an unsubstituted or substituted thiazole, or an unsubstituted or substituted triazole, wherein if ring A is substituted, ring A is replaced by p R 8 Examples of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole or an unsubstituted or substituted triazole, wherein if ring A is substituted, ring A is replaced by p R 8 The instances of substitution. In some embodiments, ring A is an unsubstituted or substituted pyrazole, wherein if ring A is substituted, ring A is replaced by p R 8 The instances of substitution. In some embodiments, ring A is an unsubstituted or substituted triazole, wherein if ring A is substituted, ring A is replaced by p R 8 The instance is replaced.

[0059] In some implementations, ring A is , , , , , , , , , or In some implementations, ring A is , , , , , , , , In some implementations, ring A is , , , , , or In some implementations, ring A is , or In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is In some implementations, ring A is .

[0060] In some implementation schemes, yes ;where A 1 and A 2 Each is independently N or C; and A 3 A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ;where A 1 and A 2 At least one of them is not C, or A 3 A 4 and A 5 At least one of them is not -CR 8 -

[0061] In some embodiments, the compound of formula (IA) is further defined as the compound of formula (IB): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0062] In some embodiments, the compound of formula (II-A) is further defined as the compound of formula (II-B): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0063] In some embodiments, the compound of formula (III-A) is further defined as the compound of formula (III-B): , Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

[0064] In some implementation schemes, A 1 It is C; A 2 It is N or C; A 3 It is N, CR 8 Or C=O; A 4 It is N, NR 8 , S or CR 8And A 5 It is N, NR 8 , S or CR 8 In some implementations, A 1 It is C; A 2 It is N or C; A 3 It is N, CR 8 Or C=O; A 4 It is NR 8 or CR 8 And A 5 It is N, NR 8 , S or CR 8 In another implementation scheme, A 1 It is C; A 2 It is N or C; A 3 Is it N or C=O; A 4 It is NR 8 or CR 8 And A 5 Is it N, S or CR? 8 .

[0065] In some implementation schemes: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 , O or S; and A 5 It is CR 8 ; Or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 , O or S; and A 5 It is N; Or A 1 It is C; A 2 It is C; A 3 It is NR 8 O or S; A 4 It is N; and A 5 It is N; Or A 1 It is C; A 2 It is C; A 3 It is NR 8 O or S; A 4 It is N; and A 5 It is CR 8 ; Or A 1 It is N; A 2 It is C; A 3 It is N; A4 It is N; and A 5 It is CR 8 ; Or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is N; and A 5 It is NR 8 ; Or A 1 It is C; A 2 It is N; A 3 It is N; A 4 It is CR 8 And A 5 It is N; Or A 1 It is C; A 2 It is N; A 3 It is N; A 4 It is N; and A 5 It is N; Or A 1 It is N; A 2 It is C; A 3 It is N; A 4 It is N; and A 5 It is N; Or A 1 It is C; A 2 It is N; A 3 It is N; A 4 It is CR 8 And A 5 It is CR 8 ; Or A 1 It is C; A 2 It is N; A 3 It is N; A 4 It is N; and A 5 It is CR 8 ; Or A 1 It is C; A 2 It is N; A 3 It is CR 8 A 4 It is N; and A 5 It is CR 8 ; Or A 1 It is C; A 2 It is N; A 3 It is CR 8 A 4 It is CR 8 And A 5 It is N; Or A1 It is N; A 2 It is C; A 3 It is N; A 4 It is CR 8 And A 5 It is CR 8 ; Or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is CR 8 And A 5 It is NR 8 , O or S; Or A 1 It is C; A 2 It is C; A 3 It is NR 8 O or S; A 4 It is CR 8 And A 5 It is N; Or A 1 It is C; A 2 It is N; A 3 It is C=O; A 4 It is NR 8 And A 5 It is N; Or A 1 It is C; A 2 It is C; A 3 Is it N or CR? 8 A 4 It is NR 8 And A 5 It is N; Or A 1 It is C; A 2 It is N; A 3 It is CR 8 A 4 It is N; and A 5 It is N.

[0066] In some implementation schemes: A 1 It is C; A 2 It is C; A 3 It is N; A 4 Is it N or NR? 8 And A 5 Is it N or NR? 8 In some implementation schemes: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8And A 5 It is N; Or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is N; and A 5 It is NR 8 .

[0067] In some implementation schemes, A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N. In some implementations, A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is N; and A 5 It is NR 8 .

[0068] In some implementation schemes: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 Is it N or CR? 8 In some implementation schemes: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N; Or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is CR 8 .

[0069] In some implementation schemes, A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N. In some implementations, A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR8 And A 5 It is CR 8 .

[0070] In some implementation schemes, A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N.

[0071] In some implementations, each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH.

[0072] In some implementations, each R 8Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH.

[0073] In some implementations, each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R 16 -CO2R 16 or -C(=O)N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH.

[0074] In some implementations, each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic, or unsubstituted or substituted heterocyclic; wherein if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 deuterated alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, or an unsubstituted or substituted heterocyclic ring; or two R atoms attached to the same carbon atom. 8 Together they form = O.

[0075] In some implementations, each R 8 Independently, it is an unsubstituted or substituted C1-C6 alkyl group. In some embodiments, each R... 8 It is methyl on its own.

[0076] In some implementations, at least one R 8 It is not methyl.

[0077] In some implementations, each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C2-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic, or unsubstituted or substituted heterocyclic; wherein if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 deuterated alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, or an unsubstituted or substituted heterocyclic ring; or two R atoms attached to the same carbon atom. 8 Together they form = O.

[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 implementations, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SO2R 17 or -SO2N(R) 16 2. In some implementations, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SO2R 17 or -SO2N(R) 16 2. In some implementations, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, -CN, -OH, -OR 17 and -N(R) 16 2. In some implementations, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 and -N(R)16 2. In some implementations, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 heteroalkyl. In some embodiments, each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 deuterated alkyl. In some embodiments, each R 6 and R 7 Independently, it is hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 heteroalkyl. In some embodiments, each R 6 and R 7 Independently, it is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 deuterated alkyl. In some embodiments, each R 6 and R 7 Independently, it is hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, or C1-C6 heteroalkyl. In some embodiments, each R 6 and R 7 It is independently hydrogen or C1-C4 alkyl. In some embodiments, each R... 6 and R 7 It is independently hydrogen or methyl. In some embodiments, each R is... 6 and R 7 It is hydrogen independently. In some implementations, each R... 6 and R 7 Independently, it is methyl. In some embodiments, an R 6 Or R 7 It is hydrogen or methyl. In some embodiments, an R 6 Or R 7 It is hydrogen. In some implementations, an R 6 Or R 7 It is a methyl group. In some embodiments, an R 6 It is hydrogen or methyl. In some embodiments, an R 6 It is hydrogen. In some implementations, an R 6 It is a methyl group. In some embodiments, an R 7 It is hydrogen or methyl. In some embodiments, an R 7 It is hydrogen. In some implementations, an R 7 It is methyl. In some embodiments, each R 6 and R 7 It is hydrogen. In some implementations, each R 6 It is methyl and each R 7 It is hydrogen. In some implementations, each R 6It is hydrogen and each R 7 It is a methyl group. In some embodiments, an R 6 It is methyl and has an R 7 It is hydrogen. In some implementations, an R 6 It is hydrogen and an R 7 It is a methyl group.

[0080] In some implementations, an R atom is attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes. In some embodiments, an R atom attached to the same carbon atom... 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O. In some embodiments, an R atom attached to the same carbon atom... 6 And an R 7 Together with the carbon atoms they are attached to, they form C3-C6 cycloalkanes. In some embodiments, an R atom attached to the same carbon atom... 6 And an R 7 Together with the carbon atoms they are attached to, they form C3-C4 cycloalkanes. In some embodiments, an R atom attached to the same carbon atom... 6 And an R 7 Together with the carbon atoms they are attached to, they form cyclopropane.

[0081] In some implementations, each R 6 and R 7 It is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 heteroalkyl; or an R bonded to the same carbon atom. 6 And an R 7 Together with the carbon atoms they are attached to, they form C3-C6 cycloalkanes. In some embodiments, each R... 6 and R 7 It is either hydrogen or methyl independently; or an R bonded to the same carbon atom. 6 And an R 7 Together with the carbon atoms they are attached to, they form cyclopropane. In some embodiments, each R... 6 and R 7 It can be either hydrogen or methyl.

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

[0083] In some implementation schemes: X 1It is CR 11 X 2 It is CR 11 And X 3 It is CR 11 ; or X 1 It is CR 11 X 2 It is CR 11 And X 3 It is N; or X 1 It is CR 11 X 2 It is N, and X 3 It is CR 11 ; or X 1 It is CR 11 X 2 It is N, and X 3 It is N; or X 1 It is N, X 2 It is CR 11 And X 3 It is CR 11 ; or X 1 It is N, X 2 It is CR 11 And X 3 It is N; or X 1 It is N, X 2 It is N, and X 3 It is CR 11 .

[0084] In some implementation schemes, X 1 It is CR 11 X 2 It is CR 11 And X 3 It is N.

[0085] In some implementations, each R 11 Independently, it is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-SO2R 17 or -SO2N(R) 16 2. In some implementations, each R 11 Independently, it is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR17 -C(=O)N(R) 16 )2、-N(R 16 )2 or -SO2N(R 16 2. In some implementations, each R 11 Independently, it is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 or -N(R) 16 2. In some implementations, each R 11 Independently, it is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR 17 or -N(R) 16 2. In some implementations, each R 11 Independently, it is hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, each R 11 Independently, it is hydrogen, halogen, C1-C6 alkyl, or -CN. In some embodiments, each R... 11 It is independently hydrogen, halogen, or -CN. In some implementations, each R... 11 Independently, it is hydrogen, halogen, or C1-C6 alkyl. In some embodiments, each R... 11 It can be hydrogen or halogen independently. In some implementations, each R... 11 It is either hydrogen or fluorine, independently. In some implementations, each R... 11 It is hydrogen. In some implementations, at least one R 11 It is hydrogen. In some implementations, at least one R 11 It's fluorine.

[0086] In some implementation schemes: X 1 It is CH, X 2 It is CH, and X 3 It is N; or X 1 It's CF, X 2 It is CH, and X 3 It is N; or X 1 It is N, X 2 It is CH, and X 3 It is N; or X 1 It is N, X 2 It is CH, and X 3 It is CH.

[0087] In some implementation schemes, X 1 It is CH, X 2 It is CH, and X3 It is N.

[0088] In some implementation schemes: X 1 It's CF, X 2 It is CH, and X 3 It is N; or X 1 It is N, X 2 It is CH, and X 3 It is N; or X 1 It is N, X 2 It is CH, and X 3 It is CH.

[0089] In some implementation schemes, X 1 It's CF, X 2 It is CH, and X 3 It is N. In some implementations, X 1 It is N, X 2 It is CH, and X 3 It is N. In some implementations, X 1 It is N, X 2 It is CH, and X 3 It is CH.

[0090] In some implementation schemes, R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 .

[0091] In some implementation schemes, R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 Ring B is an unsubstituted or substituted monocyclic carbide ring, an unsubstituted or substituted bicyclic carbide ring, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bicyclic heterocycle, an unsubstituted or substituted spirocyclic carbide ring, an unsubstituted or substituted spirocyclic heterocycle, an unsubstituted or substituted bridging carbide ring, or an unsubstituted or substituted bridging heterocycle, wherein if ring B is substituted, then ring B is q R 13 The instance is replaced.

[0092] In some implementation schemes, R 2 Ring B is an unsubstituted or substituted monocyclic carbide ring, an unsubstituted or substituted bicyclic carbide ring, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted, then ring B is q R 13 The instance is replaced.

[0093] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted monocyclic 5-membered heteroaryl, or an unsubstituted or substituted bicyclic heteroaryl, wherein if ring B is substituted, then ring B is q R 13 The instance is replaced.

[0094] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl, 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 surrounded by q R 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B 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 q R 13 The instance is replaced.

[0095] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted monocyclic 5-membered heteroaryl group, wherein if ring B is substituted, then ring B is substituted by q R groups. 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 The ring B is an unsubstituted or substituted pyrrole group, an unsubstituted or substituted furanyl group, an unsubstituted or substituted thiophene group, an unsubstituted or substituted pyrazolyl group, an unsubstituted or substituted imidazolyl group, an unsubstituted or substituted oxazolyl group, an unsubstituted or substituted isoxazolyl group, an unsubstituted or substituted thiazolyl group, an unsubstituted or substituted isothiazolyl group, an unsubstituted or substituted triazolyl group, an unsubstituted or substituted oxadiazolyl group, an unsubstituted or substituted thiadiazolyl group, or an unsubstituted or substituted tetrazolyl group, wherein if the ring B is substituted, the ring B is q R 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyrrole group, an unsubstituted or substituted imidazolyl group, an unsubstituted or substituted pyrazolyl group, an unsubstituted or substituted triazolyl group, or an unsubstituted or substituted tetrazolyl group, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In some implementations, R [is used].2 It is ring B, wherein ring B is an unsubstituted or substituted pyrrole group, an unsubstituted or substituted imidazole group, or an unsubstituted or substituted pyrazole group, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is unsubstituted or substituted pyrazolyl group, wherein if ring B is substituted, ring B is surrounded by q R groups. 13 The instance is replaced.

