TYK2 inhibitors and their use

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-references to related applications This application claims benefits based on U.S. Provisional Patent Application No. 63 / 151,287 filed February 19, 2021, U.S. Provisional Patent Application No. 63 / 193,511 filed May 26, 2021, U.S. Provisional Patent Application No. 63 / 234,934 filed August 19, 2021, and U.S. Provisional Patent Application No. 63 / 291,222 filed December 17, 2021, each of which is incorporated herein by reference to 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 this disclosure may inhibit the signaling of specific cytokines, such as IL-12, IL-23, and IFNα. Further aspects of the present invention include pharmaceutical compositions comprising the compounds described herein, methods of using the compounds to treat specific diseases, and intermediates and processes useful for the synthesis of 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 is associated with the cytoplasmic domains of type I and type II cytokine receptors, as well as type I and type III interferon receptors, and is activated by these receptors after cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-CO, and IFN-ζ (also known as limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Subsequently, activated TYK2 proceeds to phosphorylation of further signaling proteins, including members of the STAT family, such as STAT1, STAT2, STAT3, STAT4, and STAT6. [Overview of the project]

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

[0005] In one embodiment of this specification, formula (I):

[0006]

Chem.

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

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

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

[0010] In some embodiments, R 4 These are hydrogen, a C1-C4 alkyl group, or a C1-C4 duteroalkyl group.

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

[0012] [ka] It has the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0013] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 CR 11 , X 2 is N, X 3 is N, or X 1 is N, X 2 CR 11 , X 3 CR 11 is, or, X1 is N, X 2 CR 11 , X 3 is N, or X 1 is N, X 2 is N, X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2. In some embodiments, R 11 These are, independently, hydrogen or fluorocarbon.

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

[0015] [ka] It has the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

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

[0017] [ka] A compound, or a pharmaceutically acceptable salt thereof, tautomer, or solvate thereof, wherein A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0018] In some embodiments, A 1 C, A 2 C, A 3 is N, A 4 is NR 8 , A 5 CR 8 And, or, A 1 C, A 2 C, A 3 is NR 8 , A 4 is N, A 5 CR 8 And, or, A 1 C, A 2 is N, A 3 is N, A 4 CR 8 , A 5 CR 8 That is the case.

[0019] In some embodiments, the compound is of formula (VIa-1):

[0020] [ka] It has the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0021] In some embodiments, the compound is of formula (VIc-1):

[0022] [ka] It has the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0023] In some embodiments, the compound is represented by formula (VIf-1):

[0024] [ka] It has the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0025] In some embodiments, R 8 These are, independently, hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 R is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0026] In some embodiments, R 6 and R 7 Each of these is independently hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl. In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, or methyl.

[0027] In some embodiments, Z is -NR 10 -, -O-, or -SO2-. In some embodiments, Z is -NR 10 -or -O-. In some embodiments, Z is -NR 10 - In some embodiments, R 10 Z is hydrogen, a C1-C4 alkyl group, a C1-C4 deuteroalkyl group, or a cyclopropyl group. In some embodiments, Z is -O-.

[0028] In some embodiments, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted monocyclic carbon ring, an unsubstituted or substituted bicyclic carbon ring, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, and if ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where if ring B is substituted, ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is an unsubstituted or substituted phenyl ring or an unsubstituted or substituted monocyclic six-membered heteroaryl ring B, where if ring B is substituted, ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted phenyl, an unsubstituted or substituted pyridinyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridadinyl, and if ring B is substituted, ring B is a ring with q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl, and if ring B is substituted, then ring B is a ring with q examples. 13 It is replaced by R. In some embodiments, 2 R is a ring B which is either unsubstituted or substituted, and if ring B is substituted, then ring B has q examples of R 13 It will be replaced by this.

[0029] In some embodiments, R 2 teeth,

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

[0031] [ka] And q is 0, 1, 2, 3, or 4.

[0032] In some embodiments, the compound is represented by formula (VIII):

[0033] [ka] The structure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein V is N, CH, or CR 13 And q is 1, 2, or 3, A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0034] In some embodiments, V is N. In some embodiments, V is CH or CR 13 That is the case.

[0035] In some embodiments, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -CN, -OH, and -OR. 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16)2, -NR 16 C(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 13 These are, independently, -F, -Cl, -CH3, or -CF3.

[0036] 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 That is the case.

[0037] In some embodiments, the compound is of formula (IX):

[0038] [ka] Having the structure of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, in the formula, A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0039] In some embodiments, R 14is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R 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. s It is replaced by the base.

[0040] In some embodiments, B 1 CR 12a B 2 CR 12b B 1 is N, B 2 CR 12b B 1 CR 12a B 2 is N, or B 1 is N, B 2 In some embodiments, B 1 CR 12a B 2 CR 12b B 1 is N, B 2 CR 12b In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 12a and R 12b These are hydrogen atoms, respectively.

[0041] Any combination of the groups described above for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0042] This specification also describes pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to mammals by intravenous, subcutaneous, oral, inhalation, nasal, transdermal, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to mammals 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.

[0043] This specification describes compounds of formula (A1), or pharmaceutically acceptable salts, tautomers, or solvates thereof, that are useful for treating TYK2-mediated disorders. This specification also describes compounds of formula (A1), or pharmaceutically acceptable salts, tautomers, or solvates thereof, that are useful for treating inflammatory or autoimmune diseases. In some embodiments, the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal diseases, Crohn's disease, ulcerative colitis, celiac disease, Behçet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the disease is selected from psoriasis, psoriatic arthritis, vitiligo, atopic dermatitis, alopecia, and hidradenitis suppurativa. In some embodiments, the disease is selected from interferonopathy, such as Ecardi-Goutierre syndrome, to name just a few.

[0044] In any of the embodiments described above, an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered (a) systemically to a mammal, and / or (b) orally to a mammal, and / or (c) intravenously to a mammal, and / or (d) by inhalation, and / or (e) by nasal administration, and / or (f) by injection to a mammal, and / or (g) topically to a mammal, and / or (h) by ophthalmological administration, and / or (i) rectally to a mammal, and / or (j) non-systemically or topically to a mammal.

[0045] Any of the embodiments described above is a further embodiment comprising a single dose of an effective amount of the compound, and further embodiments include the compound being administered to a mammal once daily, or the compound being administered to a mammal multiple times during the day. In some embodiments, the compound is administered in a continuous dosing schedule. In some embodiments, the compound is administered in a continuous daily dosing schedule.

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

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

[0048] Provided are packaging materials, compounds described herein contained in the packaging materials, or pharmaceutically acceptable salts thereof, and products comprising compounds or compositions, or pharmaceutically acceptable salts thereof, pharmaceutically acceptable salts, tautomers, pharmaceutically acceptable N oxides, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, or pharmaceutically acceptable solvates thereof, used for the modulation of TYK2, or for the treatment, prevention, or improvement of one or more symptoms of a disease or illness that benefits from the modulation of TYK2.

[0049] Other purposes, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be noted that the detailed description and specific examples are given only as illustrations, while also illustrating specific embodiments, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description. [Modes for carrying out the invention]

[0050] TYK2 activation is associated with numerous diseases and disorders, including inflammatory diseases and disorders, autoimmune diseases and disorders, respiratory diseases and disorders, and cancer.

[0051] In particular, IL-23 activation by 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 as a downstream effector of IL-23 in psoriasis, ankylosing spondylitis, and Behçet's disease. Furthermore, TYK2 is associated with skin diseases and conditions such as psoriasis, vitiligo, atopic dermatitis, hidradenitis suppurativa, and scleroderma, as well as eye diseases and conditions such as Sjögren's syndrome, uveitis, and dry eye.

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

[0053] TYK2 is also associated with autoimmune diseases and disorders such as multiple sclerosis (MS), lupus, and systemic lupus erythematosus (SLE). Loss of functional mutations in TYK2 leads to decreased neuronal demyelination and increased remyelinating, further suggesting the role of TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders. Various type I IFN signaling pathways that depend on TYK2 signaling have TYK2 involved in SLE and other autoimmune diseases and disorders.

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

[0055] TYK2 has also been shown to play a crucial role in maintaining tumor surveillance, and TYK2 knockout mice exhibited loss of cytotoxic T cell response and accelerated tumor development. These results are largely due to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are well-suited for treating autoimmune disorders or transplant rejection. While other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 is a superior target because it is involved in more or less closely related signaling pathways, resulting in only minimal off-target effects. However, in studies on T-cell acute lymphoblastic leukemia (T-ALL), it has been observed that T-ALL is highly dependent on IL-10 via TYK2 / STAT1 signaling to maintain cancer cell survival through the upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, rather than other JAK family members, reduces cell proliferation. Therefore, selective inhibition of TYK2 is suggested as a suitable target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases.

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

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

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

[0059] In some embodiments, the TYK2 inhibitors described herein are used to treat diseases or illnesses in mammals.

[0060] compound The compounds described herein, including their pharmaceutically acceptable salts, tautomers, and solvates, are inhibitors of TYK2. In some embodiments, the compounds described herein are more selective to TYK2 than other JAKs. In some embodiments, the compounds described herein selectively / specifically bind to the pseudokinase domain (JH2) of TYK2. In some embodiments, the compounds described herein bind to the allosteric site of TYK2. In additional embodiments, the compounds described herein may be useful in treating TYK2-mediated diseases or disorders.

[0061] In one embodiment of this specification, formula (I):

[0062] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, Ring A is A 1 and A 2 If ring A is independently N or C, and is an unsubstituted or substituted pyrazole, then ring A is p examples of R8 Replaced by, R 8 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes 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 carbocyclic, unsubstituted or substituted heterocyclic, and -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-, R 10 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. X 1 , X 2, and X 3 Each of them operates independently in CR 11 or N, R 11 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 1 These are hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C2-C6 alkenyls, unsubstituted or substituted C2-C6 alkynyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted C1-C6 heteroalkyls, unsubstituted or substituted carbocyclics, unsubstituted or substituted heterocyclics, -CN, -OH, and -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, Alternatively, two R atoms on adjacent atoms of ring B 13 The groups, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring, or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring. Alternatively, R 2 is -C(=O)R 14 -C(=O)NR 14 R 15 , or -C(=O)OR 14 And, R 14These are 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 These are hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, Or, R 14 and R 15 These, by becoming one with the intervening atoms to which they are bonded, form unsubstituted or substituted 5-membered or 6-membered monocyclic heterocycles. Or, R 1 and R 15 These, by becoming one with the intervening atoms to which they are bonded, form unsubstituted or substituted 5-membered or 6-membered monocyclic heterocycles. W is -NR 3 -or -O- R 3 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. R 4 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. Or, R 3 and R 4 These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. Or, R 3 and R 12a These atoms, by becoming one with the intervening atoms to which they are bonded, form substituted or unsubstituted 5-membered or 6-membered heterocycles. R 5 These are hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. R 6 and R 7These are, independently, hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 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, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Alternatively, two R atoms on the same N atom 16 These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. R 17 Each of these is independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Here, substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are deuterium, halogen, C1-C6 alkyl, monocyclic carbocyclic, monocyclic heterocyclic, -CN, -CH2CN, and -OR, respectively. 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 2 s Substituted with the base, R 18 Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. Or, two R's 18 The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle. R 19Each of these is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. n is 1, 2, or 3. p is either 1 or 2. q is 1, 2, 3, or 4. Compounds, or pharmaceutically acceptable salts, tautomers, or solvates thereof, are provided.

[0063] In some embodiments, the compound is either 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide or 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotin It is neither amide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylnicotinamide, nor 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0064] In some embodiments, the compound of formula (I) has the following structure

[0065] [ka] It is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, which has [the specified compound].

[0066] In some embodiments, the compound of formula (I) has the following structure

[0067] [ka] It is not 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide.

[0068] In some embodiments, the compound of formula (I) has the following structure

[0069] [ka] It is not 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylnicotinamide.

[0070] In some embodiments, the compound of formula (I) has the following structure

[0071] [ka] It is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide, which has [the specified compound].

[0072] In any and all embodiments, the substituent is selected from a subset of the enumerated alternatives. For example, in some embodiments, R 1 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 1 R is hydrogen, a C1-C4 alkyl group, or a C1-C4 fluoroalkyl group. In some embodiments, R 1 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 1is hydrogen or a C1-C4 alkyl group. In some embodiments, R 1 R 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 It is methyl.

[0073] In some embodiments, R 5 is hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl. In some embodiments, R 5 R is hydrogen, a C1-C4 alkyl group, or a C1-C4 fluoroalkyl group. In some embodiments, R 5 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 5 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 5 R is hydrogen, methyl, ethyl, propyl, isopropyl, or butyl. In some embodiments, R 5 is hydrogen or methyl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 It is methyl.

[0074] In some embodiments, W is -O-.

[0075] In some embodiments, W is -NR 3 - is

[0076] In some embodiments, the compound is of formula (Ia) or formula (Ib):

[0077] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0078] In some embodiments, the compound is the compound of formula (Ia), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (Ib), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0079] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0080] In some embodiments, when W is -O-, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0081] In some embodiments, W is -NR 3 -When R 3 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 3 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 3 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 3 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 3 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 3 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -CH3. In some embodiments, R 3 It is -CD3.

[0082] In some embodiments, W is -NR 3 -When R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0083] In some embodiments, W is -NR 3 -When R 3 and R 4 Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 deuteroalkyl group, or a C1-C6 fluoroalkyl group. In some embodiments, R 3 and R 4 Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 3 and R 4 Each of these is independently hydrogen, a C1-C4 alkyl group, a C1-C4 deuteroalkyl group, or a C1-C4 fluoroalkyl group. In some embodiments, R 3 and R 4 Each of these is independently hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 3 and R 4 Each is independently hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 3 and R 4 These are, independently, hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 3 is hydrogen. In some embodiments, R 3is hydrogen, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 3 is hydrogen, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 3 is hydrogen, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 3 is hydrogen, R 4 is hydrogen. In some embodiments, R 3 is hydrogen, R 4 is a C1-C4 alkyl or C1-C4 deuteroalkyl. In some embodiments, R 3 is hydrogen, R 4 is a C1-C2 alkyl or C1-C2 deuteroalkyl. In some embodiments, R 3 is hydrogen, R 4 is -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 3 is hydrogen, R 4 is -CH3. In some embodiments, R 3 is hydrogen, R 4 It is -CD3.

[0084] In some embodiments, W is -NR 3 -When R 3 and R 4 These, by becoming one with the N atom to which they are bonded, form a substituted or unsubstituted N-containing heterocycle. In some embodiments, R 3 and R 4 These combine with the N atom to which they are bonded to form substituted or unsubstituted N-containing heterocycloalkyls. In some embodiments, R 3 and R 4 These combine with the N atom to which they are bonded to form substituted or unsubstituted monocyclic N-containing heterocycloalkyls. In some embodiments, R 3 and R 4These atoms, by integrating with the N atom to which they are bonded, form substituted or unsubstituted 3- to 6-membered N-containing heterocycloalkyl groups.

[0085] In some embodiments, the compound is of formula (II) or formula (III):

[0086] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0087] In some embodiments, the compound is the compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (III), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0088] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0089] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 CR 11 , X 2 is N, X 3 is N, or X 1 is N, X 2 CR 11 , X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X 3 is N, or X 1 is N, X 2 is N, X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 In some embodiments, X 1 CR 11 , X 2 is N, X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 is N, X 3 In some embodiments, X 1 is N, X 2CR 11 , X 3 CR 11 In some embodiments, X 1 is N, X 2 CR 11 , X 3 In some embodiments, X 1 is N, X 2 is N, X 3 CR 11 That is the case.

[0090] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X 3 CR 11 That is the case.

[0091] In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 -C(=O)N(R 16 )2, -N(R 16)2, or -SO2N(R 16 )2. In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2. In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2. In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 11 These are, independently, hydrogen, halogen, or -CN. In some embodiments, R 11 These are, independently, hydrogen or halogen. In some embodiments, R 11 These are, independently, hydrogen, fluoro, or chloro. In some embodiments, R 11 These are, independently, hydrogen or fluoro. In some embodiments, R 11 These are hydrogen atoms, respectively.

[0092] In some embodiments, X 1 , X 2 , and X 3 These are, independently, CH, CF, or N. In some embodiments, X 1 , X 2 , and X 3 These are, independently, CH or N. In some embodiments, X 1 CH or CF, X 2 CH or CF, X 3 is CH or CF, or X 1 CH or CF, X 2 CH or CF, X 3 is N, or X 1 CH or CF, X 2is N, X 3 is CH or CF, or X 1 is N, X 2 CH or CF, X 3 is CH or CF. In some embodiments, X 1 CH, X 2 CH, X 3 is CH, or X 1 CH, X 2 CH, X 3 is N, or X 1 CH, X 2 is N, X 3 is CH, or X 1 is N, X 2 CH, X 3 It is CH.

[0093] In some embodiments, X 1 CH, X 2 CH, CF, or N, X 3 is CH. In some embodiments, X 1 CH, X 2 is CF or N, X 3 is CH. In some embodiments, X 1 CH, CF, or N, X 2 CH, X 3 is CH. In some embodiments, X 1 is CF or N, X 2 CH, X 3 is CH. In some embodiments, X 1 CH, X 2 CH, X 3 is CH, CF, or N. In some embodiments, X 1 CH, X 2 CH, X 3 It is either CF or N.

[0094] In some embodiments, the compound is of formula (IV) or formula (V):

[0095] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0096] In some embodiments, the compound is the compound of formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0097] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0098] In some embodiments, R 8These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes 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 carbocyclic, unsubstituted or substituted heterocyclic, and -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 8 These are, independently, hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R8 When bonded to a nitrogen atom, R 8 This includes hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 R is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0099] In some embodiments, p is 0, 1, or 2. 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, and therefore ring A is not substituted.

[0100] In some embodiments, ring A is

[0101] [ka] In some embodiments, ring A is

[0102] [ka] That is the case.

[0103] In some embodiments,

[0104] [ka] teeth,

[0105] [ka] In some embodiments,

[0106] [ka] teeth,

[0107] [ka] In some embodiments,

[0108] [ka] teeth,

[0109] [ka] In some embodiments,

[0110] [ka] teeth,

[0111] [ka] In some embodiments,

[0112] [ka] teeth,

[0113] [ka] In some embodiments,

[0114] [ka] teeth,

[0115] [ka] That is the case.

[0116] In some embodiments,

[0117] [ka] teeth,

[0118] [ka] And in the formula, A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0119] In some embodiments, the compound is of formula (VI) or formula (VII):

[0120] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0121] In some embodiments, the compound is the compound of formula (VI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (VII), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0122] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0123] In some embodiments, A 1 C, A 2 C, A 3 is N, A 4 is NR 8 , A 5 CR 8 And, Or, A 1 C, A 2 C, A 3 is NR 8 , A 4 is N, A 5 CR 8 And, Or, A 1 C, A 2 is N, A 3 is N, A 4 CR 8 , A 5 CR 8 That is the case.

