TYK2 INHIBITORS AND USES THEREOF

Abstract

Described herein are triazole compounds that are TYK2 inhibitors, methods of making the compounds, pharmaceutical compositions and medicaments containing the compounds, and methods of using the compounds in the treatment of diseases, disorders, or conditions that would benefit from modulation of TYK2 activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 151,287, filed February 19, 2021, U.S. Provisional Patent Application No. 63 / 193,511, filed May 26, 2021, U.S. Provisional Patent Application No. 63 / 234,934, filed August 19, 2021, and U.S. Provisional Patent Application No. 63 / 291,224, filed December 17, 2021, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] The present invention relates to compounds that bind to the pseudokinase domain (JH2) of non-receptor tyrosine-protein kinase 2 (TYK2). The compounds of the present disclosure can inhibit certain cytokine signaling, such as IL-12, IL-23, and IFNα signaling. Further aspects of the present invention include pharmaceutical compositions containing the compounds described herein, methods of using the compounds to treat certain diseases, and intermediates and processes useful for synthesizing the 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, JAKl, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as type I and type III interferon receptors, and is activated by these receptors after cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then proceeds to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT3, STAT4, and STAT6. Summary of the Invention

[0004] The compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the present disclosure are inhibitors of TYK2. In some embodiments, the compounds are selective for TYK2 over other JAKs. For example, the compounds may enhance selectivity for JAK family members by specifically binding to the pseudokinase domain (JH2) of TYK2. In some embodiments, the compounds of the present disclosure may be allosteric modulators or non-competitive inhibitors of TYK2. In additional embodiments, the compounds described herein may be useful for treating TYK2-mediated diseases or disorders.

[0005] In one aspect herein, a compound of formula (I):

[0006] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is A 1 and A 2 is an unsubstituted or substituted triazole in which R is independently N or C, and if ring A is substituted, ring A has p instances of R 8 is replaced by R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -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 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17, -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-; R 10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; X 1 , X 2 , and X 3 are each independently CR 11 or N, R 11 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 N or CR 12a and B 2 is N or CR 12b and R 12a and R 12bare each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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, R 1 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 is replaced by R 13 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 on adjacent atoms of ring B13 the groups, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Alternatively, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 and R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R 15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or, R 14 and R 15 together with the intervening atoms to which they are attached form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle; Or, R 1 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; W is -NR 3 - or -O-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; Or, R 3 and R 4together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; Or, R 3 and R 12a taken together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclic ring; R 5 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle, -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, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R17 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from the group consisting of deuterium, halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -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 ) one or more R independently selected from the group consisting of s is substituted with a group, R 18are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the groups, taken together with the N atom to which they are attached, form an N-containing heterocycle; R 19 are each independently selected from C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, q is 0, 1, 2, 3, or 4; The compound is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0007] In some embodiments, R 1 is hydrogen or C1-C4 alkyl.

[0008] In some embodiments, R 5 is hydrogen or C1-C4 alkyl. In some embodiments, R 5 is hydrogen.

[0009] In some embodiments, W is —NR 3 In some embodiments, R 3 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 3 is hydrogen.

[0010] In some embodiments, R 4is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl.

[0011] In some embodiments, the compound has formula (II):

[0012] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0013] In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X 2 is CR 11 , X 3 is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is CR 11 , X 2 is N, X 3 is N, or X 1 is N, X 2 is CR 11 , X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X 3 is N, or X 1 is N, X 2 is N, X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X2 is CR 11 , X 3 is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 In some embodiments, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2. In some embodiments, R 11 are each independently hydrogen or fluoro.

[0014] In some embodiments, the compound has formula (IV):

[0015] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0016] In some embodiments, the compound has formula (VI):

[0017] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0018] In some embodiments, the compound is A 1 N, A 2 is C, A 3 N, A 4 N, A 5 is CR 8 or A 1 is C, A 2 N, A 3 N, A 4 is CR 8 , A 5 is N, or A 1 is C, A 2 is C, A 3 N, A 4 NR 8 , A 5 is N, or A 1 is C, A 2 N, A 3 N, A 4 N, A 5 is CR 8 It has the following structure.

[0019] In some embodiments, the compound has formula (VIb-1):

[0020] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0021] In some embodiments, the compound has formula (VId-1):

[0022] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0023] In some embodiments, the compound has the formula (VIg-1):

[0024] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0025] In some embodiments, R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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. In some embodiments, R 8 are each independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8is hydrogen, methyl, ethyl, isopropyl, -CD, -CHOH, -CF, cyclopropyl, oxetanyl, azetidinyl, -COH, or -COCH. In some embodiments, R 8 are each independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8 is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0026] In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C-C alkyl, or C-C deuteroalkyl. 6 and R 7 are each independently hydrogen, deuterium, F, or methyl.

[0027] In some embodiments, Z is —NR 10 In some embodiments, Z is -NR 10 - or -O-. In some embodiments, Z is -NR 10 In some embodiments, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, Z is -O-.

[0028] In some embodiments, R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 In some embodiments, R 2 is ring B which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, and when ring B is substituted, ring B is substituted with q instances of R 13In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, and when ring B is substituted, ring B is substituted with q instances of R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, and when ring B is substituted, ring B is substituted with q instances of R 13 In some embodiments, R is substituted with 2 is ring B which is unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl, and when ring B is substituted, ring B is 13 is replaced by

[0029] In some embodiments, R 2 teeth,

[0030] [ka] and q is 0, 1, 2, 3, or 4. In some embodiments, ring B is

[0031] [ka] and q is 0, 1, 2, 3, or 4;

[0032] In some embodiments, the compound has formula (VIII):

[0033] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 q is 1, 2, or 3, and A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0034] In some embodiments, V is N. In some embodiments, V is CH or CR 13 In some embodiments, R 13 are each independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -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 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 13 are each independently -F, -Cl, -CH3, or -CF3.

[0035] In some embodiments, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 In some embodiments, R 2 is -C(=O)R 14 is.

[0036] In some embodiments, the compound has formula (IX):

[0037] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0038] In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CHF2, —CF3, —OCH3, —OCHF2, and —OCF3. sThe group is substituted.

[0039] In some embodiments, B 1 is CR 12a , B 2 is CR 12b or B 1 is N, B 2 is CR 12b or B 1 is CR 12a , B 2 is N, or B 1 is N, B 2 is N. In some embodiments, B 1 is CR 12a , B 2 is CR 12b is.

[0040] Or B 1 is N, B 2 is CR 12b In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or —CN. In some embodiments, R 12a and R 12b are hydrogen atoms.

[0041] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0042] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, transdermal administration, or ocular administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. In some embodiments, the pharmaceutical composition is in the form of an ointment, lotion, cream, oil, gel, transdermal patch, or other topical formulation. In additional embodiments, the pharmaceutical composition is in the form of a liquid solution, suspension, gel, depot, or other preparation that can be administered to the eye or surrounding tissues.

[0043] Described herein is a compound of formula (A1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful for treating TYK2-mediated disorders. Described herein is a compound of formula (A1), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, useful for treating inflammatory or autoimmune diseases. In some embodiments, the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Behçet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the disease is selected from psoriasis, psoriatic arthritis, vitiligo, atopic dermatitis, alopecia, and hidradenitis suppurativa. In some embodiments, the disease is selected from interferonopathies, such as, by way of example only, Aicardi-Goutières syndrome.

[0044] Any of the foregoing aspects are further embodiments wherein an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by inhalation, and / or (e) administered by nasal administration, and / or (f) administered by injection to a mammal, and / or (g) administered topically to a mammal, and / or (h) administered by ophthalmic administration, and / or (i) administered rectally to a mammal, and / or (j) administered non-systemically or topically to a mammal.

[0045] Any of the above aspects may further comprise a single administration of an effective amount of the compound, including further embodiments in which the compound is administered to the mammal once a day, or in which the compound is administered to the mammal multiple times throughout the day. In some embodiments, the compound is administered in a continuous administration schedule. In some embodiments, the compound is administered in a continuous daily administration schedule.

[0046] In any of the embodiments disclosed herein, the mammal is a human.

[0047] In some embodiments, the compounds provided herein are administered topically to a human.

[0048] Provided are articles of manufacture that include packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof, located within the packaging material, and the compound or composition, or a pharmaceutically acceptable salt, tautomer, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, for use in the treatment, prevention, or amelioration of one or more symptoms of modulation of TYK2 or a disease or disorder that would benefit from modulation of TYK2.

[0049] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be noted, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0050] Activation of TYK2 has been implicated in many diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.

[0051] In particular, IL-23 activation of TYK2 has been implicated in inflammatory diseases such as inflammatory bowel disease (IBD), Crohn's disease, celiac disease, and ulcerative colitis. TYK2 also plays a role as a downstream effector of IL-23 in psoriasis, ankylosing spondylitis, and Behçet's disease. TYK2 has also been implicated in skin diseases and conditions such as psoriasis, vitiligo, atopic dermatitis, hidradenitis suppurativa, and scleroderma, as well as eye diseases and conditions such as Sjögren's syndrome, uveitis, and dry eye.

[0052] TYK2 is associated with respiratory diseases and disorders such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell proliferation (GCH) and mucus hypersecretion are mediated by IL-13-induced activation of the TYK2 / STAT6 pathway.

[0053] 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 reduce neuronal demyelination and increase remyelination, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders. Various type I IFN signaling pathways that depend on TYK2 signaling have TYK2 involved in SLE and other autoimmune diseases and conditions.

[0054] TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis.

[0055] TYK2 has also been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice exhibited a loss of cytotoxic T cell responses and accelerated tumor development. These results, largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggest that TYK2 inhibitors may be highly suitable for the treatment of autoimmune disorders or transplant rejection. While other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 is an excellent target due to its involvement in more or less closely related signaling pathways, resulting in minimal off-target effects. However, studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 / STAT1 signaling to maintain cancer cell survival via upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduces cell proliferation. For this reason, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases.

[0056] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-β (Aβ) peptides. Reduced TYK2 phosphorylation of STAT3 after Aβ administration reduces neuronal cell death, and increased STAT3 phosphorylation is observed in postmortem brains of Alzheimer's disease patients.

[0057] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata.

[0058] Although some TYK2 inhibitors are known, there remains a need to provide new inhibitors with more effective or advantageous pharmaceutically relevant properties. For example, compounds with increased activity or increased selectivity over other JAK kinases (particularly JAK2). In some embodiments provided herein, the invention provides inhibitors of TYK2 that exhibit selectivity over JAK1, JAK2, and / or JAK3. In some embodiments, compounds with this selectivity (particularly over JAK2) deliver a pharmacological response that advantageously treats one or more of the diseases or disorders described herein, without the side effects associated with JAK2 inhibition.

[0059] In some embodiments, the TYK2 inhibitors described herein are used to treat a disease or disorder in a mammal.

[0060] compound The compounds described herein, including pharmaceutically acceptable salts, tautomers, and solvates thereof, are inhibitors of TYK2. In some embodiments, the compounds described herein are selective for TYK2 over 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 an allosteric site of TYK2. In additional embodiments, the compounds described herein may be useful for treating TYK2-mediated diseases or disorders.

[0061] In one aspect herein, a compound of formula (I):

[0062] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is A 1 and A 2 is an unsubstituted or substituted triazole, where each of R is independently N or C, and when ring A is substituted, ring A is8 is replaced by R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -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 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-; R 10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; X 1 , X 2, and X 3 are each independently CR 11 or N, R 11 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 N or CR 12a and B 2 is N or CR 12b and R 12a and R 12b are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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, R 1 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 is replaced by R 13 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 on adjacent atoms of ring B 13 the groups, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Alternatively, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 and R 14is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R 15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; Or, R 14 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Or, R 1 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; W is -NR 3 - or -O-, R 3 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; Or, R 3 and R 4 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; Or, R 3 and R 12a taken together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclic ring; R 5 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 6 and R 7are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle, -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, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 17 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from the group consisting of deuterium, halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -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 ) one or more R independently selected from the group consisting of s is substituted with a group, R 18 are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the groups, taken together with the N atom to which they are attached, form an N-containing heterocycle; R 19are each independently selected from C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; p is 1, q is 1, 2, 3, or 4; Provided are compounds, or pharmaceutically acceptable salts, tautomers, or solvates thereof.

[0063] In some embodiments, the compound has the structure:

[0064] [ka] is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide having the formula:

[0065] In any and all embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, R 1 is hydrogen, C-C alkyl, or C-C fluoroalkyl. In some embodiments, R 1 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 1 is hydrogen or C1-C6 alkyl. In some embodiments, R 1 is hydrogen or C1-C4 alkyl. In some embodiments, R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl.

[0066] In some embodiments, R 5 is hydrogen, C-C alkyl, or C-C fluoroalkyl. In some embodiments, R 5 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 5 is hydrogen or C1-C6 alkyl. In some embodiments, R 5 is hydrogen or C1-C4 alkyl. In some embodiments, R 5 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 5 is hydrogen or methyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is methyl.

[0067] In some embodiments, W is —O—.

[0068] In some embodiments, W is —NR 3 -It is.

[0069] In some embodiments, the compound has Formula (Ia) or Formula (Ib):

[0070] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0071] In some embodiments, the compound is a compound of Formula (Ia), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (Ib), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0072] In some embodiments, R 4is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0073] In some embodiments, when W is —O—, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R4 is -CD3.

[0074] In some embodiments, W is —NR 3 -When R 3 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 3 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 3 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 3 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 3 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 3 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CD3.

[0075] In some embodiments, W is —NR 3 -When R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0076] In some embodiments, W is —NR 3 -When R 3 and R 4 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. 3 and R 4 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 3 and R 4 are each independently hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is hydrogen and R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 3 is hydrogen and R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 3 is hydrogen and R 4is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 3 is hydrogen and R 4 is hydrogen. In some embodiments, R 3 is hydrogen and R 4 is C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R 3 is hydrogen and R 4 is C1-C2 alkyl or C1-C2 deuteroalkyl. In some embodiments, R 3 is hydrogen and R 4 is -CH, -CHD, -CHD, or -CD. In some embodiments, R 3 is hydrogen and R 4 is —CH3. In some embodiments, R 3 is hydrogen and R 4 is -CD3.

[0077] In some embodiments, W is —NR 3 -When R 3 and R 4 taken together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle. In some embodiments, R 3 and R 4 taken together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, R 3 and R 4 taken together with the N atom to which they are attached form a substituted or unsubstituted monocyclic N-containing heterocycloalkyl. In some embodiments, R 3 and R 4 together with the N atom to which they are attached form a substituted or unsubstituted 3- to 6-membered N-containing heterocycloalkyl.

[0078] In some embodiments, the compound has Formula (II) or Formula (III):

[0079] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0080] In some embodiments, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (III) or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0081] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0082] In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X 2 is CR 11 , X 3is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is CR 11 , X 2 is N, X 3 is N, or X 1 is N, X 2 is CR 11 , X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X 3 is N, or X 1 is N, X 2 is N, X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is N. In some embodiments, X 1 is CR 11 , X 2 is N, X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is N, X 3 is N. In some embodiments, X 1 is N, X 2 is CR 11 , X 3 is CR 11 In some embodiments, X 1 is N, X 2 is CR 11 , X 3 is N. In some embodiments, X 1 is N, X 2 is N, X3 is CR 11 is.

[0083] In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X 2 is CR 11 , X 3 is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X 3 is CR 11 is.

[0084] In some embodiments, R 11 are each independently 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 embodiments, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)N(R 16 )2, -N(R 16 )2, or -SO2N(R 16 )2. In some embodiments, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2. In some embodiments, R 11are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2. In some embodiments, R 11 are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or —CN. In some embodiments, R 11 are each independently hydrogen, halogen, or —CN. In some embodiments, R 11 are each independently hydrogen or halogen. In some embodiments, R 11 are each independently hydrogen, fluoro, or chloro. 11 are each independently hydrogen or fluoro. In some embodiments, R 11 are hydrogen atoms.

[0085] In some embodiments, X 1 , X 2 , and X 3 are each independently CH, CF, or N. In some embodiments, X 1 , X 2 , and X 3 are each independently CH or N. In some embodiments, X 1 is CH or CF, X 2 is CH or CF, X 3 is CH or CF, or X 1 is CH or CF, X 2 is CH or CF, X 3 is N, or X 1 is CH or CF, X 2 is N, X 3 is CH or CF, or X 1 is N, X 2 is CH or CF, X 3 is CH or CF. In some embodiments, X 1 is CH, X 2 is CH, X 3 is CH, or X1 is CH, X 2 is CH, X 3 is N, or X 1 is CH, X 2 is N, X 3 is CH, or X 1 is N, X 2 is CH, X 3 is CH.

[0086] In some embodiments, X 1 is CH, X 2 is CH, CF, or N, X 3 is CH. In some embodiments, X 1 is CH, X 2 is CF or N, X 3 is CH. In some embodiments, X 1 is CH, CF, or N, X 2 is CH, X 3 is CH. In some embodiments, X 1 is CF or N, X 2 is CH, X 3 is CH. In some embodiments, X 1 is CH, X 2 is CH, X 3 is CH, CF, or N. In some embodiments, X 1 is CH, X 2 is CH, X 3 is either CF or N.

[0087] In some embodiments, the compound has Formula (IV) or Formula (V):

[0088] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0089] In some embodiments, the compound is a compound of formula (IV) or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (V) or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0090] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0091] In some embodiments, R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -N(R16 )2, -NR 16 C(=O)R 17 , -SR 16 , -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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. In some embodiments, R 8are each independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8 is hydrogen, methyl, ethyl, isopropyl, -CD, -CHOH, -CF, cyclopropyl, oxetanyl, azetidinyl, -COH, or -COCH. In some embodiments, R 8 are each independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8 is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0092] In some embodiments, p is 0 or 1. In some embodiments, p is 1. In some embodiments, p is 0, so that ring A is not substituted.

[0093] In some embodiments, ring A is

[0094] [ka] In some embodiments, ring A is

[0095] [ka] In some embodiments, ring A is

[0096] [ka] In some embodiments, ring A is

[0097] [ka] is.

[0098] In some embodiments,

[0099] [ka] teeth,

[0100] [ka] In some embodiments,

[0101] [ka] teeth,

[0102] [ka] In some embodiments,

[0103] [ka] teeth,

[0104] [ka] is.

[0105] In some embodiments,

[0106] [ka] teeth,

[0107] [ka] wherein A 1 and A 2 are each independently N or C, and A 3 , A 4, and A 5 are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0108] In some embodiments, the compound has Formula (VI) or Formula (VII):

[0109] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0110] In some embodiments, the compound is a compound of formula (VI) or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VII) or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0111] In some embodiments, R 4is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0112] In some embodiments, A 1 is N, A 2 is C, A 3 is N, A 4 is N, A 5 is CR 8 and Or, A 1 is C, A 2 is N, A 3 is N, A 4 is CR 8 , A 5 is N, Or, A 1 is C, A 2 is C, A 3 is N, A 4 is NR 8 , A 5 is N, Or, A 1 is C, A 2 is N, A 3 is N, A 4 is N, A 5 is CR 8 is.

[0113] In some embodiments, the compound has formula (VIb-1):

[0114] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0115] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0116] In some embodiments, the compound has formula (VId-1):

[0117] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0118] In some embodiments, R 4is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is —CH. In some embodiments, R 4 is -CD3.

[0119] In some embodiments, the compound has the formula (VIg-1):

[0120] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0121] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0122] In some embodiments, R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -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 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17, or -SO2N(R 16 )2.

[0123] In some embodiments, R 8 are each independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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.

[0124] In some embodiments, R 8 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2 and R 8 When is attached to a nitrogen atom, R 8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2.