[0096] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl or an unsubstituted or substituted monocyclic 6-membered heteroaryl group, wherein if ring B is substituted, ring B is surrounded by q R groups. 13 The instance is replaced.

[0097] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl, an unsubstituted or substituted pyridyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridazinyl, wherein if ring B is substituted, then ring B is q R 13 The instance is replaced.

[0098] In some implementation schemes, R 2 It is ring B, wherein ring B is an unsubstituted or substituted monocyclic 6-membered heteroaryl group, wherein if ring B is substituted, then ring B is substituted by q R groups. 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyridinyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridazinyl, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is unsubstituted or substituted pyridinyl, wherein if ring B is substituted, then ring B is surrounded by q R groups. 13 Instances of [R] are replaced. In some implementations, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyrimidine group, wherein if ring B is substituted, then ring B is surrounded by q R groups. 13 The instance is replaced.

[0099] In another implementation scheme, R 2Ring B is an unsubstituted or substituted monocyclic carbide ring, an unsubstituted or substituted bicyclic carbide ring, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, wherein if ring B is substituted, then ring B is q R 13 The instance is replaced. In yet another implementation, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl, 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 surrounded by q R 13 The instance is replaced. In yet another implementation, R 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl or an unsubstituted or substituted monocyclic 6-membered heteroaryl group, wherein if ring B is substituted, ring B is surrounded by q R groups. 13 Instances of [R] are replaced. In another implementation, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted phenyl, an unsubstituted or substituted pyridyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridazinyl, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In other implementations, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl, wherein if ring B is substituted, then ring B is q R 13 Instances of [R] are replaced. In another implementation, R [is used]. 2 It is ring B, wherein ring B is an unsubstituted or substituted pyrimidine group, wherein if ring B is substituted, then ring B is surrounded by q R groups. 13 The instance is replaced.

[0100] In some implementation schemes: R 2 yes , , , , or And q is 0, 1, 2, 3 or 4.

[0101] In some implementation schemes: R 2 yes , , , or And q is 0, 1, 2, 3 or 4.

[0102] In another implementation scheme: R 2 yes or And q is 0, 1, 2, 3 or 4.

[0103] In some implementation schemes: R 2 yes or , where q is 0, 1, 2 or 3.

[0104] In yet another implementation scheme: R 2 yes And q is 0, 1, 2 or 3.

[0105] In some implementation schemes, R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; or groups of the following formula: In some implementations, R 2 It is -C(=O)R 14 ; or groups of the following formula: In some implementations, R 2 It is -C(=O)R 14 ; or groups of the following formula: In some implementations, R 2 It is -C(=O)R 14 ; or groups of the following formula: In some implementations, R 2 It is -C(=O)R 14 ; or groups of the following formula: .

[0106] In some implementation schemes, R 2 It is a group of the following formula: In some implementations, R 2 It is a group of the following formula: In some implementations, R 2 It is a group of the following formula: In some implementations, R 2 It is a group of the following formula: In some implementations, R 2 It is a group of the following formula: .

[0107] In some implementations, q is 0, 1, 2, or 3. In some implementations, q is 0, 1, or 2. In some implementations, q is 0, 1, or 3. In some implementations, q is 1, 2, or 3. In some implementations, q is 0, 1, or 2. In some implementations, q is 0, 2, or 3. In some implementations, q is 0 or 1. In some implementations, q is 0 or 2. In some implementations, q is 0 or 3. In some implementations, q is 1 or 2. In some implementations, q is 1 or 3. In some implementations, q is 2 or 3. In some implementations, q is 1. In other implementations, q is 2. In some implementations, q is 3. In some implementations, q is 0, and ring B is therefore unsubstituted.

[0108] In some implementations, each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SO2R 17 or -SO2N(R) 16 2. In some implementations, each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, or a -C(=O)R group. 16 -CO2R 16 or -C(=O)N(R) 16) 2. In some implementation schemes, each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted heterocyclic ring. In some embodiments, each R... 13 It is independently halogenated or unsubstituted or substituted C1-C6 alkyl. In some embodiments, each R 13 Independently, it is a halogen or an unsubstituted or substituted heterocycle. In some embodiments, each R... 13 Independently, it is an unsubstituted or substituted C1-C6 alkyl group or an unsubstituted or substituted heterocyclic group. In some embodiments, each R 13 Independently, it is a halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic alkyl, -C(=O)R16 -CO2R 16 or -C(=O)N(R) 16 2. In some implementations, each R 13 Independently, it is a halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, each R 13 It is halogen independently. In some implementations, each R... 13 Independently, it is an unsubstituted or substituted C1-C6 alkyl group. In some embodiments, at least one R 13 Independently, it is an unsubstituted or substituted C1-C6 alkyl group. In another embodiment, each R... 13 Independently, it is an unsubstituted C1-C4 alkyl group. In another embodiment, at least one R 13 Independently, it is an unsubstituted C1-C4 alkyl group. In yet another embodiment, each R 13 It is methyl. In some embodiments, at least one R 13 It is methyl. In some embodiments, each R 13 Independently, it is either an unsubstituted or substituted heterocycle. In some embodiments, each R... 13 Independently, it is an unsubstituted or substituted heterocyclic alkyl group. In some embodiments, each R... 13 It is an unsubstituted heterocyclic alkyl group on its own.

[0109] In some implementation schemes, R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 In some implementations, R 2 It is -C(=O)R 14 .

[0110] In some implementation schemes, R 14 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted monocyclic carbocyclic ring, an unsubstituted or substituted bicyclic carbocyclic ring, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 14 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl group, or an unsubstituted or substituted monocyclic carbocyclic ring. In some embodiments, R 14 It is an unsubstituted or substituted C1-C6 alkyl group or an unsubstituted or substituted monocyclic carbocyclic ring. In some embodiments, R 14 It is an unsubstituted or substituted monocyclic carbon ring. In some embodiments, R14 It is an unsubstituted or substituted C3-C8 cycloalkyl group. In some embodiments, R 14 It is an unsubstituted or substituted C3-C6 cycloalkyl group. In some embodiments, R 14 It is an unsubstituted or substituted C3-C4 cycloalkyl group. In some embodiments, R 14 It is an unsubstituted or substituted cyclopropyl group. In some embodiments, R 14 It is cyclopropyl.

[0111] In some implementation schemes, R 14 It is an unsubstituted or substituted bicyclic carbocyclic ring and an unsubstituted or substituted bicyclic heterocyclic ring. In some embodiments, R 14 It is an unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 14 It is an unsubstituted or substituted bicyclic carbon ring. In some embodiments, R 14 It is C5-C 12 Bicyclic carbon ring. In some implementations, R 14 It is C5-C 12 Bicyclic cycloalkyl.

[0112] In some implementation schemes, R 14 It is a group of the following formula: ; in: x and y are independently 0, 1, 2, 3, and 4, respectively, and 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 implementation schemes, R 14 It is a group of the following formula: ; in: x and y are each independently 0, 1, or 2, where the sum of x and y is at least 1; and z can be 1, 2, 3, or 4.

[0114] In some implementation schemes, R 14 It is a group of the following formula: ; in: x and y are each independently 0 or 1, where 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 implementations, z is 1, 2, 3, 4, 5, 6, 7, or 8. In some implementations, z is 1, 2, 3, or 4. In some implementations, z is 1, 2, or 3. In some implementations, z is 1 or 2. In some implementations, z is 1.

[0117] In some implementation schemes, R 14 yes .

[0118] In some implementations, each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3- C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocyclic alkyl groups. In some embodiments, each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C 3- C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl; or two R atoms on the same N atom 16 Together with the nitrogen atoms to which they are attached, they form substituted or unsubstituted N-containing heterocyclic alkyl groups. In some embodiments, each R 16 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C 3- C7 cycloalkyl or monocyclic 3- to 8-membered heterocyclic alkyl; or two R atoms on the same N atom 16 Together with the nitrogen atoms they are attached to, they form 4- to 6-membered N-containing heterocyclic alkyl groups.

[0119] In some implementations, each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, or a substituted or unsubstituted C3- C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, or a substituted or unsubstituted C 3- C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl. In some embodiments, each R 17 Independently, it is C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C 3- C7 cycloalkyl, or monocyclic 3- to 8-membered heterocyclic alkyl.

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

[0121] In some implementation schemes, R 2 A 1 A 2 Ring A, R 8 And p as described herein. In some implementations, R 2 A 1 A 2 Ring A, R 8 And p are as described in Table 1. In some implementations, A 1 A 2 Ring A, R 8 And p is as described in Table 1 or Table 2. In some embodiments, A 1 A 2 Ring A, R 8 p is as described in Table 1.

[0122] In some embodiments, the compounds described herein have the following structures: In some implementation schemes, X 1 X 3 A 1 A 2 Ring A, R 8 And p as described herein. In some implementations, X 1 X 3 A 1 A 2 Ring A, R 8 And p are as described in Table 2. In some implementations, A 1 A 2 Ring A, R8 And p is as described in Table 1 or Table 2. In some embodiments, A 1 A 2 Ring A, R 8 And p are as described in Table 2.

[0123] The exemplary compounds described herein include those described in the following table: Table 1 = A single isomer obtained by chiral separation of a racemic compound. Absolute configuration undetermined. † = As It is obtained as a racemic mixture. ‡ = Obtained as a mixture of diastereomers.

[0124] The compounds in Table 1 are named as follows: 1: rac-(R)-1-methyl-4-((5-(propionyl-3,3,3-d3)-4-((3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(1H)-one; 5: (S)-1-methyl-4-((5-(propionyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(1H)-one; 8: rac-(R)-N-(5-(propionyl-3,3,3-d3)-4-(((S)-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)pyridin-2-yl)spiro[2,2]pentane-1-carboxamide; and 9: rac-(R)-N-(5-(propionyl-3,3,3-d3)-4-(((R)-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)pyridin-2-yl)spiro[2,2]pentane-1-carboxamide.

[0125] In some implementations, pharmaceutically acceptable salts of the compounds described in Table 1 are provided herein.

[0126] Table 2 = A single isomer obtained by chiral separation of a racemic compound. Absolute configuration undetermined. † = As It is obtained as a racemic mixture. ‡ = Obtained as a mixture of diastereomers.

[0127] The compounds in Table 2 are named as follows: 2: rac-(R)-N-(4-((9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 3: rac-(R)-N-(4-((9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide; 10: (S)-N-(5-(propionyl-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)cyclopropaneformamide; 11: Rel-(R)-N-(5-(propionyl-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-(propionyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,5]naphthidin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide; and 13: Rel-(R)-N-(5-(propionyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,5]naphthidin-6-yl)amino)pyridin-2-yl)cyclopropanecarboxamide.

[0128] In some implementations, pharmaceutically acceptable salts of the compounds described in Table 2 are provided herein.

[0129] In some embodiments, the compounds described herein have the following structures: 4.

[0130] Compound 4 was named: N -(4-((2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-1,4'-[1,2,3]triazolo[4,5-c][1,7]naphthyl]-6'-yl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide. In some embodiments, a pharmaceutically acceptable salt of compound 4 is provided herein.

[0131] In one respect, the compounds described herein are in pharmaceutically acceptable salt form. Furthermore, the compounds described herein can exist in non-solventized form as well as in solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0132] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic at the concentration or amount used, i.e., that administering the material to an individual will not cause undesirable biological effects or harmful interactions with any of the components of the composition containing it.

[0133] The term "pharmaceutically acceptable salt" refers to a form of therapeutic agent consisting of a cationic form of the therapeutic agent combined with a suitable anionic combination, or, in an alternative embodiment, a combination of an anionic form of the therapeutic agent combined with a suitable cationic combination. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. Edited by PHStahl and CG WeRmuth.) Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley-VCH / VHCA, 2002 Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than nonionic substances, thus making them suitable for solid dosage forms. Furthermore, because their solubility is typically a function of pH, they may selectively dissolve in one part of the digestive tract or another, and this ability can be manipulated as an aspect of delayed-release and sustained-release behavior. Moreover, because salt-forming molecules can be in equilibrium in a neutral form, their transmembrane migration can be modulated.

[0134] In some embodiments, pharmaceutically acceptable salts are obtained by reacting compounds of formulas (I)-(III) with an acid. In some embodiments, compounds of formulas (I)-(III) (i.e., in their free base form) are basic and react with organic or inorganic acids. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethylsulfonic 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; caproic acid; caprylic acid; captanoic acid; caprylic acid; captanoic acid; caprylic acid; captanoic acid; caprylic acid; caproic acid; caprylic ... acid); carbonic acid; cinnamic acid; citric acid; cyclohexanoic acid; dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactosidic acid; gentic acid; glucoheponic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; glycerophosphate; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid ( p ) ; and undecenoic acid.

[0135] In some embodiments, the compounds of formulas (I)-(III) are prepared as chloride salts, sulfates, bromides, methanesulfonates, maleates, citrates, or phosphates.