[0124] In some embodiments, the compound is of formula (VIa-1):

[0125] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0126] In some embodiments, the compound of formula (VIa-1) is neither 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyridine-4-yl)amino)-N-methylnicotinamide.

[0127] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0128] In some embodiments, the compound is of formula (VIc-1):

[0129] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0130] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0131] In some embodiments, the compound is represented by formula (VIf-1):

[0132] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0133] In some embodiments, the compound of formula (VIf-1) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0134] In some embodiments, R 4is 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, C1-C2 alkyl, or C1-C2 deuteroalkyl. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 is -CD3.

[0135] 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 when R 8 is bound to a nitrogen atom, R 8is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2.

[0136] In some embodiments, each R 8 is independently hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 , -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, and when R 8 is bonded 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 carbocycle, unsubstituted or substituted heterocycle, -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2.

[0137] In some embodiments, each R 8 is 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 , -CO2R16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 These include hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2.

[0138] In some embodiments, R 8 Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 These are hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3.

[0139] In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0140] In some embodiments, R 8 These are, independently, hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R. 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R8 These are, independently, hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and -C(=O)R. 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 These are, independently, hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -CO2H, or -CO2CH3. In some embodiments, R 8 These are, independently, hydrogen, methyl, -CD3, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3. In some embodiments, R 8 Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 deuteroalkyl group, or a C1-C6 fluoroalkyl group. In some embodiments, R 8 Each of these is independently hydrogen, a C1-C4 alkyl group, a C1-C4 deuteroalkyl group, or a C1-C4 fluoroalkyl group. In some embodiments, R 8 These are, independently, hydrogen, methyl, ethyl, isopropyl, -CD3, or -CF3. In some embodiments, R 8 These are, independently, hydrogen, methyl, -CD3, or -CF3. In some embodiments, R 8 These are, independently, hydrogen or methyl.

[0141] In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle, -CN, -OH, -OR 17 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SO2R17 , or -SO₂N(R 16 )₂. In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, -CN, -OH, -OR 17 , and -N(R 16 )₂. In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, or C₁-C₆ alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen or C₁-C₆ alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, halogen, C₁-C₄ alkyl, or C₁-C₄ deuterated alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen or C₁-C₄ alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, Cl, -CD₃, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 are each independently hydrogen or methyl. In some embodiments, one R 6 or R 7 is methyl. In some embodiments, one R 6 is methyl. In some embodiments, R 6 and R 7 are each hydrogen. In some embodiments, R 6 and R 7 are each deuterium. In some embodiments, R 6 and R 7 are each F.

[0142] In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C=O or C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These combine with the carbon atom to which they are bonded to form C=O. In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These atoms combine with the carbon atoms to which they are bonded to form a cyclopropyl group.

[0143] 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.

[0144] In some embodiments, Z is -NR 10 -, -O-, -S-, or -SO2-. In some embodiments, Z is -NR 10 -, -O-, or -SO2-. In some embodiments, Z is -NR 10 -, -O-, or -S-. In some embodiments, Z is -NR 10 -or -O-

[0145] In some embodiments, Z is -NR 10 - In some embodiments, R 10 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl. In some embodiments, R 10R is hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 4-6 member heterocycloalkyl. In some embodiments, R 10 R 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 10 R is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R 10 R is hydrogen, C1-C4 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or azetidinyl. In some embodiments, R 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, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is hydrogen, -CH3, or -CD3. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is -CH3. In some embodiments, R 10 It is -CD3.

[0146] 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.

[0147] 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-.

[0148] In some embodiments, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted monocyclic carboelectric ring, an unsubstituted or substituted bicyclic carboelectric ring, an unsubstituted or substituted monocyclic heterocycle, an unsubstituted or bicyclic heterocycle, an unsubstituted or substituted spirocyclic carboelectric ring, an unsubstituted or substituted spirocyclic heterocycle, an unsubstituted or substituted bridging carboelectric ring, or an unsubstituted or substituted bridging heterocycle, and if ring B is substituted, then ring B has q examples of R 13 It will be replaced by this.

[0149] In some embodiments, R 2 R is a ring B which is an unsubstituted or substituted monocyclic carbon ring, an unsubstituted or substituted bicyclic carbon ring, an unsubstituted or substituted monocyclic heterocycle, or an unsubstituted or substituted bicyclic heterocycle, and if ring B is substituted, then ring B has q examples of R 13 It will be replaced by this.

[0150] In some embodiments, R 2 R is an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, an unsubstituted or substituted monocyclic 5-membered heteroaryl, or an unsubstituted or substituted bicyclic heteroaryl, where if ring B is substituted, ring B has q examples of R 13 Replaced by,

[0151] In some embodiments, R 2R is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where if ring B is substituted, ring B has q examples of R 13 It will be replaced by this.

[0152] In some embodiments, R 2 R is a monocyclic five-membered heteroaryl ring B, which is either unsubstituted or substituted. If ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 Ring B is an unsubstituted or substituted pyrrolyl, unsubstituted or substituted furanyl, unsubstituted or substituted thiophenyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, or unsubstituted or substituted tetrazolyl, and if ring B is substituted, ring B is q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted pyrrolyl, an unsubstituted or substituted imidazolyl, an unsubstituted or substituted pyrazolyl, an unsubstituted or substituted triazolyl, or an unsubstituted or substituted tetrazolyl, and if ring B is substituted, ring B has q examples of R 13 In some embodiments, R is replaced by 2 R is a ring B which is an unsubstituted or substituted pyrrolyl, an unsubstituted or substituted imidazolyl, or an unsubstituted or substituted pyrazolyl, and if ring B is substituted, ring B is a ring with q examples of R 13 It will be replaced by this.

[0153] In some embodiments, R 2 R is an unsubstituted or substituted phenyl ring or an unsubstituted or substituted monocyclic six-membered heteroaryl ring B, where if ring B is substituted, ring B has q examples of R 13 It will be replaced by this.

[0154] In some embodiments, R 2 R is a ring B which is an unsubstituted or substituted phenyl, an unsubstituted or substituted pyridinyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridadinyl, and if ring B is substituted, ring B is a ring with q examples of R 13 It will be replaced by this.

[0155] In some embodiments, R 2 R is a monocyclic 6-membered heteroaryl ring B, which is either unsubstituted or substituted, and if ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted pyridinyl, an unsubstituted or substituted pyrimidinyl, an unsubstituted or substituted pyrazinyl, or an unsubstituted or substituted pyridadinyl, and if ring B is substituted, then ring B is a ring with q examples of R 13 In some embodiments, R is replaced by 2 R is a ring B which is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl, and if ring B is substituted, then ring B is a ring with q examples. 13 It is replaced by R. In some embodiments, 2 R is a ring B which is either unsubstituted or substituted, and if ring B is substituted, then ring B is a ring with q examples. 13 It is replaced by R. In some embodiments, 2 R is a ring B which is either unsubstituted or substituted, and if ring B is substituted, then ring B has q examples of R 13 It will be replaced by this.

[0156] In some embodiments, R 2 teeth,

[0157] [ka] And q is 0 to 4. In some embodiments, R 2 teeth,

[0158] [ka] And q is 0 to 4. In some embodiments, R 2 teeth,

[0159] [ka] Therefore, q is between 0 and 4.

[0160] In some embodiments, R 2 teeth,

[0161] [ka] In the formula, V is CH, CR 9 , or N, where q is 0, 1, 2, or 3. In some embodiments, R 2 teeth,

[0162] [ka] In the formula, V is CH, CR 9 , or N, where q is 0, 1, 2, or 3.

[0163] In some embodiments, the compound is represented by formula (VIII):

[0164] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, V is N, CH, or CR 13 And, q is 1, 2, or 3. A 1 and A 2 Each of these is independently either N or C, A 3 , A 4 , and A5 These are N and NR, respectively, independently. 8 , or CR 8 And, Here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0165] In some embodiments, the compound is of formula (VIIIa-1):

[0166] [ka] A compound of , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, where V is N, CH, or CR 13 And q is 1, 2, or 3.

[0167] In some embodiments, the compound of formula (VIIIa-1) is neither 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylnicotinamide.

[0168] In some embodiments, the compound is of formula (VIIIc-1):

[0169] [ka] A compound of , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, where V is N, CH, or CR 13 And q is 1, 2, or 3.

[0170] In some embodiments, the compound is of formula (VIIIf-1):

[0171] [ka] A compound of , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, where V is N, CH, or CR 13 And q is 1, 2, or 3.

[0172] 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 That is the case.

[0173] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0174] In some embodiments, R 13These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -CN, -OH, and -OR. 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2. In some embodiments, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 13 These are, independently, halogens, C1-C6 alkyls, C1-C6 fluoroalkyls, C3-C6 cycloalkyls, 4-6 member heterocycloalkyls, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 13 These are, independently, a halogen, a C1-C4 alkyl, or a C1-C4 fluoroalkyl. In some embodiments, R 13 These are, independently, -F, -Cl, -CH3, or -CF3.

[0175] 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, and therefore ring B is not substituted.

[0176] In some embodiments, R 2 is -C(=O)R 14 -C(=O)NR 14 R 15 , or -C(=O)OR 14 That is the case.

[0177] In some embodiments, R 2 is -C(=O)R 14 That is the case.

[0178] In some embodiments, R 2 is -C(=O)NR 14 R 15 Or -C (=O) OR 14 That is the case.

[0179] In some embodiments, the compound is of formula (IX), formula (X), or formula (XI):

[0180] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0181] In some embodiments, the compound is the compound of formula (IX), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (X), or a pharmaceutically acceptable salt, tautomer, or solvate thereof. In some embodiments, the compound is the compound of formula (XI), or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0182] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0183] In some embodiments, R 1 R is hydrogen, a C1-C6 alkyl group, or a C1-C6 fluoroalkyl group. In some embodiments, R 1 is hydrogen, C1-C4 alkyl, or C1-C4 fluoroalkyl. In some embodiments, R 1 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 1 is hydrogen or a C1-C4 alkyl group. In some embodiments, R 1R 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 It is methyl.

[0184] In some embodiments, R 1 and R 15 These, by integrating with the intervening atoms to which they are bonded, form unsubstituted or substituted five-membered or six-membered monocyclic heterocycles. In some embodiments, R 1 and R 15 These, by integrating with the intervening atom to which they are bonded, form unsubstituted or substituted five-membered or six-membered monocyclic heterocycloalkyl groups. In some embodiments, R 1 and R 15 These, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted five-membered monocyclic heterocycle. In some embodiments, R 1 and R 15 These atoms, by integrating with the intervening atoms to which they are bonded, form unsubstituted or substituted five-membered monocyclic heterocycloalkyl groups.

[0185] In some embodiments, R 1 It is hydrogen.

[0186] In some embodiments, the compound is of formula (IXa-1):

[0187] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0188] In some embodiments, the compound of formula (IXa-1) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0189] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0190] In some embodiments, the compound is of formula (IXc-1):

[0191] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0192] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0193] In some embodiments, the compound is of formula (IXf-1):

[0194] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0195] In some embodiments, the compound of formula (IXf-1) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0196] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0197] In some embodiments, R 14 R is hydrogen, an unsubstituted or substituted C1-C6 alkyl, a C1-C6 deuteroalkyl, 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 This is an 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 These are unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 heteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl.

[0198] In some embodiments, R 14R is hydrogen, an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C2-C6 alkenyl, an unsubstituted or substituted C2-C6 alkynyl, an unsubstituted or substituted C1-C6 heteroalkyl, an unsubstituted or substituted monocyclic 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 This 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 These are unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C1-C6 heteroalkyl groups, unsubstituted or substituted C3-C6 cycloalkyl groups, or unsubstituted or substituted 4- to 6-membered heterocycloalkyl groups.

[0199] In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4-6 member heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R s It is replaced by the base. 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 4-6 member heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R s It is replaced by the base. In some embodiments, R 14These are unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C6 cycloalkyl, or unsubstituted or substituted 4-6 member heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl may be deuterium, halogen, C1-C6 alkyl, -CN, -OR 18 , and -N(R 18 )One or more R independently selected from the group consisting of 2 s It is replaced by the base. In some embodiments, R 14 These are unsubstituted or substituted C1-C6 alkyl groups, unsubstituted or substituted C3-C6 cycloalkyl groups, or unsubstituted or substituted 4-6 member heterocycloalkyl groups, and the substituted alkyl groups, substituted heteroalkyl groups, substituted cycloalkyl groups, or substituted heterocycloalkyl groups are deuterium, halogens, C1-C6 alkyl groups, -CN, -OR 18 , and -N(R 18 )One or more R independently selected from the group consisting of 2 s It is replaced by the base. In some embodiments, R 14 is an unsubstituted or substituted C1-C6 alkyl, an unsubstituted or substituted C3-C4 cycloalkyl, or an unsubstituted or substituted 4-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R 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. s It is replaced by the base. In some embodiments, R 14 Methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

[0200] [ka] In some embodiments, R14 Methyl, -CD3, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl,

[0201] [ka] In some embodiments, R 14 These include methyl, ethyl, isopropyl, t-butyl, cyclopropyl, azetidinyl, oxetanyl,

[0202] [ka] That is the case.

[0203] In some embodiments, R 2 -C(=O)NR 14 R 15 When R 14 and R 15 These, by integrating with the intervening atoms to which they are bonded, form unsubstituted or substituted 4- to 6-membered monocyclic heterocycles. In some embodiments, R 14 and R 15 These atoms, by integrating with the intervening atoms to which they are bonded, form unsubstituted or substituted 4- to 6-membered monocyclic heterocycloalkyl groups.

[0204] In some embodiments, B 1 CR 12a B 2 CR 12b B 1 is N, B 2 CR 12b B 1 CR 12a B 2 is N, or B 1 is N, B 2 In some embodiments, B 1 CR 12a B 2 CR 12b In some embodiments, B 1 is N, B2 CR 12b In some embodiments, B 1 CR 12a B 2 In some embodiments, B 1 is N, B 2 It is N.

[0205] In some embodiments, B 1 CR 12a B 2 CR 12b B 1 is N, B 2 CR 12b That is the case.

[0206] In some embodiments, R 12a and R 12b These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2.

[0207] In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -SO2R17 , or -SO2N(R 16 )2. In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 -C(=O)N(R 16 )2, -N(R 16 )2, or -SO2N(R 16 )2. In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2. In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2. In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 12a and R 12b These are, independently, hydrogen, halogen, or -CN. In some embodiments, R 12a and R 12b These are, independently, hydrogen or halogen. In some embodiments, R 12a and R 12b These are, independently, hydrogen, fluoro, or chloro. In some embodiments, R 12a and R 12b These are, independently, hydrogen or fluoro. In some embodiments, R 12a and R 12b These are hydrogen atoms, respectively.

[0208] In some embodiments, B 1 and B 2These are, independently, CH, CF, or N. In some embodiments, B 1 and B 2 These are, independently, either CH or N.

[0209] In some embodiments, B 1 is CH or CF, B 2 is CH or CF, or B 1 is N, B 2 is CH or CF, or B 1 is CH or CF, B 2 is N, or B 1 is N, B 2 In some embodiments, B 1 CH, B 2 is CH, or B 1 is N, B 2 is CH, or B 1 CH, B 2 is N, or B 1 is N, B 2 It is N.

[0210] In some embodiments, R 3 and R 12a These, by becoming one with the intervening atoms to which they are bonded, form substituted or unsubstituted five-membered or six-membered heterocycles. In some embodiments, R 3 and R 12a These, by integrating with the intervening atoms to which they are bonded, form an unsubstituted or substituted five-membered heterocycle. In some embodiments, R 3 and R 12a These, by integrating with the intervening atom to which they are bonded, form a substituted or unsubstituted pyrazolidinone ring. In some embodiments,

[0211] [ka] teeth,

[0212] [ka] In some embodiments,

[0213] [ka] teeth,

[0214] [ka] In some embodiments,

[0215] [ka] teeth,

[0216] [ka] That is the case.

[0217] In some embodiments, the compound is of formula (XII):

[0218] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein A 1 and A 2 Each of these is independently N or C, and A 3 , A 4 , and A 5 These are N and NR, respectively, independently. 8 , or CR 8 And here, A 1 , A 2 , A 3 , A 4 , and A 5 Two adjacent ring atoms selected from are N or NR 8 The remaining atoms are C or CR. 8 That is the case.

[0219] In some embodiments, A 1 C, A2 C, A 3 is N, A 4 is NR 8 , A 5 It is CH.

[0220] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0221] In some embodiments, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is a monocyclic 6-membered heteroaryl ring B, which is either unsubstituted or substituted, and if ring B is substituted, then ring B has q examples of R 13 It is replaced by R. In some embodiments, 2 R is a ring B which is an unsubstituted or substituted pyridinyl or an unsubstituted or substituted pyrimidinyl, and if ring B is substituted, then ring B is a ring with q examples. 13 It will be replaced by this.

[0222] 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 That is the case.

[0223] In some embodiments, R 16 Each of these is independently a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 fluoroalkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted C3-C7 cycloalkyl group, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl group, or two R groups on the same N atom. 16 These combine with the N atom to which they are bonded to form substituted or unsubstituted N-containing heterocycloalkyls. In some embodiments, R 16 Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or a monocyclic 3- to 8-membered heterocycloalkyl, or two R atoms on the same N atom. 16 These atoms, by integrating with the N atom to which they are bonded, form a 4-6 member N-containing heterocycloalkyl group.

[0224] In some embodiments, R 17 Each of these is independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, or a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl. In some embodiments, R 17 These are, independently, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0225] In some embodiments, the compound is of formula (XV):

[0226] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, R 8 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes 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 carbocyclic, unsubstituted or substituted heterocyclic, and -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10-, -O-, -S-, -S(=O)-, or -SO2-, R 10 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. X 1 , X 2 , and X 3 Each of them operates independently in CR 11 or N, R 11 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16-C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C2-C6 alkenyls, unsubstituted or substituted C2-C6 alkynyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted C1-C6 heteroalkyls, unsubstituted or substituted carbocyclics, unsubstituted or substituted heterocyclics, -CN, -OH, and -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, Alternatively, two R atoms on adjacent atoms of ring B 13 The groups, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring, or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring. Alternatively, R 2 is -C(=O)R 14 -C(=O)NR 14 R 15 , or -C(=O)OR 14 And, R 14These are 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 These are hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, R 4 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 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, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Alternatively, two R atoms on the same N atom 16 These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. R 17 Each of these is independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Here, substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are deuterium, halogen, C1-C6 alkyl, monocyclic carbocyclic, monocyclic heterocyclic, -CN, -CH2CN, and -OR, respectively. 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 2 s Substituted with the base, R 18 Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. Or, two R's 18 The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle. R 19 Each of these is 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.