[0125] In some embodiments, R 8 are each independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8 is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3.

[0126] In some embodiments, R 8 are each independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3; R 8 When is attached to a nitrogen atom, R 8 is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0127] In some embodiments, R 8 are each independently hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 are each independently hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8are each independently hydrogen, methyl, ethyl, isopropyl, -CD, -CHOH, -CF, cyclopropyl, oxetanyl, azetidinyl, -CN, -COH, or -COCH. In some embodiments, R 8 are each independently hydrogen, methyl, —CD, —CHOH, —CF, oxetanyl, —CN, or —COCH. In some embodiments, R 8 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 8 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 8 are each independently hydrogen, methyl, ethyl, isopropyl, -CD3, or -CF3. In some embodiments, R 8 are each independently hydrogen, methyl, -CD, or -CF. In some embodiments, R 8 are each independently hydrogen or methyl.

[0128] In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle, -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 embodiments, R 6 and R 7 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , and -N(R 16 )2. In some embodiments, R6 and R 7 are each independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C-C alkyl, or C-C deuteroalkyl. 6 and R 7 are each independently hydrogen or C1-C4 alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, Cl, —CD, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, R 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 are each deuterium. In some embodiments, R 6 and R 7 are F, respectively.

[0129] In some embodiments, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atoms to which they are attached form C=O or C-C cycloalkyl. In some embodiments, two R 6 and one R 7together with the carbon atom to which they are attached to form C=O. In some embodiments, two R 6 and one R 7 together with the carbon atoms to which they are attached form a C-C cycloalkyl. In some embodiments, two R 6 and one R 7 together with the carbon atom to which they are attached form a cyclopropyl.

[0130] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0131] In some embodiments, Z is —NR 10 In some embodiments, Z is -NR 10 In some embodiments, Z is -NR 10 In some embodiments, Z is -NR 10 - or -O-.

[0132] In some embodiments, Z is —NR 10 In some embodiments, R 10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl. 10 is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4-6 membered heterocycloalkyl. 10 is hydrogen, C-C alkyl, C-C deuteroalkyl, C-C fluoroalkyl, C-C cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R 10is hydrogen, C-C alkyl, C-C fluoroalkyl, C-C cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. 10 is hydrogen, C1-C4 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R 10 is hydrogen, C-C alkyl, C-C deuteroalkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is hydrogen, -CH, or -CD. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is —CH3. In some embodiments, R 10 is -CD3.

[0133] In some embodiments, Z is NH, NCH3, or NCD3. In some embodiments, Z is NCH3 or NCD3. In some embodiments, Z is NCH3. In some embodiments, Z is NCD3.

[0134] 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-.

[0135] In some embodiments, R 2is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 In some embodiments, R 2 is Ring B which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or substituted bicyclic heterocycle, an unsubstituted or substituted spirocyclic carbocycle, an unsubstituted or substituted spirocyclic heterocycle, an unsubstituted or substituted bridged carbocycle, or an unsubstituted or substituted bridged heterocycle, and if Ring B is substituted, then Ring B is substituted with q instances of R 13 is replaced by

[0136] In some embodiments, R 2 is ring B which is an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by

[0137] In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted 6-membered monocyclic heteroaryl, unsubstituted or substituted 5-membered monocyclic heteroaryl, or unsubstituted or substituted bicyclic heteroaryl, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by

[0138] In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by

[0139] In some embodiments, R 2 is ring B which is an unsubstituted or substituted monocyclic 5-membered heteroaryl, and in some embodiments, R 2is ring B which is unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, or unsubstituted or substituted tetrazolyl, and when ring B is substituted, ring B has q instances of R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, or unsubstituted or substituted tetrazolyl, and when ring B is substituted, ring B is substituted with q instances of R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyrrolyl, unsubstituted or substituted imidazolyl, or unsubstituted or substituted pyrazolyl, and when ring B is substituted, ring B is q instances of R 13 is replaced by

[0140] In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl or unsubstituted or substituted monocyclic 6-membered heteroaryl, and when ring B is substituted, ring B is 13 is replaced by

[0141] In some embodiments, R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by

[0142] In some embodiments, R 2is ring B, which is an unsubstituted or substituted monocyclic 6-membered heteroaryl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted or substituted pyridazinyl, and when ring B is substituted, ring B is substituted with q instances of R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is 13 is replaced by

[0143] In some embodiments, R 2 teeth,

[0144] [ka] and q is 0 to 4. In some embodiments, R 2 teeth,

[0145] [ka] and q is 0 to 4. In some embodiments, R 2 teeth,

[0146] [ka] and q is 0 to 4.

[0147] In some embodiments, R 2 teeth,

[0148] [ka] wherein V is CH, CR 9 or N, and q is 0, 1, 2, or 3. In some embodiments, R 2 teeth,

[0149] [ka] wherein V is CH, CR 9 , or N, and q is 0, 1, 2, or 3.

[0150] In some embodiments, the compound has formula (VIII):

[0151] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 and q is 1, 2, or 3; A 1 and A 2 are each independently N or C, A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 and where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0152] In some embodiments, the compound has formula (VIIIb-1):

[0153] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0154] In some embodiments, the compound has formula (VIIId-1):

[0155] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0156] In some embodiments, the compound has formula (VIIIg-1):

[0157] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0158] In some embodiments, V is N. In some embodiments, V is CH or CR 13 In some embodiments, V is CH. In some embodiments, V is CR 13 is.

[0159] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0160] In some embodiments, R 13 are each independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -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 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 13 are each independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 13 are each independently halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 13are each independently halogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 13 are each independently -F, -Cl, -CH3, or -CF3.

[0161] In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 1, 2, or 3. In some embodiments, q is 1 or 2. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 0, such that ring B is not substituted.

[0162] In some embodiments, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 is.

[0163] In some embodiments, R 2 is -C(=O)R 14 is.

[0164] In some embodiments, R 2 is -C(=O)NR 14 R 15 or -C(=O)OR 14 is.

[0165] In some embodiments, the compound has formula (IX), formula (X), or formula (XI):

[0166] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5 are each independently N, NR8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0167] In some embodiments, the compound is a compound of Formula (IX), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (X), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of Formula (XI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0168] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0169] In some embodiments, R1 is hydrogen, C-C alkyl, or C-C fluoroalkyl. In some embodiments, R 1 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 1 is hydrogen or C1-C6 alkyl. In some embodiments, R 1 is hydrogen or C1-C4 alkyl. In some embodiments, R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 1 is hydrogen or methyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is methyl.

[0170] In some embodiments, R 1 and R 15 are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle. In some embodiments, R 1 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycloalkyl. In some embodiments, R 1 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5-membered monocyclic heterocycle. 1 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5-membered monocyclic heterocycloalkyl.

[0171] In some embodiments, R 1 is hydrogen.

[0172] In some embodiments, the compound has formula (IXb-1):

[0173] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0174] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0175] In some embodiments, the compound has formula (IXd-1):

[0176] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0177] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0178] In some embodiments, the compound has formula (IXg-1):

[0179] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0180] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0181] In some embodiments, R 14 is hydrogen, unsubstituted or substituted C-C alkyl, C-C deuteroalkyl, unsubstituted or substituted C-C alkenyl, unsubstituted or substituted C-C alkynyl, unsubstituted or substituted C-C heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 14 is unsubstituted or substituted C-C alkyl, C-C deuteroalkyl, unsubstituted or substituted C-C alkenyl, unsubstituted or substituted C-C alkynyl, unsubstituted or substituted C-C heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 14 is unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.

[0182] In some embodiments, R 14 is hydrogen, unsubstituted or substituted C-C alkyl, unsubstituted or substituted C-C alkenyl, unsubstituted or substituted C-C alkynyl, unsubstituted or substituted C-C heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. 14is an unsubstituted or substituted C-C alkyl, an unsubstituted or substituted C-C alkenyl, an unsubstituted or substituted C-C alkynyl, an unsubstituted or substituted C-C heteroalkyl, an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle. 14 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.

[0183] In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl may be selected from the group consisting of one or more R s In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C6 cycloalkyl, or an unsubstituted or substituted 4- to 6-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl may be selected from the group consisting of one or more R s In some embodiments, R 14 is unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, C1-C6 alkyl, -CN, -OR 18 , and -N(R 18 one or more R independently selected from the group consisting of sIn some embodiments, R 14 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, C1-C6 alkyl, -CN, -OR 18 , and -N(R 18 one or more R independently selected from the group consisting of s In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C4 cycloalkyl, or an unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CHF2, —CF3, —OCH3, —OCHF2, and —OCF3. s In some embodiments, R 14 is methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

[0184] [ka] In some embodiments, R 14 is methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

[0185] [ka] In some embodiments, R 14 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,

[0186] [ka] is.

[0187] In some embodiments, R 2 -C(=O)NR 14 R 15 When R 14 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle. In some embodiments, R 14 and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl.

[0188] In some embodiments, B 1 is CR 12a , B 2 is CR 12b or B 1 is N, B 2 is CR 12b or B 1 is CR 12a , B 2 is N, or B 1 is N, B 2 is N. In some embodiments, B 1 is CR 12a , B 2 is CR 12b In some embodiments, B 1 is N, B 2 is CR 12b In some embodiments, B 1 is CR 12a , B 2 is N. In some embodiments, B 1 is N, B 2 is N.

[0189] In some embodiments, B 1 is CR 12a , B 2 is CR12b or B 1 is N, B 2 is CR 12b That is,

[0190] In some embodiments, R 12a and R 12b are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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.

[0191] In some embodiments, R 12a and R 12b are each independently 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 embodiments, R 12a and R 12b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , -C(=O)N(R 16 )2, -N(R 16 )2, or -SO2N(R 16 )2. In some embodiments, R12a and R 12b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2. In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2. In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or —CN. In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, or —CN. In some embodiments, R 12a and R 12b are each independently hydrogen or halogen. In some embodiments, R 12a and R 12b are each independently hydrogen, fluoro, or chloro. 12a and R 12b are each independently hydrogen or fluoro. In some embodiments, R 12a and R 12b are hydrogen atoms.

[0192] In some embodiments, B 1 and B 2 are each independently CH, CF, or N. In some embodiments, B 1 and B 2 are each independently CH or N.

[0193] In some embodiments, B 1 is CH or CF, B 2 is CH or CF, or B 1 is N, B 2 is CH or CF, or B1 is CH or CF, B 2 is N, or B 1 is N, B 2 is N. In some embodiments, B 1 is CH, B 2 is CH, or B 1 is N, B 2 is CH, or B 1 is CH, B 2 is N, or B 1 is N, B 2 is N.

[0194] In some embodiments, R 3 and R 12a taken together with the intervening atoms to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocyclic ring. In some embodiments, R 3 and R 12a taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 5-membered heterocycle. 3 and R 12a taken together with the intervening atoms to which they are attached form a substituted or unsubstituted pyrazolidinone ring. In some embodiments,

[0195] [ka] teeth,

[0196] [ka] In some embodiments,

[0197] [ka] teeth,

[0198] [ka] In some embodiments,

[0199] [ka] teeth,

[0200] [ka] is.

[0201] In some embodiments, the compound has formula (XII):

[0202] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are each independently N or C, and A 3 , A 4 , and A 5 are each independently N, NR 8 , or CR 8 where A 1 , A 2 , A 3 , A 4 , and A 5 three ring atoms selected from N or NR 8 and the remaining atoms are C or CR 8 is.

[0203] In some embodiments, A 1 is C, A 2 is N, A 3 is CR 8 , A 4 is NR 8 , A 5 is N.

[0204] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0205] In some embodiments, R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 In some embodiments, R 2 is ring B, which is an unsubstituted or substituted monocyclic 6-membered heteroaryl, and when ring B is substituted, ring B is 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is 13 is replaced by

[0206] In some embodiments, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 In some embodiments, R 2 is -C(=O)R 14 is.

[0207] In some embodiments, R 16 are each independently 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, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, or two R on the same N atom 16 taken together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycloalkyl. In some embodiments, R 16 are each independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl, or two R on the same N atom 16 together with the N atom to which they are attached form a 4- to 6-membered N-containing heterocycloalkyl.

[0208] In some embodiments, R 17 are each independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C7 cycloalkyl, or substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. 17 are each independently C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0209] In some embodiments, the compound has formula (XIII):

[0210] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 8is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -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, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-; R 10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; X 1 , X 2 , and X 3 are each independently CR 11 or N, R 11 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 N or CR 12a and B 2 is N or CR 12b and R 12a and R 12b are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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, R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 is replaced by R 13 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 on adjacent atoms of ring B 13 the groups, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Alternatively, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 and R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R 15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R17 , -SR 16 , -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Or, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 17 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from the group consisting of deuterium, halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -OR 18 , -CH2OR 18 , -CO2R 18 , -CH2CO2R 18 , -C(=O)N(R 18 )2, -CH2C(=O)N(R 18 )2, -N(R18 )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 ) one or more R independently selected from the group consisting of s is substituted with a group, R 18 are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the groups, taken together with the N atom to which they are attached, form an N-containing heterocycle; R 19 are each independently selected from C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 1, 2, 3, or 4.

[0211] In some embodiments, R 8 is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, Z is -NR 10 - or -O-, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl; X 1 , X 2 , and X 3 are each independently CR 11 or N, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2, B 1 is N or CR 12a and B 2 is N or CR 12b and R 12a and R 12b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or —CN; R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by R 13 are each independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R17 , -SO2R 17 , or -SO2N(R 16 )2, Alternatively, R 2 is -C(=O)R 14 and R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CHF2, —CF3, —OCH3, —OCHF2, and —OCF3. s is substituted with a group, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl; Or, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a 4- to 6-membered N-containing heterocycloalkyl; R 17 are each independently C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0212] In some embodiments, R4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0213] In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X 2 is CR 11 , X 3 is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is N. In some embodiments, X 1 is CR 11 , X 2 is N, X 3 is CR 11 In some embodiments, X 1 is N, X 2 is CR 11 , X 3 is CR 11 is.

[0214] In some embodiments, R 11 are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or —CN. In some embodiments, R 11 are each independently hydrogen, halogen, or —CN. In some embodiments, R 11 are each independently hydrogen or halogen. In some embodiments, R 11 are each independently hydrogen, fluoro, or chloro. 11 are each independently hydrogen or fluoro. In some embodiments, R 11 are hydrogen atoms.

[0215] In some embodiments, the compound of formula (XIII) has formula (VId-1):

[0216] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0217] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0218] In some embodiments, R 8 is hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 is hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD, -CHOH, -CF, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -COH, or -COCH. In some embodiments, R 8 is hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3.

[0219] In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, Cl, —CD, or methyl. In some embodiments, R 6 and R 7are each independently hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, R 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 are each deuterium. In some embodiments, R 6 and R 7 are F, respectively.

[0220] In some embodiments, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atoms to which they are attached form C=O or C-C cycloalkyl. In some embodiments, two R 6 and one R 7 together with the carbon atom to which they are attached to form C=O. In some embodiments, two R 6 and one R 7 together with the carbon atoms to which they are attached form a C-C cycloalkyl. In some embodiments, two R 6 and one R 7 together with the carbon atom to which they are attached form a cyclopropyl.

[0221] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0222] In some embodiments, Z is —NR 10 In some embodiments, R10 is hydrogen, C-C alkyl, C-C deuteroalkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is hydrogen, -CH, or -CD. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is —CH3. In some embodiments, R 10 is -CD3.

[0223] In some embodiments, Z is NH, NCH3, or NCD3. In some embodiments, Z is NCH3 or NCD3. In some embodiments, Z is NCH3. In some embodiments, Z is NCD3.

[0224] In some embodiments, Z is —O—.

[0225] In some embodiments, R 2 is as defined herein.

[0226] In some embodiments, the compound has formula (XIV):

[0227] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein R 8is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-; R 10 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; X 1 , X 2 , and X 3 are each independently CR 11 or N, R 11 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 1is N or CR 12a and B 2 is N or CR 12b and R 12a and R 12b are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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, R 2 is ring B, which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when ring B is substituted, ring B is q instances of R 13 is replaced by R 13 are each independently 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 carbocycle, unsubstituted or substituted heterocycle, -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 on adjacent atoms of ring B 13 the groups, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Alternatively, R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 14 and R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R 15 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl; R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or a monocyclic heterocycle, -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, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R 17 are each independently 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 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from the group consisting of deuterium, halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH2CN, -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)R18 , -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 ) one or more R independently selected from the group consisting of s is substituted with a group, R 18 are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the groups, taken together with the N atom to which they are attached, form an N-containing heterocycle; R 19 are each independently selected from C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 1, 2, 3, or 4.

[0228] In some embodiments, the compound is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide.

[0229] In some embodiments, R 8is hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, Z is -NR 10 - or -O-, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl; X 1 , X 2 , and X 3 are each independently CR 11 or N, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 )2, B 1 is N or CR 12a and B 2 is N or CR 12b and R 12a and R 12b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or —CN; R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, and when ring B is substituted, ring B is substituted with q instances of R 13 is replaced by R 13 are each independently halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -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 , -SO2R 17 , or -SO2N(R 16 )2, Alternatively, R 2 is -C(=O)R 14 and R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from the group consisting of deuterium, halogen, —CN, —NH2, —OH, —NH(CH3), —N(CH3)2, —CH3, —CH2CH3, —CHF2, —CF3, —OCH3, —OCHF2, and —OCF3. s is substituted with a group, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl; Or, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atom to which they are attached form C=O or C3-C4 cycloalkyl; R 16 are each independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; Or, two R on the same N atom 16 together with the N atom to which they are attached form a 4- to 6-membered N-containing heterocycloalkyl; R 17are each independently C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0230] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0231] In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 or X 1 is CR 11 , X 2 is CR 11 , X 3 is N, or X 1 is CR 11 , X 2 is N, X 3 is CR 11 or X 1 is N, X 2 is CR 11 , X3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is CR 11 In some embodiments, X 1 is CR 11 , X 2 is CR 11 , X 3 is N. In some embodiments, X 1 is CR 11 , X 2 is N, X 3 is CR 11 In some embodiments, X 1 is N, X 2 is CR 11 , X 3 is CR 11 is.

[0232] In some embodiments, R 11 are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or —CN. In some embodiments, R 11 are each independently hydrogen, halogen, or —CN. In some embodiments, R 11 are each independently hydrogen or halogen. In some embodiments, R 11 are each independently hydrogen, fluoro, or chloro. 11 are each independently hydrogen or fluoro. In some embodiments, R 11 are hydrogen atoms.

[0233] In some embodiments, the compound of formula (XIV) has formula (XIVa):

[0234] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0235] In some embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4 is hydrogen, C-C alkyl, or C-C deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH, -CHD, -CHD, or -CD. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0236] In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0237] In some embodiments, R 6 and R 7are each independently hydrogen, deuterium, F, Cl, —CD, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, R 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 are each deuterium. In some embodiments, R 6 and R 7 are F, respectively.

[0238] In some embodiments, one R bonded to the same carbon atom 6 and one R 7 together with the carbon atoms to which they are attached form C=O or C-C cycloalkyl. In some embodiments, two R 6 and one R 7 together with the carbon atom to which they are attached to form C=O. In some embodiments, two R 6 and one R 7 together with the carbon atoms to which they are attached form a C-C cycloalkyl. In some embodiments, two R 6 and one R 7 together with the carbon atom to which they are attached form a cyclopropyl.

[0239] In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0240] In some embodiments, Z is —NR 10 In some embodiments, R 10 is hydrogen, C-C alkyl, C-C deuteroalkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is hydrogen, -CH, or -CD. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is —CH3. In some embodiments, R 10 is -CD3.

