TYK2 INHIBITORS AND USES THEREOF

Abstract

Described herein are compounds that are TYK2 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such 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, and U.S. Provisional Patent Application No. 63 / 193,514, filed May 26, 2021, each of which is incorporated by reference 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 comprising 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, JAK1, 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-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin)), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then proceeds to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. Summary of the Invention

[0004] The compounds described herein are modulators of the JAK family of kinases. More specifically, the compounds of the 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 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 pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is A 1 and A 2 is an unsubstituted or substituted 6-membered heterocyclic ring, each of which 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, or two R 8 come together to form =O, =S, or =NH, 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 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 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; Or, 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 form, together with the intermediate atoms to which they are attached, 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 independently selected from 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, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the 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 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; The compounds are described, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0007] In some embodiments, the compound has formula (II):

[0008] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0009] In some embodiments, the compound has formula (IV):

[0010] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

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

[0012] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein (i)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0013] In some embodiments, the compound has formula (VIa):

[0014] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 Or N.

[0015] In some embodiments, the compound has formula (VIb) or formula (VIc):

[0016] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0017] In some embodiments, the compound has formula (VIII):

[0018] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 and q is 1, 2, 3, or 4; A 1 and A 2 are C, respectively, A 6 , A 7 , A 8 , and A 9 are each independently CR 8 Or N.

[0019] In some embodiments, the compound has formula (VIIIa):

[0020] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 Or N.

[0021] In some embodiments, the compound has formula (IX):

[0022] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 are C, respectively, A 6 , A 7 , A 8 , and A 9 Each of the following is independently CR 8 Or N.

[0023] In some embodiments, the compound has formula (IXa):

[0024] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 Or N.

[0025] All combinations of the groups described above for the various variables are contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0026] Also described herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, 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 tissue.

[0027] Described herein is a compound of formula (A1), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, useful for treating TYK2-mediated disorders. Described herein is a compound of formula (A1), or a pharma- ceutically 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, Sjogren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Behcet'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 an interferonopathy, such as, by way of example only, Aicardi-Goutières syndrome.

[0028] In any of the foregoing aspects, it is a further embodiment that an effective amount of a compound of formula (I), or a pharma- ceutically 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.

[0029] Any of the above aspects are further embodiments that include 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 the compound is administered to the mammal multiple times during 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.

[0030] In any of the embodiments disclosed herein, the mammal is a human.

[0031] In some embodiments, the compounds provided herein are administered topically to a human.

[0032] Provided are articles of manufacture comprising packaging material, a compound described herein, or a pharma- ceutically acceptable salt thereof, in the packaging material, and the compound or composition, or a pharma- ceutically acceptable salt, tautomer, pharma- ceutically acceptable N-oxide, pharma- ceutically active metabolite, pharma- ceutically acceptable prodrug, or pharma- ceutically acceptable solvate thereof, for use in modulating TYK2 or for the treatment, prevention, or amelioration of one or more symptoms of a disease or disorder that would benefit from modulation of TYK2.

[0033] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description, but it should be noted that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] 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.

[0035] In particular, IL-23 activation of TYK2 is associated with inflammatory diseases such as inflammatory bowel disease (IBD), Crohn's disease, celiac disease, and ulcerative colitis. TYK2 also plays a role in psoriasis, ankylosing spondylitis, and Behcet's disease as a downstream effector of IL-23. TYK2 is further associated with skin diseases and disorders such as psoriasis, vitiligo, atopic dermatitis, hidradenitis suppurativa, and scleroderma, and eye diseases and disorders such as Sjogren's syndrome, uveitis, and dry eye.

[0036] 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.

[0037] 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 as well as other autoimmune diseases and conditions.

[0038] TYK2 is associated with arthritis, including psoriatic arthritis and rheumatoid arthritis. Reduction of TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis.

[0039] TYK2 has also been shown to play a key role in maintaining tumor surveillance, and TYK2 knockout mice showed loss of cytotoxic T-cell responses and accelerated tumor development. These results are in large part due to efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 is an excellent target due to its involvement in more or less closely related signal pathways, resulting in only minor off-target effects. However, tests on T-cell acute lymphoblastic leukemia (T-ALL) show 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, results in reduced cell proliferation. Selective inhibition of TYK2 has therefore 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.

[0040] 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 phosphorylation of STAT3 is observed in postmortem brains of Alzheimer's disease patients.

[0041] Inhibition of the JAK-STAT signaling pathway is also involved in hair growth and reversal of hair loss associated with alopecia areata.

[0042] Even though some TYK2 inhibitors are known, there is still a need to provide new inhibitors with more effective or advantageous pharmacologic related properties. For example, compounds with increased activity or increased selectivity over other JAK kinases (particularly JAK2). In some embodiments provided herein, the present 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 pharmacologic response that favorably treats one or more of the diseases or disorders described herein without the side effects associated with inhibition of JAK2.

[0043] In some embodiments, the TYK2 inhibitors described herein are used to treat a disease or condition in a mammal.

[0044] compound The compounds described herein, including pharma- ceutically 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.

[0045] In one aspect herein, a compound of formula (I):

[0046] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is A 1 and A 2 is an unsubstituted or substituted 6-membered heterocyclic ring, each of which is independently N or C; if ring A is substituted, ring A is substituted with p instances of R8 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, or two R 8 come together to form =O, =S, or =NH, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-; R 10is 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, -NR16 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 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 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; Or, 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 independently selected from 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, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; Or, two R's 18 the groups, together with the N atom to which they are attached, form an N-containing heterocycle; R 19are each independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 1, 2, 3, or 4; q is 1, 2, 3, or 4; Provided is a compound, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0047] In any and all of the 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 C-C 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.

[0048] 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 C-C alkyl. In some embodiments, R 5 is hydrogen or C1-C4 alkyl. In some embodiments, R 5is 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.

[0049] In some embodiments, W is --O--.

[0050] In some embodiments, W is -NR 3 -It is.

[0051] In some embodiments, the compound has formula (Ia) or formula (Ib):

[0052] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0053] In some embodiments, the compound is a compound of formula (Ia) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Ib) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0054] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 4is 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.

[0055] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0056] 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 3is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0057] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0058] In some embodiments, W is -NR 3 -When R 3 and R4 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. 3 and R 4 are each independently hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. 3 and R 4 are each independently hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. 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. 3 and R 4 are each independently hydrogen, -CH, -CHD, -CHD, or -CD. 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 4 is 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 4is 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.

[0059] 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.

[0060] In some embodiments, the compound has Formula (II) or Formula (III):

[0061] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0062] In some embodiments, the compound is a compound of formula (II) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (III) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0063] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0064] 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 CR11 , 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, X 3 is CR 11 It is.

[0065] In some embodiments, X 1 is CR 11 , X2 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 That is,

[0066] 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 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 In some embodiments, R 11 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 In some embodiments, R 11 are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 In some embodiments, R 11are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or -CN. 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. In some embodiments, R 11 are each independently hydrogen or fluoro. 11 are hydrogen.

[0067] 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 X 1 is CH, X 2 is CH, X 3 is N, or X 1 is CH, X 2 is N, X 3 is CH, or X1 is N, X 2 is CH, X 3 is CH.

[0068] 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, 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, 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.

[0069] In some embodiments, the compound has formula (IV) or formula (V):

[0070] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0071] In some embodiments, the compound is a compound of formula (IV) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (V) or a pharma- ceutically 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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, ring A is A 1 and A 2 is an unsubstituted or substituted 6-membered heterocycloalkyl ring, each of which is independently N or C; if ring A is substituted, ring A is selected from p instances of R 8 is replaced by.

[0074] 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, -NR16 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, or two R 8 taken together form =O, =S, or =NH. 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -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, or two R8 taken together form =O, =S, or =NH. 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, or two R 8 are taken together to form =O. 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, or two R 8 come together to form =O.

[0075] In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0, such that ring A is not substituted.

[0076] In some embodiments, ring A is A 1 and A 2 is an unsubstituted or substituted 6-membered heteroaryl ring, each of which is independently N or C; if ring A is substituted, ring A is selected from p instances of R 8In some embodiments, Ring A is an unsubstituted or substituted pyridine, an unsubstituted or substituted pyridazine, an unsubstituted or substituted pyrimidine, an unsubstituted or substituted pyrazine, an unsubstituted or substituted triazine, or an unsubstituted or substituted pyridone, and when Ring A is substituted, Ring A is substituted with p instances of R 8 In some embodiments, Ring A is an unsubstituted or substituted pyridine, an unsubstituted or substituted pyrimidine, an unsubstituted or substituted pyrazine, or an unsubstituted or substituted pyridone, and when Ring A is substituted, Ring A is substituted with p instances of R 8 In some embodiments, Ring A is an unsubstituted or substituted pyridine or an unsubstituted or substituted pyrimidine, and when Ring A is substituted, Ring A is substituted with p instances of R 8 is replaced by.

[0077] In some embodiments, Ring A is unsubstituted or substituted pyridine, and when Ring A is substituted, Ring A has p instances of R 8 In some embodiments, Ring A is unsubstituted or substituted pyridazine, and when Ring A is substituted, Ring A is substituted with p instances of R 8 In some embodiments, Ring A is an unsubstituted or substituted pyrimidine, and when Ring A is substituted, Ring A is substituted with p instances of R 8 In some embodiments, Ring A is an unsubstituted or substituted pyrazine, and when Ring A is substituted, Ring A is substituted with p instances of R 8 In some embodiments, ring A is an unsubstituted or substituted triazine, and when ring A is substituted, ring A is substituted with p instances of R 8 In some embodiments, ring A is an unsubstituted or substituted pyridone, and when ring A is substituted, ring A is substituted with p instances of R 8 is replaced by.

[0078] In some embodiments, ring A is

[0079] [ka] In some embodiments, ring A is

[0080] [ka] In some embodiments, ring A is

[0081] [ka] In some embodiments, ring A is

[0082] [ka] In some embodiments, ring A is

[0083] [ka] In some embodiments, ring A is

[0084] [ka] In some embodiments, ring A is

[0085] [ka] It is.

[0086] In some embodiments,

[0087] [ka] teeth,

[0088] [ka] where: (i)A 1 and A 2are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0089] In some embodiments,

[0090] [ka] teeth,

[0091] [ka] In the formula, A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N. In some embodiments,

[0092] [ka] teeth,

[0093] [ka] In the formula, A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O). In some embodiments,

[0094] [ka] teeth,

[0095] [ka] In the formula, A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N. In some embodiments,

[0096] [ka] teeth,

[0097] [ka] In the formula, A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0098] In some embodiments, the compound has formula (VI) or formula (VII):

[0099] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein (i)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0100] In some embodiments, A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N. In some embodiments, A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O). In some embodiments, A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N. In some embodiments, A 1 and A 2 are C and A, respectively. 6 , A 7 , A8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0101] In some embodiments, the compound is a compound of formula (VI) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VII) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0102] In some embodiments, A 1 is C and A 2 is C and A 6 is N and A 7 is CR 8 or N and A 8 is CR 8 or N and A 9 is CR 8 or N. In some embodiments, A 1 is C and A 2 is C and A 6 is N and A 7 is CR 8 And A 8 is CR 8 And A 9 is CR 8 It is.

[0103] In some embodiments, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 N, A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 N, A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 is CR 8 , A 9 is N.

[0104] In some embodiments, A 1 N, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 is CR 8 , A 9 is C(=O), Or, A 1 is C, A 2 N, A 6 is C(=O), A 7 is CR 8 , A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is NR 8 , A 7 is C(=O), A8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is C(=O), A 7 is NR 8 , A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is NR 8 , A 8 is C(=O), A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is C(=O), A 8 is NR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 is NR 8 , A 9 is C(=O), Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 is C(=O), A 9 is NR 8 It is.

[0105] In some embodiments, A 1 is C, A 2 is C, A6 N, A 7 N, A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 N, A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9 is N, Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 N, A 8 N, A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 N, A 8 is CR 8 , A 9 is N, Or, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 is CR 8 , A 8 N, A 9 is N.

[0106] In some embodiments, A 1 is C, A 2 is C, A 6 is CR 8 , A 7 N, A8 N, A 9 is N, Or, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 N, A 9 is N, Or, A 1 is C, A 2 is C, A 6 N, A 7 N, A 8 is CR 8 , A 9 is N, Or, A 1 is C, A 2 is C, A 6 N, A 7 N, A 8 N, A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A 7 N, A 8 N, A 9 is N.

[0107] In some embodiments, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 N, A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A7 is CR 8 , A 8 is CR 8 , A 9 is N, Or, A 1 is C, A 2 is C, A 6 is C(=O), A 7 is NR 8 , A 8 is CR 8 , A 9 is CR 8 It is.