[0136] In some embodiments, pharmaceutically acceptable salts are obtained by reacting compounds of formulas (I)-(III) with a base. In some embodiments, compounds of formulas (I)-(III) are acidic and react with a base. In this case, the acidic proton of the compound of formulas (I)-(III) is replaced by a metal ion (e.g., lithium, sodium, potassium, magnesium, calcium, or aluminum ions). In some cases, the compounds described herein coordinate with an organic base such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucosamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, etc. Acceptable inorganic bases for forming salts with compounds including acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, etc. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucosamine salts, or ammonium salts.

[0137] It should be understood that the pharmaceutically acceptable salts mentioned include solvation forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric solvent and is formed during the crystallization process by a pharmaceutically acceptable solvent (such as water, ethanol, etc.). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are conveniently prepared or formed during the methods described herein. Furthermore, the compounds provided herein are optionally present in both non-solventized and solvated forms.

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

[0139] In some embodiments, sites on the organic radicals (e.g., alkyl, aromatic rings) of compounds of formulas (I)-(III) are sensitive to various metabolic reactions. Incorporating suitable substituents into the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of aromatic rings to metabolic reactions are, by way of example, halogens, deuterium, alkyl, haloalkyl, or deuteralkyl.

[0140] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioactive isotopes) or by other means, including but not limited to the use of chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling.

[0141] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures provided herein, but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, such as... 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S, 18 F, 36 Cl、 123 I, 124 I, 125 I, 131 I, 32 P and 33 P. In one respect, the isotope-labeled compounds described herein, such as those doped with radioactive isotopes (e.g., 3 H and 14 Those of type C) can be used for drug and / or substrate tissue distribution assays. On the one hand, substitution with isotopes (such as deuterium) provides some therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dose requirements.

[0142] In some embodiments, the compounds of formula (I)-(III) have one or more stereocenters, and each stereocenter exists independently in an R or S configuration. In some embodiments, the compounds of formula (I)-(III) exist in an R configuration. In some embodiments, the compounds of formula (I)-(III) exist in an S configuration. The compounds provided herein include all diastereomers, single enantiomers, trans-blocking isomers, and epimers, and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, engegen (E), and cis (Z) isomers, and suitable mixtures thereof.

[0143] If desired, a single stereoisomer may be obtained by methods such as stereoselective synthesis and / or separation of stereoisomers using chiral columns, or separation of diastereomers using achiral or chiral columns, or by crystallization and recrystallization in a suitable solvent or solvent mixture. In some embodiments, compounds of formulas (I)-(III) are prepared as single stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers, and recovering the optically pure single enantiomer. In some embodiments, a covalent diastereomeric derivative of the compounds described herein is used to resolve the single enantiomer. In another embodiment, diastereomers are separated by a separation / resolution technique based on solubility differences. In other embodiments, stereoisomers are separated by chromatography or by forming diastereomeric salts and separating 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, the stereoisomers are obtained by stereoselective synthesis.

[0144] In some embodiments, the compounds described herein are prepared as prodrugs. A “prodrug” is a pharmaceutical agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, they can be bioavailable by oral administration, while the parent drug cannot. Furthermore or alternatively, prodrugs also have superior solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug is designed to enhance effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester (“prodrug”) but subsequently metabolized and hydrolyzed to provide the active entity. Other examples of prodrugs are short peptides (polyamino acids) bonded to acid groups, wherein the peptide is metabolized to expose the active moiety. In some embodiments, upon administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, the prodrug is enzymatically metabolized through one or more steps or processes into a biologically, pharmaceutically, or therapeutically active form of the compound.

[0145] The prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkoxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonates. See, for example, *Design of Prodrugs*, Bundgaard, A., ed., *Elseview*, 1985; and *Method in Enzymology*, Widder, K. et al., eds.; *Academic*, 1985, Vol. 42, pp. 309–396; “Design and Application of Prodrugs” in *A Textbook of Drug Design and Development*, Bundgaard, H., Krosgaard-Larsen and H. Bundgaard, eds., 1991, Chapter 5, pp. 113–191; and Bundgaard, H., *Advanced Drug Delivery Review*, 1992, 8, 1–38, each of which is incorporated herein by reference. In some embodiments, the 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, etc. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, wherein the hydroxyl group is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0146] The prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce compounds of formulas (I)-(III) as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0147] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is functionalized in a suitable manner to provide a prodrug moiety. In some embodiments, the prodrug moiety is as described above.

[0148] In addition, or in another embodiment, the compounds described herein are metabolized upon administration to an organism in need to produce metabolites, which are then used to produce the desired effects, including the desired therapeutic effects.

[0149] The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to a biologically active derivative of the compound formed when the compound is metabolized. As used herein, the term "metabolism" refers to the sum of processes by which an organism alters a particular substance (including, but not limited to, hydrolysis and enzyme-catalyzed reactions). Thus, enzymes can produce specific structural changes in compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronide transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. The metabolites of the compounds disclosed herein may optionally be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0150] In some cases, heterocycles may exist in tautomeric forms. In such cases, it should be understood that the structure of the compound is shown or named in one tautomeric form, but alternative tautomeric forms may also be shown or named. Alternative tautomeric forms are explicitly included in this disclosure, such as, for example, the structures shown below. For example, pyridones may exist in the following tautomeric forms: , and All of these are contained within the group "substituted pyridine". Similarly, triazolones can exist in the following tautomeric forms, including zwitterionic forms: , and All of these are contained within the group “substituted 5-membered heteroaryl”. Similarly, pyridazinones can exist in the following tautomeric forms, including zwitterionic forms: , and All of these are included in the group “substituted 6-membered heteroaryl”. Similarly, tautomerizations of pyrazoles, triazoles, pyrimidines, etc. are known; for the purposes of this disclosure, all tautomers (including charged and zwitterionic tautomers) are considered to be within the scope of this disclosure.

[0151] General synthesis of the compounds disclosed herein The compounds of formulas (I)-(III) described herein were synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0152] Unless otherwise specified, use standard methods such as mass spectrometry, NMR, and HPLC.

[0153] The compounds were prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variations in solvent, reaction temperature, reaction time, and different chemical reagents and other reaction conditions.

[0154] In some embodiments, the compounds described herein are prepared as described in or similarly to Scheme A.

[0155] Option A: The variables are defined in equations (I)-(III).

[0156] In some embodiments, a chlorine group of intermediate A undergoes nucleophilic substitution with the free amino group of B to yield intermediate C. In some embodiments, for example when intermediate A is a pyridazine compound (B... 1 When the intermediate B is N, the 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 (B... 1 When the amino group is substituted (=CH), the substitution is carried out by deprotonating the amino group with a suitable base (such as LDA). In other embodiments, intermediate C can be obtained by a cross-coupling reaction of intermediates A and B. The cross-coupling reaction can be an organometallic cross-coupling, such as the Suzuki-Miyaura reaction, the Buchwald-Hartwig reaction, the Heck reaction, the Ullman coupling, the Chan-Lam coupling, etc. Finally, in some embodiments, intermediate C is converted into the final compound D (e.g., compound 1) via a cross-coupling reaction. The cross-coupling reaction can be an organometallic cross-coupling, such as the Suzuki-Miyaura reaction, the Buchwald-Hartwig reaction, the Heck reaction, the Ullman coupling, the Chan-Lam coupling, etc.

[0157] In some implementations, the compound is prepared as described in the examples.

[0158] Specific terms Unless otherwise stated, the following terms as used in this application have the definitions given below. The use of the term "including" and other forms such as "include," "includes," and "included" is not restrictive. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter.

[0159] As used in this article, C1-Cx Including C1-C2, C1-C3... C1-C x For example only, a group designated as "C1-C6" indicates that the moiety contains one to six carbon atoms, that is, a group containing one, two, three, or four carbon atoms. Therefore, for example only, "C1-C4 alkyl" indicates that the alkyl group contains one to four carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0160] "Alkyl" refers to an aliphatic hydrocarbon group. Alkyl groups can be branched or straight-chained. In some embodiments, "alkyl" has 1 to 10 carbon atoms, i.e., C1-C1. 10 Alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers the occurrence of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0161] "alkylene" refers to a divalent alkyl radical. Any of the monovalent alkyl groups described above can be converted into an alkylene group by removing a second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a C1-C6 alkylene group. In other embodiments, the alkylene group is a C1-C4 alkylene group. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. In some embodiments, the alkylene group is -CH2-.

[0162] "Alkoxy" refers to an (alkyl) O- group, where the alkyl group is as defined herein.

[0163] The term "alkylamine" refers to -N (alkyl) x H y A group, wherein x is 0 and y is 2, or wherein x is 1 and y is 1, or wherein x is 2 and y is 0.

[0164] "Hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is replaced by a hydroxyl group. In some embodiments, the hydroxyalkyl group is a C1-C4 hydroxyalkyl group. Representative hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, etc.

[0165] "Aminoalkyl" refers to an alkyl group in which one hydrogen atom is replaced by an amino group. In some embodiments, the aminoalkyl group is a C1-C4 aminoalkyl group. Representative aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, etc.

[0166] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the remaining portion of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0167] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkenyl group has the formula -C≡CR, where R refers to the remaining portion of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0168] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof). The heteroalkyl group is attached to the rest of the molecule at a carbon atom. In one aspect, heteroalkyl groups are C1-C6 heteroalkyl groups.

[0169] The term "deuterated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by deuterium atoms. In one aspect, deuterated alkyl groups are C1-C6 deuterated alkyl groups.

[0170] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The term "aromatic" includes 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 sharing adjacent carbon atom pairs) groups.

[0171] The term "carbocyclic" or "carbon ring" refers to a ring or ring system in which all atoms forming the ring skeleton are carbon atoms. Therefore, this term distinguishes a carbocyclic ring from a "heterocyclic" ring or "heterocyclic ring" in which the ring skeleton contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocyclic ring is aromatic. In some embodiments, both rings of a bicyclic carbocyclic ring are aromatic. Carbocyclic rings include aryl and cycloalkyl groups. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocyclic rings can be fused, bridged, or spirocyclic systems.

[0172] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. In one embodiment, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is phenyl, naphthyl, indenyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl group is C6-C. 10 Aryl group. Depending on their structure, aryl groups can be monoradical or diradical (i.e., arylene).

[0173] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each atom forming the ring (i.e., the skeleton atom) is a carbon atom. In some embodiments, the bicyclic cycloalkyl is fused, spirocyclic, or bridged. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the bonding point is located on a carbon atom that is not an aromatic ring carbon atom. In some embodiments, the cycloalkyl comprises a group having 3 to 10 ring atoms. In some embodiments, the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl.

[0174] The term "halogenated group" or alternatively "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine. In some embodiments, the halogenated group is fluorine, chlorine, or bromine.

[0175] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, fluoroalkyl groups are C1-C6 fluoroalkyl groups.

[0176] The term “fluoroalkoxy” refers to a (fluoroalkyl) O- group, wherein the fluoroalkyl group is as defined herein.

[0177] The term "heterocyclic" or "heterocyclic" refers to a heteroaromatic ring (also called a heteroaryl ring) and a heterocyclic alkyl ring containing one to four heteroatoms, wherein each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also called heterocyclic alkyl groups) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo[a]-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinone, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxalyl, piperazine, acridineyl, aziridine, oxacyclobutane, oxacyclobutane, thiohepane, high-piperidinyl, oxacycloheptane, thiohepane, oxazacycloheptane, diazacycloheptane, thioazacycloheptane, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolane, pyrazolinyl, and dithiane. The group includes: dithiopentyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, indololin-2-one, isoindololin-1-one, isoindololin-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindololin-1,3-dithionyl, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazo-2(3H)-one, benzo[d]thiazo-2(3H)-one, and quinazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazole, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, quinolinyl, isoquinolinyl, indoleyl, benzimidazolyl, benzofuranyl, cenolinyl, indazole, indazinyl, phthalazinyl, pyridazinyl, triazinyl, isoydinolyl, pteridinyl, purine, oxadiazolyl, thiazolyl, furazonyl, benzofuranyl, benzothiophene, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphridinyl, and furanylpyridinyl. Where possible, the aforementioned groups are C-attached or C-linked. N Linked. For example, groups derived from pyrrole include pyrrole-1-yl ( N (C-linked) or pyrrole-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazole-1-yl or imidazole-3-yl (both... N(Linked), or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C-linked). Heterocyclic groups include benzo[a]-fused ring systems. The non-aromatic heterocycle is optionally substituted with one or two oxo (=O) moieties, such as pyrrolidone-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0178] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group comprising one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic and bicyclic heteroaryl groups. Monocyclic heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thiophene, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, pyridazinyl, triazinyl, oxadiazolyl, thiazolyl, and furazonyl. Monocyclic heteroaryl groups include indazine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinazine, quinoline, isoquinoline, cinnamoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthidine, and pteridine. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group.

[0179] "Heterocyclic alkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is fused with an aryl or heteroaryl group. In some embodiments, the heterocyclic alkyl group is oxazolidinone, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, piperidin-2-one, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-diketone, pyrrolidine-2,5-one, imidazoalkyl, imidazoalkyl-2-one, or thiazoalkyl-2-one. In one aspect, the heterocyclic alkyl group is C2-C 10 Heterocyclic alkyl groups. On the other hand, heterocyclic alkyl groups are C4-C6. 10Heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group is monocyclic or bicyclic. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, the heterocyclic alkyl group is monocyclic and is a 3 or 4-membered ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms in the ring. In some embodiments, the heterocyclic alkyl group contains 0-2 nitrogen atoms, 0-2 oxygen atoms, and 0-1 sulfur atoms in the ring.