[0227] In some embodiments, R 8 These are, independently, hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8This includes hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, Z is -NR 10 -or -O- R 10 These are hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. X 1 , X 2 , and X 3 Each of them operates independently in CR 11 or N, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN, R 2 R is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where if ring B is substituted, ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -CN, -OH, and -OR. 17 -C(=O)R 16, -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Alternatively, R 2 is -C(=O)R 14 And, R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R 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. s Substituted with the base, R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 fluoroalkyl, a C1-C6 heteroalkyl, a C3-C7 cycloalkyl, or a monocyclic 3- to 8-membered heterocycloalkyl. Alternatively, two R atoms on the same N atom 16 These, by becoming one with the N atom to which they are bonded, form a 4-6 member N-containing heterocycloalkyl group. R 17These are, independently, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0228] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0229] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 In some embodiments, X 1 CR 11 , X 2 is N, X 3 CR 11 In some embodiments, X 1 is N, X 2 CR 11 , X 3 CR 11 That is the case.

[0230] In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 11 These are, independently, hydrogen, halogen, or -CN. In some embodiments, R 11 These are, independently, hydrogen or halogen. In some embodiments, R 11 These are, independently, hydrogen, fluoro, or chloro. In some embodiments, R 11 These are, independently, hydrogen or fluoro. In some embodiments, R 11 These are hydrogen atoms, respectively.

[0231] In some embodiments, the compound of formula (XV) is formula (VIc-1):

[0232] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0233] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0234] In some embodiments, R 8 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 These include hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 R is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0235] In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, Cl, -CD3, or methyl. In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 These are, 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 These are hydrogen atoms, respectively. In some embodiments, R 6 and R 7 These are deuterium, respectively. In some embodiments, R 6 and R 7 These are F, respectively.

[0236] In some embodiments, one R bonded to the same carbon atom 6 and one R 7These combine with the carbon atom to which they are bonded to form a C=O or C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These combine with the carbon atom to which they are bonded to form C=O. In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These atoms combine with the carbon atoms to which they are bonded to form a cyclopropyl group.

[0237] 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.

[0238] In some embodiments, Z is -NR 10 - In some embodiments, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is hydrogen, -CH3, or -CD3. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is -CH3. In some embodiments, R 10 It is -CD3.

[0239] 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.

[0240] In some embodiments, Z is -O-.

[0241] In some embodiments, R 2 This is defined herein.

[0242] In some embodiments, the compound is of formula (XVII):

[0243] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, R 8 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8This includes 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 carbocyclic, unsubstituted or substituted heterocyclic, and -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-, R 10 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. X 1 , X 2 , and X 3 Each of them operates independently in CR 11 or N, R 11 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, B 1is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 2 R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C2-C6 alkenyls, unsubstituted or substituted C2-C6 alkynyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted C1-C6 heteroalkyls, unsubstituted or substituted carbocyclics, unsubstituted or substituted heterocyclics, -CN, -OH, and -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, Alternatively, two R atoms on adjacent atoms of ring B 13 The groups, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring, or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring. Alternatively, R 2 is -C(=O)R 14 -C(=O)NR 14 R 15 , or -C(=O)OR 14 And, R 14 These are 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 These are hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, R 4 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 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, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Alternatively, two R atoms on the same N atom 16 These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. R 17 Each of these is independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Here, substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are deuterium, halogen, C1-C6 alkyl, monocyclic carbocyclic, monocyclic heterocyclic, -CN, -CH2CN, and -OR, respectively. 18 -CH2OR 18 , -CO2R 18 , -CH2CO2R 18 -C(=O)N(R 18 )2, -CH2C(=O)N(R 18 )2, -N(R 18 )2, -CH2N(R 18 )2, -NR 18 C(=O)R 18 -CH2NR 18 C(=O)R18 , -NR 18 SO2R 19 -CH2NR 18 SO2R 19 , -SR 18 -CH2SR 18 -S(=O)R 19 -CH2S(=O)R 19 , -SO2R 19 ,-CH2SO2R 19 , -SO2N(R 18 )2, or -CH2SO2N(R 18 )One or more R independently selected from the group consisting of 2 s Substituted with the base, R 18 Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. Or, two R's 18 The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle. R 19 Each of these is 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.

[0244] In some embodiments, the compound of formula (XVII) is neither 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyridine-4-yl)amino)-N-methylnicotinamide.

[0245] In some embodiments, R 8 These are, independently, hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, Z is -NR 10 -or -O- R 10 These are hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. X 1 , X 2 , and X 3 Each of them operates independently in CR11 or N, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN, R 2 R is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where if ring B is substituted, ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -CN, -OH, and -OR. 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Alternatively, R 2 is -C(=O)R 14 And, R 14is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R 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. s Substituted with the base, R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 fluoroalkyl, a C1-C6 heteroalkyl, a C3-C7 cycloalkyl, or a monocyclic 3- to 8-membered heterocycloalkyl. Alternatively, two R atoms on the same N atom 16 These, by becoming one with the N atom to which they are bonded, form a 4-6 member N-containing heterocycloalkyl group. R 17 These are, independently, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0246] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0247] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 In some embodiments, X 1 CR 11 , X 2is N, X 3 CR 11 In some embodiments, X 1 is N, X 2 CR 11 , X 3 CR 11 That is the case.

[0248] In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 11 These are, independently, hydrogen, halogen, or -CN. In some embodiments, R 11 These are, independently, hydrogen or halogen. In some embodiments, R 11 These are, independently, hydrogen, fluoro, or chloro. In some embodiments, R 11 These are, independently, hydrogen or fluoro. In some embodiments, R 11 These are hydrogen atoms, respectively.

[0249] In some embodiments, the compound of formula (XV) is formula (VIc-1):

[0250] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0251] In some embodiments, the compound of formula (VIa-1) is neither 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyridine-4-yl)amino)-N-methylnicotinamide.

[0252] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0253] In some embodiments, R 8These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 These include hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8 Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 R is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0254] In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, Cl, -CD3, or methyl. In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, or methyl. In some embodiments, R6 and R 7 These are, 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 These are hydrogen atoms, respectively. In some embodiments, R 6 and R 7 These are deuterium, respectively. In some embodiments, R 6 and R 7 These are F, respectively.

[0255] In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C=O or C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These combine with the carbon atom to which they are bonded to form C=O. In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These atoms combine with the carbon atoms to which they are bonded to form a cyclopropyl group.

[0256] 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.

[0257] In some embodiments, Z is -NR 10 - In some embodiments, R 10is 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, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is hydrogen, -CH3, or -CD3. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is -CH3. In some embodiments, R 10 It is -CD3.

[0258] 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.

[0259] In some embodiments, Z is -O-.

[0260] In some embodiments, R 2 This is defined herein.

[0261] In some embodiments, the compound is of formula (XVIII):

[0262] [ka] A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, R 8These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes 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 carbocyclic, unsubstituted or substituted heterocyclic, and -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, Z is -NR 10 -, -O-, -S-, -S(=O)-, or -SO2-, R 10 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. X 1 , X 2 , and X 3 Each of them operates independently in CR 11or N, R 11 These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, 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 carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 -C(=O)N(R 16 )2, -N(R 16 )2, -NR 16 C(=O)R 17 , -SR 16 -S(=O)R 17 , -SO2R 17 , or -SO2N(R 16 )2, R 2R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C2-C6 alkenyls, unsubstituted or substituted C2-C6 alkynyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted C1-C6 heteroalkyls, unsubstituted or substituted carbocyclics, unsubstituted or substituted heterocyclics, -CN, -OH, and -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, Alternatively, two R atoms on adjacent atoms of ring B 13 The groups, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted 5-membered or 6-membered monocyclic carbocyclic ring, or an unsubstituted or substituted 5-membered or 6-membered monocyclic heterocyclic ring. Alternatively, R 2 is -C(=O)R 14 -C(=O)NR 14 R 15 , or -C(=O)OR 14 And, R 14 These are 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 15These are hydrogen, C1-C6 alkyl, or C1-C6 fluoroalkyl, R 4 These are hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or monocyclic heterocycle. R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, or 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, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Alternatively, two R atoms on the same N atom 16 These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. R 17Each of these is independently a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 fluoroalkyl, a substituted or unsubstituted C1-C6 heteroalkyl, a substituted or unsubstituted C3-C7 cycloalkyl, a substituted or unsubstituted monocyclic 3- to 8-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted monocyclic heteroaryl. Here, substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are deuterium, halogen, C1-C6 alkyl, monocyclic carbocyclic, monocyclic heterocyclic, -CN, -CH2CN, and -OR, respectively. 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 2 s Substituted with the base, R 18Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl. Or, two R's 18 The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle. R 19 Each of these is 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.

[0263] In some embodiments, the compound of formula (VXIII) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0264] In some embodiments, R 8 These are, independently, hydrogen, halogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 This includes hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 deuteroalkyl, unsubstituted or substituted C1-C6 fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, and -C(=O)R 16 , -CO2R16 , or -C(=O)N(R 16 )2, Z is -NR 10 -or -O- R 10 These are hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. X 1 , X 2 , and X 3 Each of them operates independently in CR 11 or N, R 11 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 fluoroalkyl, -CN, -OH, and -OR. 17 , or -N(R 16 )2, B 1 is N or CR 12a And, B 2 is N or CR 12b And, R 12a and R 12b These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN, R 2 R is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 6-membered heteroaryl, or an unsubstituted or substituted monocyclic 5-membered heteroaryl, where if ring B is substituted, ring B has q examples of R 13 Replaced by, R 13 These are, independently, halogens, unsubstituted or substituted C1-C6 alkyls, unsubstituted or substituted C1-C6 fluoroalkyls, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -CN, -OH, and -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(R16 )2, Alternatively, R 2 is -C(=O)R 14 And, R 14 is an unsubstituted or substituted C1-C6 alkyl, C1-C6 deuteroalkyl, unsubstituted or substituted C3-C4 cycloalkyl, or unsubstituted or substituted 4-membered heterocycloalkyl, and the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is one or more R 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. s Substituted with the base, R 6 and R 7 These are, independently, hydrogen, deuterium, halogen, C1-C4 alkyl, or C1-C4 deuteroalkyl, Alternatively, one R bonded to the same carbon atom 6 and one R 7 These atoms, by becoming one with the carbon atom to which they are bonded, form a C=O or C3-C4 cycloalkyl group. R 16 Each of these is independently hydrogen, a C1-C6 alkyl, a C1-C6 fluoroalkyl, a C1-C6 heteroalkyl, a C3-C7 cycloalkyl, or a monocyclic 3- to 8-membered heterocycloalkyl. Alternatively, two R atoms on the same N atom 16 These, by becoming one with the N atom to which they are bonded, form a 4-6 member N-containing heterocycloalkyl group. R 17 These are, independently, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, or monocyclic 3- to 8-membered heterocycloalkyl.

[0265] In some embodiments, R 4R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0266] In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 is, or, X 1 CR 11 , X 2 CR 11 , X 3 is N, or X 1 CR 11 , X 2 is N, X 3 CR 11 is, or, X 1 is N, X 2 CR 11 , X 3 CR 11 In some embodiments, X 1 CR 11 , X 2 CR 11 , X 3 CR 11 In some embodiments, X1 CR 11 , X 2 CR 11 , X 3 In some embodiments, X 1 CR 11 , X 2 is N, X 3 CR 11 In some embodiments, X 1 is N, X 2 CR 11 , X 3 CR 11 That is the case.

[0267] In some embodiments, R 11 These are, independently, hydrogen, halogen, C1-C4 alkyl, C1-C4 fluoroalkyl, or -CN. In some embodiments, R 11 These are, independently, hydrogen, halogen, or -CN. In some embodiments, R 11 These are, independently, hydrogen or halogen. In some embodiments, R 11 These are, independently, hydrogen, fluoro, or chloro. In some embodiments, R 11 These are, independently, hydrogen or fluoro. In some embodiments, R 11 These are hydrogen atoms, respectively.

[0268] In some embodiments, the compound of formula (XV) is formula (VIc-1):

[0269] [ka] It is a compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

[0270] In some embodiments, the compound of formula (VIf-1) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0271] In some embodiments, R 4 R is hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, or C1-C6 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C6 alkyl group, or a C1-C6 deuteroalkyl group. In other embodiments, R 4 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or C1-C4 fluoroalkyl. In some embodiments, R 4 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 4 is hydrogen, a C1-C2 alkyl group, or a C1-C2 deuteroalkyl group. In some embodiments, R 4 is hydrogen, -CH3, -CH2D, -CHD2, or -CD3. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is -CH3. In some embodiments, R 4 It is -CD3.

[0272] In some embodiments, R 8 These are, independently, hydrogen, halogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, -CN, -OH, -OR 17 -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2, R 8 When bonded to a nitrogen atom, R 8 These include hydrogen, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C3-C6 cycloalkyl, 4-6 member heterocycloalkyl, and -C(=O)R 16 , -CO2R 16 , or -C(=O)N(R 16 )2. In some embodiments, R 8Each of these is independently hydrogen, -Cl, -F, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO2H, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 R is hydrogen, methyl, ethyl, isopropyl, -CD3, -CH2OH, -CF3, cyclopropyl, oxetanyl, azetidinyl, -CO2H, or -CO2CH3. In some embodiments, R 8 These are independently hydrogen, methyl, -CD3, -OH, -CH2OH, -CF3, oxetanyl, -CN, or -CO2CH3, and R 8 When bonded to a nitrogen atom, R 8 This is hydrogen, methyl, -CD3, -CH2OH, oxetanyl, or -CO2CH3.

[0273] In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, Cl, -CD3, or methyl. In some embodiments, R 6 and R 7 These are, independently, hydrogen, deuterium, F, or methyl. In some embodiments, R 6 and R 7 These are, 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 These are hydrogen atoms, respectively. In some embodiments, R 6 and R 7 These are deuterium, respectively. In some embodiments, R 6 and R 7 These are F, respectively.

[0274] In some embodiments, one R bonded to the same carbon atom 6 and one R 7These combine with the carbon atom to which they are bonded to form a C=O or C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These combine with the carbon atom to which they are bonded to form C=O. In some embodiments, one R bonded to the same carbon atom 6 and one R 7 These combine with the carbon atom to which they are bonded to form a C3-C4 cycloalkyl group. In some embodiments, one R is bonded to the same carbon atom. 6 and one R 7 These atoms combine with the carbon atoms to which they are bonded to form a cyclopropyl group.

[0275] 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.

[0276] In some embodiments, Z is -NR 10 - In some embodiments, R 10 is hydrogen, C1-C4 alkyl, C1-C4 deuteroalkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, C1-C4 alkyl, or cyclopropyl. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is hydrogen, -CH3, or -CD3. In some embodiments, R 10 is hydrogen, a C1-C4 alkyl group, or a C1-C4 deuteroalkyl group. In some embodiments, R 10 is -CH3 or -CD3. In some embodiments, R 10 is -CH3. In some embodiments, R 10 It is -CD3.

[0277] 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.

[0278] In some embodiments, Z is -O-.

[0279] In some embodiments, R 2 This is defined herein.

[0280] In some embodiments, the compounds described herein have the following structure:

[0281] [ka] It has B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8 This is as described herein. In some embodiments, B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8 These are as shown in Table 1. In some embodiments, the compound is neither 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyridine-4-yl)amino)-N-methylnicotinamide.

[0282] In some embodiments, the compounds described herein have the following structure:

[0283] [ka] It holds.

[0284] In some embodiments, B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8 This is as described herein. In some embodiments, B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8 This is as shown in Table 2.

[0285] In some embodiments, the compounds described herein have the following structure:

[0286] [ka] It has B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8 This is as described herein. In some embodiments, B 1 B 2 , R 2 , R 4 Z, n, R 6 , R 7 , and R 8These are as shown in Table 3. In some embodiments, the compound is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0287] In some embodiments, the compounds described herein have the following structure:

[0288] [ka] It has B 1 B 2 , NR 1 R 2 , W, R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , A 1 , A 2 , ring A, R 8 , and p are as described herein. In some embodiments, B 1 B 2 , NR 1 R 2 , W, R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , and

[0289] [ka] This is as described herein. In some embodiments, B 1 B 2 , NR 1 R 2 , W, R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , A 1 , A2 , ring A, R 8 , and p are as shown in Table 4. In some embodiments, B 1 B 2 , NR 1 R 2 , W, R 4 , X 1 , X 2 , X 3 , Z, R 6 , R 7 , and

[0290] [ka] The details are as shown in Table 4. In some embodiments, the compound is either 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide or 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinate It is neither amide, nor 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylnicotinamide, nor 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide.

[0291] In some embodiments, the compounds described herein have the following structure:

[0292] [ka] It holds.

[0293] In some embodiments, R 2 , R 4, and Z are as described herein. In some embodiments, R 2 , R 4 , and Z are as shown in Table 5.

[0294] Any combination of the groups described above for various variables is contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0295] Exemplary compounds described herein include those listed in the following table.

[0296] [Table 1-1]

[0297] [Table 1-2]

[0298] [Table 1-3]

[0299] [Table 1-4]

[0300] The compounds in Table 1 are named as follows: 1:6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 2:6-(cyclopropanecarboxamide)-N-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 3:6-[(5-fluoropyridine-2-yl)amino]-N-methyl-4-{[2-(oxetan-3-yl)-2H,4H-clomeno[4,3-c]pyrazole-6-yl]amino}pyridazine-3-carboxamide, 4:6-(cyclopropanecarboxamide)-N-methyl-4-((2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 5:6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 6:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 7:6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 8:6-((5-fluoropyridine-2-yl)amino)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 9:6-((2,6-dimethylpyrimidine-4-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 10:6-(cyclopropanecarboxamide)-4-((2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-N-methylpyridazine-3-carboxamide, 11:4-((2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylpyridazine-3-carboxamide, 12:(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylpyridazine-3-carboxamide), 13:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)nicotinamide, 14:[6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide], 15:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 16:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-(methyl-d3)nicotinamide, 17:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 18:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylnicotinamide, 19:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 20:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 21:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(1-hydroxycyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 22:2-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide, 23:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 24:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(oxetane-3-carboxamide)nicotinamide, 25:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide, 26:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 27:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 28:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 29:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 30:(S)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 31:(R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 32:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2R)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 33:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 34:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylpyridazine-3-carboxamide, 35:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 36:rel-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 37:6-(cyclopropanecarboxamide)-4-((2-isopropyl-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 38:6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((2-methyl-4,5-dihydro-2H-benzo[2,3]oxepino[4,5-c]pyrazole-7-yl)amino)pyridazine-3-carboxamide, 39:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(2-hydroxy-2-methylpropanamide)-N-(methyl-d3)nicotinamide, 40:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(1-methylazetidine-3-carboxamide)nicotinamide, 41: Methyl(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-5-((methyl-d3)carbamoyl)pyridine-2-yl)carbamate, 42:3-(cyclopropanecarboxamide)-5-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide, 43:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 44:6-(cyclopropanecarboxamide)-4-((4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 45:4-((2,5-bis(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide, 46:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)nicotinamide, 47:6-(cyclopropanecarboxamide)-4-((4,4-difluoro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 48:6-(cyclopropanecarboxamide)-4-((4,4-difluoro-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, and 91:6-(cyclopropanecarboxamide)-4-((2-isopropyl-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0301] In some embodiments herein, pharmaceutically acceptable salts of the compounds listed in Table 1 are provided.