[0108] In some embodiments, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9 is CR 8 and Or, A 1 is C, A 2 is C, A 6 N, A 7 is CR 8 , A 8 N, A 9 is CR 8 It is.

[0109] In some embodiments,

[0110] [ka] teeth,

[0111] [ka] In some embodiments,

[0112] [ka] teeth,

[0113] [ka] In some embodiments,

[0114] [ka] teeth,

[0115] [ka] In some embodiments,

[0116] [ka] teeth,

[0117] [ka] It is.

[0118] In some embodiments, ring A exists in a tautomeric form, with both tautomers being considered within the scope of the disclosure. For example,

[0119] [ka] teeth,

[0120] [ka] In some embodiments,

[0121] [ka] teeth,

[0122] [ka] In some embodiments,

[0123] [ka] teeth,

[0124] [ka] In some embodiments,

[0125] [ka] teeth,

[0126] [ka] In some embodiments,

[0127] [ka] teeth,

[0128] [ka] In some embodiments,

[0129] [ka] teeth,

[0130] [ka] It is.

[0131] In some embodiments, Ring A is present as an N-oxide. In some embodiments, Ring A is a pyridine N-oxide. In some embodiments, Ring A is

[0132] [ka] It is.

[0133] In some embodiments, A 1 and A 2 are each C. In some embodiments, A 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N. In some embodiments, A 6 , A 7 , A 8 , and A 9 are each independently CR 8 In some embodiments, A 6 , A 7 , A 8 , and A 9 In some embodiments, one of A 6 , A 7 , A 8 , and A 9 and two of are N. In some embodiments,

[0134] [ka] teeth,

[0135] [ka] And A 6 , A 7 , A 8 , and A 9 are each independently CR 8 Or N.

[0136] In some embodiments,

[0137] [ka] teeth,

[0138] [ka] In some embodiments, A 6 , A 7 , A 8 , and A 9 are each independently CR 8 Or N.

[0139] In some embodiments, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9 is CR 8 and Or, A 6 is CR 8 , A 7 N, A 8 is CR 8 , A 9 is CR 8 and Or, A 6 is CR 8 , A 7 is CR 8 , A 8 N, A 9 is CR 8 and Or, A 6 is CR 8 , A 7 is CR 8 , A 8 is CR 8 , A 9 is N.

[0140] In some embodiments, A 6 N, A 7 N, A 8 is CR 8 , A 9 is CR 8 and Or, A 6 N, A 7 is CR 8 , A 8 N, A 9 is CR 8 and Or, A 6 N, A 7 is CR 8 , A 8 is CR 8 , A 9 is N, Or, A 6 is CR 8 , A 7 N, A 8 N, A 9 is CR 8 and Or, A 6 is CR 8 , A 7 N, A 8 is CR 8 , A 9 is N, Or, A 6 is CR 8 , A 7 is CR 8 , A 8 N, A 9 is N.

[0141] In some embodiments, A 6 is CR 8 or N, A 7 is CR 8 , A 8 is CR 8 or N, A 9 is CR 8 It is.

[0142] In some embodiments,

[0143] [ka] teeth,

[0144] [ka] In the formula, A 6 is CR 8 or N, A 8 is CR 8 or N. In some embodiments, A 6 N, A8 is CR 8 or N. In some embodiments, A 6 N, A 8 is CR 8 In some embodiments, A 6 N, A 8 is N.

[0145] In some embodiments, the compound has formula (VIa) or formula (VIIa):

[0146] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 Or N.

[0147] In some embodiments, the compound is a compound of formula (VIa) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIIa) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, R 8 is CR 8 In some embodiments, A 8 is N.

[0148] In some embodiments, the compound has formula (VIb) or formula (VIIb):

[0149] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0150] In some embodiments, the compound is a compound of formula (VIb) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIIb) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0151] In some embodiments, the compound has formula (VIc) or formula (VIIc):

[0152] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0153] In some embodiments, the compound is a compound of formula (VIb) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIIb) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0154] In some embodiments, the compound has formula (VId) or formula (VIId):

[0155] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0156] In some embodiments, the compound is a compound of formula (VId), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIId), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0157] In some embodiments, the compound has formula (VIe) or formula (VIIe):

[0158] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0159] In some embodiments, the compound is a compound of formula (VIe) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIIe) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0160] 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)R17 , -SO2R 17 , or -SO2N(R 16 )2.

[0161] 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -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.

[0162] 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, 4-6 membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2.

[0163] 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.

[0164] 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.

[0165] 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 In some embodiments, R 8 are each independently hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 In some embodiments, R 8are each independently hydrogen, methyl, ethyl, isopropyl, -CD, -CHOH, -CF, cyclopropyl, oxetanyl, azetidinyl, -CN, -COH, or -COCH. 8 are each independently hydrogen, methyl, -CD, -CHOH, -CF, oxetanyl, -CN, or -COCH. 8 are each independently hydrogen, C-C alkyl, C-C deuteroalkyl, or C-C fluoroalkyl. 8 are each independently hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. 8 are each independently hydrogen, methyl, ethyl, isopropyl, -CD3, or -CF3. 8 are each independently hydrogen, methyl, -CD3, or -CF3. In some embodiments, R 8 are each independently hydrogen or methyl.

[0166] 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 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 In some embodiments, R6 and R 7 are each independently hydrogen, halogen, or C1-C6 alkyl. 6 and R 7 are each independently hydrogen or C1-C6 alkyl. 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 C-C alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, Cl, -CD, or methyl. 6 and R 7 are each independently hydrogen, deuterium, F, or methyl. 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.

[0167] In some embodiments, 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 C-C cycloalkyl. In some embodiments, one R 6 and one R 7Together with the carbon atom to which they are attached, they form C=O. In some embodiments, one R 6 and one R 7 taken together with the carbon atom to which they are attached form a C3-C4 cycloalkyl.

[0168] 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.

[0169] 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-.

[0170] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C4 cycloalkyl, or 4-membered heterocycloalkyl. In some embodiments, R 10is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. 10 is hydrogen, C1-C4 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. 10 is hydrogen, C1-C4 alkyl, C1-C4 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.

[0171] 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.

[0172] 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-.

[0173] 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 substituted with q instances of R 13 In some embodiments, R 2is 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 selected from the group consisting of q instances of R 13 is replaced by.

[0174] 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 selected from q instances of R 13 is replaced by.

[0175] 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 selected from the group consisting of q instances of R 13 is replaced by,

[0176] 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 selected from q instances of R 13 is replaced by.

[0177] In some embodiments, R 2 is ring B which is an unsubstituted or substituted monocyclic 5-membered heteroaryl, and when ring B is substituted, ring B is 13 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 if Ring B is substituted, then 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 selected from 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 substituted with q instances of R 13 is replaced by.

[0178] 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.

[0179] 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 selected from q instances of R 13 is replaced by.

[0180] 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 selected from 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 selected from q instances of R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyridinyl, and when ring B is substituted, ring B is R 13 In some embodiments, R 2 is ring B which is unsubstituted or substituted pyrimidinyl, and when ring B is substituted, ring B is R 13 is replaced by.

[0181] In some embodiments, R 2 teeth,

[0182] [ka] and q is 0 to 4. In some embodiments, R 2 teeth,

[0183] [ka] and q is 0 to 4. In some embodiments, R 2 teeth,

[0184] [ka] and q is 0 to 4.

[0185] In some embodiments, R 2 teeth,

[0186] [ka] where V is CH, CR 9 or N, and q is 0, 1, 2, 3, or 4. In some embodiments, R 2 teeth,

[0187] [ka] where V is CH, CR 9 , or N, and q is 0, 1, 2, or 3.

[0188] In some embodiments, the compound has formula (VIII):

[0189] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 q is 1, 2, 3, or 4; A 1 , A 2 , A 6 , A 7 , A 8 , and A 9 is as defined herein.

[0190] 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 It is.

[0191] In some embodiments, (i)A 1 and A 2 are C and A, respectively. 6 , A 7 , A8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0192] In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0193] In some embodiments, the compound of formula (VIII) has the formula (VIIIa):

[0194] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 or N. In some embodiments, R 8 is CR 8 In some embodiments, A 8 is N.

[0195] In some embodiments, the compound has formula (VIIId) or formula (VIIIc):

[0196] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0197] In some embodiments, the compound is a compound of formula (VIIIb) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (VIIIc) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0198] In some embodiments, the compound has formula (VIIId):

[0199] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0200] In some embodiments, the compound has formula (VIIIe):

[0201] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0202] 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 It is.

[0203] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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 4is -CH3. In some embodiments, R 4 is -CD3.

[0204] 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 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 In some embodiments, R 13 are each independently halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 In some embodiments, R 13 are each independently halogen, C-C alkyl, or C-C fluoroalkyl. 13 are each independently -F, -Cl, -CH3, or -CF3.

[0205] In some embodiments, q is 0, 1, 2, 3, or 4. 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.

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

[0207] In some embodiments, R 2 is -C(=O)R 14 It is.

[0208] In some embodiments, R 2 is -C(=O)NR 14 R 15 OR -C(=O)OR 14 It is.

[0209] In some embodiments, the compound has formula (IX), formula (X), or formula (XI):

[0210] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 , A 2 , A 6 , A 7 , A 8 , and A 9 is as defined herein.

[0211] In some embodiments, (i)A 1 and A 2 are C and A, respectively. 6, A 7 , A 8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR 8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0212] In some embodiments, the compound is a compound of formula (IX) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (X) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XI) or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0213] In some embodiments, the compound has formula (IXa), formula (Xa), or formula (XIa):

[0214] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 Or N.

[0215] In some embodiments, the compound is a compound of formula (IXa), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Xa), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XIa), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, R 8 is CR 8 In some embodiments, A 8 is N.

[0216] In some embodiments, the compound has formula (IXb), formula (Xb), or formula (XIb):

[0217] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 8 is CR 8 or N. In some embodiments, the compound is a compound of formula (IXb), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Xb), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XIb), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0218] In some embodiments, the compound has formula (IXc), formula (Xc), or formula (XIc):

[0219] [ka] or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (IXc), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Xc), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XIc), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0220] In some embodiments, the compound has formula (IXd), formula (Xd), or formula (XId):

[0221] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0222] In some embodiments, the compound is a compound of formula (IXd), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Xd), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XId), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0223] In some embodiments, the compound has formula (IXe), formula (Xe), or formula (XIe):

[0224] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0225] In some embodiments, the compound is a compound of formula (IXe), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (Xe), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is a compound of formula (XIe), or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0226] 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, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0227] 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 1is hydrogen or C-C 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.

[0228] 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 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.

[0229] In some embodiments, R 1 is hydrogen.

[0230] In some embodiments, 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. In some embodiments, R 14is 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. 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 4-6 membered heterocycloalkyl.

[0231] In some embodiments, R 14 is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted bicyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, or unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted monocyclic carbocycle, an unsubstituted or substituted bicyclic carbocycle, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle. In some embodiments, R 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.

[0232] In some embodiments, R 14is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4-6 membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is selected from 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 is selected from 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 4-6 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 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 14is 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,

[0233] [ka] In some embodiments, R 14 is methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

[0234] [ka] In some embodiments, R 14 is methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,

[0235] [ka] It is.

[0236] 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 4-6 membered monocyclic heterocycle. 14and R 15 taken together with the intervening atoms to which they are attached form an unsubstituted or substituted 4-6 membered monocyclic heterocycloalkyl.

[0237] In some embodiments, B 1 is CR 12a , B 2 is CR 12b or B 1 N, B 2 is CR 12b or B 1 is CR 12a , B 2 is N, or B 1 N, B 2 is N. In some embodiments, B 1 is CR 12a , B 2 is CR 12b In some embodiments, B 1 N, B 2 is CR 12b In some embodiments, B 1 is CR 12a , B 2 is N. In some embodiments, B 1 N, B 2 is N.

[0238] In some embodiments, B 1 is CR 12a , B 2 is CR 12b or B 1 N, B 2 is CR 12b It is.

[0239] In some embodiments, 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.

[0240] 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 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 In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 In some embodiments, R 12a and R12b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, -OR 17 , or -N(R 16 In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, C-C alkyl, C-C fluoroalkyl, or -CN. 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. In some embodiments, R 12a and R 12b are each independently hydrogen or fluoro. 12a and R 12b are hydrogen.

[0241] 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.

[0242] In some embodiments, B 1 is CH or CF, B 2 is CH or CF, or B 1 N, B 2 is CH or CF, or B 1 is CH or CF, B 2 is N, or B 1 N, B 2 is N. In some embodiments, B 1 is CH, B 2 is CH, or B 1 N, B2 is CH, or B 1 is CH, B 2 is N, or B 1 N, B 2 is N.