[0241] In some embodiments, Z is NH, NCH3, or NCD3. In some embodiments, Z is NCH3 or NCD3. In some embodiments, Z is NCH3. In some embodiments, Z is NCD3.

[0242] In some embodiments, Z is —O—.

[0243] In some embodiments, R 2 is as defined herein.

[0244] In some embodiments, the compounds described herein have the following structure:

[0245] [ka] It has.

[0246] In some embodiments, B 1 , B2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 is as described herein. In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 are as listed in Table 1.

[0247] In some embodiments, the compounds described herein have the following structure:

[0248] [ka] It has.

[0249] In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 is as described herein. In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, R 6 , R 7 , and R 8 is as set forth in Table 2. In some embodiments, the compound is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide.

[0250] In some embodiments, the compounds described herein have the following structure:

[0251] [ka] It has.

[0252] In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, and R 8 is as described herein. In some embodiments, B 1 , B 2 , R 2 , R 4 , Z, n, and R 8 are as listed in Table 3.

[0253] In some embodiments, the compounds described herein have the following structure:

[0254] [ka] It has.

[0255] In some embodiments, B 1 , B 2 , N.R. 1 R 2 , R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , A 1 , A 2 , ring A, R 8 and p is as described herein. In some embodiments, B 1 , B 2 , N.R. 1 R 2 , R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , and

[0256] [ka] is as described herein. In some embodiments, B 1 , B 2 , N.R. 1 R 2 , R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , A 1 , A 2 , ring A, R 8 and p is as described in Table 4. In some embodiments, B 1 , B 2 , N.R. 1 R 2 , R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , and

[0257] [ka] are as listed in Table 4.

[0258] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0259] Exemplary compounds described herein include those set forth in the table below.

[0260] [Table 1-1]

[0261] [Table 1-2]

[0262] [Table 1-3]

[0263] [Table 1-4]

[0264] The compounds in Table 1 are named as follows: 1: 6-(cyclopropanecarboxamido)-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide, 2: 6-((5-fluoropyridin-2-yl)amino)-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide, 3: 6-(cyclopropanecarboxamido)-4-((2-(hydroxymethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 4: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide, 5: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 6: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)nicotinamide, 7: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide, 8: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((2R)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, 9: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(2-morpholinoacetamido)pyridazine-3-carboxamide, 10: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazine-3-carboxamide, 11: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-((5-methylpyridin-2-yl)amino)pyridazine-3-carboxamide, 12: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 13: 6-((5-cyanopyridin-2-yl)amino)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 14: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(2-(dimethylamino)acetamido)-N-(methyl-d3)pyridazine-3-carboxamide, 15: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 16: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((3,5-dimethylphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 17: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-isobutyramido-N-(methyl-d3)pyridazine-3-carboxamide, 18: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3,3,3-trifluoropropanamido)pyridazine-3-carboxamide, 19: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 20: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide, 21: 2-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide, 22: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide, 23: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide, 24: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)nicotinamide, 25: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)nicotinamide, 26: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-(methyl-d3)nicotinamide, 27: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)nicotinamide, 28: 6-((5-fluoropyridin-2-yl)amino)-4-((2-(hydroxymethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 29: methyl 6-((6-((5-fluoropyridin-2-yl)amino)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate, 30: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(oxetane-3-carboxamide)nicotinamide, 31: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)nicotinamide, 32: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)pyridazine-3-carboxamide, 33: 4-((2-cyano-5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide, 34: 4-((2-cyano-5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, 35: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 36: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 37: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(1-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, 38: 6-(cyclopropanesulfonamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 39 6-(cyclopropanecarboxamido)-4-((2',5'-dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxaline]-6'-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 40 6-(cyclopropanecarboxamido)-4-((2',5'-dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxaline]-6'-yl)amino)-N-(methyl-d3)nicotinamide 41 (S)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 42 (R)-6-(2,2-difluorocyclopropane-1-carboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 43 (S)-6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and 44 (R)-6-(Cyclopropanecarboxamido)-4-((2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0265] In some embodiments herein, provided are pharmaceutically acceptable salts of the compounds set forth in Table 1.

[0266] [Table 2-1]

[0267] [Table 2-2]

[0268] [Table 2-3]

[0269] The compounds in Table 2 are named as follows: 45: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide, 46: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 47: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 48: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide, 49: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 50: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide, 51: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)nicotinamide, 52: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 53: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 54: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 55: (S)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 56: (R)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 57: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 58: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)nicotinamide, 59: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide, 60: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide, 61: (S)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide, 62: (R)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)pyridazine-3-carboxamide, 63: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide, 64: 6-(3-cyclobutylureido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide, 65: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-5-fluoro-N-(methyl-d3)nicotinamide, 66: 6-(3-cyclopropylureido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide, 67: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)-6-(3-(methyl-d3)ureido)nicotinamide, 68: (S)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 69: (R)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 70: (S)-6-(2,2-difluorocyclopropane-1-carboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-(methyl-d3)nicotinamide, and 71: (R)-6-(2,2-difluorocyclopropane-1-carboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0270] In some embodiments herein, pharmaceutically acceptable salts of the compounds set forth in Table 2 are provided.

[0271] [Table 3]

[0272] The compounds in Table 3 are named as follows: 72: 6-(cyclopropanecarboxamido)-4-((5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepin-8-yl)amino)-N-methylpyridazine-3-carboxamide, 73: 4-((5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepin-8-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, 74: 4-((6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocin-9-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide, 75: 6-(cyclopropanecarboxamido)-4-((6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocin-9-yl)amino)-N-methylpyridazine-3-carboxamide, 76: [6-((5-fluoropyridin-2-yl)amino)-N-methyl-4-((7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)amino)pyridazine-3-carboxamide], 77: [6-(cyclopropanecarboxamido)-N-methyl-4-((7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)amino)pyridazine-3-carboxamide], 78: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)amino)nicotinamide, 79: 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)amino)nicotinamide, and 80: 6-((2,6-dimethylpyrimidin-4-yl)amino)-N-(methyl-d3)-4-((7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)amino)nicotinamide.

[0273] In some embodiments herein, provided are pharmaceutically acceptable salts of the compounds set forth in Table 3.

[0274] [Table 4-1]

[0275] [Table 4-2]

[0276] [Table 4-3]

[0277] [Table 4-4]

[0278] [Table 4-5]

[0279] [Table 4-6]

[0280] The compounds in Table 4 are named as follows: 81: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-6-(3-isopropyl-2-oxoimidazolidin-1-yl)-N-(methyl-d3)pyridazine-3-carboxamide, 82: 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(N-methylcyclopropanecarboxamide)nicotinamide, 83: 6-(cyclopropanecarboxamido)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide, 84: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-N-(methyl-d3)nicotinamide, 85: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 86: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-N-(methyl-d3)nicotinamide, 87: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 88: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 89: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)nicotinamide, 90: 6-(cyclopropanecarboxamido)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 91: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide, 92: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)nicotinamide, 93: 6-(cyclopropanecarboxamido)-4-((2-ethyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 94: (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide, 95: (R)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide, 96: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 97: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 98: 6-(cyclopropanecarboxamido)-4-((7-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 99: (S)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide, 100: (R)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide, 101: 4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide, 102: 6-((2,6-dimethylpyrimidin-4-yl)amino)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide, 103: 4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 104: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-5-oxo-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-7-yl)amino)-N-(methyl-d3)nicotinamide, 105: 6-(cyclopropanecarboxamido)-4-((9-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 106: (R)-6-(cyclopropanecarboxamido)-4-((8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide (absolute configuration not assigned), 107: 6-(cyclopropanecarboxamido)-4-((9-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide, 108: 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 109: (R)-6-(cyclopropanecarboxamido)-4-((8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (absolute configuration not determined), 110: (S)-6-(cyclopropanecarboxamido)-4-((8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide, 111: (S)-6-(cyclopropanecarboxamido)-4-((8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (absolute configuration not determined), 112 (S)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)amino)pyridazine-3-carboxamide, 113 (S)-6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 114 (R)-6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 115 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, and 116 4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)pyridazine-3-carboxamide.

[0281] In some embodiments herein, pharmaceutically acceptable salts of the compounds set forth in Table 4 are provided.

[0282] In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water and ethanol.The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0283] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and that is relatively non-toxic at the concentrations or amounts used; i.e., the material may be administered to an individual without producing undesired biological effects or interacting adversely with any of the compositions in which the compound is included.

[0284] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are useful in solid dosage forms because they are typically more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the gastrointestinal tract, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, allowing for tunable passage through biological membranes.

[0285] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of Formula (I) with an acid. In some embodiments, the compound of Formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and glutamic acid. These include, but are not limited to, conic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, 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), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0286] In some embodiments, the compound of formula (I) is prepared as a chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salt.

[0287] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) with a base. In some embodiments, the compound of Formula (I) is acidic and is reacted with a base. In such situations, the acidic proton of the compound of Formula (I) is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein cooperate with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0288] It should be understood that the reference to pharmaceutically acceptable salts includes solvent addition forms.In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the crystallization process using pharmaceutically acceptable solvents such as water or ethanol.When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed.Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can optionally exist in solvated as well as unsolvated forms.

[0289] The methods and formulations described herein include the use of N-oxides (where appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds that possess the same type of activity.

[0290] In some embodiments, moieties on the organic radical of a compound of Formula (I) (e.g., alkyl groups, aromatic rings) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radical will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0291] In another embodiment, the compounds described herein are isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, the use of chromophoric or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0292] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, e.g., 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 33In one embodiment, the isotopically labeled compounds described herein, for example, 3 H and 14 Incorporation of radioactive isotopes such as C is useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium offers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0293] In some embodiments, compounds of Formula (I) have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. In some embodiments, compounds of Formula (I) exist in the R configuration. In some embodiments, compounds of Formula (I) exist in the S configuration. The compounds presented herein include all enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0294] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers on chiral chromatographic columns, or separation of diastereomers on either non-chiral or chiral chromatographic columns, or crystallization and recrystallization of appropriate solvents or solvent mixtures. In certain embodiments, compounds of Formula (I) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by diastereomeric salts and separation generated by recrystallization, chromatography, or any combination thereof. "Enantiomers, Racemates and Resolutions" by Jean Jacques, Andre Collet, and Samuel H. Wilen, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0295] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is not. Additionally, or alternatively, prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design improves effective water solubility. A non-limiting example of a prodrug is a compound described herein, which is administered as an ester (the "prodrug") and then metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short-chain peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0296] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, "Design of Prodrugs," Bundgaard, A. (ed.), Elseview, 1985, and "Method in Enzymology," Widder, K. et al. (eds.), Academic, 1985, Vol. 42, pp. 309-396; "Design and Application of Prodrugs," Bundgaard, H., A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard (eds.), 1991, Chapter 5, pp. 113-191; and "Advanced Drug Delivery Review," Bundgaard, H., 1992, Vol. 8, pp. 1-38, each of which is incorporated herein by reference. In some embodiments, hydroxyl groups in the compounds disclosed herein are used to form prodrugs, where the hydroxyl group is incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, a hydroxyl group in a compound disclosed herein is a prodrug, where the hydroxyl is subsequently metabolized in vivo to yield a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), which is subsequently metabolized in vivo to yield the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0297] Prodrug forms of the compounds described herein are included within the scope of the claims, where the prodrug is metabolized in vivo to produce a compound of formula (I) described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0298] In some embodiments, any one of the hydroxyl, amino, and / or carboxylic acid groups is suitably functionalized to provide a prodrug moiety, which in some embodiments is as described above.

[0299] In additional or further embodiments, the compounds described herein, after administration to an organism in need thereof, are metabolized to produce metabolites, which are then used to provide a desired effect, including a desired therapeutic effect.

[0300] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the totality of processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes may result in specific structural alterations of the compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing multiple tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0301] In some instances, heterocycles may exist in tautomeric forms. In such situations, the structure of the compound above is illustrated or designated in one tautomeric form, but it is understood that it may also be illustrated or designated in alternative tautomeric forms. Alternative tautomeric forms, such as the structure illustrated below, are expressly included in the present disclosure. For example, pyridone can exist in the following tautomeric form:

[0302] [ka] all of which are encapsulated within the group "substituted pyridine." Similarly, triazolones can exist in the following tautomeric forms, including zwitterionic forms:

[0303] [ka] and 5-membered heteroaryl, all of which are encompassed within the group "substituted 5-membered heteroaryl." Similarly, pyrazoles, triazoles, pyrimidines, and the like are known to tautomerize. For purposes of this disclosure, all tautomeric forms (including charged and zwitterionic tautomers) are considered within the scope of this disclosure.

[0304] Compound synthesis The compounds of formula (I) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0305] Unless otherwise specified, conventional mass spectroscopy, NMR, HPLC are utilized.

[0306] The compounds are 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 utilized, including variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0307] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0308] [ka] The variables are as defined in formula (I).

[0309] In some embodiments, nucleophilic displacement of one chloro group of intermediate A by the free amino group of B provides intermediate C. In some embodiments, for example, intermediate A is a pyridazine compound (B 1 ═N), this substitution can be carried out with a suitable Lewis acid, such as Zn(OAc) 2 . In other embodiments, for example, intermediate B can be a pyridine compound (B 1 ═CH), this substitution is carried out by deprotonation of the amino group with a suitable base, such as LDA. In yet other embodiments, intermediate C may be approached by a cross-coupling reaction of intermediates A and B. The cross-coupling reaction may be an organometallic cross-coupling reaction, such as the Suzuki-Miyaura reaction, the Buchwald-Hartwig reaction, the Heck reaction, the Ullman coupling, or the Chan-Lam coupling. Finally, in some embodiments, intermediate C is converted to final compound D (e.g., compound 1) via a cross-coupling reaction. The cross-coupling reaction may be an organometallic cross-coupling reaction, such as the Suzuki-Miyaura reaction, the Buchwald-Hartwig reaction, the Heck reaction, the Ullman coupling, or the Chan-Lam coupling.

[0310] In some embodiments, the compounds are prepared as described in the Examples.

[0311] Specific Terms Unless otherwise specified, the following terms used in this application have the definitions provided below. Use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0312] As used herein, C1-C x is C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C6" indicates that there are from 1 to 6 carbon atoms present in the moiety, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are from 1 to 4 carbon atoms present in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0313] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may be branched or straight-chain. In some embodiments, an "alkyl" group may contain 1 to 10 carbon atoms, i.e., C1-C6. 10The term "alkyl" includes alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers occurrences of the term "alkyl" without any numerical range specified. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0314] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be alkylene by abstraction of another hydrogen atom from the alkyl. In some embodiments, the alkylene is a C1-C6 alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, the alkylene is -CH2-.

[0315] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0316] The term "alkylamine" refers to -N(alkyl) x H y refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0317] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0318] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0319] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0320] The term "alkynyl" refers to a species of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0321] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl.

[0322] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (i.e., "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

[0323] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocycle from "heterocyclic" or "heterocycle" rings, which have at least one atom other than carbon in the backbone of the ring. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0324] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, aryl is C6-C 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0325] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a C3-C4 cycloalkyl.

[0326] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0327] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0328] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms in the ring, where 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 known as heterocycloalkyls) 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-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups may be C-bonded (i.e., C-linked) or N-bonded, where possible. For example, pyrrole-derived groups include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, imidazole-derived groups include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0329] The term "heteroaryl," or alternatively "heteroaromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0330] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C 10 In another aspect, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0331] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining specified groups.

[0332] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0333] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CHF, -CF, -OCH, -OCHF, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0334] In some embodiments, substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from deuterium, halogen, C1-C6 alkyl, monocyclic carbocycle, monocyclic heterocycle, -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 one or more R independently selected from the group consisting of s substituted with R 18 are each independently selected from hydrogen, C-C alkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C cycloalkyl, C-C heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 18 groups, together with the N atom to which they are attached, form an N-containing heterocycle; R 19 are each 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.

[0335] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that it has no lasting adverse effects on the health of the subject being treated.

[0336] The term "modulate," as used herein, means to interact with a target either directly or indirectly to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0337] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inhibitor.

[0338] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological effect. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those of skill in the art are familiar with the 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.

[0339] "Co-administration" and like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to one patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0340] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound administered to alleviate to some extent one or more of the symptoms of the disease or disorder being treated. The result may include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the quantity of a composition comprising a compound disclosed herein required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0341] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0342] The term "pharmaceutical combination," as used herein, refers to a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient simultaneously, concurrently, or sequentially as separate entities without a specific time limit between them, such that such administration provides effective levels of the two compounds to the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0343] The terms "article of manufacture" and "kit" are used synonymously.

[0344] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, members of any of the following mammalian classes: humans, non-human primates such as chimpanzees, other apes, and monkey species; farm animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one aspect, the mammal is a human.

[0345] "Treat," "treating," or "treatment," as used herein, includes alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the onset or progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a comorbid condition caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0346] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are conventionally formulated with one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into preparations for use as pharmaceuticals. Appropriate formulations depend on the selected route of administration. Summary information on pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0347] The compounds or pharmaceutical compositions of the present disclosure are, in some embodiments, useful for treating TYK2-mediated diseases or disorders. In some embodiments, the pharmaceutical compositions are effective for treating diseases or disorders in which TYK2 is overexpressed or abnormally active. In some embodiments, the pharmaceutical compositions are effective for treating diseases or disorders that would benefit from reduced TYK2 activity or expression.

[0348] In some embodiments, the pharmaceutical compositions are useful for treating diseases or disorders associated with high levels of cytokines driven by TYK2, 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 limitin)), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31), oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF. In some embodiments, the disease or disorder is an inflammatory disease or disorder, an autoimmune disease or disorder, a respiratory disease or disorder, type 1 diabetes, and an interferonopathy such as Aicardi-Goutières syndrome, or a combination thereof.

[0349] In some embodiments, the pharmaceutical composition is useful for treating an inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder is an autoinflammatory disease or disorder, a host-mediated inflammatory disease or disorder, an injury-associated inflammatory disease or disorder, an infection-associated inflammatory disease or disorder, or a hyperproliferative (e.g., cancer, fibrosis)-mediated inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder or infection-associated inflammatory disease or disorder is a respiratory disease or disorder. In some embodiments, the respiratory disease or disorder is associated with a virus in a microbial infection. In some embodiments, the respiratory disease or disorder is a problematic immune response to a viral or microbial infection. In some embodiments, the respiratory disease or disorder is associated with a coronavirus, such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2. In some embodiments, the pharmaceutical composition is effective in reducing symptoms associated with, or immune responses associated with, COVID-19.

[0350] In some embodiments, the pharmaceutical composition is useful for treating an autoimmune disease or disorder. In some embodiments, the autoimmune disease or disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Behçet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, the autoimmune disease or disorder is psoriasis. In some embodiments, the autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, the autoimmune disease or disorder is dry eye or uveitis. In some embodiments, the autoimmune disease or disorder is Crohn's disease. In some embodiments, the autoimmune disease or disorder is atopic dermatitis.

[0351] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, additive, or vehicle in a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric, or duodenal feeding tubes, rectal medication, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, oral mucosal, sublingual, buccal, and topical (epithelial, cutaneous, enema, ophthalmic, otic, intranasal, vaginal) administration, and the most suitable route may depend, for example, on the condition or disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the area requiring treatment, for example, by topical application of a cream or ointment. Further examples of topical administration of the compounds of the invention include eye drops, eye creams, gels, or hydrogels, implants, transdermal patches, or drug depots. In some embodiments, the pharmaceutical compositions are administered orally (e.g., in a liquid formulation, tablet, capsule, nebulized liquid, aerosolized liquid, or dry powder spray).