[0180] The term "bond" or "single bond" refers to a chemical bond between two atoms, or a chemical bond between two parts when the atoms connected by the bond are considered part of a larger substructure. In one aspect, when the group described herein is a bond, the mentioned group is absent, thus allowing bonds to form between the remaining identified groups.

[0181] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0182] The terms “optionally substituted” or “substituted” mean that the mentioned group is optionally substituted by one or more additional groups selected individually and independently from the following: 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, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some other embodiments, the optional substituents are independently selected from halogens, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2(C1-C4 alkyl). In some embodiments, the optional substituents are independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, the substituted group is substituted by one or two of the aforementioned groups. In some embodiments, the optional substituents on the aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0183] In some embodiments, each substituted alkyl group, substituted deuterated alkyl group, substituted fluoroalkyl group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is independently selected from one or more of deuterium, halogen, C1-C6 alkyl group, monocyclic carbocyclic ring, monocyclic heterocyclic ring, -CN, -OR 18 -CO2R 18 -C(=O)N(R) 18 )2、-N(R 18 )2、-NR 18 C(=O)R 19 -SR 18 -S(=O)R 19 -SO2R 19 or -SO2N(R) 18 )2 of R s Group substitution; each R18 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; each R 19 It is independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

[0184] As used herein with respect to formulations, compositions or ingredients, the term "acceptable" means that it does not have a lasting harmful effect on the overall health of the person being treated.

[0185] As used herein, the term “modulation” means, directly or indirectly, interacting with a target to alter its activity, including, by way of example only, enhancing, inhibiting, limiting, or prolonging the activity of a target.

[0186] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inhibitor.

[0187] As used herein, the term "degrader" refers to a bifunctional compound that binds to and / or inhibits TYK2 kinase and E3 ubiquitin ligase, leading to ubiquitination and subsequent degradation of TYK2 kinase. Specifically, in some cases, the degrader is a bifunctional or proteolytically targeted chimeric (PROTAC®) protein degrader compound that is found to function as a regulator of targeted ubiquitination of TYK2 proteins, which are then degraded and / or inhibited by the bifunctional compound. In some cases, such bifunctional molecules function by recruiting TYK2 kinase to E3 ubiquitin ligase for ubiquitination and subsequent degradation of TYK2 kinase. The degrader comprises a TYK2-binding moiety optionally binding to the E3 ubiquitin ligase moiety via a linker (e.g., comprising the group of compounds described herein).

[0188] As used herein, the terms “administer,” “administering,” and “administration” refer to methods that can deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral, duodenal, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0189] As used herein, the term "co-administration" refers to a treatment regimen that includes the administration of a selected therapeutic agent to a single patient and is intended to include agents administered via the same or different routes of administration or at the same or different times.

[0190] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate quantity of an applied agent or compound that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. Results include a reduction and / or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. In any individual case, the appropriate "effective" amount may optionally be determined using techniques such as dose escalation studies.

[0191] As used herein, the terms “enhance” or “enhancing” refer to increasing or prolonging the potency or duration of a desired effect. Therefore, in relation to enhancing the effect of a therapeutic agent, the term “enhancement” refers to the ability to increase or prolong the effect of another therapeutic agent on the system in terms of potency or duration. As used herein, “enhancing effective amount” refers to an amount sufficient to enhance the effect of another therapeutic agent on the desired system.

[0192] As used herein, the term "drug combination" refers to a product resulting from the mixing or combination of more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of the active ingredient (e.g., a compound of formula (I)-(III) or a pharmaceutically acceptable salt thereof) and a co-administered agent to a patient as a single entity or dose. The term "non-fixed combination" refers to the simultaneous, parallel, or sequential administration of the active ingredient (e.g., a compound of formula (I)-(III) or a pharmaceutically acceptable salt thereof) and a co-administered agent as separate entities to a patient without a specific time interval, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0193] The terms “product” and “kit” are used as synonyms.

[0194] The term "object" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees) and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one respect, a mammal is a human.

[0195] As used herein, the terms “treat,” “treating,” or “treatment” include the reduction, decrease, or improvement of at least one symptom of a disease or condition, prevention of additional symptoms, suppression of a disease or condition, for example, preventing the development or progression of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, alleviating secondary conditions caused by a disease or condition, or preventively and / or therapeutically stopping the symptoms of a disease or condition.

[0196] Pharmaceutical Composition In another aspect, this disclosure provides pharmaceutical compositions comprising the compounds of this disclosure or their pharmaceutically acceptable salts, tautomers, or solvates, and pharmaceutically acceptable excipients. In some embodiments, the compounds described herein are formulated in a pharmaceutical composition. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically applicable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[0197] In some embodiments, the compounds or pharmaceutical compositions of this disclosure can be used to treat TYK2-mediated diseases or conditions. In some embodiments, the pharmaceutical compositions are effective in treating diseases or conditions in which TYK2 is overexpressed or excessively active. In some embodiments, the pharmaceutical compositions are effective in treating diseases or conditions in which TYK2 activity or expression is reduced.

[0198] In some embodiments, the pharmaceutical composition can be used to treat diseases or conditions associated with high levels of TYK2-driven cytokines such as interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-CO, and IFN-ζ (also known as restriction proteins)) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncosin M, ciliary neurotrophic factor, myocardial trophic factor 1, myocardial trophic-like cytokines, and LIF). In some embodiments, the disease or condition is an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease or condition, type 1 diabetes, and interferon disorders (such as Alcardi-Goutieres syndrome), or a combination thereof.

[0199] In some embodiments, the pharmaceutical composition can be used to treat an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is an autoinflammatory disease or condition, a host-mediated inflammatory disease or condition, an injury-related inflammatory disease or condition, an infection-related inflammatory disease or condition, or an overproliferative (e.g., cancer, fibrosis)-mediated inflammatory disease or condition. In some embodiments, the inflammatory disease or condition, or the infection-related inflammatory disease or condition, is a respiratory disease or condition. In some embodiments, the respiratory disease or condition is associated with a virus in a microbial infection. In some embodiments, the respiratory disease or condition is a problematic immune response to a viral or microbial infection. In some embodiments, the respiratory disease or condition is associated with a coronavirus (such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2). In some embodiments, the pharmaceutical composition effectively reduces symptoms associated with COVID-19 or the immune response associated with it.

[0200] In some embodiments, the pharmaceutical composition can be used to treat autoimmune diseases or conditions. In some embodiments, the autoimmune diseases or conditions are rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye syndrome, intestinal diseases, Crohn's disease, ulcerative colitis, celiac disease, Bechtel disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the autoimmune disease or condition is lupus or systemic lupus erythematosus. In some embodiments, the autoimmune disease or condition is psoriasis. In some embodiments, the autoimmune disease or condition is irritable bowel syndrome (IBS) or irritable bowel syndrome with diarrhea (IBS-D). In some embodiments, the autoimmune disease or condition is dry eye syndrome or uveitis. In some embodiments, the autoimmune disease or condition is Crohn's disease. In some implementations, the autoimmune disease or condition is atopic dermatitis.

[0201] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. The administration of the compounds and compositions described herein can be influenced by any method capable of delivering the compounds to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, although the most suitable route may depend, for example, on the recipient's condition and illness. By way of example only, the compounds described herein can be applied topically to the area requiring treatment, for example, through topical application (such as creams or ointments). Further examples of topical application of the compounds of the present invention include eye drops, eye creams, gels or hydrogels, implants, transdermal patches, or drug reservoirs. In some embodiments, the pharmaceutical composition is administered orally (e.g., as a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, or dry powder spray).

[0202] In some embodiments, the pharmaceutical composition suitable for oral administration is in the form of discrete units, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. In some embodiments, the active ingredient is in the form of pellets, saccharin, or paste.

[0203] Orally applicable pharmaceutical compositions include tablets, push-in capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compression of the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, inert diluent or lubricant, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored and formulated to provide sustained or controlled release of the active ingredient therein. The dosage of all formulations intended for oral administration should be appropriate for such administration. Push-in capsules may contain the active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The sugar-coated core has a suitable coating. For this purpose, a concentrated sugar solution may be used, which optionally contains gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or sugar-coated core coating to identify or characterize different combinations of active compound dosages.

[0204] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection (e.g., by bolus or continuous infusion). Injectable formulations may be present in single-dose units, such as in ampoules or multi-dose containers, with added preservatives. The composition may be in the form of a suspension, solution, or emulsion in an oily or aqueous medium and may contain formulations such as suspending agents, stabilizers, and / or dispersants. The composition may be present in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be in powder form or stored under lyophilized (freeze-dried) conditions, requiring only the immediate addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, prior to use. Temporary injectable solutions and suspensions may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0205] Pharmaceutical compositions can also be formulated as long-acting formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneously). Thus, for example, compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0206] The pharmaceutical composition can be administered topically, i.e., by non-systemic administration. This includes external application of the compound of this disclosure to the epidermis or buccal cavity, and placement of such compound in the ear, eye, and nose such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0207] Pharmaceutical compositions suitable for topical application include liquid or semi-liquid formulations suitable for penetrating the skin to reach the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, as well as drops suitable for application to the eyes, ears, or nose. For topical application, the active ingredient may be 0.001% to 10% w / w, for example, 1% to 2% by weight of the formulation.

[0208] Pharmaceutical compositions for inhalation administration are conveniently delivered by an inhaler, a pressurized nebulizer pack, or other convenient method of delivering aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. For pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for inhalation or inhalation administration, the pharmaceutical formulation may be in the form of a dry powder composition, such as a mixture of a compound and a suitable powder matrix (such as lactose or starch). The powder composition may be present in unit dosage forms, such as in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered by means of an inhaler or inhaler.

[0209] It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other conventional agents in the art that take into account the types of formulations discussed, such as flavoring agents, for example, those formulations suitable for oral administration.

[0210] TYK2 and Central Nervous System (CNS) Disorders TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. TYK2 is associated with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines associated with TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as restriction proteins)) and interleukins (e.g., IL-6, IL-10, IL-12, IL-23, oncosin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF).

[0211] Mice containing the loss-of-function (LoF) mutation of rs3456443 in the TYK2 pseudokinase domain showed a reduced risk of acute exacerbation of immune encephalopathy (EAE), with evidence suggesting 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 in primary human immune cells via the rs3456443 genotype confirmed a wild-type-heterozygous-homozygous dose-response to IFN-α / β, IL-23, and IL-12, confirming the TYK2 LoF mutation. This LoF mutation in TYK2 leads to reduced neuronal demyelination and increased myelin regeneration, supporting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0212] Furthermore, increased levels of IL-12 and IL-23 have been found in MS lesions, and IFN-γ and IL-17 are upregulated in active MS plaques (see Windhagen et al., J Exp Med (1996); Li et al., Brain (2007); Tzartos et al., Am J Path (2008)). IL-12 and IL-23 are broadly associated with the pathogenesis of EAE: IL-12 p40 neutralizing mAbs prevent clinical EAE; mice deficient in the IL-12 p40 or IL-23 p19 genes are resistant to EAE; and systemic injection of recombinant IL-12 or intracerebral injection of an adenovirus vector encoding IL-23 induces clinical relapse of EAE. Therefore, the use of TYK2 inhibitors could interrupt this important pathology in MS and other CNS disorders.

[0213] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death induced by amyloid-β (Aβ) peptide, demonstrating its potential role in the treatment of Alzheimer's disease (AD). Following Aβ administration, reduced TYK2 phosphorylation of STAT3 led to reduced neuronal cell death, and increased STAT3 phosphorylation has been observed in the post-mortem brains of Alzheimer's patients. (See, Wan et al., J. Neurosci. (2010) 30(20): 6873-6881).

[0214] In some embodiments, some of the TYK2 inhibitors described herein cross the blood-brain barrier. In some embodiments, some of the TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.3. In some embodiments, some of the TYK2 inhibitors described herein have a mean brain:plasma ratio greater than 0.3. In some embodiments, some of the TYK2 inhibitors described herein have a mean brain:plasma ratio of at least 0.5. In some embodiments, some of the TYK2 inhibitors described herein have a mean brain:plasma ratio greater than 0.5. In some embodiments, some of the TYK2 inhibitors described herein have a mean brain:plasma ratio of about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, or higher.

[0215] In some embodiments, the compounds of this disclosure can be used for 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 neuromyelitis optica spectrum disorders. In some embodiments, the compounds of this disclosure can be used for the treatment of multiple sclerosis (MS). In some embodiments, MS is relapsing MS or relapsing-remitting MS (RRMS). In some embodiments, the compounds of this disclosure can be used to treat neuromyelitis optica spectrum disorders, such as neuromyelitis optica. In some embodiments, the compounds of this disclosure can be used to treat encephalomyelitis, including acute disseminated encephalomyelitis. In some embodiments, the compounds of this disclosure can be used to treat polyneuropathy, such as chronic inflammatory demyelinating polyneuropathy. In some embodiments, the compounds of this disclosure can be used to treat encephalitis, including autoimmune encephalitis.