[0302] [Table 2]

[0303] The compounds in Table 2 are named as follows: 49:6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 50:6-(cyclopropanecarboxamide)-N-methyl-4-((1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, and 51:6-(cyclopropanecarboxamide)-4-((1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide.

[0304] In some embodiments herein, pharmaceutically acceptable salts of the compounds listed in Table 2 are provided.

[0305] [Table 3]

[0306] The compounds in Table 3 are named as follows: 52:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 53:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-(methyl-d3)nicotinamide, 54:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)pyridazine-3-carboxamide, 55:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)nicotinamide, 56:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 57:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 58:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)pyridazine-3-carboxamide, and 59:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)aminonicotinamide.

[0307] In some embodiments herein, pharmaceutically acceptable salts of the compounds listed in Table 3 are provided.

[0308] [Table 4-1]

[0309] [Table 4-2]

[0310] [Table 4-3]

[0311] [Table 4-4]

[0312] The compounds in Table 4 are named as follows: 60: Methyl 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)aminonicotinate, 61:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(3-isopropyl-2-oxoimidazolidine-1-yl)-N-(methyl-d3)nicotinamide, 62:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(N-methylcyclopropanecarboxamide)pyridazine-3-carboxamide, 63:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-6-(3-isopropyl-2-oxoimidazolidine-1-yl)-N-(methyl-d3)nicotinamide, 64:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)-N-(methyl-d3)nicotinamide, 65:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 66:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)nicotinamide, 67:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 68:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 69:(S)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 70:(R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 71:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)nicotinamide, 72:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 73:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 74:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 75:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide, 76:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 77:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 78:(R)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 79:4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 80:(S)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 81:(R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)pyridazine-3-carboxamide, 82:6-(cyclopropanecarboxamide)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 83:6-(cyclopropanecarboxamide)-4-((8-fluoro-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 84:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,6]naphthyridine-6-yl)amino)nicotinamide, 85:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,6]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 86:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizin-6-yl)amino)nicotinamide, and 87:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide.

[0313] In some embodiments herein, pharmaceutically acceptable salts of the compounds listed in Table 4 are provided.

[0314] [Table 5]

[0315] The compounds in Table 5 are named as follows: 88:N-(2-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide, 89:N-(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide, and 90:N-(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-2-(methyl-d3)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide.

[0316] In some embodiments herein, pharmaceutically acceptable salts of the compounds listed in Table 5 are provided.

[0317] In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, the compounds described herein may exist in an unsolvated form as well as in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

[0318] "Pharmacologically acceptable" as used herein means a material, such as a carrier or diluent, that does not halt the bioactivity or properties of a compound and is relatively non-toxic at the concentration or amount used, i.e., the material is administered to an individual without causing any undesirable biological effects or harmful interactions with any composition containing the compound.

[0319] The term "pharmaceutically acceptable salt" refers to a therapeutically active drug form consisting of the cation form of a therapeutically active drug in combination with a suitable anion, or, in alternative embodiments, the anionic form of a therapeutically active drug in combination with a suitable cation. (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PHStahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are typically more soluble than nonionic species and dissolve rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, since their solubility is often pH-dependent, selective dissolution in one or another part of the digestive tract is possible, and this ability can be manipulated as a form of delayed release and sustained release behavior. In addition, since the molecules that form salts can be in equilibrium with the neutral form, their passage through biological membranes can be regulated.

[0320] In some embodiments, pharmaceutically acceptable salts are obtained by reacting the compound of formula (I) with an acid. In some embodiments, the compound of formula (I) (i.e., the free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and gluten. Examples of undecylenic acids include, but are not limited to, cornic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0321] In some embodiments, the compound of formula (I) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

[0322] In some embodiments, pharmaceutically acceptable salts are obtained by reacting the compound of formula (I) with a base. In some embodiments, the compound of formula (I) is acidic and reacts with a base. In such circumstances, the acidic proton of the compound of formula (I) is replaced by a metal ion, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein cooperate with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts having amino acids such as arginine and lysine, though not limited to these. Acceptable inorganic bases used to form salts having compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0323] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, the solvates contain either stoichiometric or nonstoichiometric amounts of solvent and are formed during a crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein are optionally available in both unsolvated and solvated forms.

[0324] The methods and formulations described herein also include the use of N-oxides (where appropriate) or pharmaceutically acceptable salts of compounds having the structure of formula (I), as well as active metabolites of these compounds having the same type of activity.

[0325] In some embodiments, the site on the organic radical of the compound of formula (I) (e.g., alkyl group, aromatic ring) is susceptible to various metabolic reactions. The incorporation of appropriate substituents on the organic radical will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents to reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions include, but are not limited to, halogens, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0326] In another embodiment, the compounds described herein are labeled isotopically (e.g., by radioisotopes) or by other means including, but not limited to, the use of chromogenic groups or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0327] The compounds described herein include isotope-labeled compounds, which are identical to those listed in the various formulas and structures presented herein, but in which one or more atoms are replaced with atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, iodine, and phosphorus, for example, 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 33P is one example. In one embodiment, an isotope-labeled compound as described herein, for example, 3 H 14 Incorporation of radioactive isotopes such as 13C is useful in drug and / or substrate distribution assays within tissues. In one embodiment, substitution with isotopes such as deuterium results in specific therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced required dose.

[0328] In some embodiments, the compound of formula (I) has one or more stereocenters, each stereocenter independently existing in either an R or S configuration. In some embodiments, the compound of formula (I) exists in the R configuration. In some embodiments, the compound of formula (I) exists in the S configuration. The compounds presented herein include enantiomers, atrop isomers, and epimer forms, as well as suitable mixtures thereof. The compounds and methods presented herein also include cis, trans, syn, anti, entgegen (E), and tuzamen (Z) isomers, as well as suitable mixtures thereof.

[0329] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography columns, separation of diastereomers by either non-chiral or chiral chromatography columns, or crystallization and recrystallization of a suitable solvent or solvent mixture. In certain embodiments, the 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 diastereoisomer compounds / salts, separating the diastereomers, and recovering the optically pure individual enantiomers. In some embodiments, the separation of individual enantiomers is carried out using covalent diastereomer derivatives of the compounds described herein. In other embodiments, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is carried out by chromatography, or by separation of diastereomer salts resulting from recrystallization, chromatography, or a combination thereof. "Enantiomers, Racemates and Resolutions" by Jean Jacques, Andre Collet, and Samuel H. Wilen, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0330] In some embodiments, the compounds described herein are prepared as prodrugs. A “prodrug” refers to a drug that is converted to a parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than parent drugs. For example, they are available to the organism by oral administration, whereas the parent drug is not. Furthermore, or alternatively, prodrugs also have improved solubility in pharmaceutical compositions compared to parent drugs. In some embodiments, the design of the prodrug improves its effective water solubility. Non-limiting examples of prodrugs are the compounds described herein, which are administered as esters (“prodrugs”) but are subsequently hydrolyzed by metabolism to provide an active entity. Further examples of prodrugs are short-chain peptides (polyamino acids) in which the peptide is metabolized and bound to an acid group that reveals the active site. In certain embodiments, for in vivo administration, the prodrug is chemically converted to a biological, pharmaceutical, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutical, or therapeutically active compound form by one or more steps or processes.

[0331] Prodrugs of 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. For example, see Design of Prodrugs, edited by A. Bundgaard, Elseview, 1985 and Method in Enzymology, edited by K. Widder et al., Academic, 1985, Vol. 42, pp. 309-396; Design and Application of Prodrugs, A Textbook of Drug Design and Development, by H. Bundgaard, Krosgaard-Larsen and H. Bundgaard, 1991, Chapter 5, pp. 113-191; and Advanced Drug Delivery Review, by H. Bundgaard, 1992, 8, pp. 1-38. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, in which case the hydroxyl group is incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, etc. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug in which the hydroxyl group is subsequently metabolized in vivo to yield a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug) which subsequently yields a carboxylic acid group through in vivo metabolism. In some embodiments, the compounds described herein are prepared as prodrugs of alkyl esters.

[0332] The claims include prodrug forms of the compounds described herein, wherein 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 other derivatives or active compounds.

[0333] In some embodiments, one of a hydroxyl group, an amino group, and / or a carboxylic acid group is preferably functionalized to yield a prodrug moiety. In some embodiments, this prodrug moiety is as described above.

[0334] In additional or further embodiments, the compounds described herein are metabolized after administration to an organism requiring them, producing metabolites which are subsequently used to produce desired effects, including desired therapeutic effects.

[0335] The “metabolites” of the compounds disclosed herein are derivatives of the compound formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of the compound formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the entire process by which a particular substance is altered by a living organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions). Enzymes may cause structural alterations specific to a 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. The metabolites of the compounds disclosed herein are optionally identified by either administration of the compound to a host and analysis of numerous host-derived tissue samples, or by in vitro incubation of the compound with hepatocytes and analysis of the resulting compound.

[0336] In some examples, the heterocycle may exist in a tautomerized form. In such circumstances, the structure of the compound is exemplified or specified in one tautomerized form, but it is understood that alternative tautomerized forms may also be exemplified or specified. Alternative tautomerized forms, such as the structures exemplified below, are explicitly included in this disclosure. For example, pyridone has the following tautomerized forms:

[0337] [ka] These can exist in the following tautomer forms, all of which are encapsulated within the "substituted pyridine" group. Similarly, triazolone has the following tautomer forms, including the amphoteric form:

[0338] [ka] These can exist within a "substituted five-membered heteroaryl" group, and all of them are encapsulated within this group. Similarly, pyrazoles, triazoles, pyrimidines, etc., are known to tautomerize. For the purposes of this disclosure, all tautomer forms (including charged and amphoteric tautomers) are considered within the scope of this disclosure.

[0339] Compound Synthesis The compounds of formula (I) described herein are synthesized using standard synthesis techniques or by methods known in the art in combination with the methods described herein.

[0340] Unless otherwise specified, conventional mass spectrometry, NMR, and HPLC will be used.

[0341] 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 used, including variations in solvent, reaction temperature, reaction time, different chemical reagents, and other reaction conditions.

[0342] In some embodiments, the compounds described herein are prepared as described in Scheme A.

[0343] [ka] The variables are as defined in equation (I).

[0344] In some embodiments, nucleophilic substitution of one chloro group of intermediate A with a free amino group of B results in intermediate C. In some embodiments, for example, intermediate A is a pyridazine compound (B 1 If =N, this substitution can be carried out with a suitable Lewis acid such as Zn(OAc)2. In other embodiments, for example, intermediate B is a pyridine compound (B 1 If the result is CH, this substitution is carried out by deprotonation of the amino group with a suitable base such as LDA. In yet another embodiment, intermediate C may be dealt with by a cross-coupling reaction of intermediates A and B. The cross-coupling reaction may be an organometallic cross-coupling such as the Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, or Chan-Lam coupling. Finally, in some embodiments, intermediate C is converted to the final compound D (e.g., compound 1) via a cross-coupling reaction. The cross-coupling reaction may be an organometallic cross-coupling such as the Suzuki-Miyaura reaction, Buchwald-Hartwig reaction, Heck reaction, Ullman coupling, or Chan-Lam coupling.

[0345] In some embodiments, the compound is prepared as described in the examples.

[0346] Specific terms Unless otherwise specified, the following terms used in this application have the definitions given below. The use of other forms of the term, such as "include," "includes," and "included," in addition to "including," is not limited to these. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein.

[0347] When used herein, C1-C x C1-C2, C1-C3...C1-C x This includes. For example, a group designated as "C1-C6" indicates that the group contains 1 to 6 carbon atoms in that part, i.e., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. For example, "C1-C4 alkyl" indicates that 1 to 4 carbon atoms are present in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0348] The "alkyl" group refers to an aliphatic hydrocarbon group. Alkyl groups can be branched or linear. In some embodiments, the "alkyl" group consists of 1 to 10 carbon atoms, i.e., C1-C 10Alkyl is present. Wherever it appears herein, numerical ranges such as "1 to 10" refer to each integer within a given range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but this definition also covers appearances of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is a C1-C6 alkyl. In one embodiment, the alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, or hexyl.

[0349] The "alkylene" group refers to a divalent alkyl radical. Any of the monovalent alkyl groups mentioned above may be alkylenes obtained by extracting 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-, and -CH2CH2CH2CH2-. In some embodiments, the alkylene is -CH2-.

[0350] The "alkoxy" group refers to an (alkyl)O- group, where alkyl is defined as herein.

[0351] The term "alkylamine" is -N(alkyl) x H y The base is such that x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0352] "Hydroxyalkyl" refers to an alkyl group in which one hydrogen atom is substituted by a hydroxyl group. In some embodiments, the hydroxyalkyl group is a C1-C4 hydroxyalkyl group. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and -CH2CH2CH2CH2OH.

[0353] "Aminoalkyl" refers to an alkyl group in which one hydrogen atom is substituted with an amino acid. In some embodiments, the aminoalkyl is a C1-C4 aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, and -CH2CH2CH2CH2NH2.

[0354] The term "alkenyl" refers to a type of alkyl group that has at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the rest of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0355] The term "alkynyl" refers to a type of alkyl group that has at least one carbon-carbon triple bond. In one embodiment, the alkenyl group has the formula -C≡CR, where R refers to the rest of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0356] The term "heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or a combination thereof). In heteroalkyl groups, the rest of the molecule is bonded at the carbon atoms of the heteroalkyl group. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group.

[0357] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons. The term "aromatic" includes both carbocyclic aryl ("aryl," e.g., phenyl) and heterocyclic aryl (i.e., "heteroaryl" or "heterocyclic aromatic") groups (e.g., pyridine). The term includes monocyclic or polycyclic (i.e., rings sharing pairs of adjacent carbon atoms) groups.

[0358] The term "carbocyclic" or "carbocyclic" refers to a ring or ring system in which all atoms forming the ring's framework are carbon atoms. Therefore, this term distinguishes a carbocyclic from a "heterocyclic" ring or "heterocyclic" ring, which has at least one atom other than carbon in its ring framework. In some embodiments, at least one of the two rings in a bicyclic carbocyclic is aromatic. In some embodiments, both rings in a bicyclic carbocyclic are aromatic. Carbocyclics include aryl and cycloalkyl groups.

[0359] As used herein, the term “aryl” refers to an aromatic ring in which each of the ring-forming atoms is a carbon atom. In one embodiment, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, the aryl is C6-C 10 It is an aryl group. Depending on the structure, the aryl group is either a monoradical or a diradical (i.e., an arylene group).

[0360] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, where each of the ring-forming atoms (i.e., skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or crosslinked compounds. In some embodiments, cycloalkyls are optionally condensed with an aromatic ring, with the bonding site located on a carbon atom other than the aromatic ring carbon atom. Cycloalkyls include groups having 3 to 10 ring atoms. In some embodiments, cycloalkyls are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicycle[1.1.1]pentyl. In some embodiments, cycloalkyls are C3-C6 cycloalkyls. In some embodiments, cycloalkyls are C3-C4 cycloalkyls.

[0361] The term "halo," or alternatively "halogen" or "halide," refers to fluoro, chloro, bromo, or iodine. In some embodiments, the halo is fluoro, chloro, or bromo.

[0362] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are substituted with fluorine atoms. In one embodiment, the fluoroalkyl group is a C1-C6 fluoroalkyl group.

[0363] The term "heterocyclic" or "heterocyclic" refers to heterocyclic aromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing 1 to 4 heteroatoms, where each heteroatom is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, but none of the rings contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings with 3 to 10 atoms in their ring system, and aromatic heterocyclic groups contain rings with 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-condensed ring systems. Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinol, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azilidinyl, 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, and dithio These include lanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indoline-2-onyl, isoindoline-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinoline-1(2H)-onyl, 3,4-dihydroquinoline-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazole-2(3H)-onyl, 1H-benzo[d]imidazole-2(3H)-onyl, benzo[d]thiazole-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, sinnolinyl, indazolyl, indolidinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, flazanyl, benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthylidinyl, and phlopyridinyl. The aforementioned groups are, if possible, carbon-bonded (i.e., C-linked) or nitrogen-bonded. For example, pyrrole-derived groups include pyrrole-1-yl (N-bonded) or pyrrole-3-yl (C-bonded). Furthermore, imidazole-derived groups include imidazole-1-yl or imidazole-3-yl (both N-bonded), or imidazole-2-yl, imidazole-4-yl, or imidazole-5-yl (all C-bonded). Heterocyclic groups include benzo-condensed ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidine-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0364] The term "heteroaryl," or alternatively "heterocyclic aromatic," refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic 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 fluzanyl. Monocyclic heteroaryls include indidine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl ring contains 0 to 4 N atoms. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms. In some embodiments, the heteroaryl ring contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom. In some embodiments, the heteroaryl ring 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-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0365] The “heterocycloalkyl” group refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group is condensed with an aryl or heteroaryl group. In some embodiments, the heterocycloalkyl group is oxazolidinol, pyrrolidinol, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidine-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinol, imidazolidinyl, imidazolidinyl-2-onyl, or thiazolidinyl-2-onyl. In one embodiment, the heterocycloalkyl group is C2-C 10 It is a heterocycloalkyl. In another embodiment, the heterocycloalkyl is C4-C 10 It is a heterocycloalkyl. In some embodiments, the heterocycloalkyl is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl is monocyclic and has a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3, 4, 5, or 6-membered ring. In some embodiments, the heterocycloalkyl is monocyclic and has a 3 or 4-membered ring. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atom in the ring.

[0366] The terms “bond” or “single bond” refer to a chemical bond between two atoms, or between two parts when the atoms linked by the bond are considered to be part of a larger substructure. In one embodiment, if the group described herein is a bond, the group mentioned is absent, thereby allowing a bond to form between the remaining identified groups.

[0367] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is often understood as a chemical entity that is embedded in or added to a molecule.