[0352] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0353] Pharmaceutical compositions available for oral administration include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol.In some embodiments, stabilizers are added.Sugared tablet cores are provided with suitable coatings.For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.Dyes or pigments may be added to tablets or sugar-coated tablets to identify or characterize different combinations of active compound dosages.

[0354] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be provided in unit-dose or multi-dose containers, e.g., sealed ampoules or vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or pyrogen-free distilled water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0355] Pharmaceutical compositions may also be formulated as depot preparations. Such long-acting preparations may be administered by implantation (e.g., subcutaneously). To this end, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0356] The pharmaceutical composition may be administered locally, which is carried out by non-systemic administration. This includes applying the compound to the outside of the epidermis or buccal cavity, and introducing the compound into the ear, eye, and nose, so that the compound of the present invention does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0357] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations such as gels, liniments, lotions, creams, ointments, or pastes suitable for penetration through the skin to the site of inflammation, and drops suitable for administration to the eye, ear, or nose. The active ingredient may comprise 0.001% to 10% w / w, for example 1% to 2% by weight, of the formulation for topical administration.

[0358] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an air inhaler, a nebulizer, a pressurized pack, or other convenient means for delivering an aerosol spray. Pressurized packs may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in a unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered with the aid of an inhaler or air insufflator.

[0359] In addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0360] Dosage and Treatment Regimen In one embodiment, the compounds described herein, or pharmaceutically acceptable salts, tautomers, or solvates thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from modulation of TYK2 activity. Methods for treating any of the diseases or disorders described herein in a mammal in need of such treatment comprise administering to the mammal 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.

[0361] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or partially inhibit at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose-ranging clinical trials.

[0362] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." For this use, the precise amount will depend, among other factors, on the patient's health and weight. When used in a patient, the amount effective for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously suffered from at least one symptom of the disease being treated and is now in remission, to prevent the return of the disease or condition symptoms.

[0363] In certain embodiments where the patient's condition does not improve, at the physician's discretion, the compound is administered chronically, i.e., for an extended period of time, including the patient's entire life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0364] Once the patient's condition has improved, a maintenance dose is administered as needed. In certain embodiments, the dosage or frequency of administration, or both, is then reduced, depending on the symptoms, to a level at which improvement in the disease, disorder, or condition is maintained. In certain embodiments, however, the patient will require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0365] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0366] In general, however, dosages utilized in adult human treatment will typically be in the range of 0.01 mg / day to 2000 mg / day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more sub-doses per day.

[0367] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or amount of active ingredient in a dosage form will be lower or higher than the ranges set forth herein, depending on many variables related to the particular treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the health care professional.

[0368] The toxicity and therapeutic efficacy of such treatment regimens are discussed in detail below. 50 and ED 50The dose ratio between toxic and therapeutic effects is the therapeutic index, which is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of ED100 with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending upon the dosage form utilized and the route of administration used.

[0369] Any of the foregoing aspects are further embodiments in which an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal.

[0370] Any of the foregoing aspects are further embodiments that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered multiple times to the mammal during the course of a day.

[0371] Any of the foregoing aspects are further embodiments that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently in a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, and (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced, and compound dosing is resumed at the end of the drug holiday. In one embodiment, the length of the drug holiday ranges from two days to one year.

[0372] Combination therapy In certain instances, it will be appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0373] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit on its own, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit received by the patient is improved by administering one of the compounds described herein with another agent (including a therapeutic regimen) that also has a therapeutic benefit.

[0374] In one specific embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are co-administered with a second therapeutic agent, wherein the compounds described herein, or pharmaceutically acceptable salts thereof, and the second therapeutic agent collectively provide a greater benefit than administration of either therapeutic agent alone by modulating various aspects of the disease, disorder, or condition being treated.

[0375] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be merely additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0376] In the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-drug utilized, the particular drug utilized, the disease or condition being treated, etc. In additional embodiments, the compounds provided herein, when co-administered with one or more other therapeutic agents, are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0377] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single dosage form, a combined dosage form, or multiple dosage forms (e.g., as one pill or two separate pills), by way of example only.

[0378] The compounds described herein, or pharmaceutically acceptable salts thereof, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administering compositions containing the compounds can vary. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to developing a disease or condition to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject at the onset of symptoms or as soon as possible after the onset of symptoms. In specific embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the time required to treat the condition. In some embodiments, the length of treatment required can vary, and the length of treatment can be adjusted to meet the specific needs of each subject. [Example]

[0379] As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise specified, shall be understood to have the following meanings: Abbreviation: ACN Acetonitrile CAN Ammonium Cerium Nitrate DCM dichloromethane DIBAL Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMA Dimethylacetamide DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EGTA Ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid ES Electrospray FBS fetal bovine serum GST glutathione S-transferase HEK Human Embryonic Kidney HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HMD Bis(trimethylsilyl)amide HPLC High Pressure Liquid Chromatography HTRF Homogeneous Time-Resolved Fluorescence I C 50 50% inhibitory concentration IFN Interferon IL Interleukin IPA Isopropyl Alcohol JAK Janus kinase LCMS Liquid Chromatography Mass Spectrometry MDI metered drug inhalant MW Microwave NMR nuclear magnetic resonance SEAP secreted embryonic alkaline phosphatase STAT signal transducer and activator of transcription T3P Propanephosphonic Anhydride TBAF Tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TYK non-receptor tyrosine protein kinase

[0380] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0381] Compound synthesis Example 1: Preparation of 2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-amine (I-1):

[0382] [ka]

[0383] Step 1: 2-(2-Amino-6-bromophenoxy)acetonitrile (I-1b): To a stirred solution of 2-amino-6-bromophenol I-1a (10.0 g, 53.2 mmol) in acetone (80.0 mL) was added anhydrous K2CO3 (11.0 g, 79.8 mmol) and 2-chloroacetonitrile (4.82 g, 63.8 mmol). The reaction mixture was then stirred at 60 °C for 16 h. Upon completion, the volatiles were removed under reduced pressure, and water (100 mL) was added to the residue. Extraction was performed with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (30 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% EtOAc in hexanes) to give the desired compound 2-(2-amino-6-bromophenoxy)acetonitrile I-1b (11.0 g) as a pink oil. LCM (ES) m / z: 226.8 [M+H] + .

[0384] Step 2: N'-{[3-bromo-2-(cyanomethoxy)phenyl]amino}-N,N-dioxoethanimidamide (I-1c): To a suspension of I-1b (5.00 g, 22.0 mmol) in concentrated HCl (110 mL) was added a solution of sodium nitrite (1.52 g, 22.0 mmol) in water (19.0 mL) at 0 °C. This was stirred for 30 min, after which the pH of the reaction medium was adjusted to 4 by the gradual addition of sodium acetate (1.81 g, 22.0 mmol). This was followed by the addition of a solution of nitroethane sodium salt (2.16 g, 22.0 mmol) in MeOH (10 mL) with vigorous stirring at 0-5 °C. After 30 min, the observed solid was filtered and washed with water (2 x 10 mL). The filtrate was then extracted with EtOAc (3 x 50 mL), and the combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude N'-{[3-bromo-2-(cyanomethoxy)phenyl]amino}-N,N-dioxoethanimidamide I-1c (6.0 g) as an orange solid. LCM (ES) m / z: 311.0 [MH]+ .

[0385] Step 3: 6-Bromo-2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine (I-1d): To a stirred solution of I-1c (5.00 g, 16.0 mmol) in anhydrous benzene (120 mL), NaH (60% suspension) (1.92 g, 47.9 mmol) was added portionwise at 0 °C. The reaction mixture was then stirred at 85 °C for 5 h (reaction progress was monitored by TLC). The reaction mixture was then cooled to room temperature and quenched by the addition of ice-cold water (50 mL). Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The resulting crude material was purified by Combi-Flash (using a gradient elution of 0 to 15% EtOAc in hexanes) to give the desired compound 6-bromo-2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine I-1d (2.20 g) as a yellow solid. LCM (ES) m / z: 266.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.64(dd,J1=1.2Hz,J2=8.0Hz,1H);7.52(dd,J1=1.6Hz,J2=7.6Hz,1H);7.10(t,J=8.0Hz,1H);5.65(s,2H);2.39(s,3H).

[0386] Step 4: tert-Butyl (2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)carbamate (I-1e): Argon gas was purged through a stirred suspension of I-1d (2.5 g, 9.4 mmol), tert-butyl carbamate (1.65 g, 14.1 mmol), and CsCO (6.12 g, 18.8 mmol) in 1,4-dioxane (20.0 mL) for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (1.09 g, 1.88 mmol) and Pd(OAc) (0.422 g, 1.88 mmol). The reaction mixture was then stirred in a sealed tube at 100 °C for 16 h. The reaction mixture was then allowed to cool to room temperature and filtered through a bed of Celite, washing with EtOAc (2 x 50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-50% EtOAc in hexanes) to give tert-butyl (2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)carbamate I-1e (0.9 g) as a pale yellow solid. LCM (ES) m / z: 303.1 [M+H] + .

[0387] Step 5: 2-Methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-amine (I-7): To a stirred solution of I-1e (1.0 g, 3.31 mmol) in DCM (10.0 mL), trifluoroacetic acid (10.0 mL) was added at 0 °C under a nitrogen atmosphere, and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction progress was monitored by TLC. Upon completion, the volatiles were removed under reduced pressure, and saturated NaHCO3 solution (20 mL) was added to the residue. Extraction was carried out with EtOAc (30 mL x 3). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give 2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-amine I-1 (0.66 g) as a pale yellow solid. LCM (ES) m / z: 202.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 6.84-6.79(m,2H); 6.59-6.57(m,1H); 5.41(s,2H); 5.14(br s,2H); 2.33(s,3H).

[0388] Example 2: Preparation of 5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepin-8-amine (I-2):

[0389] [ka]

[0390] Step 1: Ethyl 3-bromo-2-fluorobenzoate (I-2b): To a stirred solution of I-2a (25.2 g, 115 mmol) in EtOH (250 mL), concentrated sulfuric acid (20.0 mL) was added slowly at room temperature, and the reaction mixture was stirred at reflux for 16 h. The reaction progress was monitored by TLC. Upon completion, the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was then added slowly to the residue, and extraction was carried out with DCM (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 3-bromo-2-fluorobenzoate I-2b (25.4 g) as a thick oil. LCM (ES) m / z: 247.0 [M+H] + .

[0391] Step 2: 3-Bromo-2-fluorobenzohydrazide (I-2c): To a stirred solution of I-2b (15.1 g, 61.1 mmol) in MeOH (40.0 mL), hydrazine hydrate (9.18 g, 183 mmol) was added at room temperature, and the reaction mixture was stirred at 50 °C for 16 h. After complete consumption of the starting material, the reaction mixture was cooled to room temperature. The resulting solid was filtered, washed with EtOH (20 mL), and dried to give the desired compound, 3-bromo-2-fluorobenzohydrazide I-2c (13.1 g), as an off-white solid. LCM (ES) m / z: 233.0 [M+H] + .

[0392] Step 3: N'-(3-Bromo-2-fluorobenzoyl)-N,N-dimethylformohydrazonamide (I-2d): To a stirred solution of I-2c (12.2 g, 52.4 mmol) in ACN (200 mL), DMF-DMA (27.8 mL, 209 mmol) was added at room temperature, and the reaction mixture was stirred at 90 °C for 6 h. The reaction progress was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. The resulting solid was stirred in EtO (30 mL), filtered, and dried to give the desired compound, N'-(3-bromo-2-fluorobenzoyl)-N,N-dimethylformohydrazonamide I-2d (10.8 g), as an off-white solid. LCM (ES) m / z: 288.0 [M+H] + .

[0393] Step 4: 2-(3-(3-Bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)ethan-1-ol (I-2e): To a stirred solution of I-2d (8.00 g, 27.8 mmol) in ACN (40.0 mL) was added AcOH (3.15 mL, 55.5 mmol) and ethanolamine (6.72 mL, 111 mmol) at 0 °C. The reaction mixture was then stirred at 100°C for 16 hours. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was then purified by silica gel column chromatography (using a gradient elution of 0-40% EtOAc in hexanes) to afford 2-(3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)ethan-1-ol I-2e (5.30 g, 18.5 mmol) as a pale yellow solid. LCM (ES) m / z: 286.0 [M+H] + .

[0394] Step 5: 8-Bromo-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine (I-2f): To a stirred solution of I-2e (5.30 g, 18.5 mmol) in anhydrous DMF (50.0 mL), sodium hydride (60% suspension) (2.96 g, 74.1 mmol) was added portionwise at 0 °C. The reaction mixture was then stirred at room temperature for an additional 1 h. The reaction progress was monitored by TLC. After complete consumption of the starting material, the reaction mixture was quenched by the addition of ice-water (100 mL), and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (using a gradient elution of 0-2% MeOH in DCM) to give 8-bromo-5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepine I-2f (4.50 g) as an off-white solid. An analytically pure sample was obtained by preparative HPLC purification of this intermediate. LCM (ES) m / z: 266.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.67(s,1H);8.46(dd,J1=1.6Hz,J2=8.4Hz,1H);7.7(dd,J1=1.6Hz,J2=7.6Hz,1H);7.12(t,J=8.0Hz,1H);4.58-4.54(m,4H).

[0395] Step 6: tert-Butyl (5,6-dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepin-8-yl)carbamate (I-2g): I-2g (1.2g) was synthesized by following the procedure described for the synthesis of I-1 (Step 4) using I-2f (4.46g, 16.8mmol) as the starting material. LCM (ES) m / z: 303.2 [M+H] + .

[0396] Step 7: 5,6-Dihydrobenzo[f][1,2,4]triazolo[4,3-d][1,4]oxazepin-8-amine (I-2): To a stirred solution of I-2g (1.20 g, 3.97 mmol) in DCM (20 mL) was added a 4 M solution of HCl in 1,4-dioxane (20 mL) at 0 °C. The reaction mixture was then warmed to room temperature over 2 h (reaction progress was monitored by TLC). Upon completion, the volatiles were removed under reduced pressure, and saturated NaHCO solution (30 mL) was added to the residue. Extraction was performed with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired compound I-2 (0.55 g). LCM (ES) m / z: 203.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.57(s,1H);7.54(d,J=7.6Hz,1H);6.84(t,J=7.6Hz,1H);6.71(d,J=7.2Hz,1H);5.04(br s,2H);4.44-4.42(m,4H).

[0397] Example 3: Preparation of 6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocin-9-amine (I-3):

[0398] [ka]

[0399] Step 1: 3-(3-(3-Bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)propan-1-ol (I-3a): To a stirred solution of I-2d (12.7 g, 44.1 mmol) in ACN (300.0 mL) was added AcOH (12.6 mL, 220 mmol) and 3-aminopropanol (11.8 mL, 154 mmol) at 0 °C. The reaction mixture was then stirred at 100 °C for 16 h. The reaction progress was monitored by TLC and LCMS. Upon completion, the reaction mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was then purified by silica gel column chromatography (using a gradient elution of 0-40% EtOAc in hexanes) to give the desired compound 3-(3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl)propan-1-ol I-3a (7.9 g, 18.5 mmol) as an off-white solid. LCM (ES) m / z: 299.8 [M+H] + .

[0400] Step 2: 9-Bromo-6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocine (I-3b): To a stirred solution of I-3a (7.90 g, 26.3 mmol) in anhydrous DMF (100.0 mL), sodium hydride (60% suspension) (1.37 g, 34.2 mmol) was added portionwise at 0 °C. The reaction mixture was then stirred at room temperature for an additional 1 h. The reaction progress was monitored by TLC. After complete consumption of the starting material, the reaction mixture was quenched by the addition of water (150 mL), and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with water (2 x 100 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-2% MeOH in DCM) to give the desired compound, 9-bromo-6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazine I-3b (6.0 g) as an off-white solid. An analytically pure sample was obtained by preparative HPLC purification of this material. LCM (ES) m / z: 279.8 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ 8.63(s,1H);7.85(d,J=8.0Hz,1H);7.58(d,J=7.6Hz,1H);7.24-7.20(m,1H);4.25-4.22(m,1H);4.12-4.09(m,1H);1.97(m,2H).

[0401] Step 3: tert-Butyl (6,7-dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocin-9-yl)carbamate (I-3c): I-3c (2.5 g) was synthesized by following the procedure described for the synthesis of I-1 (Step 4) using I-3b (5.00 g, 17.8 mmol) as the starting material. LCM (ES) m / z: 317.2 [M+H] + .

[0402] Step 4: 6,7-Dihydro-5H-benzo[b][1,2,4]triazolo[3,4-d][1,5]oxazocin-9-amine (I-3): I-3 (1.0 g) was synthesized by following the procedure described for the synthesis of I-1 (Step 5) using I-3c (2.90 g, 9.17 mmol) as the starting material. LCM (ES) m / z: 217.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.55(s,1H);6.93(t,J=8.0Hz,1H);6.85(dd,J1=1.6Hz,J2=8.0Hz,1H);6.85(dd,J1=1.6Hz,J2=8.0Hz,1H);5.07(br s,2H);4.09-4.03(m,4H);1.93-1.87(m,2H).

[0403] Example 4: Preparation of 7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-amine (I-4):

[0404] [ka]

[0405] Step 1: tert-Butyl N-{2-[3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl]ethyl}-N-methylcarbamate (I-4a): To a stirred solution of I-2d (3.5 g, 12.1 mmol) in ACN (50.0 mL) was added AcOH (3.7 mL, 60.7 mmol) and tert-butyl (2-aminoethyl)(methyl)carbamate (6.3 mL, 36.4 mmol) at 0 °C. The reaction mixture was then stirred at 100 °C for 16 h, with the reaction progress monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. Saturated NaHCO solution (50 mL) was added to the reaction mixture, and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using a gradient elution of 0 to 5% MeOH in DCM) to give the desired compound tert-butyl N-{2-[3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl]ethyl}-N-methylcarbamate I-4a (3.2 g) as a thick oil. LCM (ES) m / z: 399 (M+H). + .

[0406] Step 2: {2-[3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl]ethyl}(methyl)amine hydrochloride (I-4b): A 4 M solution of HCl in 1,4-dioxane (20.0 mL) was added to a stirred solution of I-4a (3.2 g, 8.01 mmol) in DCM (10.0 mL) at 0 °C, and the reaction mixture was allowed to warm to room temperature over 2 h. Upon completion (as indicated by TLC), the volatiles were removed under reduced pressure, and the residue was stirred in pentane (30 mL). It was then filtered and dried to give {2-[3-(3-bromo-2-fluorophenyl)-4H-1,2,4-triazol-4-yl]ethyl}(methyl)amine hydrochloride I-4b (2.2 g, HCl salt) as an off-white solid. LCM (ES) m / z: 299.1 [M+H]+ .

[0407] Step 3: 8-Bromo-7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepine (I-4c): To a solution of I-4b (2.2 g, 6.56 mmol) in DMF (25.0 mL) was added DIPEA (3.5 mL, 19.7 mmol) and stirred for 15 min. KCO (2.72 g, 19.7 mmol) was then added, and the reaction mixture was stirred at 80 °C for 24 h. The reaction progress was monitored by LCMS and TLC. Upon completion, the reaction mixture was cooled to room temperature, and water (50 mL) was added. Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (3 x 30 mL), brine (30 mL), dried over anhydrous MgSO, filtered, and concentrated 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 8-bromo-7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepine I-4c (0.6 g) as a pale yellow thick oil. LCMS (ES) m / z 279.1 [M+2H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.67(s,1H);8.54(dd,J1=1.6Hz,J2=8.0Hz,1H);7.72(dd,J1=1.6Hz,J2=8.0Hz ,1H);7.14(t,J=8.0Hz,1H);4.45-4.43(m,1H);3.49-3.45(m,1H);2.86(s,3H).