[0216] In one aspect, this disclosure provides a method of treating a disease or condition in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt, tautomer, or solvate thereof, or a pharmaceutical composition of this 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 is selected from multiple sclerosis, stroke, epilepsy, encephalomyelitis, polyneuropathy, encephalitis, or neuromyelitis optica spectrum disorders. 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 neuromyelitis optica spectrum disorders. 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, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye syndrome, intestinal diseases, Crohn's disease, ulcerative colitis, celiac disease, Bechtel disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

[0217] Administration method and treatment regimen In one embodiment, the compounds described herein, or pharmaceutically acceptable salts, tautomers, or solvates thereof, are used to prepare a medicament for treating diseases or conditions in mammals that would benefit from regulation of TYK2 activity. A method of treating any of the diseases or conditions described herein in mammals requiring such treatment involves administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0218] In some embodiments, a composition containing the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The effective amount for this use depends on the severity and duration of the disease or condition, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0219] In prophylactic applications, a composition containing the compounds described herein is administered to a patient susceptible to or at risk of a specific disease, condition, or illness. This amount is defined as the “preventative effective amount or dose.” In this application, the precise amount also depends on the patient’s health status, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and duration of the disease, condition, or illness, prior treatment, the patient’s health status and response to the medication, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing the compounds described herein or pharmaceutically acceptable salts thereof to a mammal who has previously experienced at least one symptom of a treated disease and is currently in remission, to prevent recurrence of the symptoms of the disease or illness.

[0220] In some implementation schemes in which the patient’s condition does not improve, the compound is administered long-term, i.e., for a long period of time, including the entire duration of the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the physician’s judgment.

[0221] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific implementation plans, the dose or frequency, or both, are reduced to a level that maintains the improvement of the disease, symptoms, or condition, depending on the symptoms. However, in some implementation plans, the patient requires long-term intermittent treatment after any recurrence of symptoms.

[0222] The amount of a given drug corresponding to this quantity varies depending on factors such as the specific compound, the disease condition and its severity, and the characteristics of the person or host to be treated (e.g., weight, sex), but is still determined based on the specific circumstances relevant to the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the person or host being treated.

[0223] However, in general, the dosage used for adult treatment is typically 0.01 mg to 2000 mg / day. In one implementation, the required dosage is conveniently presented as a single dose or in fractions administered simultaneously or at appropriate intervals, such as two, three, four or more sub-dose per day.

[0224] In one embodiment, the daily dose of the compound described herein or its pharmaceutically acceptable salt described herein is from about 0.01 to about 50 mg / kg body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form may be lower or higher than the range shown herein, based on a number of variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose vary according to a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition being treated, and the practitioner's judgment.

[0225] The toxicity and efficacy of such treatment regimens are determined in cell cultures or laboratory animals using standard pharmaceutical procedures, including but not limited to LD50. 50 and ED 50 The determination of toxicity and therapeutic effect is crucial. The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as LD50. 50 With ED 50 The ratio between. In some embodiments, data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range including ED. 50 Within the range of cyclic concentrations with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form and route of administration used.

[0226] In any of the foregoing aspects, including additional embodiments, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is administered to mammals by: (a) systemic administration; and / or (b) oral administration to mammals; and / or (c) intravenous administration to mammals; and / or (d) administration to mammals by injection; and / or (e) local administration to mammals; and / or (f) non-systemic or non-local administration to mammals.

[0227] In any of the foregoing aspects, there are additional embodiments that include a single application of an effective amount of the compound, and there are also additional embodiments in which (i) the compound is applied once daily; or (ii) the compound is applied multiple times to a mammal over a period of day.

[0228] In any of the foregoing aspects, additional embodiments are included that involve multiple administrations of an effective amount of the compound, further comprising additional embodiments wherein (i) the compound is administered continuously or intermittently as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a mammal every 12 hours; (v) the compound is administered to a mammal every 24 hours. In additional or alternative embodiments, the method includes a withdrawal period in which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the withdrawal period, administration of the compound is resumed. In one embodiment, the length of the withdrawal period ranges from 2 days to 1 year.

[0229] Combination therapy In some cases, it is appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

[0230] In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein together with another agent (which also includes treatment regimens) that also has therapeutic benefit.

[0231] In one specific implementation, the compound described herein or a pharmaceutically acceptable salt thereof is administered in combination 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, symptom, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent alone.

[0232] In any case, regardless of the disease, condition, or illness being treated, the overall benefit experienced by the patient can be simply the sum of the two treatments, or the patient may experience synergistic benefits.

[0233] For the combination therapies described herein, the dosage of the co-administered compounds varies depending on the type of co-administered drug, the specific drug used, and the disease or condition being treated. In another embodiment, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with one or more other therapeutic agents.

[0234] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. If administered simultaneously, by way of example only, the multiple therapeutic agents are provided in a single unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0235] The compounds described herein, or their pharmaceutically acceptable salts, and combination therapies are administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds varies. Thus, in one embodiment, the compounds described herein are used as a preventative medicine and are continuously administered to subjects with a predisposition to develop a condition or disease to prevent its occurrence. In another embodiment, the compounds and compositions are administered to the subject during or shortly after the onset of symptoms. In a specific embodiment, the compounds described herein are administered immediately, where feasible, upon detection or suspicion of the onset of a disease or condition, and treatment is continued for the duration required to treat the disease. In some embodiments, the required duration of treatment varies, and the duration of treatment is adjusted to suit the specific needs of each subject.

[0236] Example As used above, and throughout the entire disclosure, unless otherwise stated, the following abbreviations shall be understood to have the following meanings: abbreviation: The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0237] I. Synthesis of Compounds Example 1: Preparation of (S)-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthidine-6-amine (I-1): Step 1: 1-(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethane-1-one (I-1b): A solution of 2M isopropyl magnesium chloride in THF (91.3 mL, 183 mmol) was added to a stirred solution of I-1a (40 g, 166 mmol) in anhydrous THF (300 mL) at -30°C and stirred for 1 h at the same temperature. Then DMA (77 mL, 830 mmol) was added to the mixture at -30°C. The reaction mixture was slowly heated to room temperature over 1 h. After completion, the mixture was quenched by adding saturated NH4Cl solution (100 mL) and extracted with EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using a gradient elution of 0-10% EtOAc in heptane) to give the desired compound 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethane-1-one I-1b (19 g) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 4.23 (s, 3H), 2.59 (s, 3H).

[0238] Step 2: 1-(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethane-1-amine (I-1c): TEA (23.2 mL, 167 mmol) and methylamine hydrochloride (11.3 g, 167 mmol) were added to a stirred solution of I-1b (17 g, 83.3 mmol) in MeOH (80 mL) at 0°C. The reaction mixture was stirred at room temperature for 16 h. It was then cooled to 0°C and NaBH4 (6.3 g, 167 mmol) was added in portions. The reaction mixture was warmed to room temperature over 2 h. After completion (as indicated by LCMS), a saturated NaHCO3 solution (30 mL) was added and the mixture was washed with EtOAc (20 mL x 2). An aqueous solution of NaHCO3 containing 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylethane-1-amine I-1c was used in the next step without further purification.

[0239] Step 3: (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-1d): A solution of (Boc)₂O (35.7 mL, 155 mmol) in THF (100 mL) was added to an aqueous solution of NaHCO₃ containing I-1d, 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. Extraction was performed 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 a gradient elution of 0-50% EtOAc in heptane) to give tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate I-1d (16.0 g) as a colorless, viscous oil. LCMS (ES) m / z 220.1 [(M-100)+H] + .

[0240] Step 4: (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-1e): Argon gas was purged for 15 min onto a stirred suspension of I-1d (18.0 g, 56.4 mmol), (2-chloro-3-fluoropyridin-4-yl)boronic acid (24.7 g, 141.0 mmol), and CsF (25.7 g, 169 mmol) in THF (50 mL), followed by the addition of tri-tert-butylphosphine tetrafluoroborate (0.98 g, 3.38 mmol) and Pd2(dba)3 (2.58 g, 2.82 mmol). The reaction mixture was then stirred in a sealed tube at 70°C for 16 h. After the starting materials were completely consumed, the mixture was cooled to room temperature and filtered through a diatomaceous earth bed. The residue was washed with EtOAc (50 mL x 2) and the combined filtrates were concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–30% EtOAc in heptane) to give tert-butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate I-1e (14 g) as a pale yellow gel. LCMS (ES) m / z; 370.0 [M+H] + .

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

[0242] Step 6: N-(2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)cyclopropaneformamide (I-1g): Argon gas was purged for 15 min onto a stirred suspension of I-1f (8 g, 32.0 mmol), cyclopropaneformamide (5.45 g, 64.1 mmol), and Cs2CO3 (31.3 g, 96.1 mmol) in 1,4-dioxane (80 mL), followed by the addition of [5-(diphenylphosphine)-9,9-dimethyl-9H-xanthon-4-yl]diphenylphosphine (1.85 g, 3.2 mmol) and Pd2(dba)3 (2.93 g, 3.2 mmol). The reaction mixture was then stirred in a sealed tube at 130°C for 16 h. The solution was then cooled to room temperature, filtered through a diatomaceous earth 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 a gradient elution of 0–80% EtOAc in hexane) to give N-(2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)cyclopropaneformamide I-1 g (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-[1,2,3]triazolo[4,5-c][1,7]naphthyl-6-amine (I-1h): LiOH aqueous solution (3.61 g, 17.6 mmol in 100 mL of water) was added to a solution of 1-1 g (9.0 g, 30.2 mmol) in THF (300 mL) at room temperature. The solution was then stirred at 50°C for 5 h. After this, the solution was cooled to room temperature and water (20 mL) was added. Extraction was performed using 10% MeOH (100 mL x 2) in DCM; the combined organic extracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–10% MeOH in DCM) to give the desired compound 2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyl-6-amine I-1h (4.4 g) as a grayish-white solid. LCMS (ES) m / z: 231.2 [M+H] + .

[0244] Note: The racemic I-1h (4.4 g) was separated by chiral HPLC [column: CHIRALCEL OJ H (250 mm x 30 mm x 5 μm); mobile phase: n-hexane: ethanol containing 0.1% DEA (80:20); flow rate: 40 mL / min] to obtain two enantiomers {I-1i (1.8 g): peak-1; R t ; 6.8 min and I-1 (1.8 g): peak-2; R t ;9.44min}, the required enantiomer I-1 was used further without confirming its absolute configuration.

[0245] Example 2: Preparation of 2,4,5,8-tetramethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyl-6-amine (I-2): Step 1: Methyl (1-(2-methyl-5-(tributyltin)-2H-1,2,3-triazol-4-yl)ethyl)tert-butyl carbamate (I-2a): Argon gas was purged for 15 min onto a stirred suspension of I-1d (15.0 g, 47 mmol) in hexabutyldistin (24.5 mL, 73.8 mmol). Then Pd(OAc)₂ (0.15 g, 0.67 mmol) and tricyclohexylphosphine (0.38 g, 1.34 mmol) were added. The reaction mixture was then stirred in a sealed tube at 110°C for 24 h. It was then cooled to room temperature, filtered through a diatomaceous earth bed, and washed with EtOAc (50 mL x 2). The combined filtrates were concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give the desired compound, methyl (1-(2-methyl-5-(tributyltin)-2H-1,2,3-triazol-4-yl)ethyl)carbamate tert-butyl ester I-2a (9.2 g), as a pale yellow semi-solid.

[0246] Step 2: (1-(5-(2-chloro-3-fluoro-5-methylpyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-2b): Argon gas was purged for 15 min onto 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). Then Pd(PPh3)4 (1.53 g, 1.33 mmol) and CuI (1.26 g, 6.61 mmol) were added. The reaction mixture was then stirred in a sealed tube at 90°C for 1 h. The mixture was then cooled to room temperature, ice water (50 mL) was added, and extraction was performed using EtOAc (70 mL × 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 a gradient elution of 0–30% EtOAc in heptane) to give tert-butyl (1-(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 colorless 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-[1,2,3]triazolo[4,5-c][1,7]naphthidine (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 the starting material was completely consumed, the volatiles were removed under reduced pressure, and the residue was dried (co-evaporated with 1,4-dioxane). 1,4-dioxane (20 mL) and DIPEA (6.82 mL, 38.2 mmol) were then added to the mixture 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 a gradient elution of 0-35% EtOAc in heptane) to give the desired compound 6-chloro-9-fluoro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthidine I-2c (0.6 g) as a white solid. LCMS (ES) m / z 268.1 [M+H] + .

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

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

[0250] Note: Racemic I-2 (0.94 g) was resolved by chiral HPLC [column: CHIRALPAK IC (250 mm x 20 mm x 5 µm); mobile phase: n-hexane: IPA containing 0.1% DEA (50:50); flow rate: 40.0 mL / min] to obtain two enantiomers {I-2A (0.11 g): peak-1; R...} t ; 6.2 min and I-2B (0.11 g): peak -2; R t ;9.8 min}, which are used without their absolute configuration determined.