[0243] In some embodiments, R 3 and R 12a are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted 5- or 6-membered heterocycle. 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,

[0244] [ka] teeth,

[0245] [ka] In some embodiments,

[0246] [ka] teeth,

[0247] [ka] In some embodiments,

[0248] [ka] teeth,

[0249] [ka] It is.

[0250] In some embodiments, the compound has formula (XII):

[0251] [ka] or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 , A 2 , A 6 , A 7 , A 8 , and A 9 is as defined herein.

[0252] In some embodiments, (i)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 are each independently CR 8 or N, (ii)A 1 is N and A 2 is C and A 6 , A 7 , and A 8 are each independently CR 8 or N and A 9 is C(=O), (iii)A 1 is C and A 2 is N and A 6 is C(=O) and A 7 , A 8 , and A 9 are each independently CR 8 or N, or (iv)A 1 and A 2 are C and A, respectively. 6 , A 7 , A 8 , and A 9 One of them is NR8 and NR 8 A adjacent to 6 , A 7 , A 8 , or A 9 is C(=O) and A 6 , A 7 , A 8 , and A 9 The remaining members are each independently 8 Or N.

[0253] In some embodiments, R 4 is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, C1-C6 alkyl, or C1-C6 deuteroalkyl. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 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.

[0254] 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 substituted with 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 13In 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 selected from q instances of R 13 is replaced by.

[0255] 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 It is.

[0256] 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 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 16 form a 4-6 membered N-containing heterocycloalkyl together with the N atom to which they are attached.

[0257] In some embodiments, R 17are 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 3-8 membered heterocycloalkyl. 17 are each independently C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or a monocyclic 3- to 8-membered heterocycloalkyl.

[0258] In some embodiments, the compounds described herein have the following structure:

[0259] [ka] has.

[0260] In some embodiments, B 1 , R 2 , R 4 , Z, n, R 6 , R 7 , A 1 , A 2 , ring A, R 8 and p is as described herein. In some embodiments, B 1 , R 2 , R 4 , Z, n, R 6 , R 7 , and

[0261] [ka] is as described herein. In some embodiments, B 1 , R 2 , R 4 , Z, n, R 6 , R 7 , A 1 , A 2 , ring A, R 8 and p are as described in Table 1. In some embodiments, B1 , R 2 , R 4 , Z, n, R 6 , R 7 , and

[0262] [ka] are as shown in Table 1.

[0263] All combinations of the groups described above for the various variables are contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0264] Exemplary compounds described herein include those set forth in the table below.

[0265] [Table 1-1]

[0266] [Table 1-2]

[0267] [Table 1-3]

[0268] [Table 1-4]

[0269] [Table 1-5]

[0270] The compounds in Table 1 are named as follows: 1: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, 2: 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, and 3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 4: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-yl)amino)nicotinamide, 5: 6-(cyclopropanecarboxamido)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide, 6: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 7: 6-(cyclopropanecarboxamide)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 8: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 9: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydrobenzo[c][2,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide, 10: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 11: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydrobenzo[c][2,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 12: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide, 13: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, 14: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide, 15: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 16: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 17: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 18: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 19: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide, 20: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)nicotinamide, 21: 6-(cyclopropanecarboxamide)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 22: 6-(cyclopropanecarboxamido)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)nicotinamide, 23: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 24: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)nicotinamide, 25: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)nicotinamide, 26: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)pyridazine-3-carboxamide, 27: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 28: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)nicotinamide, 29: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, 30: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 31: 6-(cyclopropanecarboxamide)-4-((10-fluoro-5-methyl-5,6-dihydrophenanthridin-4-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 32: (R)-6-(cyclopropanecarboxamido)-4-((5,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 33: (S)-6-(cyclopropanecarboxamide)-4-((5,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0271] In some embodiments herein, pharma- ceutically acceptable salts of the compounds set forth in Table 1 are provided.

[0272] In another aspect of the invention, the compound is 3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 15: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 34: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 35: 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide, 36: 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyridin-4-yl)amino)-N-methylnicotinamide, 37: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide, and 38: 6-(Cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

[0273] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide (Compound 3), having the following structure:

[0274] [ka] has.

[0275] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide (compound 15), having the following structure:

[0276] [ka] has.

[0277] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide (compound 34), having the following structure:

[0278] [ka] has.

[0279] In some embodiments, the compound is 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide (compound 35), having the following structure:

[0280] [ka] has.

[0281] In some embodiments, the compound is 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyrimidin-4-yl)amino)-N-methylnicotinamide (compound 36), having the following structure:

[0282] [ka] has.

[0283] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide (compound 37), having the following structure:

[0284] [ka] has.

[0285] In some embodiments, the compound is 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide (compound 38), having the following structure:

[0286] [ka] has.

[0287] 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 form of the compounds provided herein is also considered to be disclosed herein.

[0288] "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 is relatively non-toxic at the concentrations or amounts used, i.e., the material may be administered to an individual without causing undesired biological effects or interacting adversely with any of the compositions in which the compound is included.

[0289] The term "pharmaceutical acceptable salt" refers to a form of a therapeutically active agent that consists 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. Moreover, their solubility is often pH-dependent, allowing for selective dissolution in one or another part of the digestive 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.

[0290] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with an acid. In some embodiments, a compound of formula (I) (i.e., in 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, dodecylsulfuric 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, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, 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.

[0291] In some embodiments, the compound of formula (I) is prepared as a chloride salt, a sulfate salt, a bromide salt, a mesylate salt, a maleate salt, a citrate salt, or a phosphate salt.

[0292] In some embodiments, pharma- ceutically acceptable salts are obtained by reacting a compound of formula (I) with a base. In some embodiments, a compound of formula (I) is acidic and is reacted with a base. In such a situation, the acidic proton of a compound of formula (I) is replaced with a metal ion, for example, an ion of lithium, sodium, potassium, magnesium, calcium, or aluminum. In some cases, the compounds described herein cooperate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, 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.

[0293] It should be understood that 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 with 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 are conveniently prepared or formed during the process described herein. In addition, the compounds provided herein are optionally present in unsolvated as well as solvated forms.

[0294] The methods and formulations described herein include the use of N-oxides (where appropriate), or pharma- ceutically acceptable salts of compounds having the structure of Formula (I), as well as active metabolites of these compounds that have the same type of activity.

[0295] 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, halogens, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0296] 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.

[0297] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but in which one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, 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, e.g., 3 H and 14 Incorporation of radioactive isotopes such as C are useful for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased half-life in vivo or reduced dosage requirements.

[0298] In some embodiments, the compounds of formula (I) have one or more stereocenters, and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compounds of formula (I) exist in the R configuration. In some embodiments, the 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.

[0299] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns, or separation of diastereomers by 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 the individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the 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 separation of diastereomeric salts produced by recrystallization, chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0300] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. They are bioavailable, for example by oral administration, whereas the parent drug is not. Additionally or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of the prodrug improves effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester ("prodrug"), but is subsequently metabolically hydrolyzed to provide the active entity. Further examples of prodrugs are short chain peptides (polyamino acids) that are bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon administration in vivo, the prodrug is chemically converted to the biologically, pharma- ceutical, 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, pharma- ceutical, or therapeutically active form of the compound.

[0301] 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" by 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" by Bundgaard, H., 1992, 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, the hydroxyl group in the compounds disclosed herein is a prodrug that is subsequently metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug) that is subsequently metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as prodrugs of alkyl esters.

[0302] 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.

[0303] 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.

[0304] In additional or further embodiments, the compounds described herein, after administration to an organism in need thereof, are metabolized to produce metabolic products which are then used to provide a desired effect, including a desired therapeutic effect.

[0305] A "metabolite" of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term "metabolized" as used herein refers to the 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 compound.

[0306] In some instances, heterocycles may exist in tautomeric forms. In such situations, the structure of the compound is illustrated or specified in one tautomeric form, but it is understood that it may also be illustrated or specified in alternative tautomeric forms. Alternative tautomeric forms, such as the structures illustrated below, are expressly included in the present disclosure. For example, pyridone can exist in the following tautomeric form:

[0307] [ka] all of which are encapsulated within the group "substituted pyridine." Similarly, triazolones can exist in the following tautomeric forms, including zwitterionic forms:

[0308] [ka] all of which are encapsulated within the group "substituted 5-membered heteroaryl." Similarly, pyrazoles, triazoles, pyrimidines, etc. 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.

[0309] 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.

[0310] Unless otherwise specified, conventional mass spectroscopy, NMR, HPLC are utilized.

[0311] 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, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions.

[0312] In some embodiments, the compounds described herein are prepared as depicted in Scheme A.

[0313] [ka] The variables are as defined in formula (I).

[0314] 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 displacement 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 addressed by a cross-coupling reaction of intermediates A and B. The cross-coupling reaction may be an organometallic cross-coupling such as Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, Chan-Lam coupling, etc. 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 such as Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, Chan-Lam coupling, etc.

[0315] In some embodiments, the compounds are prepared as described in the Examples.

[0316] Specific Terms Unless otherwise specified, the following terms used in this application have the definitions given 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 are not to be construed as limiting the subject matter described.

[0317] 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.

[0318] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight chain. In some embodiments, an "alkyl" group can have 1 to 10 carbon atoms, i.e., C1-C 10It has an alkyl. Whenever it appears herein, a numerical range such as "1-10" refers to each integer in the given range. For example, "1-10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, but this definition also covers occurrences of the term "alkyl" without any numerical range specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0319] An "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above can be an 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-.

[0320] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0321] 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.

[0322] "Hydroxyalkyl" refers to an alkyl in which one hydrogen atom is replaced by hydroxyl. In some embodiments, the hydroxyalkyl is a C1-C4 hydroxyalkyl. Exemplary hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0323] "Aminoalkyl" refers to an alkyl in which one hydrogen atom is replaced by amino. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Exemplary aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.

[0324] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0325] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡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, -CH2C≡CH.

[0326] 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, such as 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.

[0327] 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 which share adjacent pairs of carbon atoms) groups.

[0328] 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 in which the backbone of the ring includes at least one atom other than carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryl and cycloalkyl.

[0329] 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, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C 10 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0330] 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 at 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.

[0331] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0332] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0333] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1-4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and provided that each heterocyclic group has 3-10 atoms in its ring system, but no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5-10 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 quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are 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). Additionally, 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 the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0334] 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.

[0335] A "heterocycloalkyl" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, the heterocycloalkyl is a C2-C 10 In another embodiment, the heterocycloalkyl is a C4-C 10 Heterocycloalkyl. In some embodiments, heterocycloalkyl is monocyclic or bicyclic. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3-, 4-, 5-, or 6-membered ring. In some embodiments, heterocycloalkyl is monocyclic and is a 3- or 4-membered ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0336] 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 not present, thereby allowing a bond to be formed between the remaining specified groups.

[0337] 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 added to a molecule.

[0338] 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, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0339] 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, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two R 18 The groups, taken 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.

[0340] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health of the subject being treated.

[0341] 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.

[0342] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. The 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.

[0343] 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 skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0344] "Co-administration" and the like terms, as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0345] The term "effective amount" or "therapeutically effective amount" as used herein refers to a sufficient amount 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 the disease, or other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition containing a compound disclosed herein that is required to produce a clinically significant reduction in disease symptoms. An appropriate "effective" amount in any individual case is optionally determined using techniques such as dose escalation studies.

[0346] 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.

[0347] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient, including both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the co-agent are both administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the co-agent are administered to the patient simultaneously, concurrently, or sequentially as separate entities without any specific time limit between them, such administration providing the patient's body with effective levels of the two compounds. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0348] The terms "article of manufacture" and "kit" are used synonymously.

[0349] 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, 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.

[0350] "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 concomitant condition caused by a disease or condition, or prophylactically and / or therapeutically arresting a symptom of a disease or condition.

[0351] Pharmaceutical Compositions In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are conventionally formulated with one or more pharma- ceutical acceptable inactive ingredients that facilitate the processing of active compounds into preparations for use as medicines. Appropriate formulations depend on the route of administration selected. Overviews of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems 7th Ed (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0352] 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 benefit from reduced activity or expression of TYK2.

[0353] 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-a, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-co, and IFN-ζ (also known as limitin)), and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31), oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like 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.

[0354] 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 the 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.

[0355] 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, Sjogren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, bowel disease, Crohn's disease, ulcerative colitis, celiac disease, Behcet'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.

[0356] In some embodiments, the compounds described herein are administered alone or in combination with a pharma- ceutically acceptable carrier, additive, or excipient in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that allows delivery of the compounds to the site of action. These methods include, but are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tubes, rectal medication, and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, oral mucosal, sublingual, buccal, and topical (epithelial, dermal, 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 present 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).

[0357] 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.