[0408] Step 4: tert-Butyl (7-methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-yl)carbamate (I-4d): I-4d (0.52 g) was synthesized by following the procedure described for the synthesis of I-1 (Step 4) using I-4c (0.75 g, 2.69 mmol) as the starting material. LCM (ES) m / z: 316.0 [M+H] + .

[0409] Step 5: 7-Methyl-6,7-dihydro-5H-benzo[f][1,2,4]triazolo[4,3-d][1,4]diazepin-8-amine (I-4): I-4 (0.34 g) was synthesized by following the procedure described for the synthesis of I-2 (Step 7) using I-4d (0.5 g, 1.59 mmol) as the starting material. LCM (ES) m / z: 216.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.56(s,1H);7.69(dd,J1=0.8Hz,J2=8.0Hz,1H);6.91(t,J=8.0Hz,1H);6.74(dd,J1=1.6Hz,J2=8.0Hz,1H);5.02(br s,2H);4.40-4.37(m,2H);3.43-3.38(m,2H);2.59(s,3H).

[0410] Example 5: Preparation of 2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-5):

[0411] [ka]

[0412] Step 1: tert-Butyl (2-amino-2-oxoethyl)(methyl)carbamate (I-5b): To a stirred solution of I-5a (15.0 g, 79.3 mmol) in THF (150 mL) was added TEA (14.5 mL, 103 mmol) and ethyl chloroformate (9.03 mL, 83.2 mmol) at 0 °C. This was then stirred at 0 °C for 1 h (Part A). 150 mL of THF in a separate round-bottom flask was purged with NH gas at 0 °C for 15 min (Part B). The NH in THF solution was poured into the previous reaction mixture (Part A) at 0 °C. This was then stirred at room temperature for 16 h. Upon completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using a gradient elution of 0 to 30% EtOAc in hexanes) to give the desired compound, tert-butyl (2-amino-2-oxoethyl)(methyl)carbamate I-5b (10.0 g) as an off-white solid. LCM (ES) m / z: 189.2 [M+H] + .

[0413] Step 2: tert-Butyl (E)-(2-((1-(dimethylamino)ethylidene)amino)-2-oxoethyl)(methyl)carbamate (I-5c): To a stirred solution of I-5b (16.0 g, 85.0 mmol) in 1,4-dioxane (160 mL), 1,1-dimethoxy-N,N-dimethylethan-1-amine (37.3 mL, 255 mmol) was added at room temperature. This was then stirred at 60° C. for 2 hours. Upon completion, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give tert-butyl (E)-(2-((1-(dimethylamino)ethylidene)amino)-2-oxoethyl)(methyl)carbamate I-5c (20.0 g) as a yellow oil. LCM (ES) m / z: 258.2 [M+H] + .

[0414] Step 3: tert-Butyl ((1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-5d): To a stirred solution of I-5c (11.2 g, 43.9 mmol) and (3-bromo-2-fluorophenyl)hydrazine (9.00 g, 43.9 mmol) in 1,4-dioxane (100 mL), acetic acid (100 mL) was added slowly at room temperature. This was then stirred at 80 °C for 1 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure, and saturated NaHCO solution (300 mL) was added to the residue. Extraction was carried out with EtOAc (2 x 300 mL). The combined organic extracts were washed with water (50 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The resulting crude material was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give the desired compound tert-butyl ((1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate I-5d (15.0 g) as a yellow oil. LCM (ES) m / z: 399.1 [M+H] + .

[0415] Step 4: 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-5e): A 4 M solution of HCl in 1,4-dioxane (100 mL, 400 mmol) was added to I-5d (15.0 g, 37.6 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. After completion, the volatiles were removed under reduced pressure and dried (co-evaporated with 1,4-dioxane) to give the desired compound 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine I-5e (15.0 g) as a pale yellow solid. LCM (ES) m / z: 299.1 [M+H] + This crude material was used in the next step without further purification.

[0416] Step 5: 6-Bromo-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-5f): To a stirred solution of I-5e (11.0 g, 36.8 mmol) in 1,4-dioxane (200 mL) was added DIPEA (150 mL) slowly at 0 °C. The reaction mixture was then stirred at 80 °C for 1 h. Upon completion, the reaction mixture was diluted with saturated NaHCO solution (300 mL) and extracted with EtOAc (3 x 70 mL). The combined organic extracts were washed with water (100 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give the desired compound 6-bromo-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline I-5f (7.0 g) as a yellow oil. LCM (ES) m / z: 279.0 [M+H] + .

[0417] Step 6: tert-Butyl (2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-5g): Argon gas was purged through a stirred suspension of I-5f (3.0 g, 10.7 mmol), tert-butyl carbamate (1.89 g, 16.1 mmol), and CsCO (7.0 g, 21.5 mmol) in 1,4-dioxane (30 mL) for 15 minutes. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.62 g, 1.07 mmol) and Pd(OAc) (0.24 g, 1.07 mmol). The reaction mixture was then stirred in a sealed tube at 100 °C for 16 hours. The reaction mixture was then allowed to cool to room temperature and filtered through a bed of Celite, washing with EtOAc (2 x 150 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-5% MeOH in DCM) to give tert-butyl (2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate I-5g (3.2 g) as a pale yellow oil. LCM (ES) m / z: 316.0 [M+H] + .

[0418] Step 7: 2,5-Dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-5): To a stirred solution of I-5g (3.0 g, 9.51 mmol) in DCM (30.0 mL) was added a 4 M solution of HCl in 1,4-dioxane (60.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Upon completion, the volatiles were removed under reduced pressure, and saturated sodium bicarbonate solution (30 mL) was added to the residue. Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (75 mL), dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0 to 60% EtOAc in hexanes) to give the desired compound 2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine I-5 (1.6 g) as a yellow solid. LCM (ES) m / z: 216.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.98(t,J=8.0Hz,1H);6.86(dd,J1=1.2Hz,J2=7.6Hz,1H);6.62(dd,J1=1.2Hz,J2=8.0Hz,1H);5.23(s,2H);4.25(s,2H);2.44(s,2H);2.35(s,3H).

[0419] Example 6: Preparation of 8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-6)

[0420] [ka]

[0421] Step 1: tert-Butyl ((1-(3-bromo-2,5-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-6a): I-6a (2.6 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-5c (1.96 g, 7.62 mmol) and (3-bromo-2,5-difluorophenyl)hydrazine (1.7 g, 7.62 mmol) as starting materials. LCM (ES) m / z: 416.9 [M+H] + .

[0422] Step 2: 1-(1-(3-Bromo-2,5-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-6b): I-6b (1.2 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-6a (2.6 g, 6.23 mmol) as starting material. LCM (ES) m / z: 317 [M+H] + .

[0423] Step 3: 6-Bromo-8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-6c): I-6c (0.9 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-6b (1.2 g, 3.78 mmol) as the starting material. LCM (ES) m / z: 297.0 [M+H] + .

[0424] Step 4: tert-Butyl (8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-6d): I-6d (0.7 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-6c (0.9 g, 3.03 mmol) as the starting material. LCM (ES) m / z: 334.2 [M+H] + .

[0425] Step 5: 8-Fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-6): I-6 (0.4 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-29d (0.7 g, 2.1 mmol) as the starting material. LCM (ES) m / z: 234.1 [M+H] + .

[0426] Example 7: Preparation of 7-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-7)

[0427] [ka]

[0428] Step 1: tert-Butyl ((1-(3-bromo-2,4-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-7a): I-7a (13.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-5c (11.5 g, 44.8 mmol) and (3-bromo-2,4-difluorophenyl)hydrazine (10 g, 58.6 mmol) as starting materials. LCM (ES) m / z: 417.1 [M+H] + .

[0429] Step 2: 1-(1-(3-Bromo-2,4-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-7b): I-7b (11.6 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-7a (13.8 g, 24.8 mmol) as starting material. LCM (ES) m / z: 317.0 [M+H] + .

[0430] Step 3: 6-Bromo-7-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-7c): I-7c (3.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-7b (11.6 g, 29.5 mmol) as the starting material. LCM (ES) m / z: 297.0 [M+1H] + .

[0431] Step 4: N-(7-Fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)-1,1-diphenylmethanimine (I-7d): Argon gas was purged through a stirred suspension of I-7c (2.0 g, 6.5 mmol), diphenylmethanimine (1.83 g, 10.1 mmol), and NaOtBu (1.94 g, 20.2 mmol) in toluene (15.0 mL) for 15 minutes. To this was then added Pd2(dba)3 (0.62 g, 0.65 mmol) and BINAP (1.26 g, 2.02 mmol). The reaction mixture was then stirred in a sealed tube at 95 °C for 12 hours. The reaction mixture was then cooled to room temperature, filtered through a Celite bed, and washed with EtOAc (2 x 50 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0–50% EtOAc in hexanes) to give N-(7-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)-1,1-diphenylmethanimine I-7d (2.3 g) as a yellow oil. LCM (ES) m / z: 398.2 [M+H] + .

[0432] Step 5: 7-Fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-7): A 4 M solution of HCl in 1,4-dioxane (15 mL) was added to I-7d (1.9 g, 5.31 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 12 h. After completion, the volatiles were removed under reduced pressure, and saturated NaHCO solution (50 mL) was added to the residue. Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (100 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0 to 70% EtOAc in hexanes) to give the desired compound 7-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine I-7 (1.3 g) as an off-white solid. LCM (ES) m / z: 234.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.01(dd,J1=2.0Hz,J2=8.4Hz,1H);6.85(dd,J1=2.0Hz,J2=8.4Hz,1H);5.24(s,2H);4.33(s,2H);2.47(s,2H);2.40(s,3H).

[0433] Example 8: Preparation of 9-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-8)

[0434] [ka]

[0435] Step 1: tert-Butyl ((1-(3-bromo-2,6-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-8a): I-8a (11.3 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-5c (9.92 g, 38.6 mmol) and (3-bromo-2,6-difluorophenyl)hydrazine (8.6 g, 38.6 mmol) as starting materials. LCM (ES) m / z: 417.1 [M+H] + .

[0436] Step 2: 1-(1-(3-Bromo-2,6-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-8b): I-8b (8.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-8a (11.3 g, 27.1 mmol) as starting material. LCM (ES) m / z: 317.0 [M+H] + .

[0437] Step 3: 6-Bromo-9-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-8c): I-8c (3.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-8b (8.8 g, 24.1 mmol) as the starting material. LCM (ES) m / z: 297.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 7.45-7.41(m,1H);6.91(t,J=10.0Hz,1H);4.31(s,2H);2.77(s,3H);2.51(s,3H).

[0438] Step 4: tert-Butyl (9-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-8d): I-8d (4.2 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-8c (3.75 g, 12.6 mmol) as the starting material. LCM (ES) m / z: 334.2 [M+H] + .

[0439] Step 5: 9-Fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-8): I-8 (2.6 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-8d (4.2 g, 12.6 mmol) as the starting material. LCM (ES) m / z: 234.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 6.9-6.88(m,1H);6.58-6.55(m,1H);4.22(s,2H);4.00(s,2H);2.51(s,6H).

[0440] Example 9: Preparation of 5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-9):

[0441] [ka]

[0442] Step 1: tert-Butyl (E)-(2-(((dimethylamino)methylene)amino)-2-oxoethyl)(methyl)carbamate (I-9a): I-9a (7.1 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 2) using I-9b (7.8 g, 41.4 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (18.2 mL, 124 mmol) as starting materials. LCM (ES) m / z: 244.1 [M+H] + .

[0443] Step 2: tert-Butyl ((1-(3-bromo-2-fluorophenyl)-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-9b): I-9b (4.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-9a (7.1 g, 29.3 mmol) and (3-bromo-2-fluorophenyl)hydrazine (6.0 g, 29.3 mmol) as starting materials. LCM (ES) m / z: 385.2 [M+H] + .

[0444] Step 3: 1-(1-(3-Bromo-2-fluorophenyl)-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-9c): I-9c (3.2 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-9b (4.3 g, 11.2 mmol) as the starting material. LCM (ES) m / z: 284.9 [M+H] + .

[0445] Step 4: 6-Bromo-5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-9d): I-9d (2.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-9c (3.2 g, 11.2 mmol) as the starting material. LCM (ES) m / z: 265.0 [M+H] + .

[0446] Step 5: tert-Butyl (5-methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-9e): I-9e (2.1 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-9d (2.5 g, 9.43 mmol) as the starting material. LCM (ES) m / z: 302.2 [M+H] + .

[0447] Step 6: 5-Methyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-9): I-9 (1.3 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-9e (2.1 g, 6.97 mmol) as the starting material. LCM (ES) m / z: 202.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.15(s,1H);7.00(t,J=8.0Hz,1H);6.98-6.87(m,1H);6.65(d,J=8.4Hz,1H);5.30(br s,2H);4.31(s,2H);2.42(s,3H).

[0448] Example 10: Preparation of 2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-amine (I-10)

[0449] [ka]

[0450] Step 1: tert-Butyl ((1-(3-bromo-2-chloropyridin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-10a): I-10a (7.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-5c (7.5 g, 29.2 mmol) and 3-bromo-2-chloro-4-hydrazineylpyridine (6.5 g, 29.2 mmol) as starting materials. LCM (ES) m / z: 416.0 [M+H] + .

[0451] Step 2: 1-(1-(3-Bromo-2-chloropyridin-4-yl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-10b): I-10b (2.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-10a (4.6 g, 11 mmol) as starting material. LCM (ES) m / z: 316.6 [M+H] + .

[0452] Step 3: 6-Chloro-2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazine (I-10c): Argon gas was purged through a stirred suspension of I-10b (2.5 g, 7.9 mmol) and CsOAc (3.03 g, 15.8 mmol) in DMSO (25 mL) for 15 minutes. Copper powder (50.2 mg, 0.790 mmol) was then added at room temperature. The reaction mixture was then stirred at 100 °C in a sealed tube for 16 hours. The reaction mixture was then cooled to room temperature, and saturated NaHCO solution (30 mL) was added. Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0 to 80% EtOAc in hexanes) to give the desired compound, 6-chloro-2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazine I-10c (0.89 g) as an off-white solid. LCM (ES) m / z: 236.1 [M+H] + .

[0453] Step 4: N-(2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)cyclopropanecarboxamide (I-10d): Argon gas was passed through a stirred suspension of I-10c (2.0 g, 8.49 mmol), cyclopropanecarboxamide (1.08 g, 12.7 mmol), and CsCO (5.53 g, 17.0 mmol) in 1,4-dioxane (20 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.49 g, 0.85 mmol), and Pd(dba) (0.69 g, 0.85 mmol). The reaction mixture was then stirred in a sealed tube at 130 °C for 8 h. The reaction mixture was then allowed to cool to room temperature and filtered through a bed of Celite, washing with EtOAc (2 x 50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0 to 100% EtOAc in hexanes) to give N-(2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)cyclopropanecarboxamide I-10d (3.2 g) as a pale yellow solid. LCM (ES) m / z: 285.2 [M+H] + .

[0454] Step 5: 2,5-Dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-amine (I-10): To a stirred solution of I-10d (0.7 g, 2.46 mmol) in THF (7.0 mL) was added LiOH (0.31 g, 12.2 mmol) in water (4.0 mL) at room temperature. This was then stirred at 50 °C for 16 h. Upon completion, the reaction was diluted with water (20 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, 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 2,5-dimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrazin-6-amine I-10 (0.35 g) as a pale yellow solid. LCM (ES) m / z: 217.0 [M+H] + .

[0455] Example 11: Preparation of 2,5-dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazin-6-amine (I-11)

[0456] [ka]

[0457] Step 1: tert-Butyl ((1-(3-bromo-4-chloropyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (I-11a): I-11a (7.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-5c (7.5 g, 29.2 mmol) and 3-bromo-4-chloro-2-hydrazineylpyridine (6.5 g, 29.2 mmol) as starting materials. LCM (ES) m / z: 416.0 [M+H] + .

[0458] Step 2: 1-(1-(3-Bromo-4-chloropyridin-2-yl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethanamine (I-11b): I-10b (2.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-11a (4.6 g, 11 mmol) as starting material. LCM (ES) m / z: 316.6 [M+H] + .

[0459] Step 3: 6-Chloro-2,5-dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazine (I-11c): I-11c (0.89 g) was synthesized by following the procedure described for the synthesis of I-10 (Step 3) using I-11b (2.5 g, 7.9 mmol) as the starting material. LCM (ES) m / z: 236.1 [M+H] + .

[0460] Step 4: N-(2,5-dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazin-6-yl)cyclopropanecarboxamide (I-11d): I-11d (1.4g) was synthesized by following the procedure described for the synthesis of I-10 (Step 4) using I-11c (2.0g, 8.49mmol) and cyclopropanecarboxamide (1.08g, 12.7mmol) as starting materials. LCM (ES) m / z: 285.2 [M+H] + .

[0461] Step 5: 2,5-Dimethyl-4,5-dihydropyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrazin-6-amine (I-11): I-11 (0.8 g) was synthesized by following the procedure described for the synthesis of I-10 (Step 5) using I-11d (1.5 g, 5.28 mmol) as the starting material. LCM (ES) m / z: 217.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.94(d,J=8.0Hz 1H);7.12(d,J=8.0Hz,1H);5.51(s,2H);4.32(s,2H);2.64(s,3H);2.52(s,3H).

[0462] Example 12: Preparation of 2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-12)

[0463] [ka]

[0464] Step 1: Ethyl (E)-2-((1-(dimethylamino)ethylidene)amino)-2-oxoacetate (I-12b): I-12b (10.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 2) using I-12a (10 g, 85.4 mmol) and 1,1-dimethoxy-N,N-dimethylethan-1-amine (37.5 mL, 256 mmol) as starting materials. LCM (ES) m / z: 187.1 [M+H] + .

[0465] Step 2: Ethyl 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazole-5-carboxylate (I-12c): I-12c (5.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-12b (4.54 g, 24.4 mmol) and (3-bromo-2-fluorophenyl)hydrazine (5.0 g, 24.4 mmol) as starting materials. LCM (ES) m / z: 328.0 [M+H] + .

[0466] Step 3: (1-(1-(3-Bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-methan-d2-ol (I-12d): To a stirred solution of sodium borodeuteride (2.68 g, 64 mmol) in anhydrous THF (70 mL) was added I-12c (7 g, 21.3 mmol) in THF (100 mL) over 20 min at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Upon completion (as indicated by TLC), water (30 mL) was added to the reaction mixture and extraction was carried out using EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated NaOHCO3 (30 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash chromatography (using a gradient elution of 0 to 50% EtOAc in hexanes) to give (1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-methane-d2-ol I-12d (4.2 g) as an off-white solid. LCM (ES) m / z: 288.1 [M+H] + .

[0467] Step 4: 1-(3-Bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazole-5-carbaldehyde (I-12e): To a stirred solution of I-12d (6.50 g, 31.2 mmol) in DCM (100.0 mL), DMP (22.5 g, 53.1 mmol) was added at 0 °C, and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction progress was monitored by LCMS. Upon completion, the reaction mixture was filtered through a celite bed and washed with DCM (100 mL × 2). The resulting filtrate was washed with saturated NaOHCO3 solution (50 mL), water (100 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0 to 50% EtOAc in hexanes) to give 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazole-5-carbaldehyde-d I-12e (6.5 g) as a yellow semi-solid. LCM (ES) m / z: 285.1 [M+H] +.