[0251] Example 3: Preparation of 2',5'-dimethyl-2',5'-dihydrospiro[cyclopropane-1,4'-[1,2,3]triazolo[4,5-c][1,7]naphthylidine]-6'-amine (I-3): Step 1: 5-Bromo-2-methyl-2H-1,2,3-triazol-4-carboxaldehyde (I-3a): A solution of 2 M isopropyl magnesium chloride in THF (22.8 mL, 45.6 mmol) was added to a stirred solution of I-1a (10 g, 41.6 mmol) in THF (100 mL) at -30°C and stirred for 1 h at the same temperature. DMF (16.08 mL, 208 mmol) was then added to the solution at -30°C. The reaction mixture was slowly heated to room temperature over 1 h. After completion, the mixture was quenched by adding saturated NH4Cl solution (30 mL) and extracted with EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using a gradient elution of 0-10% EtOAc in heptane) to give the desired compound 5-bromo-2-methyl-2H-1,2,3-triazol-4-carboxaldehyde I-3a (6 g) as a grayish-white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.95 (s, 1H); 4.26 (s, 3H).

[0252] Step 2: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol (3b): Sodium borohydride (2.78 g, 73.4 mmol) was added to a stirred solution of I-3a (9.3 g, 48.9 mmol) in MeOH (100 mL) at 0°C, and the mixture was stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LC-MS. After the reaction was complete, the reaction was quenched by adding water (100 mL), and the MeOH was concentrated under reduced pressure. Extraction was then performed 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 a gradient elution of 0-30% EtOAc in n-heptane) to give (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methanol I-3b (8.0 g) as a colorless, viscous oil. LCMS (ES) m / z: 192.9 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 4.63 (s, 2H), 4.10 (s, 3H), 2.22 (bs, 1H).

[0253] Step 3: 4-Bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole (I-3c): CBr4 (18.0 g, 54.2 mmol) and triphenylphosphine (14.2 g, 54.2 mmol) were added to a solution of I-3b (8.0 g, 41.7 mmol) in DCM (80 mL) at 0°C, and the reaction was stirred at room temperature for 1 h. After the reaction was complete (as indicated by TLC), water (100 mL) was added and the mixture was extracted with DCM (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash (using a gradient elution of 0-15% EtOAc in n-heptane) to give 10.2 g of 4-bromo-5-(bromomethyl)-2-methyl-2H-1,2,3-triazole I-3c as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.44 (s, 2H), 4.15 (s, 3H).

[0254] Step 4: 2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile (I-3d): To the stirred solution of I-3c (10.2 g, 40.0 mmol) in ACN (100 mL), add TMSCN (7.51 mL, 60.0 mmol) and tetrabutylammonium fluoride (1.0 M in THF) (60.0 mL, 60.0 mmol), and stir the reaction mixture at room temperature for 1 h. After the reaction is complete (as indicated by TLC), dilute the reaction mixture with EtOAc (200 mL) and wash with water (100 mL). Extract the aqueous layer again with EtOAc (250 mL). Dry the combined organic extracts over sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in n-heptane) to give (5-2-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)acetonitrile I-3d (7.4 g) as a white solid. 1 H NMR (400MHz, CDCl3) δ 4.18 (s, 3H), 3.74 (s, 2H).

[0255] Step 5: 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carboxynitrile (I-3e): Sodium hydride (3.68 g, 92 mmol) was added to a stirred solution of I-3d (7.4 g, 36.8 mmol) in DMF (70 mL) at 0°C and stirred for 30 min, followed by the addition of 1,2-dibromoethane (6.37 mL, 73.6 mmol). The reaction was stirred at room temperature for 2 h while monitoring the reaction progress by TLC. After the reaction was complete, it was quenched by adding ice water (100 mL). Extraction was performed 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 a gradient elution of 0-20% EtOAc in n-heptane) to give 1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropane-1-carboxynitrile I-3e (7.1 g) as a colorless oil. LCMS (ES) m / z: 227.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 4.13 (s, 3H), 1.77-1.70 (m, 2H), 1.58 -1.51 (m, 2H).

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

[0257] Step 7: (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropyl)tert-butyl carbamate (I-3g): Triethylamine (10.5 mL, 74.4 mmol) and DPPA (11.3 mL, 59.5 mmol) were added to a solution of I-3f (12.2 g, 49.6 mmol) in tert-butanol (250 mL). The resulting mixture was heated at 100°C for 16 h, with the reaction progress monitored by LCMS. After completion, the reaction mixture was cooled to room temperature and volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (500 mL) and 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 a gradient elution of 0-25% EtOAc in n-heptane) to give tert-butyl 1-3 g (9.3 g) of (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropyl)carbamate as a grayish-white solid. LCMS (ES) m / z: 263.0 [(M-56)+H] + . 1 H NMR (400MHz, CDCl3) δ5.31 (bs, 1H), 4.07 (s, 3H), 1.42 (s, 9H), 1.38-133 (m, 2H), 1.21 (bs, 2H).

[0258] Step 8: (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate tert-butyl ester (I-3h): Sodium hydride (0.41 g, 10.2 mmol) was added to a stirred solution of 1-3 g (2.7 g, 8.51 mmol) in DMF (30 mL) at 0°C and stirred for 20 min at 0°C. Iodomethane (0.64 mL, 10.2 mmol) was then added and the reaction was stirred at room temperature for 1 h. After the reaction was complete (as indicated by TLC), the reaction mixture was quenched by adding ice water (50 mL) and extracted with 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 a gradient elution of 0-20% EtOAc in n-heptane) to give a colorless, viscous oil, tert-butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate I-3h (2.8 g). LCMS (ES) m / z; 277.0 [(M-56)+H] + . 1 H NMR (400MHz, CDCl3) δ 4.06 (s, 3H), 2.94 (s, 3H), 1.43 (s, 11H), 1.30 (s, 2H).

[0259] Step 9: (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)cyclopropyl)(methyl)carbamate tert-butyl ester I-3i): I-3i (2.7 g) was synthesized 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 starting materials, following the synthetic procedure of I-1 (Step 4). LCMS (ES) m / z 382.1 [M+H] + .

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

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

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

[0263] Example 4: Preparation of 3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyl-6-amine (I-4): Step 1: 4-Bromo-1-methyl-1H-1,2,3-triazol-5-carboxaldehyde (I-4b): A solution of 2 M isopropyl magnesium chloride in THF (49.8 mL, 99.6 mmol) was added to a stirred solution of I-4a (20 g, 83 mmol) in THF (200 mL) at -30°C and stirred for 1 h at the same temperature. DMF (32.1 mL, 415 mmol) was then added at -30°C. The reaction mixture was slowly heated to room temperature over 1 h. After completion, it was quenched by adding saturated NH4Cl solution (100 mL) and extracted with EtOAc (75 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in heptane) to give the desired compound 4-bromo-1-methyl-1H-1,2,3-triazol-5-carboxaldehyde I-4b (11 g) as a grayish-white solid. 1 H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H); 4.32 (s, 3H). LCMS(ES) m / z 189.9 [M+H] + .

[0264] Step 2: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-ol (I-4c): A solution of 3 M MeMgBr in Et2O (26.3 mL, 78.9 mmol) was added to a stirred solution of I-4b (10 g, 52.6 mmol) in anhydrous THF (100 mL), and the reaction mixture was allowed to warm to room temperature over 20 min. After the starting material was completely consumed, it was quenched by adding saturated NH4Cl solution (100 mL) and extracted with EtOAc (70 mL x 3). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in heptane) to give the desired compound 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-ol I-4c (9 g) as a grayish-white solid. LCMS (ES) m / z 206.1 [M+H] + .

[0265] Step 3: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-one (I-4d): DMP (24.1 g, 56.8 mmol) was added to a stirred solution of I-4c (9 g, 43.7 mmol) in DCM (90.0 mL) 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, the mixture was filtered through a diatomaceous earth bed and washed with DCM (50 mL x 2). The resulting filtrate was washed with saturated NaHCO3 solution (100 mL), water (100 mL), and brine (70 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexane) to give the desired compound 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethane-1-one I-4d (7.0 g) as a grayish-white solid. LCMS (ES) m / z 204.0 [M+H] + .

[0266] Step 4: 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethane-1-amine (I-4e): Titanium isopropoxide (IV) (49.3 mL, 152.70 mmol) was added to a stirred solution of I-4d (17 g, 83.3 mmol) in THF (150 mL) at 0°C in a sealed tube. A solution of 2 M MeNH2 in THF (76.3 mL, 167.0 mmol) was then added, 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 NaBH4 (9.46 g, 250 mmol) was added at 0°C. The reaction mixture was then warmed to room temperature over 2 h. After completion, add saturated NaHCO3 solution (100 mL) and wash with EtOAc (30 mL x 2). The NaHCO3 aqueous solution containing 1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)-N-methylethane-1-amine I-4e is then used for the next step.

[0267] Step 5: (1-(4-bromo-1-methyl-1H-1,2,3-triazol-5-yl)ethyl)(methyl)carbamate tert-butyl ester (I-4f): I-4f (18 g) was synthesized using I-4e as the starting material by following the procedure described for the synthesis of I-1 (Step 3). LCMS (ES) m / z319.0 [M+H] + .

[0268] Step-6: 5-[1-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-(2-chloro-3-fluoro-4-pyridyl)-1-methyl-1H-1,2,3-triazole (I-4g): I-4g (7.1 g) was synthesized 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 starting materials by following the procedure described for the synthesis of I-1 (Step-4). LCMS (ES) m / z 370.1 [M+H] + .

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

[0270] Step-8: N-(3,4,5-trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)cyclopropaneformamide (I-4i): I-4i (4.8 g) was synthesized using I-4h (3.6 g, 14.4 mmol) and cyclopropaneformamide (1.84 g, 21.6 mmol) as starting materials by following the procedure described for the synthesis of I-1 (Step-6). LCMS (ES) m / z 299.0 [M+H] + .

[0271] Step-9: 3,4,5-Trimethyl-4,5-dihydro-3H-[1,2,3]triazolo[4,5-c][1,7]naphthyl-6-amine (I-4): I-4 (1.2 g) was synthesized using I-4i (4.8 g, 6.44 mmol) as the starting material by following the procedure described for the synthesis of I-1 (Step-7). LCMS (ES) m / z 231.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J= 5.2 Hz, 1H); 7.17 (d, J = 5.2 Hz, 1H); 4.77 (s, 2H); 4.23 (q, J = 7.2 Hz, 1H); 3.99 (s, 3H); 2.49 (s, 3H); 1.11 (d, J = 6.8 Hz, 3H).

[0272] Note: Racemic I-4 (1.2 g) was resolved by chiral HPLC [column: CHIRALPAK IC (250 mm x 20 mm x 5 µm); mobile phase: n-hexane: ethanol containing 0.1% DEA (50:50); flow rate: 19.0 mL / min] to obtain two enantiomers {I-4A (0.43 g): peak-1; R} t ; 7.11 min and I-4B (0.43 g): peak -2; R t ;8.80min}, which are used without their absolute configuration determined.

[0273] Example 5: Preparation of 2,3,4,5-tetramethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthidine-6-amine (I-5): Step 1: 3-Bromo-5-methyl-1H-pyrazole-4-carboxaldehyde (I-5b): POBr3 (66.6 g, 232 mmol) was added 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, 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 the reaction was complete, it was cooled to 0°C and quenched by adding saturated sodium bicarbonate solution (100 mL). Extraction was performed using EtOAc (50 mL x 3), and the combined organic extracts were concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–30% EtOAc in heptane) to give the desired compound 3-bromo-5-methyl-1H-pyrazole-4-carboxaldehyde I-5b (9.5 g mmol) as a white solid. LCMS (ES) m / z 189.0 [M+H] + .

[0274] Step 2: 3-Bromo-1,5-Dimethyl-1H-pyrazole-4-carboxaldehyde (I-5c): Sodium hydride (1.14 g, 1.8 equivalents, 28.6 mmol) was added to a solution of I-5b (3 g, 15.9 mmol) in N,N-dimethylformamide (20 mL) at 0°C under a nitrogen atmosphere and stirred for 15 min. Iodomethane (1.19 mL, 19 mmol) was then 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 the reaction was complete, the reaction mixture was quenched by adding sodium bicarbonate solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in heptane) to give the desired compound 3-bromo-1,5-dimethyl-1H-pyrazole-4-carboxaldehyde I-5c (0.4 g) as a white solid. LCMS (ES) m / z 202.9[M+H] + .

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

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

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

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

[0279] Step 7: (1-(3-(2-chloro-3-fluoropyridin-4-yl)-1,5-dimethyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-5h): I-5h (4.2 g) was synthesized using I-5 g (6.0 g, 18.1 mmol) as the starting material by following the procedure described for the synthesis of I-1 (Step 4). 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][1,7]naphthidine (I-5i): I-5i (1.7 g) was synthesized using I-5h (4.2 g, 11 mmol) as the starting material, following the procedure described for the synthesis of I-1 (Step-5). 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][1,7]naphthid-6-yl)cyclopropaneformamide (I-5j): I-5j (1.7 g) was synthesized using I-5i (1.7 g, 6.47 mmol) as the starting material by following the procedure described for the synthesis of I-1 (Step-6). LCMS (ES) m / z 312.2 [M+H] + .