[0358] Pharmaceutical compositions that can be used orally 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 powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surface active agent, 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, the tablets are coated or scored and are formulated so as to provide a delayed or controlled release of the active ingredient therein. All formulations 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, 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. Dragee 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 dragees to identify or characterize different combinations of active compound doses.

[0359] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Preparations 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 water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.

[0360] The pharmaceutical composition may also be formulated as a depot preparation. Such long-acting preparations may be administered by implantation (e.g., subcutaneously). For this purpose, for example, the compound 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.

[0361] Pharmaceutical compositions 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.

[0362] 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 from 0.001% to 10% w / w, for example from 1% to 2% by weight, of the formulation for topical administration.

[0363] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an air inhaler, a nebulizer, a pressurized pack, or other convenient means of 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 unit dosage form, for example in capsules, cartridges, gelatin, blister packs, in which the powder can be administered with the aid of an inhaler or air inhaler.

[0364] 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.

[0365] Dosing Methods and Treatment Regimens In one embodiment, the compounds described herein, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, are used in the preparation of a medicament for the treatment of a disease or condition in a mammal that would benefit from modulation of TYK2 activity. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprise the administration to the mammal of a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt, active metabolite, prodrug, or pharma- ceutically acceptable solvate thereof.

[0366] In certain embodiments, compositions containing the compounds described herein are administered for preventive 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 prevent at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous 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.

[0367] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the exact amount also depends on the patient's health, weight, and the like. When used in patients, 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 pharma- ceutically 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.

[0368] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is chronic, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or disorder.

[0369] 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 over the long term upon any recurrence of symptoms.

[0370] The amount of a given agent 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 agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0371] 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 subdoses per day.

[0372] In one embodiment, a suitable daily dosage for the compounds described herein or a pharma- ceutically 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 the dosage form is less than or greater than the ranges set forth herein, based on many variables related to the individual 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 medical practitioner.

[0373] The toxicity and therapeutic efficacy of such treatment regimens are 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 a 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 ED 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.

[0374] Any of the foregoing aspects are further embodiments in which an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered intravenously to the mammal, and / or (d) administered by injection to the mammal, and / or (e) administered locally to the mammal, and / or (f) administered non-systemically or locally to the mammal.

[0375] 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.

[0376] Any of the above 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 dosing of the compound 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.

[0377] Combination therapy In certain instances, it will be appropriate to administer at least one compound described herein, or a pharma- ceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0378] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., an adjuvant has minimal therapeutic benefit by itself, 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.

[0379] In one specific embodiment, the compounds described herein, or a pharma- ceutically acceptable salt thereof, are co-administered with a second therapeutic agent, where the compounds described herein, or a pharma- ceutically acceptable salt 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.

[0380] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0381] In the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug being utilized, the particular drug being utilized, the disease or condition being treated, and the like. In additional embodiments, the compounds provided herein, when co-administered with one or more other therapeutic agents, are administered simultaneously with the one or more other therapeutic agents, or sequentially.

[0382] 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 as two separate pills), by way of example only.

[0383] The compounds described herein, or pharma- ceutically acceptable salts thereof, as well as combination therapy, are administered before, during, or after the onset of a disease or condition, and the timing of administering the compositions containing the compounds varies. 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 subjects at or as soon as possible after the onset of symptoms. In a specific embodiment, 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 varies, and the length of treatment is adjusted to meet the specific needs of each subject. EXAMPLES

[0384] 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

[0385] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0386] Compound synthesis Example 1: Preparation of 6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine (I-1):

[0387] [ka]

[0388] Step 1: 1-(2-chloropyridin-3-yl)-N-methylmethanamine (I-1b): To a stirred solution of 2-chloropyridine-3-carbaldehyde I-1a (5.00 g, 35.3 mmol) in MeOH (50 mL), 2M MeNH2 in EtOH (6.00 mL, 63.6 mmol) was added and the reaction mixture was stirred for 16 h (progress of the reaction was monitored by TLC). After complete consumption of the starting material, the reaction mixture was cooled to 0° C. and NaBH4 (10.5 g, 293 mmol) was added in small portions. The reaction mixture was allowed to warm to room temperature gradually over 2 h. Upon completion (as shown by TLC), the volatiles were removed under reduced pressure and water (50 mL) was added. Extraction was performed with DCM (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(2-chloropyridin-3-yl)-N-methylmethanamine I-1b (5.5 g) as a pale yellow oil. LCM (ES) m / z; 157.1 [M+H] + .

[0389] Step 2: tert-Butyl ((2-chloropyridin-3-yl)methyl)(methyl)carbamate (I-1c): To a stirred solution of I-1b (5.00 g, 31.9 mmol) in DCM (80.0 mL) was added TEA (22.4 mL, 160 mmol) and (Boc)2O (36.7 mL, 160 mmol). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by LCMS. After completion, the volatiles were removed under reduced pressure and to it was added water (50 mL). Extraction was carried out with 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 resulting residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in hexanes) to give the desired compound tert-butyl ((2-chloropyridin-3-yl)methyl)(methyl)carbamate I-5c (7.00 g) as a pale yellow oil. LCM (ES) m / z; 257.1 [M+H] + .

[0390] Step 3: tert-Butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)methyl)(methyl)carbamate (I-1d): Argon gas was passed through a stirred suspension of I-1c (3.0 g, 11.7 mmol), 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.43 g, 12.9 mmol), and KOAc (3.44 g, 35.1 mmol) in 1,4-dioxane (25.0 mL) and purged for 15 minutes. To this was then added Pd(dppf)Cl2.DCM (61.2 mg, 0.0749 mmol). The reaction mixture was then stirred in a sealed tube at 80° C. for 16 hours. The reaction mixture was then cooled to room temperature and filtered through a celite bed, washing with EtOAc (2×50 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give tert-butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)methyl)(methyl)carbamate I-1d (1.3 g) as a yellow oil. LCM (ES) m / z; 362.2 [M+H] + .

[0391] Step 4: 6-Methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine (I-1e): To a stirred solution of I-1d (1.3 g, 3.6 mmol) in DCM (10.0 mL) was added TFA (5.0 mL) at 0 °C under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction progress was monitored by LCMS. Upon completion, the volatiles were removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was performed with DCM (30 mL x 3). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 6-methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine I-1e (0.68 g) as a brown solid. LCM(ES) m / z: 242.1 [M+H] + .

[0392] Step 5: 6-Methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine (I-1): To a stirred solution of I-1e (0.27 g, 1.12 mmol) in MeOH (20.0 mL) was added 10% Pd / C (59 mg) at room temperature. The reaction mixture was then stirred under hydrogen atmosphere (balloon) for 2 h. Upon completion, the catalyst was filtered off through a celite bed and washed with MeOH (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was then stirred in pentane (15 mL), filtered and dried to give 6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine I-1 (0.2 g) as an orange solid. LCM (ES) m / z; 212.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.52(dd,J1=1.2Hz,J2=4.8Hz,1H);7.69(d,J=6.0Hz,1H);7.46(dd,J1=1.2Hz,J2=7.6Hz,1H);7.30(dd,J1=4.8Hz ,J2=7.2Hz,1H);6.96(t,J=7.6Hz,1H);6.74(dd,J1=1.2Hz,J2=7.6Hz,1H);4.95(s,2H);4.14(s,2H);2.40(s,3H).

[0393] Example 2: Preparation of 6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-amine (I-2):

[0394] [ka]

[0395] Step 1: Methyl 3-((2-bromophenyl)amino)propanoate (I-2b): A mixture of 2-bromoaniline I-2a (6.00 g, 34.9 mmol) and methyl prop-2-enoate (9.48 mL, 105 mmol) in AcOH (3.99 mL, 69.8 mmol) was stirred in a sealed tube at 90 °C for 48 h. The reaction progress was monitored by TLC. After complete consumption of starting material, the reaction mixture was cooled to room temperature and the volatiles were concentrated under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the reaction mixture and extraction was carried out using EtOAc (3 x 70 mL). The combined organic extracts were washed with brine (70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-10% EtOAc in hexanes) to give methyl 3-((2-bromophenyl)amino)propanoate I-2b (3.1 g) as a viscous liquid. LCM (ES) m / z; 258.0 [M+H] + .

[0396] Step 2: 3-((2-bromophenyl)amino)propanoic acid (I-2c): To a stirred solution of I-2b (2.50 g, 9.69 mmol) in THF:MeOH (8.0:8.0:8.0 mL), an aqueous solution of LiOH.H2O (1.22 g, 29.1 mmol in 8 mL water) was added and stirred at room temperature for 2 h. Upon completion, the volatiles were removed under reduced pressure and the aqueous layer was washed with diethyl ether (2 x 30 mL). The aqueous layer was then acidified with 1N HCl and extraction was performed with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-((2-bromophenyl)amino)propanoic acid I-1c (1.9 g) as a thick oil. LCM (ES) m / z; 244.0 [M+H] + .

[0397] Step 3: 8-Bromo-2,3-dihydroquinolin-4(1H)-one (I-2d): A solution of I-2c (2.5 g, 10.2 mmol) in Eaton's reagent (100 mL) was stirred at 80 °C for 16 h. The reaction mixture was then cooled to room temperature and ice-cold water (100 mL) was added to it. The aqueous layer was then made alkaline by slowly adding 50% aqueous NaOH. Extraction was carried out with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-10% EtOAc in hexanes) to give the desired compound 8-bromo-2,3-dihydroquinolin-4(1H)-one I-2d (1.8 g) as a pale yellow oil. LCM(ES) m / z: 226.0 [M+H] + .

[0398] Step 4: 8-Bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one (I-2e): To a stirred solution of I-2d (2.5 g, 11.1 mmol) in anhydrous DMF (25 mL), anhydrous K2CO3 (4.58 g, 33.3 mmol) was added and stirred at room temperature for 10 min. To this was then added iodomethane (1.38 mL, 22.2 mmol) and the reaction mixture was stirred in a sealed tube at 80 °C for 24 h. The progress of the reaction was monitored by TLC. After completion, water (70 mL) was added to the reaction mixture and extraction was carried out with EtOAc (3 x 70 mL). The combined organic extracts were washed with water (2 x 75 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using a gradient elution of 0-10% EtOAc in hexanes) to give the desired compound 8-bromo-1-methyl-2,3-dihydroquinolin-4(1H)-one I-2e (1.1 g) as a yellow solid. LCM (ES) m / z; 239.9 [M+H] + .

[0399] Step 5: 7-Bromo-6-methyl-5,6-dihydropyrimido[5,4-c]quinolone (I-2f): To a stirred solution of anhydrous ZnCl2 (56.8 mg, 0.416 mmol) and triethyl orthoformate (1.85 g, 12.5 mmol) in anhydrous toluene (10.0 mL) was added I-2e (1.0 g, 4.16 mmol) and NHOAc (0.64 g, 8.33 mmol). The reaction mixture was then stirred in a sealed tube at 100 °C for 24 h. After completion, the reaction mixture was cooled to room temperature and saturated NaHCO3 solution (30 mL) was added to it. Extraction was performed with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in hexanes) to give the desired compound 7-bromo-6-methyl-5,6-dihydropyrimido[5,4-c]quinolone I-2f (0.62 g) as a pale yellow solid. LCM (ES) m / z; 276.0 [M+H] + .

[0400] Step 6: tert-Butyl (6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-yl)carbamate (I-2g): Argon gas was purged through a stirred suspension of I-2f (1.3 g, 4.71 mmol), tert-butyl carbamate (1.1 g, 9.42 mmol), and Cs2CO3 (3.07 g, 9.42 mmol) in 1,4-dioxane (10 mL) for 15 minutes. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.27 g, 0.47 mmol), and Pd(OAc)2 (0.11 g, 0.47 mmol). The reaction mixture was then stirred in a sealed tube at 100° C. for 16 hours. The reaction mixture was then cooled to room temperature and filtered through a bed of Celite, washing with EtOAc (2×50 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 I-2g (1.3 g). LCM (ES) m / z; 313.0 [M+H] + .

[0401] Step 7: 6-Methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-amine (I-2): To a stirred solution of I-2g (1.3 g, 4.16 mmol) in DCM (20.0 mL) was added TFA (5.0 mL) at 0° C. under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature for 2 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 performed with EtOAc (30 mL x 3). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give I-2 (0.7 g). LCM (ES) m / z; 213.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.07(s,1H);8.66(s,1H);7.44(dd,J1=1.6Hz,J2=7.6Hz,1H);6.99(t,J=7.6Hz, 1H);6.83(dd,J1=1.2Hz,J2=7.6Hz,1H);5.07(s,2H);4.17(s,2H);2.39(s,3H).