[0468] Step 5: 1-(1-(3-Bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylmethan-d2-amine (I-12f): To a stirred solution of I-12e (6.5 g, 22.8 mmol) in MeOH (72 mL) was added methylamine hydrochloride (3.08 g, 45.6 mmol) and TEA (6.15 mL, 45.6 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Sodium borodeuteride (1.91 g, 45.6 mmol) was then added to the reaction mixture at 0 °C, and the reaction mixture was stirred at room temperature for an additional 2 h. After completion, saturated NH4Cl solution (20 mL) was added, and extraction was carried out using 10% MeOH in DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material (5 g) was used in the next step without further purification. LCM (ES) m / z: 301.1 [M+H] + .

[0469] Step 6: 6-Bromo-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-4,4-d2 (I-12g): I-12g (4g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-12f (5g, 16.6mmol) as the starting material. LCM (ES) m / z: 281.0 [M+H] + .

[0470] Step 7: tert-Butyl (2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl-4,4-d2)carbamate (I-12h): I-12h (3.6g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-12g (4g, 14.2mmol) as the starting material. LCM (ES) m / z: 318.0 [M+H] + .

[0471] Step 8: 2,5-Dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-12): I-12 (1.72 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-12h (3.6 g, 11.3 mmol) as the starting material. LCM (ES) m / z: 218.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.98(d,J=8.0 Hz.1H);6.86(dd,J1=0.8Hz,J2=7.6Hz,1H);6.62(dd,J1=0.8Hz,J2=7.6Hz,1H);5.24(s,2H);2.45(s,3H);2.30(s,3H).

[0472] Example 13: Preparation of 2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-13)

[0473] [ka]

[0474] Step 1: tert-Butyl (1-amino-1-oxopropan-2-yl)(methyl)carbamate (I-13b): I-13b (10g) was synthesized by following the procedure described for the synthesis of I-5 (Step 1) using I-13a (15g, 73.8mmol) as the starting material. LCM (ES) m / z: 203.1 [M+H] + .

[0475] Step 2: tert-Butyl (E)-(1-((1-(dimethylamino)ethylidene)amino)-1-oxopropan-2-yl)(methyl)carbamate (I-13c): I-13c (23.1 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 2) using I-13b (17.5 g, 86.5 mmol) and 1,1-dimethoxy-N,N-dimethylethan-1-amine (34.6 g, 260.0 mmol) as starting materials. LCM (ES) m / z: 272.3 [M+H] + .

[0476] Step 3: tert-Butyl (1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)ethyl)(methyl)carbamate (I-13d): I-13d (3.7 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-13c (3.31 g, 12.2 mmol) and (3-bromo-2-fluorophenyl)hydrazine (2.5 g, 12.2 mmol) as starting materials. LCM (ES) m / z: 413.1 [M+H] + .

[0477] Step 4: 1-(1-(3-Bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylethan-1-amine (I-13e): I-13e (5.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-13d (6.7 g, 16.2 mmol) as the starting material. LCM (ES) m / z: 313.2 [M+H] + .

[0478] Step 5: 6-Bromo-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-13f): I-13f (3.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-13e (5.0 g, 16.0 mmol) as the starting material. LCM (ES) m / z: 293.0 [M+H] + .

[0479] Step 6: tert-Butyl (2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-13g): I-13g (1.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-35f (1.5 g, 5.12 mmol) as the starting material. LCM (ES) m / z: 330.1 [M+H] + .

[0480] Step 7: 2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-13): I-13 (2.8 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-13g (5.0 g, 15.2 mmol) as the starting material. LCM (ES) m / z: 230.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.96(t,J=8.0Hz,1H);6.83(d,J=7.2Hz,1H);6.60(d,J=8.0Hz,1H);5.19(s,2H );4.39-4.34(q,J=7.2Hz,1H);2.37(s,3H);2.31(s,3H);1.15(d,J=7.2Hz,3H).

[0481] [ka]

[0482] I-13R and I-13S were enantiospecifically synthesized starting from N-(tert-butoxycarbonyl)-N-methyl-D-alanine and N-(tert-butoxycarbonyl)-N-methyl-L-alanine, respectively. Alternatively, they could be obtained by chiral HPLC separation of racemic I-13 (2.3 g) [column: CHIRALCEL OJ-H (250 mm × 20 mm × 5 μm); mobile phase: 1PA with n-hexane:0.1% DEA (80:20); flow rate: 19.0 mL / min]. {I-13R (0.6 g): Peak 1; Rt 8.48 min, and I-I3S (0.45 g): Peak-2; R t ;12.73 minutes}.

[0483] Example 14: Preparation of 8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-14)

[0484] [ka]

[0485] Step 1: tert-Butyl (1-(1-(3-bromo-2,5-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)ethyl)(methyl)carbamate (I-14a): I-14a (12.6 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-13c (11.1 g, 40.8 mmol) and (3-bromo-2,5-difluorophenyl)hydrazine (9.1 g, 40.8 mmol) as starting materials. LCM (ES) m / z: 431.1 [M+H] + .

[0486] Step 2: 1-(1-(3-Bromo-2,5-difluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylethan-1-amine (I-14b): I-14b (12.6 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-14a (12.6 g, 29.2 mmol) as starting material. LCM (ES) m / z: 331.1 [M+H] + .

[0487] Step 3: 6-Bromo-8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxaline (I-14c): I-14c (6.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-14b (12.6 g, 34.3 mmol) as the starting material. LCM (ES) m / z: 311.2 [M+H] + .

[0488] Step 4: tert-Butyl (8-fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)carbamate (I-14d): I-14d (6.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-14c (6.0 g, 19.3 mmol) as the starting material. LCM (ES) m / z: 348.2 [M+H] + .

[0489] Step 5: 8-Fluoro-2,4,5-trimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-amine (I-14): I-14 (4.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using I-14d (6.5 g, 18.7 mmol) as the starting material. LCM (ES) m / z: 248.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 6.87-6.84(m,1H);6.36-6.33(m,1H);4.39-4.32(q,J=7.2Hz,1H);2.48(s,6H);1.44(d,J=7.2Hz,3H).

[0490] Example 15: Preparation of 2',5'-dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxaline]-6'-amine (I-15)

[0491] [ka]

[0492] Step 1: 1-((tert-Butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid (I-15b): To a stirred solution of 1-(methylamino)cyclopropane-1-carboxylic acid I-15a (13.0 g, 85.8 mmol) in 1,4-dioxane (130 mL) and water (130 mL) was added TEA (35.9 mL, 257.0 mmol) and (Boc)O (23.6 mL, 103.0 mmol). This was then stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with 10% potassium bisulfate solution (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the desired compound 1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylic acid I-15b (20 g, crude) as a yellow solid. LCM (ES) m / z: 214.0 [MH] + .

[0493] Step 2: tert-Butyl (1-carbamoylcyclopropyl)(methyl)carbamate (I-15c): I-15c (15.0 g) was synthesized by using I-15b (20.0 g, 92.9 mmol) as the starting material and following the procedure described for the synthesis of I-5 (Step 1). 1 H NMR(400MHz, CDCl3)δ 6.03(s,1H);5.58(s,1H);2.94(s,3H);1.64-1.54(m,2H);1.44(s,9H);1.14-1.06(m,2H).

[0494] Step 3: tert-Butyl (E)-(1-((1-(dimethylamino)ethylidene)carbamoyl)cyclopropyl)(methyl)carbamate (I-15d): I-15d (20.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 2) using I-15c (15.0 g, 70.0 mmol) and 1,1-dimethoxy-N,N-dimethylethan-1-amine (28.2 g, 210.0 mmol) as starting materials. LCM (ES) m / z: 284.2 [M+H] + .

[0495] Step 4: tert-Butyl (1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)cyclopropyl)(methyl)carbamate (I-15e): I-15e (13.0 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-15d (19.3 g, 68.3 mmol) and (3-bromo-2-fluorophenyl)hydrazine (14.0 g, 68.3 mmol) as starting materials. LCM (ES) m / z: 425.0 [M+H] + .

[0496] Step 5: 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylcyclopropan-1-amine (TFA salt) (I-15f): To a stirred solution of I-15e (13.0 g, 30.6 mmol) in DCM (130 mL), TFA (70 mL) was added at 0° C., and the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure, and the residue was dried to give 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-N-methylcyclopropan-1-amine TFA salt I-15f (9.0 g). LCM (ES) m / z: 325.0 [M+H] + .

[0497] Step 6: 6'-Bromo-2',5'-dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxaline] (I-15g): I-15g (6.7g) was synthesized by following the procedure described for the synthesis of I-5 (Step 5) using I-15f (10.0g, 30.8mmol) as the starting material. LCM (ES) m / z: 305.1 [M+H] + .

[0498] Step 7: tert-Butyl (2',5'-dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxalin]-6'-yl)carbamate (I-15h): I-15h (3.5g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using I-15g (6.2g, 20.3mmol) as the starting material. LCM (ES) m / z: 342.2 [M+H] + .

[0499] Step 8: 2',5'-Dimethyl-5'H-spiro[cyclopropane-1,4'-[1,2,4]triazolo[1,5-a]quinoxaline]-6'-amine (I-15): I-15 (1.8 g) was synthesized by following the procedure described for the synthesis of I-1 (Step 5) using I-15h (3.5 g, 10.3 mmol) as the starting material. LCM (ES) m / z: 242.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.02(t,J=8.0Hz,1H);6.88(d,J=7.2Hz,1H);6.63(d,J=8.0Hz,1H);5.19(br s,2H);2.37(s,3H);2.32(s,3H);1.22-1.18(m,4H).

[0500] Example 16: Preparation of 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-16)

[0501] [ka]

[0502] Step 1: 5-Bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde (I-16b): To a stirred solution of I-16a (10 g, 41.6 mmol) in THF (100 mL) was added a 2 M solution of isopropylmagnesium chloride in THF (22.8 mL, 45.6 mmol) at −30° C. and stirred at the same temperature for 1 h. DMF (16.08 mL, 208 mmol) was then added at −30° C. The reaction mixture was gradually warmed to room temperature over 1 h. Upon completion, the reaction mixture was quenched by the addition of saturated NH4Cl solution (30 mL), and extraction was carried out using EtOAc (3×75 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Combi-Flash (using a gradient elution of 0 to 10% EtOAc in heptane) to give the desired compound 5-bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde I-16b (6 g) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ 9.95 (s, 1H); 4.26 (s, 3H).

[0503] Step 2: 1-(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethanamine (I-16c): To a stirred solution of I-16b (6.0 g, 26.5 mmol) in MeOH (25 mL) was added TEA (8.8 mL, 63.2 mmol) and methylamine hydrochloride (6.4 g, 94.8 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then cooled to 0 °C, and NaBH (3.58 g, 94.8 mmol) was added in small portions. The reaction mixture was gradually warmed to room temperature over 2 h. Upon completion (as indicated by LCMS), the reaction mixture was added saturated NaHCO solution (30 mL) and washed with EtOAc (2 x 20 mL). 1-(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethanamine I-16c in aqueous NaHCO was used in the next step without further purification. LCM (ES) m / z: 205.0 [M+1H] + .

[0504] Step 3: tert-Butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-16d): A solution of (Boc)O (33.6 mL, 146.2 mmol) in THF (60 mL) was added to the aqueous NaHCO solution containing I-16c, and the reaction mixture was stirred at room temperature for 16 h. After completion, the volatiles were removed under reduced pressure, and water (50 mL) was added to it. Extraction was carried out with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Combi-Flash (using a gradient elution of 0 to 50% EtOAc in hexanes) to afford tert-butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate I-16d (6.0 g) as a colorless thick oil. LCM (ES) m / z: 305.1 [M+H] + .

[0505] Step 4: tert-Butyl ((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-16e): Argon gas was passed through a stirred suspension of I-16d (6.0 g, 19.6 mmol), 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.56 g, 26.6 mmol), and KF (5.2 g, 49.2 mmol) in THF (20.0 mL) and purged for 15 min. To this was then added Pd(OAc)2 (0.18 g, 0.82 mmol) and dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphane (0.67 g, 1.64 mmol). The reaction mixture was then stirred in a sealed tube at 70 °C for 16 h. The reaction mixture was then cooled to room temperature, filtered through a Celite bed, and washed with EtOAc (2 x 50 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give the desired compound, tert-butyl ((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate I-16e (6.0 g) as a yellow semi-solid. LCM (ES) m / z: 366.1 [M+H] + .

[0506] Step 5: 2,5-Dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-16f): To a stirred solution of I-16e (6.0 g, 16.4 mmol) in DCM (70.0 mL), TFA (35.0 mL) was added under a nitrogen atmosphere at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by TLC. Upon completion, the volatiles were removed under reduced pressure, and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was carried out with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-40% EtOAc in hexanes) to give 2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline I-16f (3.0 g) as an orange solid. LCM (ES) m / z: 246.0 [M+H] + .

[0507] Step 6: 2,5-Dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-16): To a stirred solution of I-16f (3.0 g, 12.24 mmol) in MeOH (40.0 mL), 10% Pd / C (520 mg) was added at room temperature. This was then stirred under a hydrogen atmosphere (H balloon) for 2 h. Upon completion, the catalyst was filtered off through a Celite bed and washed with MeOH (2 x 30 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0 to 55% EtOAc in hexanes) to give the desired compound, 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine I-16 (1.2 g) as a pale yellow solid. LCM(ES) m / z: 216.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 6.95-6.89(m,2H);6.68(dd,J1=1.2Hz,J2=7.6Hz,1H);5.03(s,2H);4.17(s,3H);4.15(s,2H);2.41(s,3H).

[0508] Example 17: Preparation of 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-17):

[0509] [ka]

[0510] Steps 1 & 2: tert-Butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl) (methyl-d3)carbamate (I-17b): I-17b (3.5 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 2 / 3) using I-16b (4.1 g, 21.6 mmol) and methyl-d3-amine hydrochloride (3.05 g, 43.2 mmol) as starting materials. LCM (ES) m / z: 308.4 [M+H] + .

[0511] Step 3: tert-Butyl ((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl-d3)carbamate (I-17c): I-17c (3.0 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 4) using I-17b (3.5 g, 11.4 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.55 g, 17.0 mmol) as starting materials. LCM (ES) m / z: 369.9 [M+H] + .

[0512] Step 4: 2-Methyl-5-(methyl-d3)-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-17d): I-17d (1.05 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 5) using I-17c (3.0 g, 8.14 mmol) as the starting material. LCM (ES) m / z: 249.4 [M+H] + .

[0513] Step 5: 2-Methyl-5-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-17): I-17 (0.75 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 6) using I-17d (1.05 g, 4.23 mmol) as the starting material. LCM (ES) m / z: 219.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.95-6.87(m,2H);6.67(dd,J1=1.6Hz,J2=8.0Hz,1H);5.04(s,2H);4.21(s,2H);4.08(s,3H).

[0514] Example 18: Preparation of 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-18)

[0515] [ka]

[0516] Step 1: tert-Butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-18a): Argon gas was passed through a solution of I-16d (5.0 g, 16.4 mmol), (2-chloro-3-fluoropyridin-4-yl)boronic acid (2.87 g, 16.4 mmol), and CsF (7.47 g, 49.2 mmol) in THF (25 mL) and purged for 15 minutes. To this was added tri-tert-butylphosphonium tetrafluoroborate (0.475 g, 1.64 mmol) and Pd(dba) (1.5 g, 1.64 mmol). The reaction mixture was then stirred in a sealed tube at 50 °C for 16 hours. Upon completion, the reaction mixture was filtered through a Celite bed and washed with EtOAc (2 x 50 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-5% MeOH in DECM) to give tert-butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate I-18a (5.1 g) as a brown solid. LCM (ES) m / z: 356.1 [M+H] + .

[0517] Step 2: 6-Chloro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-18b): A 4 M solution of HCl in 1,4-dioxane (30 mL) was added to I-18a (2.9 g, 8.15 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After completion, the volatiles were removed under reduced pressure and dried (coevaporated with 1,4-dioxane). To this was added 1,4-dioxane (10 mL) and DIPEA (6.81 mL, 39.1 mmol) at room temperature. The reaction mixture was then stirred at 85 °C for 5 h. Upon completion, the volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-35% EtOAc in hexanes) to give the desired compound 6-chloro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine I-18b (1.5 g) as an off-white solid. LCM (ES) m / z: 236.1 [M+H] + .

[0518] Step 3: N-(2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-18c): Argon gas was passed through a stirred suspension of I-18b (1.5 g, 6.36 mmol), cyclopropanecarboxamide (0.81 g, 9.55 mmol), and CsCO (4.15 g, 12.7 mmol) in 1,4-dioxane (10 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.37 g, 0.636 mmol), and Pd(dba) (0.58 g, 0.636 mmol). The reaction mixture was then stirred in a sealed tube at 130 °C for 16 h. The reaction mixture was then allowed to cool to room temperature and filtered through a bed of Celite, washing with EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0 to 80% EtOAc in hexanes) to give N-(2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide I-18c (1.1 g) as a pale yellow solid. LCM (ES) m / z: 285.1 [M+H] + .

[0519] Step 4: 2,5-Dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-18): To a stirred solution of I-18c (1.0 g, 3.52 mmol) in THF (12 mL) was added an aqueous solution of LiOH (0.42 g, 17.6 mmol in 5 mL of water) at room temperature. This was then stirred at 50 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and water (20 mL) was added. Extraction was carried out using 10% MeOH in DCM (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous NaSO, 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 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine I-18 (0.31 g) as an off-white solid. LCM (ES) m / z: 217.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR(400MHz,DMSO-d6)δ 7.80(d,J=5.2Hz,1H);6.82(d,J=5.2Hz,1H);5.86(s,2H);4.21(s,3H);4.20(s,2H);2.45(s,3H).

[0520] Example 19: Preparation of 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-4,4-d2-6-amine (I-19)

[0521] [ka]

[0522] Step 1: 5-Bromo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde-d (I-19a): I-19a (2.5 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 1) using I-16a (5.0 g, 20.8 mmol) and DMF-d7 (8.07 mL, 104 mmol) as starting materials. LCM (ES) m / z: 191.0 [M+H] + .

[0523] Steps 2-3: tert-Butyl ((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl-d2) (methyl)carbamate (I-19c): I-19c (2.4 g) was synthesized by following the procedure described for the synthesis of I-16 (Steps 2 and 3) using I-19a (5.8 g, 30.4 mmol) and NaBD4 (2.54 g, 60.7 mmol) as starting materials. LCM (ES) m / z: 307.1 [M+H] + .

[0524] Step 4: tert-Butyl ((5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl-d2)(methyl)carbamate (I-19d): I-19d (2.4 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 4) using I-19c (3.0 g, 9.77 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.91 g, 14.6 mmol) as starting materials. LCM (ES) m / z: 368.1 [M+H] + .

[0525] Step 5: 1-(5-(2-Fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethan-d2-amine (TFA salt) (I-19e): To a stirred solution of I-19d (2.1 g, 5.72 mmol) in DCM (5.0 mL) was added TFA (8.0 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. After complete consumption of the starting material, the volatiles were removed under reduced pressure to give 1-(5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)-N-methylmethan-d2-amine TFA salt I-19e (1.5 g) as an orange solid. LCM (ES) m / z: 268.0 [M+H] + .

[0526] Step 6: 2,5-Dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline-4,4-d2 (I-19f): To a stirred solution of I-19e (1.8 g, 6.73 mmol) in 1,4-dioxane (20 mL) was added DIPEA (6 mL, 33.7 mmol) slowly at 0 °C. This was then stirred at room temperature for 16 h. After completion, saturated NaHCO3 solution (10 mL) was added to the reaction mixture, and extraction was carried out using DCM (2 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0 to 50% EtOAc in hexanes) to give 2,5-dimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline-4,4-d2 I-19f (1.6 g) as an orange solid. LCM (ES) m / z: 248.1 [M+H] + .