[0368] The terms "optionally substituted" or "substituted" mean that the group mentioned is optionally substituted by one or more additional groups individually and independently selected from halogens, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituent is independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl, and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituent is independently selected from halogens, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, the substituted group is substituted with one or two of the aforementioned groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0369] In some embodiments, substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are deuterium, halogen, C1-C6 alkyl, monocyclic carbocyclic, monocyclic heterocyclic, -CN, -OR, respectively. 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 2 s Substituted with R 18 Each of these is independently selected from hydrogen, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl, or two R 18 The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle, R 19 Each of these is independently selected from C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.

[0370] When used herein, the term “acceptable” in relation to a formulation, composition, or component means that it does not have any lasting adverse effect on the health of the subject being treated.

[0371] When used herein, the term “modulate” means to interact with a target, either directly or indirectly, in order to modify its activity, including, but not limited to, enhancing, inhibiting, limiting, or expanding its activity.

[0372] The term "modulator," as used herein, refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an antagonist. In some embodiments, the modulator is an inhibitor.

[0373] The terms “administer,” “administering,” and “administration,” as used herein, refer to methods that may be used to enable the delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art will be familiar with the administration techniques available with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0374] When used herein, terms such as “co-administration” mean the administration of a selected therapeutic agent 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.

[0375] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an agent or compound administered that, to some extent, alleviates one or more symptoms of the disease or illness being treated. Results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or other desired alterations of the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing the compound disclosed herein required to produce a clinically significant reduction in disease symptoms. The appropriate “effective” dose in any individual case is determined at will using techniques such as dose-escalation studies.

[0376] The terms “enhance” or “enhancing,” as used herein, mean increasing or extending a desired effect in terms of either potency or duration. Therefore, with respect to the enhancement of the effect of a therapeutic agent, “enhancing” refers to the ability to increase or extend the effect of another therapeutic agent on a system in terms of either potency or duration. “Amount effective for enhancement,” as used herein, refers to an appropriate amount for enhancing the effect of another therapeutic agent on a desired system.

[0377] The term "pharmaceutical combination," as used herein, means a product obtained by mixing or combining one or more active ingredients, and includes both fixed and unfixed combinations of active ingredients. The term "fixed combination" means that an active ingredient, e.g., the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent are administered together to the patient simultaneously in the form of a single entity or dose. The term "unfixed combination" means that an active ingredient, e.g., the compound of formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent are administered to the patient simultaneously, concurrently, or sequentially as separate entities without the intervention of specific time constraints, thereby providing the patient's body with effective levels of two compounds. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0378] The terms "manufactured product" and "kit" are used as synonyms.

[0379] The terms “subject” or “patient” encompass mammals. Examples of mammals include, but are not limited to, members of any of the following mammalian classifications: humans, non-human primates such as chimpanzees, other apes and monkey species, domestic animals such as cattle, horses, sheep, goats and pigs, household animals such as rabbits, dogs and cats, and laboratory animals such as rats, mice and guinea pigs. In one aspect, a mammal is a human.

[0380] When used herein, “treat,” “treating,” or “treatment” includes, for example, alleviating, reducing or improving at least one symptom of a disease or illness; preventing additional symptoms; inhibiting a disease or illness, such as preventing the onset or progression of a disease or illness; mitigating a disease or illness; causing regression of a disease or illness; alleviating complications arising from a disease or illness; or preventing and / or curatively stopping the symptoms of a disease or illness.

[0381] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are conventionally formulated using one or more pharmaceutically acceptable inactive components that facilitate the processing of the active compound into a preparation for use as a pharmaceutical. The appropriate formulation depends on the selected route of administration. Outlines of the 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, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0382] The compounds or pharmaceutical compositions of this disclosure are useful in some embodiments 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 in which a reduction in TYK2 activity or expression would be beneficial.

[0383] In some embodiments, the pharmaceutical composition is useful for treating diseases or disorders associated with high levels of cytokines driven by TYK2, such as interferons (e.g., IFN-α, IFN-β, IFN-K, IFN-δ, IFN-ε, IFN-τ, IFN-CO, and IFN-ζ (also known as limitin)), as well as 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 interferonopathy such as Ecardi-Goutierre syndrome, or a combination thereof.

[0384] In some embodiments, the pharmaceutical composition is useful for treating inflammatory diseases or disorders. In some embodiments, the inflammatory disease or disorder is an autoinflammatory disease or disorder, a host-mediated inflammatory disease or disorder, a damage-related inflammatory disease or disorder, an infection-related inflammatory disease or disorder, or an overgrowth (e.g., cancer, fibrosis)-mediated inflammatory disease or disorder. In some embodiments, the inflammatory disease or disorder, or infection-related inflammatory disease or disorder, is a respiratory disease or disorder. In some embodiments, the respiratory disease or disorder is related to viruses in microbial infections. 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 related to coronaviruses such as MERS-CoV, SARS-CoV-1, or SARS-CoV-2. In some embodiments, the pharmaceutical composition is effective in reducing symptoms associated with COVID-19 or the associated immune response.

[0385] In some embodiments, the pharmaceutical composition is useful for treating autoimmune diseases or disorders. In some embodiments, the autoimmune diseases or disorders are rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, lupus, systemic lupus erythematosus, Sjögren's syndrome, ankylosing spondylitis, vitiligo, atopic dermatitis, scleroderma, alopecia, hidradenitis suppurativa, uveitis, dry eye, intestinal diseases, Crohn's disease, ulcerative colitis, celiac disease, Behçet's disease, type 1 diabetes, systemic sclerosis, and idiopathic pulmonary fibrosis. In some embodiments, the autoimmune disease or disorder is lupus or systemic lupus erythematosus. In some embodiments, the autoimmune disease or disorder is psoriasis. In some embodiments, the autoimmune disease or disorder is irritable bowel disease (IBS) or irritable bowel disease with diarrhea (IBS-D). In some embodiments, the autoimmune disease or disorder is dry eye or uveitis. In some embodiments, the autoimmune disease or disorder is Crohn's disease. In some embodiments, the autoimmune disease or disorder is atopic dermatitis.

[0386] In some embodiments, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, additives, or excipients in pharmaceutical compositions. Administration of the compounds and compositions described herein can be achieved by any means that enables delivery of the compounds to the site of action. These methods include, but are not limited to, delivery via intestinal routes (including oral, gastric or duodenal nutrient tube, transrectal drugs, and rectal enemas), parenteral routes (injection or infusion including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrasacral, intravascular, intravenous, intravitreous, epidural, and subcutaneous), inhalation, transdermal, oral mucosa, sublingual, buccal, and topical (epithelial, skin, enema, eye drops, ear drops, intranasal, and vaginal) administration, and the most preferred route may depend, for example, on the recipient's condition or impairment. As just one example, the compounds described herein can be administered topically to the area requiring treatment, for example, by topical application such as creams or ointments. 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 composition is administered orally (for example, as a liquid formulation, tablet, capsule, mist of liquid, aerosolized liquid, or spray of dry powder).

[0387] In some embodiments, pharmaceutical compositions suitable for oral administration are provided as separate units such as capsules, cachetes, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. In some embodiments, the active ingredient is provided as pills, licks, or pastes.

[0388] Pharmaceutical compositions for oral administration include tablets, gelatin push-fit capsules, and soft-seal capsules made of gelatin and plasticizers such as glycerol and sorbitol. Tablets may be produced by compression or casting, optionally with one or more minor components. Compressed tablets may be prepared by compressing an active ingredient in a free-flowing form, such as a powder or granules, mixed with an optionally binder, inert diluent, or lubricant, surfactant, or dispersant, using a suitable machine. Wet tablets may be produced by molding a mixture of powdered compounds moistened with an inert liquid diluent using a suitable machine. In some embodiments, tablets are coated or scored to provide delayed or controlled release of the active ingredient within. All formulations for oral administration must be in a dosage suitable for such administration. Push-fit capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The sugar-coated tablet core is coated with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets or sugar-coated tablets to identify or characterize different combinations of active compound dosages.

[0389] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, such as bolus injection or continuous infusion. Formulations for injection may be provided in unit dosage forms, such as ampoules with preservatives or multi-dose containers. The composition may exist in the form of a suspension, solution, or emulsion in an oily or aqueous vehicle and may contain formulation agents such as suspending agents, stabilizers, and / or dispersing agents. The composition may be provided in unit or multi-dose containers, such as sealed ampoules or vials, in powder form, or stored under freeze-drying conditions requiring only the addition of a sterile liquid carrier, such as physiological saline or pyrogenically decontaminated distilled water, immediately before use. Solutions and suspensions for immediate injection may be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0390] The pharmaceutical composition may also be formulated as a Devot preparation. Such long-acting preparations may be administered by implantation (e.g., subcutaneously). For this purpose, the compound may be formulated with a suitable polymer material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a slightly soluble derivative, for example, as a slightly soluble salt.

[0391] The pharmaceutical composition may be administered topically, which is done by non-systemic administration. This includes the application of the compound to the epidermis or outside the cheek cavity, such that the compound does not significantly enter the bloodstream, as well as the introduction of the compound into the ear, eye, and nose. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0392] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin into the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eyes, ears, or nose. The active ingredient may be present in a concentration of 0.001% to 10% w / w of the formulation, for example, 1% to 2% by weight, for topical administration.

[0393] Pharmaceutical compositions for inhalation administration are conveniently delivered by air inhalers, nebulizers, pressurized packs, or other convenient means of delivering aerosol sprays. Pressurized packs may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dose unit may be determined by providing a valve for delivering the measured amount. Alternatively, for administration by inhalation or venting, the pharmaceutical preparation may be in the form of a dry powder composition, for example, a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be provided in unit dose forms, such as capsules, cartridges, gelatin, or blister packs, in which the powder can be administered with the assistance of an inhaler or air inhaler.

[0394] In addition to the components specifically described above, the compounds and compositions described herein may also include other conventional agents in the art, depending on the type of formulation in question. For example, those suitable for oral administration may include fragrances.

[0395] Medication methods and treatment regimens In one embodiment, the compounds described herein, or pharmaceutically acceptable salts, tautomers, or solvates thereof, are used to prepare agents for the treatment of mammalian diseases or illnesses that benefit from the modulation of TYK2 activity. A method for treating any of the mammalian diseases or illnesses described herein that require such treatment comprises administering to a mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate thereof.

[0396] In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic purposes. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or illness in an amount sufficient to cure or partially block at least one of the symptoms of the disease or illness. The effective dose for this use depends on the severity and course of the disease or illness, the patient's treatment history, the patient's health status, weight, and response to the drug, as well as the judgment of the physician administering the treatment. The therapeutically effective dose may be determined at the discretion of methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0397] For preventive purposes, compositions containing the compounds described herein are administered to patients who are sensitive to or otherwise at risk of a particular disease, disorder, or illness. Such amounts are defined as “an effective amount or dose for prevention.” In this use, the exact amount also depends on the patient’s health condition, weight, etc. When administered to a patient, the effective amount for this use depends on the severity and course of the disease, disorder, or illness, the patient’s treatment history, the patient’s health condition and response to the drug, and the judgment of the physician administering the treatment. In one embodiment, preventive treatment involves administering a pharmaceutical composition containing the compounds described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously suffered at least one symptom of the disease being treated and is currently in remission, in order to prevent the recurrence of the disease or symptoms of the illness.

[0398] In certain embodiments where the patient's condition does not improve, the compound may be administered over a long period, including the patient's entire lifespan, at the physician's discretion, to alleviate or otherwise control or limit the symptoms of the patient's disease or illness.

[0399] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dose, or frequency of administration, or both, is reduced to a level that maintains improvement in the disease, impairment, or illness, depending on the symptoms. However, in certain embodiments, the patient requires intermittent treatment over a long period of time in response to any recurrence of symptoms.

[0400] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the state and severity of the disease, and the identity of the subject or host requiring treatment (e.g., weight, sex). Nevertheless, it is determined by the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the disease being treated, and the subject or host being treated.

[0401] However, doses used for treating adult humans are typically in the range of 0.01 mg / day to 2000 mg / day. In one embodiment, the desired dose is conveniently provided as a single dose, or as divided doses administered simultaneously or at appropriate intervals as subdose, for example, two, three, four, or more times per day.

[0402] In one embodiment, an appropriate daily dose of the compounds described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form is less or more than the range shown herein, based on many variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose are modified depending on many variables, including but not limited to the activity of the compound used, the disease or illness being treated, the form of administration, the requirements of the individual subject, the severity of the disease or illness being treated, and the judgment of the healthcare professional.

[0403] The toxicity and therapeutic efficacy of such treatment regimens are LD 50 and ED 50This is determined by standard pharmaceutical procedures for cell cultures or experimental animals, including but not limited to the determination of the following: The dose-to-toxicity ratio is the therapeutic index, which is the LD50. 50 and ED 50 This is expressed as a ratio to . In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or a therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is the ED with minimal toxicity. 50 It is within the range of circulating concentrations, including [specific component]. In certain embodiments, the daily dose range and / or unit dose varies within this range depending on the dosage form used and the route of administration used.

[0404] Any of the embodiments described herein is a further embodiment in which an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is administered (a) systemically to a mammal and / or (b) orally to a mammal and / or (c) intravenously to a mammal and / or (d) by injection to a mammal and / or (e) topically to a mammal and / or (f) non-systemically or topically to a mammal.

[0405] Any of the embodiments described above is a further embodiment comprising a single dose of an effective amount of the compound, including (i) the compound is administered once daily, or (ii) the compound is administered to a mammal multiple times during the day.

[0406] Any of the embodiments described above is a further embodiment involving multiple doses of an effective amount of the compound, including a further embodiment in which (i) the compound is administered in a single dose, continuously or intermittently, (ii) the interval between multiple doses is 6 hours, (iii) the compound is administered to a mammal every 8 hours, (iv) the compound is administered to a mammal every 12 hours, and (v) the compound is administered to a mammal every 24 hours. In further or alternative embodiments, the method includes a drug-free day, during which the administration of the compound is temporarily discontinued or the dose of the compound being administered is temporarily reduced, and the administration of the compound is resumed at the end of the drug-free day. In one embodiment, the length of the drug-free day varies from 2 days to 1 year.

[0407] Combination therapy In certain cases, it is appropriate to administer at least one of the compounds described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0408] In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic benefit, but when combined with another therapeutic agent, it enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit received by the patient is enhanced by administering one of the compounds described herein together with another agent (including a therapeutic regimen) that also has a therapeutic benefit.

[0409] In a specific embodiment, the compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, in which case the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent together provide greater overall benefits than either therapeutic agent alone, by modulating various aspects of the disease, disorder, or illness being treated.

[0410] In all cases, regardless of the disease, disorder, or illness being treated, the overall benefit received by the patient may be simply the additive effect of the two treatments, or the patient may receive a synergistic benefit.

[0411] In the combination therapies described herein, the dosage of co-administered compounds varies depending on the type of co-drug used, the specific drug used, the disease or illness being treated, etc. In additional embodiments, when the compounds provided herein are co-administered with one or more other therapeutic agents, they are administered simultaneously with or sequentially with one or more other therapeutic agents.

[0412] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) may be administered in any order or simultaneously. When administered simultaneously, the multiple therapeutic agents may be provided in single-dose, combined-dose, or multi-dose forms (e.g., one pill or two separate pills), as just a few examples.

[0413] The compounds described herein, or their pharmaceutically acceptable salts, as well as combination therapies, are administered before, during, or after the onset of a disease or illness, and the timing of administration of compositions containing the compounds varies. For this reason, in one embodiment, the compounds described herein are used as prophylactic agents and are administered sequentially to subjects prone to developing a disease or illness in order to prevent the onset of the disease or illness. In another embodiment, the compounds and compositions are administered to the subject at the onset of symptoms or as soon as possible after the onset. In a specific embodiment, the compounds described herein are administered as soon as possible after the onset of a disease or illness is detected or suspected, and for the duration necessary to treat the disease. In some embodiments, the length of treatment varies, and the length of treatment is adjusted to meet the specific needs of each subject. [Examples]

[0414] As used above and throughout the description of this invention, the following abbreviations are understood to have the following meanings unless otherwise specified. Abbreviation: ACN Acetonitrile CAN Ammonium nitrate cerium DCM Dichloromethane DIBAL Diisobutylaluminum Hydrogenate DIPEA N,N-diisopropylethylamine DMA (dimethylacetamide) DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) HCl 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-piperazine ethanesulfonic acid HMD (Bis(trimethylsilyl)amide) HPLC (High-Pressure Liquid Chromatography) HTRF homogenization time decomposition 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 Inhalation) MW Microwave NMR nuclear magnetic resonance SEAP secreted embryonic alkaline phosphatase STAT signaling and transcriptional activator T3P Propanephosphonic Acid Anhydride TBAF Tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) TYK non-receptor tyrosine protein kinase

[0415] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0416] Compound Synthesis Example 1: Preparation of 2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-1):

[0417] [ka]

[0418] Step 1: 3-Bromo-2-(propa-2-in-1-yloxy)benzaldehyde (I-1b): 3-Bromo-2-hydroxybenzaldehyde I-1a (10.0 g, 49.7 mmol) was mixed in DMF (500.0 mL) and anhydrous K2CO3 (20.6 g, 149 mmol) was added at 0°C and the mixture was stirred for 10 minutes. Then, propargyl bromide (7.54 g, 99.5 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After complete removal of the starting materials, water (250 mL) was added to the reaction mixture, and extraction was performed using siRNA (100 mL three times). The combined organic extracts were washed with water (100 mL three times) and brine (100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain 3-bromo-2-(propa-2-in-1-yloxy)benzaldehyde I-1b (11.3 g) as a yellow solid. LCM(ES)m / z;239.1[M+H] + .

[0419] Step 2: 6-bromo-2,4-dihydrochromeno[4,3-c]pyrazole (I-1c):I-1b (11.3 g, 47.3 mmol) was mixed with MeOH (25.0 mL) and water (25.0 mL) and KOtBu (8.03 g, 70.9 mmol) and p-toluenesulfonyl hydrazide (17.6 g, 93.8 mmol) were added at room temperature. The reaction mixture was then stirred at 70 °C for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was cooled to room temperature and water (250 mL) was added. Extraction was performed with ELISA (100 mL three times). The combined organic extract was washed with brine (100 mL twice), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution with 0-20% SiO2 in hexane) to obtain 6-bromo-2,4-dihydrochromeno[4,3-c]pyrazole I-1c (10 g) as an off-white solid. LCM(ES)m / z;251.0[M+H] + .