[0402] Example 3: Preparation of 6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-amine (I-3):

[0403] [ka]

[0404] Step 1: tert-Butyl ((3-cyclopyrazin-2-yl)methyl)carbamate (I-3b): To a stirred solution of 1-3a (6.00 g, 33.3 mmol) in THF (100.0 mL) was added DIPEA (11.4 mL, 66.7 mmol) and (Boc)2O (7.61 mL, 33.3 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. After completion, water (50 mL) was added to the reaction mixture and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give the desired compound tert-butyl ((3-cyclopyrazin-2-yl)methyl)carbamate I-3b (7.0 g) as an off-white solid. LCM (ES) m / z; 244.1 [M+H] + .

[0405] Step 2: tert-Butyl ((3-chloropyrazin-2-yl)methyl)(methyl)carbamate (I-3c): To a stirred solution of I-3b (9.50 g, 39.0 mmol) in THF (100.0 mL) was added sodium hydride (60% in mineral oil) (2.34 g, 58.5 mmol) at 0° C. and stirred at the same temperature for 1 h. To this was then added iodomethane (7.28 mL, 117 mmol) at 0° C. Then it was allowed to warm to room temperature gradually over 1 h. After complete consumption of the starting material, to this was added water (50.0 mL) and extracted with EtOAc (3×70 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting crude was purified by Combi-Flash (using a gradient elution of 0-20% EtOAc in heptane) to give the desired compound tert-butyl ((3-chloropyrazin-2-yl)methyl)(methyl)carbamate I-3c (7.0 g) as a yellow liquid. LCM (ES) m / z; 258.1 [M+H] + .

[0406] Step 3: tert-Butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-yl)methyl)(methyl)carbamate (I-3d): Argon gas was passed through a stirred suspension of I-3c (2.5 g, 9.7 mmol), 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.89 g, 14.6 mmol), and KF (1.69 g, 29.1 mmol) in THF (30.0 mL) and purged for 15 min. To this was then added Pd(OAc)2 (0.109 g, 0.485 mmol) and dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphane (0.398 g, 0.97 mmol). The reaction mixture was then stirred at 70° C. for 16 h in a sealed tube. The reaction mixture was then cooled to room temperature and filtered through a bed of celite, washing with EtOAc (2×50 mL). The combined filtrates were concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-30% EtOAc in hexanes) to give tert-butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-yl)methyl)(methyl)carbamate I-3d (3.3 g) as a yellow solid. LCM (ES) m / z; 363.2 [M+H] + .

[0407] Step 4: 6-Methyl-7-nitro-5,6-dihydropyrazino[2,3-c]quinoline (I-3e): To a stirred solution of I-3d (3.8 g, 10.5 mmol) in DCM (60.0 mL) was added TFA (20.0 mL) at 0° C. under nitrogen atmosphere and the reaction mixture was allowed to warm to room temperature over 16 h. After completion, the volatiles were removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was performed with EtOAc (2×50 mL). The combined organic extracts were washed with water (20 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to give 6-methyl-7-nitro-5,6-dihydropyrazino[2,3-c]quinoline I-3e (2.2 g) as an orange solid. LCM(ES) m / z: 243.1 [M+H] + .

[0408] Step 5: 6-Methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-amine (I-3): To a stirred solution of Raney Ni (500 mg, 8.52 mmol) in MeOH (30.0 mL) was added hydrazine hydrate (5.27 mL, 108.0 mmol) and I-3e (2.10 g, 8.67 mmol) in MeOH (30.0 mL) at 0° C. The reaction mixture was then stirred at room temperature for 1 h. Upon completion (as shown by LCMS), the reaction mixture was filtered through a celite bed and washed with 20% MeOH in DCM (2×30 mL). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-55% EtOAc in hexanes) to give the desired compound 6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-amine I-3 (1.80 g) as a yellow solid. LCM (ES) m / z; 213.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.57(d,J=2.8Hz,1H);8.51(d,J=2.4Hz,1H);7.42(dd,J1=1.2Hz,J2=7.6Hz,1H);7.01(t, J=8.0Hz,1H);6.81(dd,J1=1.2Hz,J2=8.0Hz,1H);5.08(s,2H);4.24(s,2H);2.46(s,3H).

[0409] Example 4: Preparation of 6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-amine (I-4):

[0410] [ka]

[0411] Step 1: tert-Butyl ((3-chloropyrazin-2-yl)methyl)(methyl-d3)carbamate (I-4a): I-4a (2.5 g) was synthesized by following the procedure described for the synthesis of I-3 (step 2) using I-3b (3.0 g, 12.3 mmol) and iodomethane-d3 (1.15 mL, 18.5 mmol) as starting materials. LCM (ES) m / z; 261.1 [M+H] + .

[0412] Step 2: tert-Butyl ((3-(2-fluoro-3-nitrophenyl)pyrazin-2-yl)methyl)(methyl-d3)carbamate (I-4b): I-4b (2.9 g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-4a (2.5 g, 9.59 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.84 g, 14.4 mmol) as starting materials. LCM (ES) m / z; 366.1 [M+H] + .

[0413] Step 3: 6-(methyl-d3)-7-nitro-5,6-dihydropyrazino[2,3-c]quinoline (I-4c): I-4c (1.8g) was synthesized by following the procedure described for the synthesis of I-3 (Step 4) using I-4b (2.9g, 7.94mmol) as starting material. LCM (ES) m / z; 246.1 [M+H] + .

[0414] Step 4: 6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-amine (I-4): I-4 (1.6 g) was synthesized by following the procedure described for the synthesis of I-3 (Step 5) using I-4c (1.9 g, 7.75 mmol) as starting material. LCM (ES) m / z; 216.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.57(d,J=2.4Hz,1H);8.51(d,J=2.8Hz,1H);7.42(dd,J1=1.6Hz,J2=7.6Hz,1H);7 .01(t,J=8.0Hz,1H);6.82(dd,J1=1.2Hz,J2=8.0Hz,1H);5.07(s,2H);4.24(s,3H).

[0415] Example 5: 6-Methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-amine (I-5):

[0416] [ka]

[0417] Step 1: tert-Butyl ((3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-yl)methyl)(methyl)carbamate (I-5a): Argon gas was passed through a solution of I-3c (5.3 g, 20.6 mmol), (2-chloro-3-fluoropyridin-4-yl)boronic acid (12.6 g, 72.0 mmol), and CsF (9.37 g, 61.7 mmol) in THF (50.0 mL) and purged for 15 minutes. To this was then added tri-tert-butylphosphonium tetrafluoroborate (0.36 g, 1.23 mmol) and tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (0.94 g, 1.03 mmol). The reaction mixture was then stirred at 50° C. for 16 hours in a sealed tube. 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 0-30% EtOAc in hexanes) to give tert-butyl ((3-(2-chloro-3-fluoropyridin-4-yl)pyrazin-2-yl)methyl)(methyl)carbamate I-5a (3.8 g) as a yellow oil. LCM (ES) m / z; 353.1 [M+H] + .

[0418] Step 2: 7-Chloro-6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridine (I-5b): A 4M solution of HCl in 1,4-dioxane (80 mL) was added to I-5a (4.1 g, 11.6 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. After completion, the volatiles were removed under reduced pressure and dried (coevaporation with 1,4-dioxane). To this was then added 1,4-dioxane (40 mL) and DIPEA (13.6 mL, 79.2 mmol) at room temperature. The reaction mixture was then stirred at 85° C. for 5 hours. Upon completion, the volatiles were removed under reduced pressure and the residue was purified by Combi-Flash (using gradient elution from 0 to 55% EtOAc in hexanes) to give the desired compound 7-chloro-6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridine I-5b (2.4 g) as a yellow solid. LCM (ES) m / z; 233.1 [M+H] + .

[0419] Step 3: N-(6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide (I-5c): Argon gas was passed through a stirred suspension of I-5b (2.3 g, 9.89 mmol), cyclopropanecarboxamide (1.68 g, 19.8 mmol), and Cs2CO3 (9.66 g, 29.7 mmol) in 1,4-dioxane (30 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.57 g, 0.989 mmol), and Pd(dba)3 (0.9 g, 0.989 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 0-80% EtOAc in hexanes) to give N-(6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)cyclopropanecarboxamide I-5c (1.8 g) as a pale yellow solid. LCM (ES) m / z; 282.1 [M+H]+ .

[0420] Step 4: 6-Methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-amine (I-5): To a stirred solution of I-5c (1.8 g, 6.4 mmol) in THF (20 mL), an aqueous solution of LiOH-H2O (1.07 g, 25.6 mmol in 5 mL water) was added and the reaction mixture was stirred at 50 °C for 16 h. After completion, the reaction mixture was cooled to room temperature and water (20 mL) was added to it. Extraction was carried out with 10% MeOH in DCM (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-10% MeOH in DCM) to give the desired compound 6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-amine I-5 (0.8 g) as a yellow solid. LCM (ES) m / z; 214.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.59(d,J=2.4Hz,1H);8.54(d,J=2.4Hz,1H);8.03(d,J=5.2Hz,1H);7.59(d,J=5.2Hz,1H);4.93(s,2H);4.36(s,2H);2.65(s,3H).

[0421] Example 6: Preparation of 6-methyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7-amine (I-6):

[0422] [ka]

[0423] Step 1: tert-Butyl ((2'-chloro-3'-fluoro-[2,4'-bipyridin]-3-yl)methyl)(methyl)carbamate (I-6a): I-6a (5.9 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 1) using I-1c (6.0 g, 19.9 mmol) and (2-chloro-3-fluoropyridin-4-yl)boronic acid (8.73 g, 49.8 mmol) as starting materials. LCM (ES) m / z; 352.1 [M+H] + .

[0424] Step 2: 7-Chloro-6-methyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridine (I-6b): I-6b (4.1 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 2) using I-6a (6.0 g, 20.8 mmol) as starting material. LCM (ES) m / z; 232.0 [M+H] + .

[0425] Step 3: N-(6-methyl-5,6-dihydropyrido[3,4-c][1,6]naphthyridin-7-yl)cyclopropanecarboxamide (I-6c): I-6c (1.3g) was synthesized by following the procedure described for the synthesis of I-5 (Step 3) using I-6b (4.0g, 7.18mmol) and cyclopropanecarboxamide (1.22g, 14.4mmol) as starting materials. LCM (ES) m / z; 281.0 [M+H] + .

[0426] Step 4: 6-Methyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7-amine (I-6): I-6 (0.45 g) was synthesized by following the procedure described for the synthesis of I-5 (Step 4) using I-6c (1.3 g, 4.64 mmol) as starting material. LCM (ES) m / z; 213.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 1H NMR(400MHz,CDCl3)δ 8.67(dd,J1=1.6Hz,J2=8.0Hz,1H);8.03(d,J=5.2Hz,1H);7.60-7.49(m,2H);7.37-7.26(m,1H);4.89(s,2H);4.20(s,2H);2.56(s,3H).

[0427] Example 7: Preparation of 6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-7):

[0428] [ka]

[0429] Step 1: 2-Chloro-N-methoxy-N-methylnicotinamide (I-7b): To a stirred solution of I-7a (4.5 g, 28.6 mmol) in DMF (40 mL) was added DIPEA (14.6 mL, 85.7 mmol) and HATU (21.7 g, 57.1 mmol) at 0° C. Then, N,O-dimethylhydroxyamine hydrochloride (5.57 g, 57.1 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After complete consumption of the starting material, water (30 mL) was added and extracted with EtOAc (75 times 3 mL). The combined organic extracts were washed with brine (2 times 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-50% EtOAc in heptane) to give 2-chloro-N-methoxy-N-methylnicotinamide I-7b (3.5 g) as an off-white solid. LCM (ES) m / z; 201.1 [M+H] + .

[0430] Step 2: 2-Chloronicotinaldehyde-d (I-7c): To a stirred solution of I-7b (3.2 g, 16.0 mmol) in anhydrous THF (15.0 mL) was added LiAlD4 (0.65 g, 16.0 mmol) in small portions at -78 °C. It was then stirred at 0 °C for 1 h. After completion, saturated NH4Cl solution (20 mL) was added to the reaction mixture and extraction was carried out with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-25% EtOAc in heptane) to give 2-chloronicotinaldehyde-d I-7c (6 g) as an off-white solid. LCM (ES) m / z; 143.1 [M+H] + .

[0431] Step 3: 1-(2-chloropyridin-3-yl)-N-methylmethane-d2-amine (I-7d): To a stirred solution of I-7c (1.1 g, 7.72 mmol) in MeOH (15.0 mL) was added TEA (2.3 mL, 15.4 mmol) and methylamine hydrochloride (1.04 g, 15.4 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. After completion, the reaction mixture was cooled to 0 °C and NaBD4 (0.65 g, 15.4 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was added with saturated NaHCO3 solution (10 mL) and washed with EtOAc (2 x 10 mL). The resulting 1-(2-chloropyridin-3-yl)-N-methylmethane-d2-amine I-7d in aqueous NaHCO3 was used in the next step. LCM(ES)m / z;159.1[M+H] + .