[0527] Step 7: 2,5-Dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-4,4-d2-6-amine (I-19): I-19 (1.2 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 6) using I-19f (2.0 g, 8.09 mmol) as the starting material. LCM (ES) m / z: 218.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.95-6.87(m,2H);6.68(dd,J1=1.2Hz,J2=7.6Hz,1H);5.04(s,2H);4.17(s,3H);2.40(s,3H).

[0528] Example 20: Preparation of 2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-4,4-d2-6-amine (1-20)

[0529] [ka]

[0530] Step 1: tert-Butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)methyl-d2)(methyl)carbamate (I-20a): I-20a (3.0 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 1) using I-19c (4.3 g, 14.0 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (6.14 g, 35.0 mmol) as starting materials. LCM (ES) m / z: 358.0 [M+H] + .

[0531] Step 2: 6-Chloro-2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine-4,4-d2 (I-20b): I-20b (2.0 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 2) using I-20a (3.0 g, 8.38 mmol) as the starting material. LCM (ES) m / z: 238.0 [M+H] + .

[0532] Step 3: N-(2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl-4,4-d2)cyclopropanecarboxamide (I-20c): I-20c (0.5 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 3) using I-20b (0.8 g, 3.37 mmol) and cyclopropanecarboxamide (0.57 g, 6.73 mmol) as starting materials. LCM (ES) m / z: 287.0 [M+H] + .

[0533] Step 4: 2,5-Dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-4,4-d2-6-amine (I-20): I-20 (0.6 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 4) using I-20c (1.4 g, 4.89 mmol) as the starting material. LCM (ES) m / z: 219.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400MHz, CDCl3) δ 7.95(d,J=5.2Hz,1H);7.05(d,J=5.2Hz,1H);4.89(s,2H);4.27(s,3H);2.60(s,3H).

[0534] Example 21: Preparation of 5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-21)

[0535] [ka]

[0536] Step 1: 4,5-Dibromo-2-(methyl-d3)-2H-1,2,3-triazole (I-21b): To a stirred solution of I-21a (10.0 g, 44.1 mmol) in DMF (100.0 mL) was added potassium carbonate (12.2 g, 88.2 mmol) at 0 °C and stirred for 5 min. To this was then added iodomethane-d3 (5.5 mL, 88.2 mmol) in small portions at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. Upon completion, water (80 mL) was added to the reaction mixture, and extraction was carried out using Et2O (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-8% EtOAc in pentane) to give 4,5-dibromo-2-(methyl-d3)-2H-1,2,3-triazole 4 I-16b (7.22 g) as an off-white solid. 13 C NMR(400MHz, CDCl3)δ 124.3,42.4.

[0537] Step 2: 5-Bromo-2-(methyl-d3)-2H-1,2,3-triazole-4-carbaldehyde (I-21c): I-21c (3.8 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 1) using I-21b (7.2 g, 29.5 mmol) as the starting material. 1 H NMR (400MHz, DMSO-d6) δ 9.98 (s, 1H).

[0538] Steps 3-4: tert-Butyl ((5-bromo-2-(methyl-d3)-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-21e): I-21e (2.0 g) was synthesized by following the procedure described for the synthesis of I-16 (Steps 2 and 3) using I-21c (3.8 g, 3.06 mmol) and methylamine hydrochloride (2.66 g, 39.4 mmol) as starting materials. LCM (ES) m / z: 308.1 [M+H]+ .

[0539] Step 5: tert-Butyl ((5-(2-fluoro-3-nitrophenyl)-2-(methyl-d3)-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-21f): I-21f (2.28 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 4) using I-21e (2.0 g, 6.49 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.60 g, 9.73 mmol) as starting materials. LCM (ES) m / z: 369.1 [M+H] + .

[0540] Step 6: 5-Methyl-2-(methyl-d3)-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-21g): I-21g (1.2g) was synthesized by following the procedure described for the synthesis of I-16 (Step 5) using I-21f (2.28g, 6.19mmol) as the starting material. LCM (ES) m / z: 249.1 [M+H] + .

[0541] Step 7: 5-Methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-21): I-21 (0.7 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 6) using I-21g (1.2 g, 4.83 mmol) as the starting material. LCMS (ES) m / z: 219.2 [M+H] + .

[0542] Example 22: Preparation of 5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-22)

[0543] [ka]

[0544] Step 1: tert-Butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-(methyl-d3)-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-22a): I-22a (4.5 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 1) using I-21e (4.0 g, 13.0 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (5.7 g, 32.4 mmol) as starting materials. LCM (ES) m / z: 359.2 [M+H] + .

[0545] Step 2: 6-Chloro-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-22b): I-22b (2.38 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 2) using I-22a (4.5 g, 12.5 mmol) as the starting material. LCM (ES) m / z: 239.0 [M+H] + .

[0546] Step 3: N-(5-methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-22c): I-22c (1.5 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 3) using I-22b (2.38 g, 9.97 mmol) and cyclopropanecarboxamide (1.7 g, 19.9 mmol) as starting materials. LCM (ES) m / z: 288.2 [M+H] + .

[0547] Step 4: 5-Methyl-2-(methyl-d3)-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-22): I-22 (0.57 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 4) using I-22c (1.5 g, 5.22 mmol) as the starting material. LCM (ES) m / z: 220.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.77 (d, J = 4.8 Hz, 1H); 6.79 (d, J = 5.2 Hz, 1H); 5.87 (s, 2H); 4.18 (s, 2H); 2.41 (s, 3H).

[0548] Example 23: Preparation of 2-ethyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-23)

[0549] [ka]

[0550] Step 1: 4,5-Dibromo-2-ethyl-2H-1,2,3-triazole (I-23a): To a stirred solution of I-21a (15 g, 66.2 mmol) in DMF (160 mL) was added potassium carbonate (9.14 g, 66.2 mmol) at −10° C. and stirred for 5 minutes. Bromoethane (4.90 g, 66.2 mmol) was then added, and the reaction mixture was stirred at room temperature for 4 hours. After completion, ice-cold water (150 mL) was added to the reaction mixture, and extraction was carried out using EtO (75 mL x 3). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-8% EtOAc in n-pentane) to give 4,5-dibromo-2-ethyl-2H-1,2,3-triazole I-23a (8.5 g) as a colorless oil. LCM (ES) m / z: 254.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ 4.42 (q, J = 7.6 Hz, 2H); 1.54 (t, J = 7.6 Hz, 3H). 13 C NMR(100MHz, CDCl3)δ 123.9,51.7,14.5.

[0551] Step 2: 5-Bromo-2-ethyl-2H-1,2,3-triazole-4-carbaldehyde (I-23b): I-23b (5.6 g) was synthesized by using I-23a (8.5 g, 33.3 mmol) as the starting material and following the procedure described for the synthesis of I-16 (Step 1). 1 H NMR (400MHz, DMSO-d6) δ 9.96 (s, 1H); 4.54 (q, J = 7.3Hz, 2H); 1.47 (t, J = 7.2Hz, 3H).

[0552] Steps 3-4: tert-Butyl ((5-bromo-2-ethyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-23d): I-23d (3.9 g) was synthesized by following the procedure described for the synthesis of I-16 (Steps 2-3) using I-23b (5.6 g, 27.4 mmol) and methylamine hydrochloride (3.71 g, 54.9 mmol) as starting materials. LCM (ES) m / z: 319.1 [M+H] + .

[0553] Step 5: tert-Butyl ((5-(2-chloro-3-fluoropyridin-4-yl)-2-ethyl-2H-1,2,3-triazol-4-yl)methyl)(methyl)carbamate (I-23e): I-23e (4.1 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 1) using I-23d (3.9 g, 12.2 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (5.36 g, 30.5 mmol) as starting materials. LCM (ES) m / z: 370.2 [M+H] + .

[0554] Step 6: 6-Chloro-2-ethyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-23f): I-23f (2.6 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 2) using I-23e (4.1 g, 11.1 mmol) as the starting material. LCM (ES) m / z: 250.1 [M+H] + .

[0555] Step 7: N-(2-ethyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-23g): I-23g (2.4 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 3) using I-23f (2.6 g, 10.4 mmol) and cyclopropanecarboxamide (1.77 g, 20.8 mmol) as starting materials. LCM (ES) m / z: 299.2 [M+H] + .

[0556] Step 8: 2-Ethyl-5-methyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-23): I-23 (0.67 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 4) using I-23g (2.4 g, 8.04 mmol) as the starting material. LCM (ES) m / z: 231.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.76(d,J=5.2Hz,1H);6.79(d,J=5.2Hz,1H);5.84(s,2H);4.47(q,J=7.2Hz,2H);4.18(s,2H);2.41(s,3H);1.46(t,J=7.2Hz,3H).

[0557] Example 24: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-24)

[0558] [ka]

[0559] Step 1: 1-(5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethan-1-one (I-24a): I-24a (4.5 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 1) using I-16a (8.0 g, 33.2 mmol) and dimethylacetamide (14.5 g, 166.0 mmol) as starting materials. LCM (ES) m / z: 204.1 [M+H] + .

[0560] Steps 2-3: tert-Butyl (1-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-24c): I-24c (8.5 g) was synthesized by following the procedure described for the synthesis of I-16 (Steps 2-3) using I-24a (7.4 g, 36.3 mmol) and methylamine hydrochloride (4.9 g, 72.5 mmol) as starting materials. LCM (ES) m / z: 319.0 [M+H] + .

[0561] Step 4: tert-Butyl (1-(5-(2-fluoro-3-nitrophenyl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-24d): I-24d (1.0 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 4) using I-24c (0.85 g, 2.66 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 3.99 mmol) as starting materials. LCM (ES) m / z: 380.1 [M+H] + .

[0562] Step 5: 2,4,5-Trimethyl-6-nitro-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinoline (I-24e): I-24e (2.0 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 5) using I-24d (5.7 g, 15.0 mmol) as the starting material. LCM (ES) m / z: 260.1 [M+H] + .

[0563] Step 6: 2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-amine (I-24): I-24 (1.4 g) was synthesized by following the procedure described for the synthesis of I-16 (Step 6) using I-24e (2.0 g, 7.71 mmol) as the starting material. LCM (ES) m / z: 230.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.20(dd,J1=1.2Hz,J1=7.6Hz,1H);7.05(t,J=8.0Hz,1H);6.62(dd,J1=1.2Hz,J1=8.0Hz,1H);4.27(q,J=6.8Hz,1H);4.26(s,3H);4.16(br s,2H);2.52(s,3H);1.26(d,J=6.8Hz,3H).

[0564] Racemic I-24 (2.3 g) was separated by chiral HPLC [column: CHIRALPAK IJ (250 mm × 21 mm × 5 μm); mobile phase: n-hexane:ethanol with 0.1% DEA (70:30); flow rate: 20 mL / min] to give two enantiomers: I-24A (0.85 g): peak 1; R t 17.42 min, and I-24B (1.0 g): Peak-2; R t 20.93 min} were obtained and carried forward without confirming their absolute configuration.

[0565] Example 25: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-25)

[0566] [ka]

[0567] Step 1: tert-Butyl (1-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)ethyl)(methyl)carbamate (I-25a): I-25a (3.0 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 1) using I-24c (4.5 g, 14.1 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (6.18 g, 35.2 mmol) as starting materials. LCM (ES) m / z: 370.0 [M+H] + .

[0568] Step 2: 6-Chloro-2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridine (I-25b): I-25b (3.6 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 2) using I-25a (6.2 g, 16.8 mmol) as the starting material. LCM (ES) m / z: 250.0 [M+H] + .

[0569] Step 3: N-(2,4,5-trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-yl)cyclopropanecarboxamide (I-25c): I-25c (3.5 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 3) using I-25b (3.0 g, 12.0 mmol) and cyclopropanecarboxamide (2.05 g, 24.0 mmol) as starting materials. LCM (ES) m / z: 299.2 [M+H] + .

[0570] Step 4: 2,4,5-Trimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c][1,7]naphthyridin-6-amine (I-25): I-25 (1.6 g) was synthesized by following the procedure described for the synthesis of I-18 (Step 4) using I-25c (3.5 g, 11.7 mmol) as the starting material. LCM (ES) m / z: 231.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.77(d,J=4.8Hz,1H);6.80(d,J=4.8Hz,1H);5.80(s,2H);4.31(q,J=7.2Hz,1H);4.17(s,2H);2.40(s,3H);1.08(d,J=7.2Hz,3H).

[0571] Example 26: Preparation of 4,6-dichloro-N-methylpyridazine-3-carboxamide (A-1)

[0572] [ka]

[0573] To a stirred solution of A-1a (10.0 g, 50.3 mmol) in anhydrous DCM (100 mL), catalytic amounts of DMF (2–3 drops) and oxalyl chloride (9.11 mL, 101.0 mmol) were added portionwise at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 h. The volatiles were then removed under reduced pressure, and the residue was dried. The residue was then dissolved in anhydrous DCM (50 mL), and to a stirred solution of methylamine hydrochloride (5.09 g, 75.4 mmol) and DIPEA (13.2 mL, 75.4 mmol) in DCM (50 mL) was added under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 16 h. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. It was then washed with saturated NaOHCO3 solution (30 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0-40% EtOAc in hexanes) to give the desired compound 4,6-dichloro-N-methylpyridazine-3-carboxamide A-1 (3.2 g) as an off-white solid. LCM (ES) m / z: 206.0 [M+H] + .

[0574] Example 27: Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (A-2)

[0575] [ka]

[0576] To a stirred solution of A-1a (5.0 g, 25.1 mmol) in anhydrous DCM (40 mL), catalytic amounts of DMF (2–3 drops) and oxalyl chloride (4.6 mL, 50.3 mmol) were added portionwise at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 h. The volatiles were removed under reduced pressure, and the residue was dried. The residue was then dissolved in anhydrous DCM (25 mL), and to a stirred solution of methane-d3-amine hydrochloride (2.13 g, 30.2 mmol) and DIPEA (13.2 mL, 75.4 mmol) in anhydrous DCM (25 mL) was added under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 16 h. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. It was then washed with saturated NaOHCO3 solution (30 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0-40% EtOAc in hexanes) to give the desired compound 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide A-2 (2.6 g) as an off-white solid. LCM (ES) m / z: 209.0 [M+H] + .

[0577] Example 28: Preparation of 4,6-dichloro-N-(methyl-d3)nicotinamide (A-3):

[0578] [ka]

[0579] Using A-3a (3 g) as the starting material, A-3 (2.6 g) was synthesized as described for the synthesis of A-2. LCMS (ES) m / z 208.0 [M+H] + .

[0580] Example 29: Preparation of 4,6-dichloro-N-methylnicotinamide (A-4):

[0581] [ka]

[0582] Using A-3a (3 g) as the starting material, A-4 (2.5 g) was synthesized as described for the synthesis of A-1. LCM (ES) m / z: 204.9 [M+H] + .

[0583] Example 30: Preparation of 4-bromo-6-chloro-N-(methyl-d3)nicotinamide (A-5):

[0584] [ka]

[0585] To a stirred solution of A-5a (4.75 g, 20.1 mmol) in DCM (15 mL) was added HATU (11.5 g, 30.1 mmol), DIPEA (10.4 mL, 60.3 mmol), and methan-d3-amine hydrochloride (1.7 g, 24.1 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. After completion, water (50 mL) was added to the reaction mixture, and extraction was carried out using DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0 to 20% EtOAc in heptane) to give the desired compound, 4-bromo-6-chloro-N-(methyl-d3)nicotinamide A-5 (3.1 g) as an off-white solid. LCM(ES) m / z: 252.0 [M+H] + .

[0586] Example 31: Preparation of 4,6-dichloropyridazine-3-carboxamide (A-6):

[0587] [ka]

[0588] To a stirred solution of A-1a (2.5 g, 12.6 mmol) in anhydrous DCM (50 mL) was added catalytic DMF (2–3 drops) and oxalyl chloride (2.5 mL, 25.1 mmol) in small portions at 0° C. The reaction mixture was then gradually warmed to room temperature over 2 h. Upon completion, the volatiles were removed under reduced pressure, and the residue was dried. The residue was then dissolved in anhydrous DCM (25 mL) and added to a stirred solution of 0.5 M ammonia in dioxane (10.0 mL) and DIPEA (6.5 mL, 37.3 mmol) in anhydrous DCM (25 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. It was then washed with saturated NaOHCO3 solution (30 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0-60% EtOAc in hexanes) to give the desired compound 4,6-dichloropyridazine-3-carboxamide A-6 (4.2 g) as an off-white solid. LCM (ES) m / z: 193.0 [M+H] + .

[0589] Example 32: Preparation of 4,6-dichloronicotinamide (A-7):

[0590] [ka]

[0591] Starting from A-3a (0.25 g), A-7 (0.14 g) was synthesized as described for the synthesis of A-6. LCM (ES) m / z: 190.9 [M+H] + .

[0592] Example 33: General Procedure 1 for the preparation of compounds of formula I:

[0593] [ka]

[0594] Step 1: To a stirred solution of Intermediate-1 and A-1 in propan-2-ol and water, Zn(OAc) was added at room temperature. The reaction mixture was then stirred in a sealed tube at 75°C for 16 hours. The reaction progress was monitored by LCMS. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and stirred for 1 hour. The resulting solid was filtered, washed with water, and dried (co-evaporated with toluene). This was further stirred in diethyl ether, filtered, and dried to give the intermediate compound Intermediate-1a.

[0595] Step 2: Argon gas was purged through a stirred suspension of Intermediate-1a, an appropriate aniline or aminopyridine compound (such as 5-fluoropyridin-2-amine), and CsCO in 1,4-dioxane for 15 minutes. [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane and Pd(dba) were then added. The reaction mixture was then stirred in a sealed tube at 130° C. for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through a Celite bed. This was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash to give the desired compound of Formula (I).

[0596] Example 34: General Procedure 1 for the preparation of alternative compounds of formula I:

[0597] [ka]

[0598] Alternatively, argon gas was passed through a stirred suspension of Intermediate-1a, the appropriate amide, urea, or carbamate (e.g., cyclopropanecarboxamide), and CsCO in DMA for 15 minutes. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane and Pd(dba) . The reaction mixture was then irradiated in a MW reactor at 130 °C for 1 hour. Upon completion, the reaction mixture was cooled to room temperature and filtered through a bed of Celite, which was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash to give the desired compound of Formula (I).

[0599] Example 35: Preparation of 6-(cyclopropanecarboxamido)-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide (Compound 1)

[0600] [ka]

[0601] Step 1: Preparation of 6-chloro-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide (1a): To a stirred solution of I-1 (0.66 g, 3.26 mmol) and A-1 (0.81 g, 3.92 mmol) in propan-2-ol (5.0 mL) and water (5.0 mL), Zn(OAc) (1.08 g, 5.87 mmol) was added at room temperature. The reaction mixture was then stirred in a sealed tube at 75 °C for 16 h. The reaction progress was monitored by LCMS. After complete consumption of the starting material, the reaction mixture was allowed to cool to room temperature and stirred for 1 h. The resulting solid was filtered, washed with water (2 x 5 mL), and dried (coevaporated with toluene). This was further stirred in diethyl ether (20.0 mL), filtered, and dried to give the desired compound 6-chloro-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide 1a (0.6 g) as an off-white solid. LCM (ES) m / z: 372.1 [M+H] + .