[0420] Step 3: 6-bromo-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole (I-1d) and 6-bromo-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole (1-1e): I-1c (4.00 g, 15.9 mmol) were mixed in DMF (60.0 mL) and Cs2CO3 (10.4 g, 31.9 mmol) was added under a nitrogen atmosphere and the mixture was stirred for 30 minutes. Then, MeI (1.20 mL, 19.1 mmol) was added, and the reaction mixture was stirred in a sealed tube at 80°C for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and water (50 mL) was added. Extraction was performed using ELISA (50 mL three times). The combined organic extracts were washed with water (50 mL three times) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution of 0-20% siRNA in hexane) to obtain 6-bromo-2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole Id (3.4 g) as an off-white solid {LCMS(ES) m / z; 265.0[M+H] + . 1 ¹H NMR (400MHz, DMSO-d6) δ 7.61(s,1H);7.58(d,J=7.2Hz,1H);7.46(d,J=7.6Hz,1H);6.93(t,J=7.6Hz,1H);5.36(s,2H);3.89(s,3H)}, and 6-bromo-1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole 1-1e (0.8g) was obtained as an off-white solid {LCM(ES)m / z;265.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72(d,J=8.0Hz,1H);7.55(d,J=8.0Hz,1H);7.34(s,1H);6.99(t,J=8.0Hz,1H);5.30(s,2H);3.87(s,3H)}.

[0421] Step 4: tert-butyl(2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate (I-1f): Argon gas was passed through a suspension of I-1d (3.40 g, 12.8 mmol), tert-butylcarbamate (2.25 g, 19.2 mmol), and Cs2CO3 (8.36 g, 25.6 mmol) stirred in 1,4-dioxane (20.00 mL), and purged for 15 minutes. Then, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphan (1.48 g, 2.56 mmol) and Pd(OAc)2 (576 mg, 2.56 mmol) were added. The reaction mixture was then stirred in a sealed tube at 100°C for 16 hours. Next, the reaction mixture was cooled to room temperature, filtered through a Celite bed, and washed with ethyl phosphate (50 mL twice). The combined filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-50% ethyl phosphate in hexane) to obtain tert-butyl(2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate I-1f (2.30 g) as a pale yellow solid. LCM(ES)m / z;301.9[M+H] + .

[0422] Step 5: 2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-1): I-1f (2.30 g, 7.63 mmol) was stirred in DCM (40.0 mL) and trifluoroacetic acid (10.0 mL) was added at 0°C under a nitrogen atmosphere. The reaction mixture was warmed to room temperature over 2 hours. The progress of the reaction was monitored by TLC. After completion, volatile matter was removed under reduced pressure and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was performed using ELISA (30 mL three times). The combined organic extract was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine I-1 (1.20 g) as a pale yellow solid. LCMS(ES)m / z;202.1[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.53(s,1H);6.81(d,J=7.2Hz,1H);6.70(t,J=7.2Hz,1H);6.57(d,J=7.6Hz,1H);5.19(s,2H);4.75(br s,2H);3.86(s,3H).

[0423] Example 2: Preparation of 1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-2):

[0424] [ka]

[0425] Step 1: tert-butyl(1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate (I-2a): I-2a (0.8g) was synthesized using I-1e (1.4g, 5.28mmol) as the starting material, following the experimental procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;302.1[M+H] + .

[0426] Step 2: 1-Methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-2): I-2 (0.4 g) was synthesized using I-2a (0.8 g, 2.65 mmol) as a starting material, following the procedure described for the synthesis of I-1. LCM(ES)m / z;201.9[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.31(s,1H);6.91(dd,J1=1.6Hz,J2=7.6Hz,1H);6.81(t,J=8.0Hz,1H);6.67(dd,J1=1.6Hz,J2=8.0Hz,1H);5.15(s,2H);4.86(br s,2H);4.04(s,3H).

[0427] Example 3: Preparation of 2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine(I-3):

[0428] [ka]

[0429] Step 1: 6-Bromo-2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole (I-3a):I-1c (2.20 g, 8.76 mmol) was stirred in DMF (20.0 mL) to which Cs2CO3 (5.71 g, 17.5 mmol) and 3-bromooxetane (2.40 g, 17.5 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was then stirred in a sealed tube at 80°C for 16 hours. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was cooled to room temperature and water (50 mL) was added. Extraction was carried out with ELISA (50 mL three times). The combined organic extract was washed with water (50 mL three times) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using a gradient elution of 0-20% ELISA in hexane) to obtain 6-bromo-2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole I-3a (1.9 g) as an off-white solid. LCM(ES)m / z;306.9[M+H] + .

[0430] Step 2: tert-butyl(2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate (I-3b): I-3b (0.92g) was synthesized using I-3a (1.7g, 5.53 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;344.0[M+H] + .

[0431] Step 3: Using 2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-3): I-3b (0.92 g, 2.68 mmol) as a starting material, I-3 (0.55 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z;244.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72(s,1H);6.90(dd,J1=1.6Hz,J2=8.0Hz,1H);6.87(t,J=8.0Hz,1H);6.70(dd,J1=1.6H z,J2=8.0Hz,1H);6.81(pentet,J=7.2Hz,1H);5.18(s,2H);4.90(d,J=7.2Hz,4H);4.85(br s,2H).

[0432] Example 4: Preparation of 2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine(I-4):

[0433] [ka]

[0434] Step 1: Buta-3-in-2-yl 4-methylbenzenesulfonate (I-4b): To a 50 mL solution of N,N-dimethylpyridine-4-amine (261 mg, 0.03 eq, 2.14 mmol) in DCM, a 5.59 mL aqueous solution of buta-3-in-2-ol (71.3 mmol), a 12.5 mL aqueous solution of sodium hydroxide, and 13.6 g of 4-methylbenzene-1-sulfonyl chloride (71.3 mmol) were successively added, and the mixture was stirred at room temperature for 2 hours. After completion, 100 mL of water was added to the reaction mixture, and extraction was carried out using DCM (50 mL three times). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% siRNA in hexane) to obtain the desired compound, buta-3-in-2-yl-4-methylbenzene-1-sulfonate I-4b (7.5 g), as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 7.82(d,J=8.4Hz,2H);7.33(d,J=8.4Hz,2H);5.18-5.15(m,1H);2.44(s,2H);3.41(s,1H);1.58(s,3H).

[0435] Step 2: 3-Bromo-2-(buta-3-in-2-yloxy)benzaldehyde (I-4c): To a solution of I-1a (5.0 g, 24.9 mmol) stirred in ACN (30 mL), anhydrous K2CO3 (5.16 g, 37.3 mmol) and I-4b (7.25 g, 36.1 mmol) were added at room temperature. The reaction mixture was then stirred at 90 °C for 3 hours. After completion (as shown by TLC), volatiles were removed under reduced pressure, and water (100 mL) was added to the residue. Extraction was carried out with  (50 mL three times). The combined organic extract was washed with water (50 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-10% siRNA in hexane) to obtain 3-bromo-2-(buta-3-in-2-yloxy)benzaldehyde I-4c (4.00 g, 15.8 mmol) as a colorless oil. LCM(ES)m / z;253.0[M+H] + .

[0436] Step 3: 6-Bromo-4-methyl-2,4-dihydrochromeno[4,3-c]pyrazole (I-4d): I-4d (2.62 g) was synthesized using I-4c (2.5 g, 9.88 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 2). LCM(ES)m / z; 264.8[M+H] + .

[0437] Step 4: Using 6-bromo-2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole (I-14e) and 6-bromo-1,4-dimethyl-1,4-dihydrochromeno[4,3-c]pyrazole (1-4f):I-4d (2.62 g, 9.88 mmol) as starting materials, a mixture of I-4e and I-4f (1.1 g) was synthesized by following the procedure described for the synthesis of I-1 (Step 3). LCM(ES)m / z;279.0[M+H] + .

[0438] Step 5: Using tert-butyl(2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate (I-4g) and tert-butyl(1,4-dimethyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)carbamate (I-4h): a mixture of I-4e and I-4f (1.1g, 3.94 mmol) as starting materials, I-4g (0.42g) and I-4h (0.28g) were synthesized according to the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;316.2[M+H] + .

[0439] Step 6: Using 2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-amine (I-4): I-4 (0.21 g) was synthesized using I-4 g (0.42 g, 1.33 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z;216.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.56(s,1H);6.82(dd,J1=1.2Hz,J2=7.6Hz,1H);6.69(t,J=7.6Hz,1H);6.57(dd,J1=1.2H z,J2=7.6Hz,1H);5.34(q,J=6.4Hz,1H);4.72(s,2H);3.89(s,3H);1.57(d,J=6.4Hz,3H).

[0440] Example 5: Preparation of 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine(I-5):

[0441] [ka]

[0442] Step 1: Methyl 3-bromo-2-(methylamino)benzoate (I-5b): To a solution of methyl 3-bromo-2-fluorobenzoate I-5a (5.0 g, 21.5 mmol) stirred in 1,4-dioxane (20 mL), potassium carbonate (5.93 g, 42.9 mmol) and a solution of 2 M MeNH2 in THF (21.5 mL, 42.9 mmol) were added. The reaction mixture was then monitored by LCMS while stirring in a sealed tube at 40°C for 16 hours. After completion, volatile matter was removed under reduced pressure, and the residue was separated into DCM (100 mL) and water (50 mL). The organic layer was separated, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired compound methyl 3-bromo-2-(methylamino)benzoate I-5b (5.0 g) as a yellow oil. LCM(ES)m / z;244.0[M+H] + ;246.0.

[0443] Step 2: (3-bromo-2-(methylamino)phenyl)methanol (I-5c):I-5b (9.50 g, 38.9 mmol) was stirred in anhydrous DCM (100 mL) and a 1 M solution of DIBAL-H (117 mL, 117 mmol) was added dropwise at 0°C. The reaction mixture was then warmed to room temperature over 4 hours while monitoring the progress of the reaction by TLC. After completion, the reaction mixture was cooled to 0°C and quenched by gradually adding a 10% aqueous solution of citric acid (30 mL). Extraction was performed using DCM (100 mL twice). The combined organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using a gradient elution of 0-60% SiO2 in hexane) to obtain the desired compound (3-bromo-2-(methylamino)phenyl)methanol I-5c (6.5 g) as a colorless oil. LCM(ES)m / z; 216.0[M+H] + ,217.8.

[0444] Step 3: 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline (I-5d):I-5c (6.50 g, 30.1 mmol) was stirred in anhydrous DMF (60 mL) to which 1H-imidazole (3.07 g, 45.1 mmol) and TBDMSCl (5.67 g, 37.6 mmol) were added at room temperature. The reaction mixture was then stirred at room temperature for 16 hours. Saturated NaHCO3 solution (50 mL) was added to the reaction mixture, and extraction was carried out using diethyl ether (70 mL three times). The combined organic extract was washed with water (50 mL three times) and brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% dimethyl in hexane) to obtain the desired compound 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-methylaniline I-5d (6.5 g) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.41(d,J=8.0Hz,1H);7.30(d,J=8.0Hz,1H);6.82(t,J=8.0Hz,1H);4.74(s,2H);3.95(s,1H);2.82(s,3H);0.92(s,9H);0.08(s,6H).

[0445] Step 4: 2-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-N-methyl-N-(propa-2-in-1-yl)aniline (I-5e):I-5d (6.50 g, 19.7 mmol) was stirred in ACN (65 mL) to which anhydrous K2CO3 (8.16 g, 59.0 mmol) and propargyl bromide (4.47 mL, 59.0 mmol) were added at room temperature. The reaction mixture was then stirred at 80 °C for 24 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, the substrate was filtered through Celite, and washed with ACN (10 mL twice). The filtrate was concentrated under reduced pressure, and the residue was diluted with Â100 mL. The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-50% SiO in hexane) to obtain 2-bromo-6-{[(tert-butyldimethylsilyl)oxy}methyl)-N-methyl-N-(propa-2-in-1-yl)aniline I-5e (7.0 g) as a brown solid. 1 H NMR(400MHz,CDCl3)δ 7.50(d,J=7.6Hz,1H);7.43(d,J=8.0Hz,1H);7.09(t,J=8.0Hz,1H);4.95-4.77(m,2 H);4.00-3.82(m,2H);2.90(s,3H);2.19(t,J=2.4Hz,1H);0.92(s,9H);0.08(s,6H).

[0446] Step 5: A 1M solution of TBAF in (3-bromo-2-(methyl(propa-2-in-1-yl)amino)phenyl)methanol (I-5f):THF (22.8 mL, 22.8 mmol) was added at 0°C to a stirred solution of I-5e (7.00 g, 19.0 mmol) in THF (70 mL), and the reaction mixture was stirred for 30 minutes. After complete consumption of the starting materials (as shown by TLC), saturated NH4Cl solution (50 mL) was added to the reaction mixture, and extraction was carried out using  (70 mL twice). The combined organic extract was washed with brine (70 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-100% siRNA in hexane) to obtain the desired compound (3-bromo-2-[methyl(propa-2-in-1-yl)amino]phenyl)methanol I-5f (4.5 g) as a colorless oil. LCM(ES)m / z; 254.0[M+H] + ,256.0.

[0447] Step 6: (3-bromo-2-(methyl(propa-2-in-1-yl)amino)benzaldehyde (I-5g): I-5f (4.50g, 17.7 mmol) was stirred in DCM (50.0 mL) and DMP (11.3g, 26.6 mmol) was added at 0°C. The reaction mixture was warmed to room temperature over 1 hour. The progress of the reaction was monitored by LC-MS. After completion, the reaction mixture was filtered through a Celite bed and washed with DCM (20 mL twice). The resulting filtrate was saturated. The solution was washed with 30 mL of sodium OHCO3 solution, 100 mL of water, and 30 mL of brine. The mixture was dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-50% siRNA in hexane) to obtain (3-bromo-2-[methyl(propa-2-in-1-yl)amino]benzaldehyde I-5 g (3.60 g) as a yellow oil. LCM(ES) m / z; 252.0 [M+H] + ,254.0.

[0448] Step 7: 6-bromo-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-5h): I-5g (3.60g, 14.3 mmol) was stirred in MeOH (20.0 mL) and water (20.0 mL) to which KOtBu (2.75g, 24.3 mmol) and p-toluenesulfonyl hydrazide (3.99g, 21.4 mmol) were successively added at room temperature. The reaction mixture was then stirred at 70°C for 16 hours, and the progress of the reaction was monitored by TLC. After the consumption of the starting materials was complete, the reaction mixture was cooled to room temperature, and the MeOH was removed under reduced pressure. Water (30 mL) was added to the residue, and extraction was carried out using ELISA (50 mL three times). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Next, the residue was stirred with pentane (30 mL), filtered, and dried to obtain the desired compound 6-bromo-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone I-5h (3.5 g) as an off-white solid. LCM(ES)m / z;264.0[M+H] + ,266.0.

[0449] Step 8: 6-Bromo-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-5i) and 6-bromo-1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinolone (I-5j):I-5h (5.00 g, 18.9 mmol) were stirred in DCM (60.0 mL) to which Cs2CO3 (12.3 g, 37.9 mmol) and iodomethane (1.42 mL, 22.7 mmol) were added. The reaction mixture was then stirred in a sealed tube at 80°C for 16 hours. After complete consumption of the starting materials, the reaction mixture was allowed to cool to room temperature and water (60 mL) was added. Extraction was performed using ELISA (50 mL three times). The combined organic extracts were washed with water (50 mL three times) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4.16 g of a mixture of 6-bromo-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-5i) and 6-bromo-1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinolone (I-5j). LCM(ES)m / z;278.1[M+H] + ,280.1.

[0450] Step 9: tert-butyl(2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)carbamate (I-11k) and tert-butyl(1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-yl)carbamate (I-5l): Argon gas was passed through a stirred suspension of (I-5i+I-5j) (4.00 g, 14.4 mmol), tert-butylcarbamate (2.53 g, 21.6 mmol), and Cs2CO3 (9.37 g, 28.8 mmol) in 1,4-dioxane (50.0 mL), and purged for 15 minutes. Next, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphan (1.66 g, 2.88 mmol) and Pd(OAc)2 (646 mg, 2.88 mmol) were added. The reaction mixture was then stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was then allowed to cool to room temperature, filtered through a Celite pad, and washed with siRNA (50 mL twice). The filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-50% ethyl acetate in hexane) to obtain tert-butyl{2,5-dimethyl-2H,4H,5H-pyrazolo[4,3-c]quinoline-6-yl)carbamate I-5k (2.0 g) (off-white solid) and tert-butyl(1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-yl)carbamate I-5l (0.8 g). LCM(ES)m / z;314.9[M+H] + .

[0451] Step 10: 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine(I-5):I-5k (1.00 g, 3.18 mmol) was stirred in DCM (10.0 mL) and a 4 M solution of HCl in 1,4-dioxane (5.00 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion, volatile matter was removed under reduced pressure and saturated sodium bicarbonate solution (30 mL) was added to the residue. Extraction was performed using ethyl acetate (30 mL three times). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-80% ethyl acetate in hexane) to obtain the desired compound, 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine I-5 (0.5 g), as a semi-solid. LCM(ES)m / z; 215.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.49(s,1H);6.94-6.80(m,2H);6.57(dd,J1=1.6Hz,J2=7.6Hz,1H);4.87(s,2H);3.93(s,2H);3.83(s,3H);2.34(s,3H).

[0452] Example 6: Preparation of 1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-amine (I-6):

[0453] [ka]

[0454] Step 1: 1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-amine (I-6):I-5l (contaminated with I-5k) (0.8g, 2.54 mmol) was stirred in DCM (10.0 mL) and added to the solution at 0°C. A 4M solution of HCl in 1,4-dioxane (5.00 mL) was stirred. The reaction mixture was stirred at room temperature for 16 hours. After completion, volatile matter was removed under reduced pressure, and saturated NaHCO3 solution (20 mL) was added to the residue. Extraction was performed using ethyl acetate (30 mL three times). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using a gradient elution of 0-80% ethylethanol in hexane) to obtain the desired compound, 1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-amine I-6 (contaminated with I-5) (0.5 g), as a semi-solid (a mixture of positional isomers was carried over to the next step). LCM(ES)m / z; 214.9[M+H] + .

[0455] Example 7: Preparation of 5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine(I-7):

[0456] [ka]

[0457] Step 1: Using 6-bromo-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-7a) and 6-bromo-5-methyl-1-(methyl-d3)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolone (I-7b): I-7a (4.0g) and I-7b (1.5g) were synthesized using I-5h (6.0g, 22.7mmol) as starting materials, following the procedure described for the synthesis of I-5 (Step 8). LCM(ES)m / z;281.0[M+H] + .

[0458] Step 2: tert-butyl(5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)carbamate (I-7c): I-7c (3.0g) was synthesized using I-7a (3.5g, 12.4 mmol) as the starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;318.0[M+H] + .

[0459] Step 3: Using 5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-7): I-7 (1.1g) was synthesized using I-7c (3.0g, 9.45 mmol) as the starting material, following the procedure described for the synthesis of I-5 (Step 10). LCM(ES)m / z;218.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.49(s,1H);6.89-6.81(m,1H);6.56(dd,J1=1.6Hz,J2=8.0Hz,1H);4.88(s,2H);3.92(s,2H);2.48(s,3H).