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

[0283] Note: Racemic I-5 (0.75 g) was resolved by chiral HPLC [column: CHIRALPAK IC (250 mm x 20 mm x 5 µm); mobile phase: n-hexane: ethanol containing 0.1% DEA (80:20); flow rate: 40.0 mL / min] to obtain two enantiomers {I-5A (0.3 g): peak-1; R...} t ; 10.71 min and I-5B (0.3 g): peak -2; R t ;12.77min}, which are used without their absolute configuration determined.

[0284] Example 6: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidine-6-amine (I-6): Step 1: 1-(3-bromo-1-methyl-1H-pyrazol-4-yl)ethane-1-ol (I-6b): Using I-6a (25 g, 132.3 mmol) as the starting material, I-6b (23 g) was synthesized by following the procedure described for the synthesis of I-4 (Step 2). LCMS (ES) m / z 205 [M+H] + .

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

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

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

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

[0289] Step-6: (1-(3-(6-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-6 g): I-6 g (5 g) was synthesized using I-6f (10 g, 18.9 mmol) as the starting material by following the procedure described for the synthesis of I-2 (Step-2). LCMS (ES) m / z 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-d]pyrimidine (I-6h): I-6h (1.5 g) was synthesized using I-6 g (5 g, 13.5 mmol) as the starting material by following the procedure described for the synthesis of I-3 (Step-10). 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]pyrimidine-6-amine (I-6): A mixture of I-6h (1.3 g, 5.21 mmol) and ammonium hydroxide (20 mL) in a steel reactor was stirred at 100°C for 16 h. The reaction progress was monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature and extracted with 5% MeOH (50 mL x 2) in DCM. The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–10% MeOH in DCM) to give the desired compound 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[3',4':4,5]pyrido[3,2-d]pyrimidine-6-amine I-6 (0.850 g) as a grayish-white solid. LCMS (ES) m / z 231.2 [M+H] + .

[0292] Example 7: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,5]naphthidine-6-amine (I-7): Step-1: (1-(3-(4-chloro-3-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)ethyl)(methyl)carbamate tert-butyl ester (I-7a): I-7a (5.2 g) was synthesized using I-6f (15 g, 28.4 mmol) as the starting material by following the procedure described for the synthesis of I-2 (Step-2). 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][1,5]naphthidine (I-7b): I-7b (2.5 g) was synthesized using I-7a (5.2 g, 14.1 mmol) as the starting material by following the procedure described for the synthesis of I-3 (Step-10). LCMS (ES) m / z 249.1 [M+H] + .

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

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

[0296] Note: Racemic I-7 (1.1 g) was separated by chiral HPLC [column: CHIRALPAK IC (250 mm X 20 mm X 5 µm); mobile phase: methanol (100%) containing 0.1% DEA; flow rate: 38.0 mL / min] to obtain 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 without determination of their absolute configuration.

[0297] Example 8: Preparation of N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide (A-1): Step 1: 4,6-Dichloro-N-methoxy-N-methylnicotinamide (A-1b): TEA (43.6 mL, 313.0 mmol) and HATU (39.6 g, 104 mmol) were added to a stirred solution of A-1a (20.0 g, 104.0 mmol) in DCM (50.0 mL) at 0 °C. N,O-dimethylhydroxylamine hydrochloride (15.9 g, 260.0 mmol) was then added, and the reaction mixture was allowed to stir for 16 h at room temperature. After the starting material was completely consumed, water (100 mL) was added, and extraction was performed 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 a gradient elution of 0–15% EtOAc in heptane) to give 18.0 g of 4,6-dichloro-N-methoxy-N-methylnicotinamide A-1b as a colorless liquid. LCMS (ES) m / z 235.1[M+H] + .

[0298] Step 2: 1-(4,6-Dichloropyridin-3-yl)ethane-1-one (A-1c): A solution of 3M MeMgBr in Et2O (45 mL, 134 mmol) was added to a stirred solution of A-1b (15 g, 63.8 mmol) in anhydrous THF (50.0 mL) at 0 °C, and the reaction mixture was heated to room temperature over 20 min. After the starting material was completely consumed, it was quenched by adding saturated NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 2). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give the desired compound 1-(4,6-dichloropyridin-3-yl)ethane-1-one A-1c (10.0 g) as a viscous yellow liquid. LCMS (ES) m / z ;190.1 [M+H] + .

[0299] Step 3: Methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropionate (A-1d): NaH (60% suspension) (6.31 g, 158 mmol) was added in portions to a stirred solution of A-1c (10 g, 52.6 mmol) in dimethyl carbonate (150 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After the starting material was completely consumed, it was quenched by adding 2N HCl aqueous solution (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–15% EtOAc in heptane) to give the desired compound methyl 3-(6-chloro-4-methoxypyridin-3-yl)-3-oxopropionate A-1d (8.6 g) as a yellow solid. LCMS (ES) m / z 244.1 [M+H] + .

[0300] Step 4: Methyl 2-(6-chloro-4-methoxynicotinyl)propionate-3,3,3-d3 (A-1e): Potassium carbonate (5.37 g, 38.8 mmol) was added to a stirred solution of A-1d (8.6 g, 35.3 mmol) in DMF (50.0 mL) at 0 °C, and the mixture was stirred for 5 min. Then, iodomethane-d was added dropwise to the solution at 0 °C. 3 (2.45 mL, 38.8 mmol) and the reaction mixture was stirred at room temperature for 6 h. Afterward, water (80 mL) was added and extraction was performed 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 a gradient elution of 0–8% EtOAc in heptane) to give methyl 2-(6-chloro-4-methoxynicotinyl)propionate-3,3,3-d3 A-1e (5.6 g) as a grayish-white solid. LCMS (ES) m / z ;261.1 [M+H] + .

[0301] Step 5: 1-(6-chloro-4-hydroxypyridin-3-yl)propane-1-one-3,3,3-d3 (A-1f): Hydrogen chloride (80 mL) was added to a solution of A-1e (5.6 g, 21.5 mmol) in AcOH (40 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 extracted with EtOAc (100 x 2 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 a gradient elution of 0–20% EtOAc in heptane) to give 1-(6-chloro-4-hydroxypyridin-3-yl)propane-1-one-3,3,3-d3 A-1f (3.8 g). LCMS(ES) m / z 189.6 [M+H] + .

[0302] Step 6: 1-(4,6-Dichloropyridin-3-yl)propane-1-one-3,3,3-d3 (A-1g): POCl3 (7 mL) was added to a solution of A-1f (3.8 g, 20.1 mmol) in ACN (15 mL) at room temperature. The reaction mixture was then heated to 85 °C for 1 h. After complete consumption of the starting material, volatiles were removed under reduced pressure and a saturated NaHCO3 solution (20 mL) was added to the residue. Extraction was performed using EtOAc (3 x 30 mL); the combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–20% EtOAc in heptane) to give 11-(4,6-dichloropyridin-3-yl)propane-1-one-3,3,3-d3(A-1g) (2.6 g). LCMS (ES) m / z 207.1 [M+H] + .

[0303] Step 7: N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropaneformamide (A-1): Argon gas was purged for 15 min onto a stirred suspension of A-1 g (3.0 g, 14.5 mmol), cyclopropaneformamide (1.11 g, 13.0 mmol), and Cs2CO3 (9.44 g, 29.0 mmol) in 1,4-dioxane (50.0 mL). Then, rac-BINAP (0.9 g, 1.45 mmol) and Pd2(dba)3-CHCl3 (1.5 g, 1.45 mmol) were added. The reaction mixture was then heated at 110 °C in a sealed tube for 2 h. After completion, it was cooled to room temperature and filtered through a diatomaceous earth bed. It was washed with EtOAc (50 mL x 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-25% EtOAc in heptane) to give the desired compound N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide A-1 (1.8 g) as a yellow solid. LCMS (ES) m / z 256.6 [M+H] + .

[0304] Example 9: Preparation of N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)spiro[2.2]pentane-1-carboxamide (A-2): Step 1: Spiro[2.2]pentane-1-carboxamide (A-2b): Oxaloyl chloride (1.75 mL, 20.1 mmol) was added dropwise to a solution of A-2a (0.75 g, 6.69 mmol) in DCM (6 mL) over 15 min at 0°C, followed by a catalytic amount of DMF. The reaction mixture was heated 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. A solution of ammonia in MeOH (10.0 mL) was added to the residue. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure and the residue was milled with 10% EtOAc in hexane to obtain the desired spiro[2.2]pentane-1-carboxamide A-2b (0.72 g) as a grayish-white solid. LCMS (ES) m / z ; 112.1 [M+H] + .

[0305] Step 2: N-(4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)spiro[2.2]pentane-1-carboxamide (A-2): A-2 (0.13 g) was synthesized using A-2b (0.27 g, 2.41 mmol) and A-1g (0.5 g, 2.41 mmol) as starting materials by following the procedure described for the synthesis of A-1 (Step-7). LCMS (ES) m / z 282.1 [M+H] + .

[0306] Example 10: Preparation of 4-((4-chloro-5-(propionyl-3,3,3-d3)pyridin-2-yl)amino)-1-methylpyrimidin-2(1H)-one (A-3): Step 1: 4-Amino-1-methylpyrimidin-2(1H)-one (A-3b): Tetrabutylammonium hydroxide (17 mL, 27 mmol) and iodomethane (6.72 mL, 108 mmol) were added to a solution of A-3a (3 g, 27 mmol) in dichloromethane (90.0 mL, 1.41 mol); and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by LC-MS. After the reaction was complete, the reaction mixture was diluted with water (150 mL) and washed with DCM (100 mL). The aqueous layer was then concentrated under reduced pressure and the product was recrystallized from the residue using EtO to give 1-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-(propionyl-3,3,3-d3)pyridin-2-yl)amino)-1-methylpyrimidin-2(1H)-one (A-3): A-3 (0.48 g) was synthesized using A-3b (0.3 g, 2.41 mmol) and A-1g (0.5 g, 2.41 mmol) as starting materials by following the procedure described for the synthesis of A-1 (Step-7). LCMS (ES) m / z 296.1 [M+H] + .

[0308] Example 11: Preparation of (S)-1-methyl-4-((5-(propionyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthid-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(1H)-one (compound 5): Argon gas was purged for 15 min onto a stirred suspension of I-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), followed by the addition of rac-BINAP (0.027 g, 0.043 mmol) and Pd₂(dba)₃-CHCl₃ (0.045 g, 0.043 mmol). The reaction mixture was stirred in a sealed tube at 110°C for 4 h, with the reaction progress monitored by TLC. After completion, the mixture was cooled to room temperature and filtered through a diatomaceous earth bed. It was washed with DCM (40 mL × 2) and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash elution (using a gradient elution of 0–50% EtOAc in heptane). The obtained solid was further purified by preparative HPLC to obtain the desired compound (S)-1-methyl-4-((5-(propionyl-3,3,3-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthidin-6-yl)amino)pyridin-2-yl)amino)pyrimidin-2(1H)-one 5 (0.14 g), which was a pale yellow solid. LCMS (ES) m / z = 490.5 [M+H] + . 1 HNMR (400 MHz, DMSO- d 6 ): δ 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, J = 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: A single isomer was prepared, but the absolute configuration was not determined.

[0309] The following compounds were synthesized using appropriate intermediates and starting materials, following the procedure described above. = A single isomer obtained by chiral separation of a racemic compound. Absolute configuration undetermined. † = It was obtained as a racemic mixture. ‡ = Obtained as a mixture of diastereomers.

[0310] The “or1” designation throughout the structure of this application refers to any designated stereocenter. Compounds are prepared as a single stereoisomer (including relative stereochemistry for other stereocenters designated with “or1”), but the absolute stereochemistry is unknown. For example, compounds containing a single “or1” or pure (R) or pure (S) are non-racemic mixtures.

[0311] The “&1” designation throughout the structure of this application refers to a stereocenter existing as a mixture of two enantiomers. For example, a compound containing “&1” in its structure represents a mixture of (R) and (S). This mixture can exist in any ratio; and includes racemic mixtures (1:1 ratio).

[0312] II. Biological Evaluation Example B-1: HEK-Blue for analyzing TYK2 pseudokinase (JH2) inhibition TM IL-23 and IFNα / β reporter gene assay HEK-Blue contains stably integrated cytokine receptors and STAT3 or STAT1. TMIL-23 and IFNα / β cells expressed a STAT-induced secretory embryonic alkaline phosphatase (SEAP) reporter gene after cytokine stimulation. These cells were seeded in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U / mL PenStrep (Gibco) and cultured for 20–22 h at 37 °C and 5% CO2. Cells were then pretreated with serially diluted test compounds for 60 min, followed by stimulation with 10 ng / mL recombinant human IL-23 (Miltenyl Biotech) or 1 ng / mL recombinant human IFNα (InvivoGen) for 22–24 h (for IL-23) or 16–18 h (for IFNα) according to the manufacturer's instructions. Quanti Blue was used. TM Solution (InvivoGen) was used to measure SEAP-induced levels. Inhibition data were calculated by comparison with control wells showing 0% inhibition and 100% inhibition. Dose-response curves were generated to determine the concentration (IC50) required to inhibit a 50% cellular response. 50 ), such as that derived through nonlinear regression analysis.