[0432] Step 4: tert-Butyl ((2-chloropyridin-3-yl)methyl-d2)(methyl)carbamate (I-7e): A solution of (Boc)2O (9.0 mL, 39.4 mmol) in THF (20 mL) was added to the aqueous NaHCO3 solution containing I-7d and the reaction mixture was stirred at room temperature for 16 h. After completion, water (70 mL) was added to the reaction mixture and extraction was carried out with EtOAc (30 mL x 3). 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 0-10% EtOAc in hexanes) to afford the desired compound tert-butyl ((2-chloropyridin-3-yl)methyl-d2)(methyl)carbamate I-7e (1.2 g) as a colorless thick oil. LCM(ES)m / z;259.1[M+H] + .

[0433] Step 5: tert-Butyl ((2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)methyl-d2)(methyl)carbamate (I-7f): I-7f (1.3g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-7e (1.0 g, 3.86 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.55 g, 5.8 mmol) as starting materials. LCM (ES) m / z; 364.1 [M+H] + .

[0434] Step 6: 6-Methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2 (I-7g): I-7g (0.75 g) was synthesized by following the procedure described for the synthesis of I-3 (step 4) using I-7e (1.4 g, 3.86 mmol) as starting material. LCM (ES) m / z; 244.1 [M+H] + .

[0435] Step 7: 6-Methyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-7): To a stirred solution of I-7g (0.75 g, 3.08 mmol) in MeOH (20.0 mL) was added 10% Pd / C (250 mg) at room temperature. It was then stirred under hydrogen atmosphere (H2 balloon) for 2 h. After completion, the catalyst was filtered off through a Celite bed and washed with MeOH (20 mL x 2). The combined filtrate was concentrated under reduced pressure and the residue was purified by Combi-Flash (using a gradient elution of 0-55% EtOAc in hexanes) to give 6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine I-7 (0.54) as a yellow solid. LCM (ES) m / z; 214.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.61(dd,J1=1.6Hz,J2=4.8Hz,1H);7.75(dd,J1=1.2Hz,J2=7.6Hz,1H);7.53(dd,J1=1.2Hz,J2=7.6Hz,1H);7.21( dd,J1=4.8Hz,J2=7.2Hz,1H);7.11(t,J=7.6Hz,1H);6.82(dd,J1=1.2Hz,J2=7.6Hz,1H);4.17(s,2H);2.53(s,3H).

[0436] Example 8: Preparation of 3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-8):

[0437] [ka]

[0438] Step 1: 2-Chloro-5-fluoro-N-methoxy-N-methylnicotinamide (I-8b): I-8b (2.6 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 1) using I-8a (2.5 g, 14.2 mmol) as starting material. LCM (ES) m / z; 219.1 [M+H] + .

[0439] Step 2: 2-Chloro-5-fluoronicotinaldehyde-d (I-8c): I-8c (1.5g) was synthesized by following the procedure described for the synthesis of I-7 (Step 2) using I-8b (2.5g, 11.4mmol) as starting material. LCM (ES) m / z; 161.0 [M+H] + .

[0440] Steps 3-4: tert-Butyl ((2-chloro-5-fluoropyridin-3-yl)methyl-d2)(methyl)carbamate (I-8e): I-8e (1.3 g) was synthesized by following the procedure described for the synthesis of I-7 (steps 3-4) using I-8c (2.0 g, 12.5 mmol) as starting material. LCM (ES) m / z; 277.1 [M+H] + .

[0441] Step 5: tert-Butyl ((5-fluoro-2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)methyl-d2)(methyl)carbamate (I-8f): I-8f (1.0 g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-8e (0.9 g, 3.25 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 4.88 mmol) as starting materials. LCM (ES) m / z; 382.1 [M+H] + .

[0442] Step 6: 3-Fluoro-6-methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2 (I-8g): I-8g (0.75 g) was synthesized by following the procedure described for the synthesis of I-3 (step 4) using I-8f (1.3 g, 3.41 mmol) as starting material. LCM (ES) m / z; 262.1 [M+H] + .

[0443] Step 7: 3-Fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-8): I-8 (0.8 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 7) using I-8g (1.1 g, 4.21 mmol) as starting material. LCM (ES) m / z; 232.2 [M+H] + .

[0444] Example 9: Preparation of 2,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-9):

[0445] [ka]

[0446] Step 1: 2-Chloro-N-methoxy-N,6-dimethylnicotinamide (I-9b): I-9b (2.6 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 1) using I-9a (2.5 g, 14.2 mmol) as starting material. LCM (ES) m / z; 215.1 [M+H] + .

[0447] Step 2: 2-Chloro-6-methylnicotinaldehyde-d (I-9c): I-9c (5.8 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 2) using I-9b (5.0 g, 29.1 mmol) as starting material. LCM (ES) m / z; 157.0 [M+H] + .

[0448] Steps 3-4: tert-Butyl ((2-chloro-6-methylpyridin-3-yl)methyl-d2)(methyl)carbamate (I-9e): I-9e (3.3g) was synthesized by following the procedure described for the synthesis of I-7 (steps 3-4) using I-9c (2.3g, 14.7mmol) as starting material. LCM (ES) m / z; 273.1 [M+H] + .

[0449] Step 5: tert-Butyl ((2-(2-fluoro-3-nitrophenyl)-6-methylpyridin-3-yl)methyl-d2)(methyl)carbamate (I-9f): I-9f (2.8g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-9e (3.5g, 12.8mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.14g, 19.2mmol) as starting materials. LCM (ES) m / z; 378.2 [M+H] + .

[0450] Step 6: 2,6-Dimethyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2 (I-9g): I-9g (1.5g) was synthesized by following the procedure described for the synthesis of I-3 (step 4) using I-9f (2.8 g, 7.42 mmol) as starting material. LCM (ES) m / z; 258.1 [M+H] + .

[0451] Step 7: 2,6-Dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-9): I-9 (0.49 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 7) using I-9g (0.6 g, 2.33 mmol) as starting material. LCM (ES) m / z; 228.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.54(d,J=7.6Hz,1H);7.42(dd,J1=1.2Hz,J2=8.0Hz,1H);7.12(d,J=8.0Hz,1H);6.91(t, J=7.6Hz,1H);6.99(dd,J1=1.6Hz,J2=7.6Hz,1H);4.91(s,2H);2.45(s,3H);2.35(s,3H).

[0452] Example 10: Preparation of 6-methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-10):

[0453] [ka]

[0454] Step 1: 2-Chloro-N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (I-10b): I-10b (5.7 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 1) using I-10a (5.0 g, 22.2 mmol) as starting material. LCM (ES) m / z; 269.1 [M+H] + .

[0455] Step 2: 2-Chloro-6-(trifluoromethyl)nicotinaldehyde-d (I-10c): I-10c (3.2g) was synthesized by following the procedure described for the synthesis of I-7 (Step 2) using I-10b (5.7g, 21.2mmol) as starting material. LCM (ES) m / z; 211.0 [M+H] + .

[0456] Steps 3-4: tert-Butyl ((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl-d2)(methyl)carbamate (I-10e): I-10e (2.2 g) was synthesized by following the procedure described for the synthesis of I-7 (steps 3-4) using I-10c (3.2 g, 15.2 mmol) as starting material. LCM (ES) m / z; 327.1 [M+H] + .

[0457] Step 5: tert-Butyl ((2-(2-fluoro-3-nitrophenyl)-6-(trifluoromethyl)pyridin-3-yl)methyl-d2)(methyl)carbamate (I-10f): I-10f (2.6g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-10e (2.2g, 6.73mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.7g, 10.1mmol) as starting materials. LCM (ES) m / z; 432.2 [M+H] +.

[0458] Step 6: 6-Methyl-7-nitro-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2 (I-10g): I-10f (2.6 g, 6.03 mmol) was used as starting material to synthesize I-10g (1.4 g) by following the procedure described for the synthesis of I-3 (step 4). LCM (ES) m / z; 312.1 [M+H] + .

[0459] Step 7: 6-Methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridine-5,5-d2-7-amine (I-10): I-10 (1.2g) was synthesized by following the procedure described for the synthesis of I-7 (Step 7) using I-10g (1.4g, 4.63mmol) as starting material. LCM (ES) m / z; 282.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.99(d,J=7.6Hz,1H);7.79(d,J=7.6Hz,1H);7.45(dd,J1=1.6Hz,J2=8.0Hz,1H);7 .00(t,J=7.6Hz,1H);6.81(dd,J1=1.2Hz,J2=8.0Hz,1H);5.04(s,2H);2.37(s,3H).

[0460] Example 11: Preparation of 7-amino-2,6-dimethyl-5,6-dihydropyridazino[4,5-c]quinolin-1(2H)-one (I-11):

[0461] [ka]

[0462] Step 1: 4-Chloro-5-iodo-2-methylpyridazin-3(2H)-one (I-11b): To a stirred solution of I-11a (36.0 g, 201.0 mmol) in DMF (360 mL) was added sodium iodide (90.4 g, 603.0 mmol) at room temperature. The reaction mixture was then stirred at 160° C. for 36 h. After completion, the reaction mixture was cooled to room temperature and ice-cold water (700 mL) was added to it. Extraction was carried out with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained crude was dissolved in MeOH (170.0 mL) at 65° C., and then water (340 mL) was added to it with continuous stirring. The precipitated solid was filtered, washed with water (200 mL) and dried. This was then stirred in n-pentane (100 mL), filtered, and dried to give the desired compound 4-chloro-5-iodo-2-methylpyridazin-3(2H)-one I-11b (11.6 g) as a light brown solid. LCM (ES) m / z: 271.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 7.96 (s, 1H); 3.78 (s, 3H).

[0463] Step 2: (E)-4-Chloro-2-methyl-5-styrylpyridazin-3(2H)-one (I-11c): To a stirred solution of I-11b (11.6 g, 35.6 mmol) in 1,4-dioxane (100.0 mL) and water (50.0 mL) was added (E)-styrylboronic acid (5.3 g, 35.6 mmol) and potassium carbonate (7.38 g, 53.4 mmol). Argon gas was purged through the mixture for 10 minutes. PdCl2(PPh3)2 (1.0 g, 1.42 mmol) was then added and the reaction was stirred at 90 °C in a sealed tube for 2 hours. After complete consumption of the starting material, it was cooled to room temperature and diluted with EtOAc (300 mL). The combined layers were washed with water (80 mL), brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was washed with DCM (50 mL), n-pentane (80 mL) and dried under reduced pressure to give (E)-4-chloro-2-methyl-5-styrylpyridazin-3(2H)-one I-11c (7.0 g) as a pale yellow solid. LCM (ES) m / z; 247.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.05 (s, 1H); 7.59-7.58 (m, 2H); 7.42-7.38 (m, 3H); 7.29 (s, 2H); 3.84 (s, 3H).

[0464] Step 3: 5-Chloro-1-methyl-6-oxo-1,6-dihydropyridazine-4-carbaldehyde (1-11d): To a stirred solution of I-11c (7.0 g, 28.4 mmol) in THF (70.0 mL) and water (35.0 mL), osmium tetroxide (2.5 wt % in n-butanol) (14.4 mL, 1.42 mmol) was added at room temperature and stirred for 30 min. To this was then added NaIO4 (12.1 g, 56.8 mmol) in small portions and the reaction was stirred at room temperature for another 16 h. After completion of the reaction, water (60 mL) was added to the reaction and extraction was carried out with EtOAc (3 times 70 mL). The combined organic extracts were washed with brine (2 times 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-2% MeOH in DCM) to give 5-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-4-carbaldehyde 1-11d (2.5 g) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 10.43 (s, 1H); 8.08 (s, 1H); 3.90 (s, 3H).

[0465] Steps 4-5: tert-Butyl ((5-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methyl)(methyl)carbamate (I-11f): I-11f (2.0g) was synthesized by following the procedure described for the synthesis of I-7 (steps 3-4) using I-11d (4.0g, 23.2mmol) as starting material and NaBH4 (1.71g, 46.4mmol) as reducing reagent. LCM (ES) m / z; 288.0 [M+H] + .

[0466] Step 6: tert-Butyl ((5-(2-fluoro-3-nitrophenyl)-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methyl)(methyl)carbamate (I-11g): I-11g (2.3 g) was synthesized by following the procedure described for the synthesis of I-3 (step 3) using I-11f (1.5 g, 5.21 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.10 g, 7.82 mmol) as starting materials. LCM (ES) m / z; 393.2 [M+H] + .