[0460] Example 8: Preparation of 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-8):

[0461] [ka]

[0462] Step 1: 3-Bromo-1-methyl-1H-pyrazole-4-carbaldehyde (I-8b):I-8a (10.0 g, 6.21 mmol) was stirred in DCM (30.0 mL) and POCl3 (30.0 mL) was gradually added at 0°C. The reaction mixture was then stirred at 95°C for 4 hours. After complete consumption of the starting material, the reaction mixture was quenched with saturated NaHCO3 solution (300 mL) and extracted with ELISA (100 mL three times). The combined organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was purified by Combi-Flash (using gradient elution of 0-20% phenylethylamine in heptane) to obtain the desired compound 3-bromo-1-methyl-1H-pyrazole-4-carbaldehyde I-8b (10.8 g) as an off-white solid. LCM(ES)m / z;188.9[M+H] + .

[0463] Steps 2-3: tert-butyl((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate (I-8b): To a solution of I-8b (5.0 g, 26.5 mmol) stirred in MeOH (50 mL), TEA (7.37 mL, 52.9 mmol) and methyl-d3-amine hydrochloride (3.73 g, 52.9 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours, then cooled to 0°C. Next, NaBH4 (1.95 g, 52.9 mmol) was added to the reaction mixture in small amounts, and the reaction mixture was warmed to room temperature over 2 hours. Then, saturated NaHCO3 solution (10 mL) was added to the reaction mixture, and it was washed with ELISA (20 mL twice). Next, (Boc)2O (27.7 mL, 121 mmol) was added to an aqueous NaHCO3 solution and stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched by adding water (50 mL), and extraction was performed using SiO4 (50 mL three times). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution of 0-10% SiO4 in hexane) to obtain the desired compound tert-butyl((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate I-8d (7.00 g) as a colorless oil. LCM(ES)m / z;307.0[M+H] + .

[0464] Step 4: tert-butyl((3-(2-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate (I-8e): Argon gas was passed through a suspension of I-8d (2.5 g, 8.14 mmol), 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.26 g, 12.2 mmol), and KF (1.42 g, 24.4 mmol) stirred in THF (40.0 mL), and purged for 15 minutes. Next, Pd(OAc)2 (0.0914 g, 0.407 mmol) and dicyclohexyl({2',6'-dimethoxy-[1,1'-biphenyl]-2-yl})phosphane (0.334 g, 0.814 mmol) were added. The reaction mixture was then stirred in a sealed tube at 70°C for 16 hours. The reaction mixture was then cooled to room temperature, filtered through a Celite bed, and washed with ELISA (50 mL twice). The combined filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-30% ELISA in hexane) to obtain tert-butyl((3-(2-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate I-8e (2.3 g) as a yellow oil. LCM(ES)m / z;368.2[M+H] + .

[0465] Step 5: 2-methyl-5-(methyl-d3)-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-8f):I-8e (2.3 g, 6.26 mmol) was stirred in DCM (30.0 mL), and trifluoroacetic acid (15.0 mL) was added at 0°C under a nitrogen atmosphere. The reaction mixture was warmed to room temperature over 2 hours. The progress of the reaction was monitored by TLC. After completion, volatile matter was removed under reduced pressure, and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was performed using ethyl acetate (30 mL twice). The combined organic extracts were washed with water (20 mL) and brine (10 mL), dried over anhydrous sodium 2SO4, filtered, and evaporated under reduced pressure to obtain 2-methyl-5-(methyl-d3)-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone I-8f (1.4 g) as a pale yellow solid. LCM(ES)m / z;248.1[M+H] + .

[0466] Step 6: 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-8): I-8f (1.4 g, 5.66 mmol) was stirred in methanol (20.0 mL), and 10% Pd / C (241 mg) was added at room temperature. This was then stirred under a hydrogen atmosphere (H2 balloon) for 2 hours. After completion, the reaction mixture was filtered through a Celite bed and washed with methanol (20 mL twice). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using gradient elution of 0-55% siRNA in hexane) to obtain 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine I-8 (1.2 g) as a brown viscous liquid. LCM(ES)m / z;218.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.51(s,1H);6.92(dd,J1=1.6Hz,J2=7.6Hz,1H);6.86(t,J=7.6Hz,1H);6.60(dd,J1=1.6Hz,J2=7.6Hz,1H);4.90(s,2H);3.95(s,2H);3.86(s,3H).

[0467] Example 9: Preparation of 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-amine (I-9):

[0468] [ka]

[0469] Step 1: tert-butyl((3-(2-chloro-3-fluoropyridine-4-yl)-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate (I-9a): Argon gas was passed through a 30 mL solution of I-8d (2.5 g, 8.14 mmol), (2-chloro-3-fluoropyridine-4-yl)boronic acid (3.57 g, 20.3 mmol), and CsF (3.71 g, 24.4 mmol) in THF (30 mL) and purged for 15 minutes. Then, tri-tert-butylphosphonium tetrafluoroborate (142 mg, 0.488 mmol) and tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (373 mg, 0.407 mmol) were added. The reaction mixture was then stirred in a sealed tube at 50°C for 16 hours. After completion, the reaction mixture was filtered through a Celite bed and washed with ethyl phosphate (50 mL twice). The combined filtrate was concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using gradient elution of 0-30% ethyl phosphate in hexane) to obtain tert-butyl((3-(2-chloro-3-fluoropyridine-4-yl)-1-methyl-1H-pyrazole-4-yl)methyl)(methyl-d3)carbamate I-9a (1.9 g) as a brown viscous liquid. LCM(ES) m / z; 358.1[M+H] + .

[0470] Step 2: 6-Chloro-2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine (I-9b): A 4M solution of HCl in 1,4-dioxane (50 mL) was added to I-9a (1.9 g, 5.31 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, volatile matter was removed under reduced pressure and the mixture was dried (co-evaporation with 1,4-dioxane). Then, 1,4-dioxane (20 mL) and DIPEA (4.98 mL, 29.1 mmol) were added at room temperature, and the reaction mixture was stirred at 85°C for 5 hours. After completion, volatile matter was removed under reduced pressure, and the residue was purified by Combi-Flash (using gradient elution of 0-55% SiO2 in hexane) to obtain the desired compound 6-chloro-2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine I-9b (1.5 g) as a thick yellow oil. LCM(ES)m / z;238.1[M+H] + .

[0471] Step 3: N-(2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)cyclopropanecarboxamide (I-9c): Argon gas was passed through a stirred suspension of I-9b (1 g, 4.21 mmol), cyclopropanecarboxamide (0.72 g, 8.41 mmol), and Cs2CO3 (4.11 g, 12.6 mmol) in 1,4-dioxane (20 mL) and purged for 15 minutes. Then, [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphan (0.24 g, 0.421 mmol) and Pd(dba)3 (0.38 g, 0.421 mmol) were added. The reaction mixture was then stirred in a sealed tube at 130°C for 16 hours. Next, the reaction mixture was cooled to room temperature, filtered through a Celite bed, and washed with ELISA (50 mL twice). The filtrate was concentrated under reduced pressure, and the residue was purified by Combi-Flash (using a gradient elution of 0-80% ELISA in hexane) to obtain N-(2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthirizine-6-yl)cyclopropanecarboxamide I-9c (0.8 g) as a pale yellow solid. LCM(ES)m / z;287.1[M+H] + .

[0472] Step 4: 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizine-6-amine(I-9):I-9c (0.7 g, 2.44 mmol) was stirred in THF (10 mL) and LiOH (0.29 g, 12.2 mmol) in water (5.0 mL) was added at room temperature. This was then stirred at 50 °C for 16 hours. After completion, the reaction mixture was diluted with water (20 mL) and extracted with 10% MeOH in DCM (50 mL twice). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by Combi-Flash (using gradient elution of 0-10% MeOH in DCM) to obtain the desired compound 2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizine-6-amine I-9 (0.4g) as a pale yellow solid. LCM(ES)m / z;219.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.78 (d, J = 5.6 Hz, 1H); 7.40 (s, 1H); 7.12 (d, J = 5.6 Hz, 1H); 5.54 (s, 2H); 4.07 (s, 2H); 3.98 (s, 3H).

[0473] Example 10: Preparation of 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-amine (I-10):

[0474] [ka]

[0475] Steps 1-2: tert-butyl((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl)carbamate (I-10b): I-10b (5.7g) was synthesized using I-8b (5.7g, 30.2mmol) and methylamine hydrochloride (6.11g, 30.2mmol) as starting materials, following the procedure described for the synthesis of I-8 (Steps 2-3). LCM(ES)m / z;304.0[M+H] + .

[0476] Step 3: Using tert-butyl((3-(2-chloro-3-fluoropyridine-4-yl)-1-methyl-1H-pyrazole-4-yl)methyl)(methyl)carbamate (I-10c): I-10b (5.7g, 18.7mmol) and (2-chloro-3-fluoropyridine-4-yl)boronic acid (8.7g, 18.7mmol) as starting materials, I-10c (2.8g) was synthesized according to the procedure described for the synthesis of I-9 (Step 1). LCM(ES)m / z;355.1[M+H] + .

[0477] Step 4: 6-Chloro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine (I-10d): I-10d (2.8g) was synthesized using I-10c (4.8g, 13.5 mmol) as the starting material, following the procedure described for the synthesis of I-9 (Step 2). LCM(ES)m / z;235.1[M+H] + .

[0478] Step 5: N-(2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)cyclopropanecarboxamide (I-10e): I-10e (1.5g) was synthesized using I-10d (1.5g, 6.39 mmol) and cyclopropanecarboxamide (1.09g, 12.8 mmol) as starting materials, following the procedure described for the synthesis of I-9 (Step 3). LCM(ES)m / z;284.2[M+H] + .

[0479] Step 6: Using 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizine-6-amine (I-10): I-10e (2.0 g, 7.06 mmol) as a starting material, I-10 (1.2 g) was synthesized according to the procedure described for the synthesis of I-9 (Step 4). LCM(ES)m / z; 216.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.73(d,J=5.2Hz,1H);7.59(s,1H);6.82(d,J=5.2Hz,1H);5.76(s,2H);4.01(s,2H);3.8(s,3H);2.46(s,3H).

[0480] Example 11: Preparation of 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-4,4-d2-6-amine (I-11):

[0481] [ka]

[0482] Step 1: To a solution of ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate (I-11b):I-11a (6.5 g, 29.7 mmol) in THF (60 mL), sodium hydride (1.78 g, 44.5 mmol) was added in small amounts at 0°C and the mixture was stirred for 30 minutes. Then, iodomethane (8.31 mL, 134 mmol) was added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion, ice-cold water (50 mL) was added to the reaction mixture and extracted with ethyl phosphate (70 mL three times). The combined organic extract was washed with brine (50 mL twice), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using gradient elution of 0-20% phenylethylamide in heptane) to obtain ethyl 3-bromo-1-methyl-1H-pyrazole-4-carboxylate I-11b (5.5 g) as an off-white solid. LCM(ES)m / z;233.1[M+H] + .

[0483] Step 2: To a solution of 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (I-11c):I-11b (5 g, 21.5 mmol) in MeOH (30 mL), an aqueous solution of NaOH (4.29 g, 107 mmol in 15 mL of water) was added, and the resulting mixture was stirred at 85°C for 1 hour. After completion, volatiles were removed under reduced pressure, and the aqueous layer was acidified with 5N HCl aqueous solution to pH 4. The resulting precipitate was filtered, washed with water (5 mL three times), and dried to obtain the desired compound 3-bromo-1-methyl-1H-pyrazole-4-carboxylic acid I-11c (4 g) as an off-white solid. LCM(ES)m / z;205.0[M+H] + .

[0484] Step 3: 3-Bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (I-11d):I-11c (8 g, 39 mmol) was stirred in DMF (80 mL) and DIPEA (20 mL, 117 mmol) and HATU (29.7 g, 78 mmol) were added at 0°C. Then, N,O-dimethylhydroxyamine hydrochloride (7.61 g, 78 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After complete consumption of the starting materials, water (20 mL) was added, and the mixture was extracted with siRNA (75 mL three times). The combined organic extract was washed with brine (50 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution of 0-50% phenylethylamine in heptane) to obtain 3-bromo-N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide I-11d (5g) as an off-white solid. LCM(ES)m / z;248.0[M+H] + .

[0485] Step 4: 3-Bromo-1-methyl-1H-pyrazole-4-carbaldehyde-d(I-11e):I-11d (10 g, 40.3 mmol) was stirred in anhydrous THF (100 mL) solution, and LiAlD4 (1.69 g, 40.3 mmol) was added in small amounts at -78°C. The reaction mixture was warmed to 0°C over 1 hour. After completion, saturated NH4Cl solution (20 mL) was added to the reaction mixture, and extraction was performed using ELISA (50 mL three times). The combined organic extract was washed with brine (50 mL twice), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combi-Flash (using gradient elution of 0-50% ELISA in heptane) to obtain 3-bromo-1-methyl-1H-pyrazole-4-carbaldehyde-d I-11e (6 g) as an off-white solid. LCM(ES)m / z;190.0[M+H] + .

[0486] Step 5: 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)-N-methylmethane-d2-amine (I-11f):I-11e (7.0 g, 36.8 mmol) was stirred in MeOH (70 mL) to which TEA (10.3 mL, 52.9 mmol) and methylamine hydrochloride (4.97 g, 73.7 mmol) were added at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. Next, the reaction mixture was cooled to 0°C and NaBD4 (3.08 g, 73.7 mmol) was added in small amounts. The reaction mixture was then gradually warmed to room temperature over 2 hours. Next, saturated NaHCO3 solution (10 mL) was added to the reaction mixture and washed with ELISA (20 mL twice). The resulting aqueous NaHCO3 solution containing 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)-N-methylmethane-d2-amine I-11f was carried over to the next step.

[0487] Step 6: tert-butyl((3-bromo-1-methyl-1H-pyrazole-4-yl)methyl-d2)(methyl)carbamate (I-11g): I-11g (7.5g) was synthesized according to the procedure described for the synthesis of I-8 (Step 3). LCM(ES)m / z;306.0[M+H]+ .

[0488] Step 7: Using tert-butyl((3-(2-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole-4-yl)methyl-d2)(methyl)carbamate (I-11h): I-11g (1.1g, 3.59 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.44g, 5.39 mmol) as starting materials, I-11h (1.0g) was synthesized according to the procedure described for the synthesis of I-8 (Step 4). LCM(ES)m / z;367.1[M+H] + .

[0489] Step 8: Using 2,5-dimethyl-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-4,4-d2(I-11i):I-11h (1.1 g, 3 mmol) as the starting material, I-11i (0.66 g) was synthesized by following the procedure described for the synthesis of I-8 (Step 5). LCM(ES)m / z;247.1[M+H] + .

[0490] Step 9: Using 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-4,4-d2-6-amine (I-11): I-11i (0.66 g, 2.68 mmol) as a starting material, I-11 (0.5 g) was synthesized according to the procedure described for the synthesis of I-8 (Step 6). LCM(ES)m / z; 217.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.52(s,1H);6.91(dd,J1=1.6Hz,J2=7.6Hz,1H);6.85(t,J=7.6Hz,1H);6.91(dd,J1=1.6Hz,J2=7.6Hz,1H);4.90(s,2H);3.86(s,3H);2.37(s,3H).

[0491] Example 12: Preparation of 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-4,4-d2-6-amine (I-12):

[0492] [ka]

[0493] Step 1: Using tert-butyl((3-(2-chloro-3-fluoropyridine-4-yl)-1-methyl-1H-pyrazole-4-yl)methyl-d2)(methyl)carbamate (I-12a): I-11g (4.5g, 14.7mmol) and (2-chloro-3-fluoropyridine-4-yl)boronic acid (6.44g, 36.7mmol) as starting materials, I-12a (3.8g) was synthesized according to the procedure described for the synthesis of I-9 (Step 1). LCM(ES)m / z;357.0[M+H] + .

[0494] Step 2: 6-Chloro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-4,4-d2(I-12b): I-12b (0.6g) was synthesized using I-12a (2.0g, 5.61 mmol) as a starting material, following the procedure described for the synthesis of I-9 (Step 2). LCM(ES)m / z;237.0[M+H] + .

[0495] Step 3: N-(2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)cyclopropanecarboxamide (I-12c): I-12c (0.4g) was synthesized using I-12b (0.63g, 2.06 mmol) and cyclopropanecarboxamide (1.73g, 5.32 mmol) as starting materials, following the procedure described for the synthesis of I-9 (Step 3). LCM(ES)m / z;286.2[M+H] + .

[0496] Step 4: Using 2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizine-4,4-d2-6-amine (I-12): I-12 (0.28 g) was synthesized using I-12c (0.63 g, 2.21 mmol) as a starting material, following the procedure described for the synthesis of I-9 (Step 4). LCM(ES)m / z; 218.0[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.73 (d, J = 5.2 Hz, 1H); 7.59 (s, 1H); 6.82 (d, J = 4.8 Hz, 1H); 5.68 (s, 2H); 3.89 (s, 3H); 2.41 (s, 3H).

[0497] Example 13: Preparation of 5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-13):

[0498] [ka]

[0499] Step 1: Using 6-bromo-5-methyl-2-(oxetane-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinolone (I-13a): I-13a (0.6g) was synthesized using I-5h (1.35g, 5.11 mmol) and 3-bromooxetane (0.85mL, 10.2 mmol) as starting materials, following the procedure described for the synthesis of I-3 (Step 1). LCM(ES)m / z;320.1[M+H] + .

[0500] Step 2: tert-butyl(5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)carbamate (I-13b): I-13b (0.5g) was synthesized using I-13a (0.6g, 1.87 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;357.1[M+H] + .

[0501] Step 3: Using 5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-13): I-13b (0.5 g, 1.4 mmol) as a starting material, I-13 (0.2 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z; 257.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72(s,1H);6.96(d,J=6.8 Hz.1H);6.86(t,J=8.0Hz,1H);6.60(d,J=6.8Hz,1H);5.57(m,1H);4.92(s,2H);4.90(m,4H);3.98(s,2H);2.48(s,3H).

[0502] Example 14: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-14):

[0503] [ka]

[0504] Step 1: 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)ethane-1-ol (I-14a):I-8b (25 g, 132.3 mmol) was stirred in anhydrous THF (250 mL) and a 1 M solution of MeMgBr in Et2O (198.3 mL, 198.4 mmol) was added at -78°C. The reaction mixture was warmed to room temperature over 20 minutes. After complete consumption of the starting material, the reaction mixture was quenched by adding saturated NH4Cl solution (100 mL), and extraction was performed using ELISA (70 mL three times). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain the desired compound 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)ethane-1-ol I-14a (23 g) as a brown semi-solid. LCM(ES)m / z;205.0[M+H] + .