[0602] Step 2: 6-(cyclopropanecarboxamide)-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide (compound 1): Argon gas was passed through a stirred suspension of 1a (0.3 g, 0.81 mmol), cyclopropanecarboxamide (0.103 g, 1.21 mmol), and CsCO (0.526 g, 1.61 mmol) in 1,4-dioxane (6.0 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.047 g, 0.081 mmol) and Pd(dba) (0.074 g, 0.081 mmol). The reaction mixture was then stirred in a sealed tube at 130 °C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through a Celite bed. It was washed with EtOAc (2 x 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–5% MeOH in DCM) to give the desired compound 6-(cyclopropanecarboxamido)-N-methyl-4-((2-methyl-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)pyridazine-3-carboxamide 1 (0.14 g) as an off-white solid. LCM (ES) m / z: 421.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H); 10.79 (s, 1H); 9.18-9.12 (m, 1H); 8.01 (s, 1H); 7.46 (d, J = 8.0 Hz, 1H); 7.32 (d, J = 8.0 Hz, 1H); 7.18 (apparent t, J = 8.0 Hz, 1H); 5.58 (s, 2H); 2.83 (d, J = 5.2 Hz, 3H); 2.37 (s, 3H); 2.10-2.00 (m, 1H); 0.82-0.72 (m, 4H).

[0603] Example 36: 6-(cyclopropanecarboxamido)-4-((2-(hydroxymethyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-N-methylpyridazine-3-carboxamide (compound 3):

[0604] [ka]

[0605] Step 1: Ethyl (E)-2-((3-bromo-2-(cyanomethoxy)phenyl)diazenyl)-2-chloroacetate (7a): To a suspension of I-1b (10.0 g, 44.0 mmol) in concentrated HCl (280 mL) was added an aqueous solution of sodium nitrite (3.04 g, 44.0 mmol in 30 mL of water) at 0 °C. This was stirred for 30 min, and then the pH of the reaction medium was adjusted to 4 by gradually adding sodium acetate (3.61 g, 44.0 mmol). This was followed by the addition of a solution of ethyl 2-chloro-3-oxobutanoate (7.25 g, 44.0 mmol) in MeOH (20 mL) with vigorous stirring at 0-5 °C. After 30 min, extraction was carried out with EtO (2 x 75 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl (E)-2-((3-bromo-2-(cyanomethoxy)phenyl)diazenyl)-2-chloroacetate 7a (7.00 g, 19.4 mmol) as a yellow solid. The crude product was not stable and was carried to the next step without any purification. LCM (ES) m / z: 358.0 [M−H] + .

[0606] Step 2: Ethyl 6-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate (7b): To a stirred solution of 7a (8.0 g, 22.2 mmol) in toluene (150 mL), TEA (12.5 mL, 88.7 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was then cooled to room temperature, and water (200 mL) was added. Extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–20% EtOAc in hexanes) to give the desired compound, ethyl 6-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine-2-carboxylate 7b (3.80 g, 11.7 mmol) as a yellow oil. LCM (ES) m / z: 324.0 [M+H] + .

[0607] Step 3: (6-Bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol (7c): To a stirred solution of 7b (3.3 g, 10.2 mmol) in THF (60 mL) was added DIBAL-H (50.9 mL, 50.9 mmol) at 0 °C. It was then stirred at room temperature for 4 h. After completion, the reaction mixture was quenched by the addition of saturated NH4Cl solution (30 mL) and extraction was carried out using 10% MeOH in DCM (50 x 3). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude (6-bromo-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol 7c (2.30 g) as a yellow oil. LCM (ES) m / z: 282.0 [M+H] + .

[0608] Step 4: 6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine (7d): To a stirred solution of 7c (500 mg, 1.77 mmol) in DCM (70.0 mL) and DMF (30.0 mL) was added 1H-imidazole (0.6 g, 8.86 mmol) and tert-butyl(chloro)dimethylsilane (1.87 g, 12.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion, water (50 mL) was added to the reaction mixture, and extraction was carried out using DCM (2 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–5% EtOAc in hexanes) to give 6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazine 7d (0.57 g) as an off-white solid. LCM (ES) m / z: 396.0 [M+H] + .

[0609] Step 5: tert-Butyl (2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)carbamate (7e): 7e (1.1 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 6) using 7d (1.5 g, 5.32 mmol) as the starting material. LCM (ES) m / z: 432.9 [M+H] + .

[0610] Step 6: (6-amino-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-2-yl)methanol (7f): 7f (0.5 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 7) using 7e (1.0 g, 2.31 mmol) as the starting material. LCM (ES) m / z: 218.9 [M+H] + .

[0611] Step 7: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-amine (7g): To a stirred solution of 7f (0.5 g, 2.29 mmol) in anhydrous DMF (30 mL) was added 1H-imidazole (0.78 g, 11.5 mmol) and TBDMSCl (2.42 g, 16.0 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 16 h. Saturated NaHCO3 solution (20 mL) was added to the reaction mixture, and extraction was carried out using diethyl ether (3 x 20 mL). The combined organic extracts were washed with water (3 x 10 mL), brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-50% EtOAc in hexanes) to give 2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-amine 7g (0.62 g) as an off-white solid. LCM (ES) m / z: 333.2 [M+H] + .

[0612] Step 8: 4-((2-(((tert-Butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (7h): 7h (0.64g) was synthesized by following the procedure described for the synthesis of compound 5 (Step 1) using 7g (0.62g, 1.86mmol) and A-1 (0.58g, 2.8mmol) as starting materials. LCM (ES) m / z: 502.1 [M+H] + .

[0613] Step 9: 4-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (7i): 7i (0.18 g) was synthesized by following the procedure described for the synthesis of compound 5 (Step 2) using 7h (0.29 g, 0.578 mmol) as the starting material. LCM (ES) m / z: 551.3 [M+H] + .

[0614] Step 10: 4-((2-(((tert-Butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide (compound 3): To a stirred solution of 7i (150 mg, 0.272 mmol) in THF (10 mL) was added TBAF (1.63 mL, 1.63 mmol) at 0° C. and stirred at the same temperature for 1 hour. After completion, water (10 mL) was added thereto and the observed solid was filtered and washed with water (2×3 mL). This was then stirred in pentane (10 mL), filtered, and dried to give the desired compound 4-((2-(((tert-butyldimethylsilyl)oxy)methyl)-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]oxazin-6-yl)amino)-6-(cyclopropanecarboxamide)-N-methylpyridazine-3-carboxamide compound 3 (80 mg) as an off-white solid. LCM (ES) m / z: 437.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.33(s,1H);10.82(s,1H);9.15(d,J=4.4Hz,1H);8.04(s,1H);7.52(dd,J1=1.2Hz,J2=8.0Hz,1H);7.37(dd,J1=1.2Hz,J2=7.6Hz,1H);7. 23(t,J=8.0Hz,1H);5.64(s,2H);5.45(t,J=5.6Hz,1H);4.55(d,J=5.2Hz,2H);2.87(d,J=4.8Hz,3H);2.10-2.04(m,1H);0.86-0.78(m,4H).

[0615] Example 37 Preparation of 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Compound 5)

[0616] [ka]

[0617] Step 1: 6-chloro-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (14a): To a stirred solution of I-5 (1.5 g, 6.97 mmol) and A-2 (1.46 g, 6.97 mmol) in anhydrous DMA (15.0 mL) was added a 1 M solution of LiHMDS in THF (5.57 mL, 27.9 mmol) in portions at 0 °C. The reaction mixture was stirred at the same temperature for 1 h, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched by the addition of cold water (50 mL), and extraction was carried out using 10% MeOH in DCM (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Combi-Flash (using a gradient elution of 0 to 5% MeOH in DCM) to give a solid, which was stirred in pentane (15 mL), filtered, and dried to give the desired compound 6-chloro-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide 14a (1.9 g) as an off-white solid. LCM (ES) m / z: 388.2 [M+H] + .

[0618] Step 2: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (compound 5): Argon gas was passed through a stirred suspension of 14a (1.9 g, 4.9 mmol), cyclopropanecarboxamide (0.54 g, 6.37 mmol), and Cs2CO3 (4.79 g, 14.7 mmol) in 1,4-dioxane (20.0 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.28 g, 0.49 mmol) and Pd(dba) (0.45 g, 0.49 mmol). The reaction mixture was then stirred in a sealed tube at 130 °C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through a Celite bed. It was washed with MeOH (2 x 50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–5% MeOH in DCM) to give the desired compound 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide 5 (1.8 g) as an off-white solid. LCM (ES) m / z: 437.3 [MH] + . 1 H NMR(400MHz,DMSO-d6)δ 11.32(s,1H);10.96(s,1H);9.11(s,1H);8.18(s,1H);7.48(dd,J1=1.6Hz,J2=7.6Hz,1H);7. 36-7.28(m, 2H); 4.42(s, 2H); 2.55(s, 3H); 2.38(s, 3H); 2.11-2.07(m, 1H); 0.85-0.80(m, 4H).

[0619] Example 38: Preparation of 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide (Compound 19)

[0620] [ka]

[0621] Step 1: 4-((2,5-Dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide (Compound 19): Argon gas was passed through a stirred suspension of 14a (0.3 g, 0.739 mmol), 1-methylurea (0.082 g, 1.11 mmol), and KOAc (0.181 g, 1.85 mmol) in 1,4-dioxane (10.0 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.043 g, 0.074 mmol) and Pd(dba) (0.068 g, 0.074 mmol). The reaction mixture was then stirred in a sealed tube at 110 °C for 3 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the reaction mixture was cooled to room temperature and filtered through a Celite bed. It was washed with MeOH (2 x 10 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0–5% MeOH in DCM) to give the desired compound 4-((2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide 19 (0.11 g) as an off-white solid. LCM (ES) m / z: 426.4 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.94(s,1H);9.52(s,1H);9.08(s,1H);7.76(s,1H);7.49(dd,J1=1.6Hz,J2=7.6Hz, 1H);7.38-7.26(m,1H);4.45(s,2H);2.69(d,J=4.8Hz,3H);2.56(s,3H);2.39(s,3H).

[0622] Example 39 Preparation of 6-(cyclopropanecarboxamido)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide (Compound 83)

[0623] [ka]

[0624] Step 1: 6-chloro-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-[1,2,4]triazolo[1,5-a]quinoxalin-6-yl)amino)-N-(methyl-d3)nicotinamide (34a): 34a (0.9 g) was synthesized by following the procedure des...

Claims

1. Formula (XIV): 【Chemistry 1】 or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R 8 is hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C １ -C ６ Deuteroalkyl, unsubstituted or substituted C ２ -C ６ Alkenyl, unsubstituted or substituted C ２ -C ６ Alkynyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ Heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16, -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -S(=O)R 17, -SO ２ R １７ , or -SO ２ N (R １６ ) ２ and Z is -NR １０ -, -O-, -S-, -S(=O)-, or -SO ２ - and R 10 is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, or a monocyclic heterocycle; X １ , X ２ , and X ３ are each independently CR １１ or N, R 11 is independently hydrogen, halogen, or unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ２ -C ６ Alkenyl, unsubstituted or substituted C ２ -C ６ Alkynyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ Heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N (R １６ ) ２ and B １ is N or CR １２ａ and B ２ is N or CR １２ｂ and R and R １２ｂ are each independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ２ -C ６ Alkenyl, unsubstituted or substituted C ２ -C ６ Alkynyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ Heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N (R １６ ) ２ and R 2 is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbocycle, and when said ring B is substituted, said ring B is selected from q instances of R １３ is replaced by Each of the R 13 's is independently a halogen atom or an unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted or substituted C ２ -C ６ Alkenyl, unsubstituted or substituted C ２ -C ６ Alkynyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted C １ -C ６ Heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N (R １６ ) ２ and Or, two R on adjacent atoms of the ring B １３ the groups, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle; Alternatively, the R ２ is -C(=O)R １４ , -C(=O)NR １４ R １５ or -C(=O)OR １４ and R 14 is hydrogen or unsubstituted or substituted C １ -C ６ Alkyl, C １ -C ６ Deuteroalkyl, unsubstituted or substituted C ２ -C ６ Alkenyl, unsubstituted or substituted C ２ -C ６ Alkynyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle; R 15 is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ is a fluoroalkyl; R 4 is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ cycloalkyl, or a monocyclic heterocycle; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Deuteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ Cycloalkyl, or monocyclic heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N (R １６ ) ２ and Or, one of the R ６ and one of the R ７ are taken together with the carbon atom to which they are attached to form C=O or C ３ -C ４ Forming a cycloalkyl, R １６ are each independently hydrogen, substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C ７ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; Or, two of the R on the same N atom １６ together with the N atom to which they are attached form a substituted or unsubstituted N-containing heterocycle; R １７ each independently represents a substituted or unsubstituted C １ -C ６ Alkyl, substituted or unsubstituted C １ -C ６ Fluoroalkyl, substituted or unsubstituted C １ -C ６ Heteroalkyl, substituted or unsubstituted C ３ -C ７ cycloalkyl, substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; wherein substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle are each selected from the group consisting of deuterium, halogen, C １ -C ６ Alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ２ CN, -OR １８ , -CH ２ OR １８ , -CO ２ R １８ , -CH ２ CO ２ R １８ , -C(=O)N(R １８ ) ２ , -CH ２ C(=O)N(R １８ ) ２ , -N(R １８ ) ２ , -CH ２ N (R １８ ) ２ , -NR １８ C(=O)R １８ , -CH ２ N.R. １８ C(=O)R １８ , -NR １８ SO ２ R １９ , -CH ２ N.R. １８ SO ２ R １９ , -SR １８ , -CH ２ S.R. １８ , -S(=O)R １９ , -CH ２ S(=O)R １９ , -SO ２ R １９ , -CH ２ SO ２ R １９ , -SO ２ N (R １８ ) ２ , or -CH ２ SO ２ N (R １８ ) ２ One or more R independently selected from the group consisting of ｓ is substituted with a group, R 18 is independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ６ selected from heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's １８ the groups, together with the N atom to which they are attached, form an N-containing heterocycle; Each R 19 is independently C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ６ selected from heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 1, 2, 3, or 4; The compound is not 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

2. The X 1 is CR 11 , the X 2 is CR 11 , and the X 3 is CR 11 ; Or, said X 1 is CR 11 , said X 2 is CR 11 , and said X 3 is N; Or, said X 1 is CR 11 , said X 2 is N, and said X 3 is CR 11 ; Or, said X 1 is N, said X 2 is CR 11 , and said X 3 is CR 11 ; each R 11 is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN; B 1 is CH or CF, B 2 is CH or CF, Or, B 1 is N and B 2 is CH or CF; 2. The compound of claim 1, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

3. The X 1 is CR 11 , the X 2 is CR 11 , and the X 3 is CR 11 ; Or, said X 1 is CR 11 , said X 2 is CR 11 , and said X 3 is N; Each of the R 11 's is hydrogen; said B 1 is CH, said B 2 is CH; Or, B 1 is N and B 2 is CH; 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is C1-C4 alkyl or C1-C4 deuteroalkyl.

5. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R4 is C1-C4 deuteroalkyl.

6. R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO 2 R 16 , or -C(=O)N(R 16 ) 2 ; each R 16 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two of said R 16 on the same N atom together with the N atom to which they are attached form a 4- to 6-membered N-containing heterocycloalkyl; each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; 6. A compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

7. The compound of any one of claims 1 to 6, wherein R 8 is hydrogen, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CO 2 H, or -CO 2 CH 3 , or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

8. The Z is -NR 10 -, said R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; The n is 1, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; 8. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

9. The Z is -NR 10 -, said R 10 is -CH 3 or -CD 3 ; The n is 1, R 6 and R 7 are each independently hydrogen, deuterium, F, or methyl; 8. A compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

10. R 2 is ring B which is unsubstituted or substituted pyridinyl or unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is substituted with q instances of R 13 ; each R 13 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(═O)R 16 , -CO 2 R 16 , -C(═O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(═O)R 17 , -SO 2 R 17 , or -SO 2 N(R 16 ) 2 ; 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

11. The compound according to claim 10, wherein R 2 is —C(═O)R 14 ; said R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, or unsubstituted or substituted 4-6 membered heterocycloalkyl, where the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, C 1 -C 6 alkyl, -CN, -OR 18 , and -N(R 18 ) 2 ; 10. A compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

12. The compound of claim 11, wherein R 14 is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCHF 2 , and -OCF 3 .

12. The compound of claim 11, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

13. The compound according to claim 1, wherein R 8 is hydrogen, halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(═O)R 16 , -CO 2 R 16 , or -C(═O)N(R 16 ) 2 ; The Z is —NR 10 — or —O—; said R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; each of X 1 , X 2 and X 3 independently represents CR 11 or N; each R 11 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 ) 2 ; B 1 is N or CR 12a ; B 2 is N or CR 12b ; R 12a and R 12b are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or -CN; said R 2 is ring B which is unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl, or unsubstituted or substituted monocyclic 5-membered heteroaryl, and when said ring B is substituted, said ring B is substituted with q instances of R 13 ; each R 13 is independently halogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(═O)R 16 , -CO 2 R 16 , -C(═O)N(R 16 ) 2 , -N(R 16 ) 2 , -NR 16 C(═O)R 17 , -SO 2 R 17 , or -SO 2 N(R 16 ) 2 ; Alternatively, said R 2 is —C(═O)R 14 ; said R 14 is unsubstituted or substituted C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, unsubstituted or substituted C 3 -C 4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, where the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more R s groups independently selected from the group consisting of deuterium, halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 , -OCHF 2 , and -OCF 3 ; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; or one of said R 6 and one of said R 7 bound to the same carbon atom together with the carbon atom to which they are bound form C═O or C 3 -C 4 cycloalkyl; each R 16 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two of said R 16 on the same N atom are joined together with the N atom to which they are attached to form a 4- to 6-membered N-containing heterocycle; each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; 2. The compound of claim 1, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

14. The Z is -NR 10 -, said R 10 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 deuteroalkyl, or cyclopropyl; said X 1 is CR 11 , said X 2 is CR 11 , said X 3 is CR 11 ; Or, said X 1 is CR 11 , said X 2 is CR 11 , and said X 3 is N; each R 11 is hydrogen; said B 1 is CH, said B 2 is CH; Or, B 1 is N and B 2 is CH; said R 4 being C 1 -C 4 alkyl or C 1 -C 4 deuteroalkyl; R 6 and R 7 are each independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; said R 8 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, -C(=O)R 16 , -CO 2 R 16 , or -C(=O)N(R 16 ) 2 ; each of said R 16 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; or two of said R 16 on the same N atom together with the N atom to which they are attached form a 4- to 6-membered N-containing heterocycloalkyl; each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; n is 1; 14. The compound of claim 13, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

15. The Z is -NR 10 -, said R 10 is -CH 3 or -CD 3 ; said X 1 is CR 11 , said X 2 is CR 11 , said X 3 is CR 11 ; Or, said X 1 is CR 11 , said X 2 is CR 11 , and said X 3 is N; each R 11 is hydrogen; said B 1 is CH, said B 2 is CH; Or, B 1 is N and B 2 is CH; said R 4 being C 1 -C 4 deuteroalkyl; R 6 and R 7 are each independently hydrogen, deuterium, F, or methyl; said R 8 is hydrogen, methyl, ethyl, isopropyl, -CD 3 , -CH 2 OH, -CF 3 , cyclopropyl, oxetanyl, azetidinyl, -CO 2 H, or -CO 2 CH 3 ; each R 17 is independently C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl; n is 1; 14. The compound of claim 13, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

16. 【Chemical 2-1】 【Chemistry 2-2】 2. The compound of claim 1 selected from:

17. A compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof; Pharmaceutically acceptable excipients and 23. A pharmaceutical composition comprising:

18. The pharmaceutical composition of claim 17, formulated for administration to a mammal by oral administration.

19. The pharmaceutical composition of claim 17 or 18 in the form of a tablet, pill, or capsule.

20. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a medicament for use in the treatment of rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal disease, Crohn's disease, ulcerative colitis, celiac disease, Behcet's disease, type 1 diabetes, systemic sclerosis, or idiopathic pulmonary fibrosis.

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