[0467] Step 7: 2,6-Dimethyl-7-nitro-5,6-dihydropyridazino[4,5-c]quinolin-1(2H)-one (I-11i): I-11h (1.4g) was synthesized by following the procedure described for the synthesis of I-3 (Step 4) using I-11h (2.3g, 5.86mmol) as starting material. LCM (ES) m / z; 273.0 [M+H] + .

[0468] Step 8: 7-Amino-2,6-dimethyl-5,6-dihydropyridazino[4,5-c]quinolin-1(2H)-one (I-11): I-11 (0.65 g) was synthesized by following the procedure described for the synthesis of I-3 (Step 5) using I-11h (1.3 g, 4.77 mmol) as starting material. LCM (ES) m / z; 243.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.32(dd,J1=1.2Hz,J2=8.0Hz,1H);7.68(s,1H);7.09(t,J=8.0Hz,1H);6.83(dd ,J1=1.2Hz,J2=8.0Hz,1H);4.06(s,2H);3.97(s,2H);3.89(s,3H);2.49(s,3H).

[0469] Example 12: 3-Fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine (I-12):

[0470] [ka]

[0471] Steps 1-2: tert-Butyl ((2-chloro-5-fluoropyridin-3-yl)methyl)(methyl)carbamate (I-12c): I-12c (3.5 g) was synthesized by following the procedure described for the synthesis of I-7 (steps 3-4) using I-12a (4.5 g, 28.2 mmol) as starting material. LCM (ES) m / z; 275.1 [M+H] + .

[0472] Step 3: tert-Butyl ((5-fluoro-2-(2-fluoro-3-nitrophenyl)pyridin-3-yl)methyl)(methyl)carbamate (I-12d): I-2d (1.6g) was synthesized by following the procedure described for the synthesis of I-3 (Step 3) using I-12c (3.5g, 12.7mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.42g, 16.6mmol) as starting materials. LCM (ES) m / z; 380.1 [M+H] + .

[0473] Step 4: 3-Fluoro-6-methyl-7-nitro-5,6-dihydrobenzo[h][1,6]naphthyridine (I-12e): I-12e (0.6 g) was synthesized by following the procedure described for the synthesis of I-3 (Step 4) using I-12d (1.6 g, 4.22 mmol) as starting material. LCM (ES) m / z; 260.1 [M+H] + .

[0474] Step 5: 3-Fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-amine (I-12): I-12 (0.3 g) was synthesized by following the procedure described for the synthesis of I-7 (Step 7) using I-12e (0.6 g, 2.31 mmol) as starting material. LCM (ES) m / z; 230.2 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ 8.48(d,J=2.4Hz,1H);7.68(dd,J1=2.8Hz,J2=8.4Hz,1H);7.37(dd,J1=2.4Hz,J2=8.0Hz,1H);6 .93(t,J=7.6Hz,1H);6.71(dd,J1=2.8Hz,J2=8.0Hz,1H);4.97(s,2H);4.14(s,2H);2.36(s,3H).

[0475] Example 13: Preparation of 4,6-dichloro-N-methylpyridazine-3-carboxamide (A-1):

[0476] [ka]

[0477] To a stirred solution of A-1a (10.0 g, 50.3 mmol) in anhydrous DCM (100 mL) was added catalytic amounts of DMF (2-3 drops) and oxalyl chloride (9.11 mL, 101.0 mmol) in small portions at 0 °C. The reaction mixture was then allowed to warm to room temperature gradually over 2 h. After completion, the volatiles were removed under reduced pressure and the residue was dried. The residue was then dissolved in anhydrous DCM (50 mL) and added 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) under 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] + .

[0478] Example 14: Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (A-2):

[0479] [ka]

[0480] To a stirred solution of A-1a (5.0 g, 25.1 mmol) in anhydrous DCM (40 mL) was added catalytic amounts of DMF (2-3 drops) and oxalyl chloride (4.6 mL, 50.3 mmol) in small portions at 0 °C. The reaction mixture was then allowed to warm to room temperature gradually 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 methane-d3-amine hydrochloride (2.13 g, 30.2 mmol) and DIPEA (13.2 mL, 75.4 mmol) in anhydrous DCM (25 mL) under 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 gradient elution from 0 to 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] + .

[0481] Example 15: Preparation of 4,6-dichloro-N-(methyl-d3)nicotinamide (A-3):

[0482] [ka]

[0483] A-3 (2.6g) was synthesized by following the procedure described for the synthesis of A-2 using A-3a (3g) as the starting material. LCMS (ES) m / z 208.0 [M+H] + .

[0484] Example 16: Preparation of 4,6-dichloro-N-methylnicotinamide (A-4):

[0485] [ka]

[0486] A-4 (2.5g) was synthesized by following the procedure described for the synthesis of A-1 using A-3a (3g) as the starting material. LCM (ES) m / z; 204.9 [M+H] + .

[0487] Example 17: Preparation of 4-bromo-6-chloro-N-(methyl-d3)nicotinamide (A-5):

[0488] [ka]

[0489] To a stirred solution of A-5a (4.75 g, 20.1 mmol), methane-d3-amine hydrochloride (1.7 g, 24.1 mmol), and DIPEA (10.4 mL, 60.3 mmol) in DCM (15 mL), HATU (11.5 g, 30.1 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 3 h. After completion, water (50 mL) was added to the reaction mixture and extracted with DCM (2 x 75 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 0-20% EtOAc in heptane) to give the desired compound 4-bromo-6-chloro-N-(methyl-d3)nicotinamide A-7 (3.1 g) as an off-white solid. LCM(ES) m / z: 252.0 [M+H]+ .

[0490] Example 18: Preparation of 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (Compound 1)

[0491] [ka]

[0492] Step 1: 6-Chloro-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (1a): To a stirred solution of I-1 (0.35 g, 1.66 mmol) and A-2 (0.74 g, 2.48 mmol) in anhydrous DMA (10.0 mL), a 1 M solution of LiHMDS in THF (6.63 mL, 6.63 mmol) was added in small portions at 0 °C. The reaction mixture was then stirred at the same temperature for 1 h while the progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched by the addition of water (20 mL) and extraction was carried out using 10% MeOH in DCM (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0-5% MeOH in DCM) to give 6-chloro-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide 1a (0.27 g) as an off-white solid. LCM (ES) m / z; 384.2 [M+H] + .

[0493] Step 2: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide (compound 1): Argon gas was passed through a stirred suspension of 6-chloro-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide 1a (0.27 g, 0.703 mmol), cyclopropanecarboxamide (0.078 g, 0.914 mmol), and Cs2CO3 (0.46 g, 1.41 mmol) in 1,4-dioxane (8.0 mL) and purged for 15 min. To this was then added [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (0.041 g, 0.07 mmol), and Pd(dba)3 (0.064 g, 0.07 mmol). The reaction mixture was then stirred in a sealed tube at 130° C. for 3 h. After completion, the reaction mixture was cooled to room temperature and filtered through a Celite bed. It was washed with EtOAc (2×50 mL) and the filtrate was concentrated under reduced pressure. The residue was then purified by Combi-Flash (using a gradient elution of 0-5% MeOH in DCM) to give the desired compound 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide 1 (0.15 g) as a pale yellow solid. LCM(ES) m / z: 433.2[MH] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H); 10.86 (s, 1H); 9.07 (s, 1H); 8.56 (d, J = 3.2 Hz, 1H); 8.19 (s, 1H); 8.02 (d, J = 7.6 Hz, 1H); 7.72 (d, J = 6.8 Hz, 1H); 7.43 (d, J = 7.6 Hz, 1H); 7.36-7.33 (m, 1H); 7.24 (apparent t, J = 7.6 Hz, 1H); 4.24 (s, 2H); 2.44 (s, 2H); 2.10-2.00 (m, 1H); 0.82-0.72 (m, 4H).

[0494] Example 19: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide (compound 14):

[0495] [ka]

[0496] Step 1: 6-Chloro-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide (11a): 14a (0.15 g) was synthesized by following the procedure described for the synthesis of compound 1 (step 2) using I-5 (0.203 g, 0.95 mmol) and A-5 (0.2 g, 0.792 mmol) as starting materials. LCM (ES) m / z; 385.1 [M+H] + .

[0497] Step 2: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide (compound 14): Compound 14 (51 mg) was synthesized by following the procedure described for the synthesis of compound 1 (step 2) using 14a (0.18 g, 0.468 mmol) and cyclopropanecarboxamide (0.06 g, 0.702 mmol) as starting materials. LCM (ES) m / z; 434.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H);10.67(s,1H);9.49(s,1H);8.63(dd,J1=2.4Hz,J2=8.4Hz,2H);8.55(s,1H);8.51(s,1H);8. 13(d,J=5.2Hz,1H);7.58(d,J=5.2Hz,1H);4.37(s,2H);2.55(s,3H);1.97-1.95(m,1H);0.77-0.73(m,4H).

[0498] The following compounds were synthesized by following the procedures described in the previous examples using the appropriate intermediates. In the final Buchwald coupling, the corresponding amine coupling partner (e.g., 2-amino-5-fluoropyridine or 2-amino-4,6-dimethylpyrimidine) or the corresponding amide coupling partner (e.g., cyclopropanecarboxamide) was used as appropriate.

[0499] [Table 2-1]

[0500] [Table 2-2]

[0501] [Table 2-3]

[0502] [Table 2-4]

[0503] [Table 2-5]

[0504] [Table 2-6]

[0505] Example A-1: ​​Oral tablet Tablets are prepared by mixing 20-50% by weight of a compound of formula (A1) or a pharma- ceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropylcellulose, and 1-10% by weight of magnesium stearate or other suitable excipient. Tablets are prepared by direct compression. The total weight of the compressed tablets is kept between 100 and 500 mg.

[0506] Example A-2: Topical cream Topical creams (i.e., ointments, gels, oils, etc.) are prepared by mixing a compound of formula (A1) with a non-toxic vehicle, such as an oil and water emulsion, and optionally diluting with additional buffers, stabilizers, fragrance ingredients, emulsifiers, oils, alcohols, or other additives. Creams, for purposes of this disclosure, encompass topical compositions of various viscosities (e.g., lotions, ointments, pastes, gels, tinctures, etc.).

[0507] Example A-3: Eye drops An eye drop comprising a compound of formula (A1) is prepared by dissolving an appropriate amount of the compound of formula (A1) in water or a buffer (e.g., buffered for salinity and / or pH) and optionally diluting with additional excipients or vehicles. The eye drop may be further compounded with stabilizers, sustained release polymers, or other excipients to enhance the therapeutic effect or duration of action at the treatment site (e.g., ocular tissue or surrounding area). Viscous liquids and gels are also included within the definition of eye drop.

[0508] Example A-4: Metered Dose Inhaler (MDI) The compound of formula (A1) is dissolved in a liquid or liquefied gas propellant, optionally combined with a stabilizer or flavored excipient, and administered in a metered dose to the lungs or airways of a patient by aerosol spray. The aerosol may optionally be further compounded with a bronchodilator, a corticosteroid, or a combination of the two. MDIs for use of the compound of formula (A1) may be self-administered, or in the case of significant host-mediated pulmonary inflammation requiring mechanical ventilation (e.g., respiratory inflammation associated with Covid-19), the inhalant may be administered by tracheal intubation, nasopharyngeal catheterization, or similar device following advanced airway procedures.

[0509] Example B-1: HEK-Blue™ IL-23 and IFNα / β reporter assays to profile TYK2 pseudokinase (JH2) inhibition HEK-Blue™ IL-23 and IFNα / β cells with stably integrated cytokine receptors and STAT3 or STAT1 express a STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. The cells are seeded in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U / mL PenStrep (Gibco) at 37°C under 5% CO2 for 20-22 hours. Cells are then pre-treated with serially diluted test compounds for 60 minutes before stimulation with either 10 ng / mL human recombinant IL-23 (Miltenyl Biotech) for 22-24 hours or 1 ng / mL human recombinant IFNα (InvivoGen) for 16-18 hours. SEAP induction is measured using QUANTI Blue™ solution (InvivoGen) according to the manufacturer's instructions. Inhibition data are calculated by comparing to control wells without inhibitor for 0% inhibition and to control wells without stimulation for 100% inhibition. Dose-response curves are generated to determine the concentration required to inhibit 50% of the cellular response (IC) derived by nonlinear regression analysis. 50 ) is determined.

[0510] Table B-1 provides the TYK2 inhibitory activity of exemplary compounds, where A is the IC 50 is less than 30 nM, B is the IC 50 is between 30 and 300 nM, and C is the IC 50 is between 300 and 1000 nM, and D is the IC 50 means greater than 1000 nM, n / a means no activity observed at 1000 nM, and nd means not determined.