[0313] Table B-1 provides the TYK2 inhibitory activity of illustrative compounds, where A refers to IC50. 50 <30 nM; B refers to IC 50 Between 30 and 300 nM; C refers to IC. 50 Between 300 and 1000 nM; D refers to IC 50 >1000 nM; n / a means no activity was observed at 1000 nM; and nd means undetermined.

[0314] Table B-1: Representative TYK2 inhibitory activities The embodiments and implementations described herein are for illustrative purposes only, and various modifications or alterations suggested to those skilled in the art will be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound of formula (I): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X 2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is a group of the following formula: ； in: Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It consists of unsubstituted or substituted bicyclic carbon rings and unsubstituted or substituted bicyclic heterocycles; R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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 can be 0, 1, 2 or 3.

2. A compound of formula (II): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 Is it CF or N, X 2 It is CH or CF, and X 3 It is N; or X 1 It is N, X 2 It is CH or CF, and X 3 Is it CH or CF? B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 6 and R 7 Independently, it is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, monocyclic heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or an R atom attached to the same carbon atom 6 And an R 7 Together with the carbon atoms they are attached to, they form C=O or C3-C6 cycloalkanes; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is when X 1 It is N, X 2 It is CH, and X 3 When it is N, then no .

3. A compound of formula (III): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: Ring A is an unsubstituted or substituted carbon ring, wherein A 1 and A 2 All are C; or unsubstituted or substituted 5- or 6-membered heterocycles, where A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 Instance replacement; Each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 ynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; where if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; or two R atoms attached to the same carbon atom 8 Together they form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(=O)- or -SO2-; R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; X 1 X 2 and X 3 Each is CR independently 11 Or N; Each R 11 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; B 1 Is it N or CR? 12a ; B 2 Is it N or CR? 12b ; R 12a and R 12b Each of these elements independently represents hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, or -OR. 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; R 1 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; Each R 13 Independently, it is a halogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 fluoroalkyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted carbocyclic ring, an unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 -C(=O)R 16 -CO2R 16 -C(=O)N(R) 16 )2、-N(R 16 )2、-NR 16 C(=O)R 17 -SR 16 -S(=O)R 17 -SO2R 17 or -SO2N(R) 16 )2; Or two R atoms on adjacent atoms of ring B 13 The groups together with the intermediate atoms to which they are attached form unsubstituted or substituted 5- or 6-membered monocyclic carbon rings or unsubstituted or substituted 5- or 6-membered monocyclic heterocycles. or R 2 It is -C(=O)R 14 -C(=O)NR 14 R 15 or -C(=O)OR 14 ; R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocyclic, unsubstituted or substituted bicyclic carbocyclic, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. R 15 It is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; or R 14 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles; or R 1 and R 15 Together with the intermediate atoms to which they are attached, they form unsubstituted or substituted 5- or 6-membered monocyclic heterocycles; R 4 It is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 deuterated alkyl, C1-C6 fluoroalkyl, or C3-C6 cycloalkyl; or R 4 and R 12a Together with the intermediate atoms to which they are attached, they form substituted or unsubstituted C5-C6 cycloalkyl groups; R 5 It is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocyclic; Each R 16 Independently, it is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. Or two R atoms on the same N atom 16 Together with the N atoms they are attached to, they form substituted or unsubstituted N-containing heterocycles; and Each R 17 Independently, it is a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocyclic alkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Each substituted alkyl group, substituted fluoroalkyl group, substituted deuterated alkyl group, substituted alkoxy group, substituted fluoroalkoxy group, substituted heteroalkyl group, substituted carbocyclic ring, and substituted heterocyclic ring is represented by one or more R groups. s Group substitution, the R s The groups are independently selected from deuterium, halogens, C1-C6 alkyl groups, monocyclic carbocyclic rings, monocyclic heterocyclic rings, -CN, -CH2CN, and -OR. 18 -CH2OR 18 -CO2R 18 -CH2CO2R 18 -C(=O)N(R) 18 )2、-CH2C(=O)N(R 18 )2、-N(R 18 )2、-CH2N(R 18 )2、-NR 18 C(=O)R 18 -CH2NR 18 C(=O)R 18 -NR 18 SO2R 19 -CH2NR 18 SO2R 19 -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 -SO2R 19 -CH2SO2R 19 -SO2N(R) 18 )2 or -CH2SO2N(R 18 )2; Each R 18 It is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; Or two Rs 18 The groups, together with the N atoms they are attached to, form N-containing heterocycles; Each R 19 Independently selected from C1-C6 alkyl, C1-C6 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; The condition is that when m is 1, then no .

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 4 It is a C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 deuterated alkyl, or C3-C6 cycloalkyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 4 It is a C1-C4 deuterated alkyl group.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 4 It is 2,2,2-trideuterated ethyl-1-yl.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 1 It is 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 R 1 It is hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 5 It is 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 R 5 It is hydrogen.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein B 1 It is CR 12a .

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 12a It is hydrogen or an unsubstituted or substituted C1-C6 alkyl group.

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

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein B 2 It is CR 12b .

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 12b It is hydrogen or an unsubstituted or substituted C1-C6 alkyl group.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 12b It is hydrogen.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Z is -NR 10 -、-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 -NR 10 - 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 10 It is hydrogen, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 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 R 10 It is a C1-C6 alkyl, C1-C6 deuterated alkyl, or C3-C6 cycloalkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 10 It is a C1-C6 alkyl group.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 10 It is a methyl group.

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 according to any one of claims 1 and 4-23, further defined as formula (IA): ， Or its pharmaceutically acceptable salts, tautomers or solvates.

25. The compound according to any one of claims 2 and 4-23, further defined as formula (II-A): Or its pharmaceutically acceptable salts, tautomers or solvates.

26. The compound according to any one of claims 3-23, further defined as formula (III-A): ， Or its pharmaceutically acceptable salts, tautomers or solvates.

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 A 1 and A 2 All are C, where if ring A is replaced, then ring A is replaced by p R. 8 The instance is replaced.

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 group, wherein if ring A is substituted, ring A is p-R 8 The instance is replaced.

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 heterocycle, wherein A 1 and A 2 Independently, it is N or C, where if ring A is replaced, then ring A is replaced by p R. 8 The instance is replaced.

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, an unsubstituted or substituted furan, an unsubstituted or substituted thiophene, an unsubstituted or substituted pyrazole, an unsubstituted or substituted imidazole, an unsubstituted or substituted oxazole, an unsubstituted or substituted isoxazole, an unsubstituted or substituted thiazole, an unsubstituted or substituted isothiazole, an unsubstituted or substituted triazole, an unsubstituted or substituted oxadiazole, an unsubstituted or substituted thiadiazole, an unsubstituted or substituted tetraazole, an unsubstituted or substituted triazolone, an unsubstituted or substituted pyridine, an unsubstituted or substituted pyrazine, an unsubstituted or substituted pyridazine, an unsubstituted or substituted pyridazinone, or an unsubstituted or substituted pyrimidine, wherein if ring A is substituted, ring A is p-R 8 The instance is replaced.

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 an unsubstituted or substituted triazole, wherein if ring A is substituted, ring A is p-R 8 The instance is replaced.

32. The compound according to any one of claims 1 and 4-31, further defined as formula (IB): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

33. The compound of any one of claims 1 and 4-32, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 It is C; A 2 It is C; A 3 It is N; A 4 Is it N or NR? 8 And A 5 Is it N or NR? 8 .

34. The compound of any one of claims 1 and 4-33, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N; or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is N; and A 5 It is NR 8 .

35. The compound according to any one of claims 2 and 4-31, further defined as formula (II-B): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 Each is either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

36. The compound of any one of claims 2, 4-31 and 35, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 Is it N or CR? 8 .

37. The compound of any one of claims 2, 4-31, 35 and 36, or a pharmaceutically acceptable salt, tautomer or solvate thereof, wherein: A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N; or A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is CR 8 .

38. The compound according to any one of claims 3-31, further defined as formula (III-B): ， Or its pharmaceutically acceptable salts, tautomers, or solvates, wherein: A 1 and A 2 It can be either N or C independently; A 3 It is S, O, N, NR 8 CR 8 Or C=O; and A 4 and A 5 Each is independently S, O, N, NR 8 or CR 8 ; Where A 1 and A 2 At least one of them is C, or A 3 A 4 and A 5 At least one of them is CR 8 .

39. The compound of any one of claims 3-31 and 38, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 It is C; A 2 It is C; A 3 It is N; A 4 It is NR 8 And A 5 It is N.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic, or unsubstituted or substituted heterocyclic; wherein if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 deuterated alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, or an unsubstituted or substituted heterocyclic ring; or two R atoms attached to the same carbon atom. 8 Together they form = O.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 It is independently an unsubstituted or substituted C1-C6 alkyl group.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 It is a methyl group.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein at least one R 8 It is not methyl.

44. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 8 Independently, it is hydrogen, halogen, unsubstituted or substituted C2-C6 alkyl, unsubstituted or substituted C1-C6 deuterated alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic, or unsubstituted or substituted heterocyclic; wherein if R 8 If it is attached to a nitrogen atom, then R 8 It is hydrogen, an unsubstituted or substituted C1-C6 alkyl group, an unsubstituted or substituted C1-C6 deuterated alkyl group, an unsubstituted or substituted C1-C6 fluoroalkyl group, an unsubstituted or substituted carbocyclic ring, or an unsubstituted or substituted heterocyclic ring; or two R atoms attached to the same carbon atom. 8 Together they form = O.

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 R 6 and R 7 It is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, or C1-C6 heteroalkyl; or an R bonded to the same carbon atom. 6 And an R 7 Together with the carbon atoms they are attached to, they form C3-C6 cycloalkanes.

47. The compound of any one of claims 1, 2, and 4-46, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 6 and R 7 It can be either 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: X 1 It is CR 11 X 2 It is CR 11 And X 3 It is CR 11 ; or X 1 It is CR 11 X 2 It is CR 11 And X 3 It is N; or X 1 It is CR 11 X 2 It is N, and X 3 It is CR 11 ; or X 1 It is CR 11 X 2 It is N, and X 3 It is N; or X 1 It is N, X 2 It is CR 11 And X 3 It is CR 11 ; or X 1 It is N, X 2 It is CR 11 And X 3 It is N; or X 1 It is N, X 2 It is N, and X 3 It is CR 11 .

50. The compound of any one of claims 1 and 3-49, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X 1 It is CR 11 X 2 It is CR 11 And X 3 It is N.

51. The compound of any one of claims 1 and 3-50, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 11 Independently, it is hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 -N(R) 16 )2.

52. The compound of any one of claims 1 and 3-51, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each R 11 It is hydrogen on its own.

53. The compound of any one of claims 1 and 3-52, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X 1 It is CH, X 2 It is CH, and X 3 It is N.

54. The compound of any one of claims 2 and 4-48, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: X 1 Is it CF or N, X 2 It is CH, and X 3 It is N; or X 1 It is N, X 2 It is CH, and X 3 It is CH.

55. The compound of any one of claims 2, 4-48 and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X 1 It's CF, X 2 It is CH, and X 3 It is N.

56. The compound of any one of claims 2, 4-48 and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X 1 It is X 1 It is N, X 2 It is CH, and X 3 It is N.

57. The compound of any one of claims 2, 4-48 and 54, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein X 1 It is N, X 2 It is CH, and X 3 It is CH.

58. The compound of any one of claims 2-57, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 It is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, wherein if ring B is substituted, then ring B is substituted by q R. 13 Instance replacement; or R 2 It is -C(=O)R 14 .

59. The compound of any one of claims 2-58, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 It is -C(=O)R 14 .

60. The compound of any one of claims 2-59, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 14 It is hydrogen, unsubstituted or substituted C1-C6 alkyl, or unsubstituted or substituted monocyclic carbon ring.

61. The compound of any one of claims 2-60, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 14 Unsubstituted or substituted monocyclic carbon rings.

62. The compound of any one of claims 2-61, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 14 It is an unsubstituted or substituted C3-C8 cycloalkyl group.

63. The compound of any one of claims 2-62, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 14 It is cyclopropyl.

64. The compound of any one of claims 1 and 4-57, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 It is a group of the following formula: 。 65. The compound of any one of claims 1, 4-57 and 64, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 2 It is a group of the following 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 R 2 It is a group of the following 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 R 13 It is an unsubstituted or substituted C1-C6 alkyl group.

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 R 13 It is a methyl group.

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 R 2 It is -C(=O)R 14 .

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 R 14 It is an unsubstituted or substituted bicyclic carbon ring.

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 R 14 It is C5-C 12 Bicyclic carbon ring.

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 R 14 It is C5-C 12 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 R 14 It is a group of the following formula: ； in: x and y are independently 0, 1, 2, 3, and 4, respectively, and 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 R 14 yes: 。 78. The compound of claim 1, wherein the compound is selected from: , , , , , , , , , and ; Or its pharmaceutically acceptable salts, tautomers or solvates.

79. A compound, said compound being selected from: and ; Or its pharmaceutically acceptable salts, tautomers or solvates.

80. A pharmaceutical composition comprising a compound as described in 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, the method comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1-79, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, or a pharmaceutical composition as described in 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 neuromyelitis optica spectrum disorders.

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 relapsing-remitting.

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

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, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye syndrome, intestinal diseases, Crohn's disease, ulcerative colitis, celiac disease, Bechtel disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

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