[0511] [Table 3]

[0512] Example B-2: HTRF-based selectivity assay: The ability of compounds to inhibit the activity of JAK1, JAK2, JAK3, and TYK2 is measured using recombinant purified His- or GST-tagged catalytic domains for each enzyme (JAK1, JAK2, and TYK2 were produced in-house, and JAK3 was purchased from Carna biosciences, Cat#08-046) in a biochemical assay in HTRF format. The reactions utilize commercially available peptide substrates by Cisbio (Cat#62TK0PEC). The basic assay protocol is as follows: First, dispense 2.5 μL of compound (4x) diluted in DMSO into a 384-well Optiplate. Next, add 2.5 μL of enzyme (final enzyme concentrations are 700 ng / mL for TYK2, 80.6 ng / mL for JAK1, 2.1 ng / mL for JAK2, and 171.8 ng / mL for JAK3) and incubate at room temperature for 5-20 minutes. Finally, 5 μL of the mixture of 2x ATP [final concentrations are 20 μM for TYK2, 21.43 μM for JAK1, 14.7 μM for JAK2, and 2.12 μM for JAK3] + 2x substrate [final concentrations are 217 nM for TYK2, 454.7 nM for JAK1, 200 nM for JAK2, and 257.4 nM for JAK3] is added to a 384-well Optiplate. The composition of the kinase assay buffer used for the assay is as follows: HEPES 50 mM, EGTA 1 mM, MgCl2 10 mM, DTT 2 mM, Tween-20 0.01%, and water. The plate is then shaken and then incubated at 26.5°C for 60 min. At the end of the incubation, 10 μL of a mixture of 2x detection mix [(EU3 + Cryptate (1x) + Streptavidin-XL665 (final concentration: 62.5 nM) (HTRF KinEASE-TK kit Cat#62TK0PEC)] is added to the assay plate, shaken and incubated at 26.5° C. for 60 minutes. The HTRF signal of the plate is then read (665 nm reading / 615 nm reading) on ​​a Perkin Elmer Envision. The percentage inhibition of the HTRF signal at each compound concentration is calculated after normalization to the untreated control. A plot of the percentage inhibition versus the logarithm of the compound concentration gives the IC 50A four-parameter dose-response equation is fitted to calculate values.

[0513] Table B-2 provides selectivity data for exemplary compounds across the kinase domain (JH1) of the JAK family (TYK2, JAK1, JAK2, and JAK3), where A is the IC 50 is less than 30 nM, B is the IC 50 is between 30 and 300 nM, and C is the IC 50 is between 300 and 1000 nM, and D is the IC 50 means greater than 1000 nM, and n / a means no activity observed at 1000 nM.

[0514] [Table 4]

[0515] Example B-3: HEK-Blue™ IL-2 and IFNγ reporter assays to determine selectivity HEK-Blue™ IL-2 and IFNγ reporter cells with stably integrated cytokine receptors and STAT5 or STAT1 express a STAT-inducible secreted embryonic alkaline phosphatase (SEAP) reporter gene upon cytokine stimulation. The cells were seeded in DMEM (Gibco) containing 10% heat-inactivated FBS (Gibco) and 100 U / mL PenStrep (Gibco) at 37°C under 5% CO2 for 20-22 hours. Cells were then pretreated with serially diluted test compounds for 60 minutes before stimulation with 4 ng / mL human recombinant IL-2 (Miltenyl Biotech) or 50 ng / mL human recombinant IFNγ (InvivoGen) for 24 hours. SEAP induction was measured using QUANTI Blue™ solution (InvivoGen) according to the manufacturer's instructions. Inhibition data were calculated by comparing control wells without inhibitor for 0% inhibition and without stimulation for 100% inhibition. Dose-response curves were generated to determine the concentration required to inhibit 50% of the cellular response (IC 50 ) was determined.

[0516] Table B-3 provides selectivity data (SEAP) for exemplary compounds for IL-2 and IFN-γ, where A is the IC 50 is less than 30 nM, B is the IC 50 is between 30 and 300 nM, and C is the IC 50 is between 300 and 1000 nM, and D is the IC 50 means greater than 1000 nM, and n / a means no activity observed at 1000 nM.

[0517] [Table 5]

[0518] The examples and embodiments described herein are intended for illustrative purposes only, and various modifications or alterations suggested to those skilled in the art are intended to be encompassed within the spirit and scope of this application and the appended claims.

Claims

1. 3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 15: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 34: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-N-methylpyridazine-3-carboxamide, 35: 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide, 36: 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-6-yl)amino)-6-((2,6-dimethylpyridin-4-yl)amino)-N-methylnicotinamide, 37: 6-(cyclopropanecarboxamido)-4-((2,5-dimethyl-4,5-dihydro-2H-[1,2,3]triazolo[4,5-c]quinolin-6-yl)amino)-N-methylnicotinamide, and 38: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxalin-6-yl)amino)-N-methylpyridazine-3-carboxamide or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

2. Formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is an unsubstituted or substituted 6-membered heterocyclic ring in which A 1 and A 2 are independently N or C, and if said ring A is substituted, said ring A is substituted with p instances of R 8 ; Each of the R 8 s independently represents hydrogen, halogen, 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -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 when R 8 is bonded to a nitrogen atom, 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 or two of said R 8 s bonded to the same carbon atom together form =O, =S, or =NH; Z is -NR 10 -, -O-, -S-, -S(═O)-, or -SO 2 -; 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 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, B 1 is N or CR 12a ; B 2 is N or CR 12b ; R 12a 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 2N(R16)2, R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl; R 2 is 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 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 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, or two of said R 13 groups on adjacent atoms of said ring B, taken together with the intervening atoms to which they are attached, form an unsubstituted or substituted 5- or 6-membered monocyclic carbocyclic ring, or an unsubstituted or substituted 5- or 6-membered monocyclic heterocyclic ring; Alternatively, said R 2 is —C(═O)R 14 , —C(═O)NR 14 R 15 , or —C(═O)OR 14 ; R 14 is hydrogen, 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 fluoroalkyl; or R 14 and R 15 taken together with the intermediate atom 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 atom 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, 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 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; 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 together with the intermediate atom to which they are attached form a substituted or unsubstituted 5- or 6-membered heterocycle; R 5 is hydrogen, C 1 -C 6 alkyl, 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 ; 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, 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 said R 16 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; each R 17 is independently 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 independently selected from 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 NR 18 C(═O)R 18 , -NR 18SO2R19, -CH2NR18SO2R19, -SR18, -CH2SR18, -S(=O)R19, -CH2S(=O)R19, -SO2R19, -CH2SO2R19, -SO2N(R18)2, or -CH2SO2N(R18)2; R 18 is independently selected from 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 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 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; n is 1, 2, or 3; q is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

3. R 1 is hydrogen or C 1 -C 4 alkyl; said W is -NR 3 -; said R 3 being hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; said R 4 being hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; 3. The compound of claim 2, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R5 is hydrogen or C1-C4 alkyl.

4. Formula (II): 【Chemistry 2】 3. The compound of claim 2 having the structure: or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

5. 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 ; 5. The compound of any one of claims 2 to 4, wherein 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 , or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

6. Formula (IV): 【Chemistry 3】 3. The compound of claim 2 having the structure: or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

7. The compound of any one of claims 2 to 6, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein ring A is an unsubstituted or substituted 6-membered heteroaryl ring, A1 and A2 are independently N or C, and when ring A is substituted, ring A is substituted with p instances of R8.

8. Formula (VIa): 【Chemistry 4】 3. The compound of claim 2 having the structure: wherein A 8 is CR 8 or N, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

9. Formula (VIb) or Formula (VIc): 【Chemistry 5】 3. The compound of claim 2 having the structure: or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

10. Each of the R 8 s is independently 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -CN, -OH, -OR 17 , -C(═O)R 16 , -CO 2 R 16 , or -C(═O)N(R 16 ) 2 , and when R 8 is bonded to a nitrogen atom, R 8 is hydrogen, 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 carbocyclic ring, unsubstituted or substituted heterocyclic ring, -C(═O)R 16 10. The compound of any one of claims 2 to 9, wherein R 16 is -CO 2 R 16 , or -C(=O)N(R 16 ) 2 , or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

11. A compound described in any one of claims 2 to 10, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein each R8 is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and when R8 is bonded to a nitrogen atom, R8 is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3.

12. The R 6 and R 7 are each independently hydrogen, deuterium, halogen, C 1 -C 4 alkyl, or C 1 -C 4 deuteroalkyl; The Z is —NR 10 — or —O—; 12. The compound of any one of claims 2 to 11, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl.

13. The R 2 is 【Chemistry 6】 wherein q is 0, 1, 2, 3, or 4; The compound of any one of claims 2 to 12, wherein 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 .

14. The compound according to claim 1, wherein R 2 is -C(=O)R 14 , -C(=O)NR 14 R 15 , or -C(=O)OR 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, 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, C 1 -C 6 alkyl, -CN, -OR 18 , and -N(R 18 ) 2 ; said R 15 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl; or the compound according to any one of claims 2 to 12, wherein R 14 and R 15 together with the intervening atom to which they are attached form an unsubstituted or substituted 4- to 6-membered monocyclic heterocycle, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

15. The compound of claim 14, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R2 is -C(=O)R14, R14 is unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted cycloalkyl, or substituted heterocycloalkyl is substituted with one or more Rs groups independently selected from the group consisting of deuterium, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3.

16. B 1 is CR 12a and B 2 is CR 12b ; Or, said B 1 is N, said B 2 is CR 12b ; Or, said B 1 is CR 12a and said B 2 is N; Or, B 1 is N and B 2 is N; 16. The compound of any one of claims 2 to 15, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, wherein R12a and R12b are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN.

17. The B 1 is CH, the B 2 is CH, Or, the compound of any one of claims 2 to 16, wherein said B 1 is N and said B 2 is CH, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

18. 1: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, 2: 6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, and 3: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 4: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-yl)amino)nicotinamide, 5: 6-(cyclopropanecarboxamido)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide, 6: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrimido[5,4-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 7: 6-(cyclopropanecarboxamide)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 8: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 9: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydrobenzo[c][2,6]naphthyridin-7-yl)amino)-N-(methyl-d3)nicotinamide, 10: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 11: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydrobenzo[c][2,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 12: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide, 13: 4-((3-cyano-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide, 14: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c][1,7]naphthyridin-7-yl)amino)nicotinamide, 15: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)nicotinamide, 16: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 17: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 18: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-(methyl-d3)-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)pyridazine-3-carboxamide, 19: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydropyrido[3,4-h][1,6]naphthyridin-7-yl)amino)nicotinamide, 20: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)nicotinamide, 21: 6-(cyclopropanecarboxamide)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 22: 6-(cyclopropanecarboxamido)-4-((3-fluoro-6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)nicotinamide, 23: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 24: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)-N-(methyl-d3)nicotinamide, 25: 6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((6-methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)nicotinamide, 26: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((6-methyl-2-(trifluoromethyl)-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl-5,5-d2)amino)pyridazine-3-carboxamide, 27: 6-(cyclopropanecarboxamide)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 28: 6-(cyclopropanecarboxamido)-4-((2,6-dimethyl-1-oxo-1,2,5,6-tetrahydropyridazino[4,5-c]quinolin-7-yl)amino)-N-(methyl-d3)nicotinamide, 29: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)pyridazine-3-carboxamide, 30: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-methyl-5,6-dihydropyrazino[2,3-c]quinolin-7-yl)amino)nicotinamide, 31: 6-(cyclopropanecarboxamide)-4-((10-fluoro-5-methyl-5,6-dihydrophenanthridin-4-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 32: (R)-6-(cyclopropanecarboxamide)-4-((5,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, and 33: (S)-6-(cyclopropanecarboxamide)-4-((5,6-dimethyl-5,6-dihydrobenzo[h][1,6]naphthyridin-7-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, and a pharma- ceutically acceptable excipient.

20. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a medicament for treating a TYK2-mediated disease or condition in a patient in need of such treatment, wherein said treatment comprises administering to said patient a therapeutically effective amount of said compound, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

21. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a medicament for treating an inflammatory disease or condition, or an autoimmune disease or condition, in a patient in need of such treatment, wherein said treatment comprises administering to said patient a therapeutically effective amount of said compound, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

22. The use of claim 20 or 21, wherein the disease or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal disease, Crohn's disease, ulcerative colitis, celiac disease, Behcet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis.

23. Use of a compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a medicament for treating an ocular disease or condition in a patient in need of such treatment, wherein said treatment comprises administering to said patient a therapeutically effective amount of said compound, or a pharma- ceutically acceptable salt, tautomer, or solvate thereof.

24. The use described in claim 23, wherein the eye disease or condition is selected from Sjogren's syndrome, uveitis, and dry eye, or a combination thereof.

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