[0505] Step 2: 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)ethane-1-one (I-14b): I-14b (15.5g) was synthesized using I-14a (23g, 122.0 mmol) as the starting material, following the procedure described for the synthesis of I-5 (Step 6). LCM(ES)m / z;203.0[M+H] + .

[0506] Step 3: 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)-N-methylethane-1-amine (I-14c):I-14b (15.5 g, 76.35 mmol) was stirred in THF (150 mL) and titanium(IV) isopropoxide (45.2 mL, 152.70 mmol) was added in a sealed tube at 0°C. Next, a 2 M solution of MeNH2 in THF (76.3 mL, 152.70 mmol) was added, and the reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was then cooled to room temperature, and volatile matter was removed under reduced pressure. Next, the mixture was diluted with semi-solid MeOH (180 mL), and sodium borohydride (8.66 g, 229.06 mmol) was added at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 hours. After completion, saturated NaHCO3 solution (100 mL) was added to the reaction mixture and washed with ELISA (30 mL twice). The NaHCO3 aqueous solution containing 1-(3-bromo-1-methyl-1H-pyrazole-4-yl)-N-methylethane-1-amine I-14c was carried over to the next step.

[0507] Step 4: tert-butyl(1-(3-bromo-1-methyl-1H-pyrazole-4-yl)ethyl)(methyl)carbamate (I-14d): I-14d (19g) was synthesized according to the procedure described for the synthesis of I-8 (Step 3). LCM(ES)m / z;318.0[M+H] + .

[0508] Step 5: Using tert-butyl(1-(3-(2-fluoro-3-nitrophenyl)-1-methyl-1H-pyrazole-4-yl)ethyl)(methyl)carbamate (I-14e): I-14d (5.5 g, 17.3 mmol) and 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.92 g, 35.9 mmol) as starting materials, I-14e (6.0 g) was synthesized according to the procedure described for the synthesis of I-8 (Step 4). LCM(ES)m / z;379.0[M+H] + .

[0509] Step 6: Using 2,4,5-trimethyl-6-nitro-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (I-14f): I-14f (3.0 g) was synthesized using I-14e (6.0 g, 15.9 mmol) as a starting material, following the procedure described for the synthesis of I-8 (Step 5). LCM(ES)m / z; 259.0[M+H] + .

[0510] Step 7: Using 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-amine (I-14): I-14 (2.2 g) was synthesized using I-14f (3.0 g, 11.6 mmol) as a starting material, following the procedure described for the synthesis of I-8 (Step 6). LCM(ES)m / z; 229.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.25(d,J=8.0Hz,1H);7.15(s,1H);6.99(t,J=8.0Hz,1H);6.68(d,J=8.0Hz,1H);4.26(br s,2H);4.10(q,J=7.2Hz,1H);3.94(s,3H);2.46(s,3H);1.19(d,J=7.2Hz,3H).

[0511] Example 15: Preparation of 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-amine (I-15):

[0512] [ka]

[0513] Step 1: Using tert-butyl(1-(3-(2-chloro-3-fluoropyridine-4-yl)-1-methyl-1H-pyrazole-4-yl)ethyl)(methyl)carbamate (I-15a): I-14d (5.0 g, 15.7 mmol) and (2-chloro-3-fluoropyridine-4-yl)boronic acid (4.13 g, 23.6 mmol) as starting materials, I-15a (3.0 g) was synthesized according to the procedure described for the synthesis of I-9 (Step 1). LCM(ES)m / z;369.1[M+H] + .

[0514] Step 2: 6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine (I-15b): I-15b (5.0g) was synthesized using I-15a (12.0g, 32.5 mmol) as a starting material, following the procedure described for the synthesis of I-9 (Step 2). LCM(ES)m / z;249.1[M+H] + .

[0515] Step 3: N-(2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)cyclopropanecarboxamide (I-15c): I-15c (0.6g) was synthesized using I-15b (1.0g, 4.02 mmol) and cyclopropanecarboxamide (0.68g, 8.04 mmol) as starting materials, following the procedure described for the synthesis of I-9 (Step 3). LCM(ES)m / z;298.0[M+H] + .

[0516] Step 4: Using 2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyrizine-6-amine (I-15): I-15 (2.1 g) was synthesized using I-15c (3.36 g, 11.3 mmol) as a starting material, following the procedure described for the synthesis of I-9 (Step 4). LCM(ES)m / z;230.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.70(d,J=5.2Hz,1H);7.57(s,1H);6.79(d,J=4.8Hz,1H);5.63(br s,2H);4.11(q,J=6.8Hz,1H);3.86(s,3H);2.35(s,3H);1.4(d,J=7.2Hz,3H).

[0517] Racemic I-15 (2.1g) was decomposed by chiral HPLC separation [column: CHIRALPAK IC (250mm × 30mm × 5μm); mobile phase: n-hexane:IPA and 0.1% DEA (80:20); flow rate: 40mL / min] to obtain two enantiomers {I-15A (0.6g) and I-15B (0.6g)}; peak 1; R t ;12.06 min, and I-15B (0.6g): Peak 2;R t ;16.23 minutes}, it was used without determining its absolute position.

[0518] Example 16: Preparation of 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-amine (I-16):

[0519] [ka]

[0520] Step 1: Ethyl 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (I-16a): To a solution of (3-bromo-2-fluorophenyl)hydrazine (8.0 g, 39.0 mmol) stirred in AcOH (60 mL), I-16a (6.06 mL, 49.9 mmol) was added at room temperature. The reaction mixture was then stirred at 100 °C for 4 hours. After completion, volatiles were evaporated under reduced pressure, and saturated NaHCO3 solution (50 mL) was added to the residue. Extraction was performed using ELISA (75 mL three times). The combined organic extracts were washed with water (50 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-15% ethyl hexane) to obtain the desired compound, ethyl 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate I-16b (4.0 g), as a yellow liquid. LCM(ES)m / z; 327.0[M+H] + . 1 ¹H NMR (400MHz, DMSO-d6) δ 7.62 (td, J1=2.0Hz, J2=9.2Hz, 1H); 7.43 (td, J1=2.0Hz, J2=9.2Hz, 1H); 7.14 (dd, J1=2.0Hz, J2=9.2Hz, 1H); 6.82 (s, 1H); 4.24 (q, J=7.2Hz, 2H); 2.38 (s, 3H); 1.25 (t, J=7.2Hz, 3H), and 1-(3-bromo-2-fluorophenyl)-5-methyl-1H-pyrazole-3-carboxylate I-16b' (6.0g) was obtained as a yellow liquid. LCM(ES)m / z; 327.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72-7.68(m,1H);7.49-7.45(m,1H);7.21-7.17(m,1H);6.77(s,1H);4.43(q,J=7.2Hz,2H);2.16(s,3H);1.41(t,J=7.2Hz,3H).

[0521] Step 2: (1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-yl)methanol (I-16c):I-16b (3.5 g, 10.7 mmol) was stirred in anhydrous THF (25 mL) and a 1 M solution of DIBAL-H (45 mL, 22.9 mmol) was added dropwise at 0°C. The reaction mixture was then warmed to room temperature over 1 hour while monitoring the progress of the reaction by TLC. After completion, the reaction mixture was cooled to 0°C and quenched by gradually adding a 10% aqueous solution of citric acid (20 mL). Extraction was performed using DCM (100 mL twice). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution with 0-40% ELISA in hexane) to obtain the desired compound (1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-yl)methanol I-16c (3.0 g) as a concentrated oil. LCM(ES)m / z;285.1[M+H] + .

[0522] Step 3: Using 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-carbaldehyde (I-16d): I-16d (2.5g) was synthesized using I-16c (3.0g, 10.12 mmol) as the starting material, following the procedure described for the synthesis of I-5 (Step 6). LCM(ES)m / z;283.0[M+H] + .

[0523] Step 4: Using 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-yl)-N-methylmethanamine (I-16e): I-16e (2.2g) was synthesized using I-16d (2.5g, 0.18 mmol) and methylamine hydrochloride (0.86g mg, 12.7 mmol) as starting materials, following the procedure described for the synthesis of I-8 (Step 2). LCM(ES)m / z;298.2[M+H] + .

[0524] Step 5: 6-bromo-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline (I-16f):I-16e (2.2 g, 9.39 mmol) was mixed with 1,4-dioxane (10 mL) and DIPEA (3.1 mL, 18.1 mmol) was added. The reaction mixture was then stirred at 80°C for 6 hours. After completion, the reaction mixture was allowed to cool to room temperature, and volatiles were removed under reduced pressure. Water (50 mL) was added to the residue, and extraction was performed using ethyl acetate (50 mL twice). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution with 0-50% dimethyl in hexane) to obtain the desired compound 6-bromo-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline I-16f (2.0 g) as a yellow oil. LCM(ES)m / z;278.2[M+H] + .

[0525] Step 6: Using tert-butyl(2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl) carbamate (I-16g): I-16f (2.0g, 8.01 mmol) as a starting material, I-16g (0.8g) was synthesized according to the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;315.4[M+H] + .

[0526] Step 7: 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-amine (I-16): Using I-16 g (0.8 g, 4.45 mmol) as a starting material, I-16 (0.5 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z; 215.4[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 6.93-6.86(m,2H);6.53-6.46(m,1H);6.06(s,1H);5.08(s,2H);4.08(s,2H);2.31(s,3H);3.98(s,3H).

[0527] Example 17: Preparation of 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-17):

[0528] [ka]

[0529] Step 1: 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid (I-17a): I-17a (4.0g) was synthesized using I-16b (4.5g, 13.8 mmol) as a starting material, following the procedure described for the synthesis of I-11 (Step 2). LCM(ES)m / z;299.0[M+H] + .

[0530] Step 2: 1-(3-bromo-2-fluorophenyl)-N-methoxy-N,3-dimethyl-1H-pyrazole-5-carboxamide (I-17d): I-17b (3.5g) was synthesized using I-17a (3.5g, 11.7mmol) as a starting material, following the procedure described for the synthesis of I-11 (Step 3). LCM(ES)m / z;342.1[M+H] + .

[0531] Step 3: Using 1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-carbaldehyde-d(I-17c):I-17b (3.5g, 10.2 mmol) as a starting material, I-17c (2.8g) was synthesized according to the procedure described for the synthesis of I-11 (Step 4). LCM(ES)m / z;284.0[M+H] + .

[0532] Step 4: Using 1-(1-(3-bromo-2-fluorophenyl)-3-methyl-1H-pyrazole-5-yl)-N-methylmethane-d2-amine (I-12f):I-17c (3 g, 10.6 mmol) as a starting material, I-17 (1.5 g) was synthesized according to the procedure described for the synthesis of I-11 (Step 5). LCM(ES)m / z;300.1[M+H] + .

[0533] Step 5: Using 6-bromo-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2(I-17e):I-17d (2.2 g, 7.33 mmol) as a starting material, I-17e (1.5 g) was synthesized according to the procedure described for the synthesis of I-16 (Step 5). LCM(ES)m / z;279.9[M+H] + .

[0534] Step 6: Using tert-butyl(2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2) carbamate (I-17f): I-17f (1.2g) was synthesized using I-17e (1.0g, 3.57 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;317.2[M+H] + .

[0535] Step 7: Using 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-17): I-17f (1.5 g, 4.74 mmol) as a starting material, I-17 (1.1 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z; 217.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.42(d,J=8.0Hz,1H);7.17(t,J=8.0Hz,1H);6.95(d,J=8.0Hz,1H);6.14(s,1H);5.12(s,2H);3.14(s,3H);2.25(s,3H).

[0536] Example 18: Preparation of 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-amine (I-88):

[0537] [ka]

[0538] Step 1: Ethyl 1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-carboxylate (I-18a): I-18a (6.0 g) was synthesized using I-16a (7.5 mL, 50.3 mmol) and 3-bromo-2-chloro-4-hydrazinalepyridine (12.5 g, 56.2 mmol) as starting materials, following the procedure described for the synthesis of I-16 (Step 1). LCM(ES)m / z;344.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.44(d,J=4.8Hz,1H);7.29(d,J=4.8Hz,1H);6.86(s,1H);4.25(q,J=7.2Hz,2H);2.37(s,3H);1.24(t,J=7.2Hz,3H).

[0539] Step 2: (1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-yl)methanol (I-18c): I-18c (1.9g) was synthesized using I-18a (3.0g, 8.71 mmol) as a starting material, following the procedure described for the synthesis of I-16 (Step 2). LCM(ES)m / z;302.2[M+H] + .

[0540] Step 3: Using 1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-carbaldehyde (I-38d): I-18d (3.2g) was synthesized using I-18c (3.4g, 11.24 mmol) as a starting material, following the procedure described for the synthesis of I-5 (Step 6). LCM(ES)m / z;300.5[M+H] + .

[0541] Step 4: Using 1-(1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-yl)-N-methylmethanamine (I-18e): I-18e (3.0 g) was synthesized using I-18d (3.0 g, 9.98 mmol) and methylamine hydrochloride (2.02 g mg, 29.9 mmol) as starting materials, following the procedure described for the synthesis of I-8 (Step 2). LCM(ES)m / z;314.9[M+H] + .

[0542] Step 5: 6-Chloro-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine (I-18f): Argon gas was passed through a suspension of I-18e (1.0 g, 3.17 mmol) and CsOAc (1.22 g, 6.34 mmol) stirred in DMSO (10 mL), and purged for 15 minutes. Copper powder (20.1 mg, 0.317 mmol) was then added at room temperature, and the reaction mixture was stirred in a sealed tube at 100 °C for 16 hours. The reaction mixture was then cooled to room temperature, and saturated NaHCO3 solution (30 mL) was added. Extraction was performed using ethyl acetate (50 mL three times). The combined organic extracts were washed with water (50 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-88% phenylethylamine in hexane) to obtain the desired compound 6-chloro-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine I-18f (0.8 g) as a yellow oil. LCM(ES)m / z;235.4[M+H] + .

[0543] Step 6: Using N-(2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)cyclopropanecarboxamide (I-18g): I-18f (1.7g, 7.63 mmol) as a starting material, I-18g (0.7g) was synthesized according to the procedure described for the synthesis of I-9 (Step 3). LCM(ES)m / z;284.3[M+H] + .

[0544] Step 7: 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-amine (I-18): Using I-18 g (0.7 g, 2.47 mmol) as a starting material, I-18 (0.4 g) was synthesized according to the procedure described for the synthesis of I-9 (Step 4). LCM(ES)m / z; 216.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.74(d,J=5.2Hz,1H);6.86(d,J=5.2Hz,1H);6.13(s,1H);5.90(s,2H);4.13(s,2H);2.42(s,3H);2.24(s,3H).

[0545] Example 19: Preparation of 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-4,4-d2-6-amine (I-19):

[0546] [ka]

[0547] Step 1: 1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (I-19a): I-19a (6.5g) was synthesized using I-18a (12.0g, 51.03 mmol) as a starting material, following the procedure described for the synthesis of I-11 (Step 2). LCM(ES)m / z;316.4[M+H] + .

[0548] Step 2: (1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-yl)methane-d2-ol (I-19b): To a solution of I-19a (6.0 g, 17.4 mmol) stirred in THF (50 mL), TEA (7.33 mL, 52.1 mmol) and isobutyl chloroformate (5.65 mL, 43.4 mmol) were added at 0°C. The mixture was then stirred for 30 minutes. After complete consumption of the starting materials, the reaction mixture was filtered through a Celite bed, and the resulting filtrate was added dropwise to a solution of NaBD4 (1.2 g, 26.1 mmol) in water (5 mL) at 0°C. The reaction mixture was then stirred at room temperature for 1 hour. After completion, saturated NH4Cl solution (50 mL) was added to the reaction mixture, and extraction was performed using  (70 mL three times). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Combi-Flash (using gradient elution with 0-30% siRNA in hexane) to obtain the desired compound (1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-yl)methane-d2-ol I-19b (3.5 g) as an off-white solid. LCM(ES)m / z;304.4[M+H] + .

[0549] Step 3: Using 1-(2-bromo-3-fluoropyridine-4-yl)-3-methyl-1H-pyrazole-5-carbaldehyde-d(I-19c):I-19b (2.3g, 7.55 mmol) as a starting material, I-19c (1.4g) was synthesized according to the procedure described for the synthesis of I-5 (Step 6). LCM(ES)m / z;285.1[M+H] + .

[0550] Step 4: Using 1-(1-(3-bromo-2-chloropyridine-4-yl)-3-methyl-1H-pyrazole-5-yl)-N-methylmethane-d2-amine (I-19d):I-19d (1.2g) was synthesized using I-19c (1.1g, 3.65 mmol) as the starting material, following the procedure described for the synthesis of I-11 (Step 5). LCM(ES)m / z;317.1[M+H] + .

[0551] Step 5: Using 6-chloro-2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-4,4-d2(I-19e):I-19d (2.6 g, 8.19 mmol) as a starting material, I-19e (2.0 g) was synthesized according to the procedure described for the synthesis of I-18 (Step 5). LCM(ES)m / z;237.4[M+H] + .

[0552] Step 6: N-(2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl-4,4-d2)cyclopropanecarboxamide (I-19f): I-19f (1.8g) was synthesized using I-19e (2.0g, 13.01mmol) and cyclopropanecarboxamide (0.65g, 7.6mmol) as starting materials, following the procedure described for the synthesis of I-9 (Step 3). LCM(ES)m / z;286.4[M+H] + .

[0553] Step 7: Using 2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-4,4-d2-6-amine (I-19): I-19f (1.8 g, 6.31 mmol) as a starting material, I-19 (0.8 g) was synthesized according to the procedure described for the synthesis of I-9 (Step 4). LCM(ES)m / z; 218.4[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.92(d,J=5.6Hz,1H);7.18(d,J=5.6Hz,1H);6.06(s,1H);4.99(s,2H);2.56(s,3H);2.39(s,3H).

[0554] Example 20: Preparation of 5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-20):

[0555] [ka]

[0556] Step 1: Ethyl 1-(3-bromo-2-fluorophenyl)-1H-pyrazole-5-carboxylate (I-20b): I-20b (7.5g) was synthesized using I-20a (6.68g, 39.0mmol) and (3-bromo-2-fluorophenyl)hydrazine (8.0g, 39.0mmol) as starting materials, following the procedure described for the synthesis of I-16 (Step 1). LCM(ES)m / z;313.2[M+H] + .

[0557] Step 2: 1-(3-bromo-2-fluorophenyl)-1H-pyrazole-5-carboxylic acid (I-20c): I-20c (6.2g) was synthesized using I-20b (6.5g, 21.7mmol) as the starting material, following the procedure described for the synthesis of I-17 (Step 1). LCM(ES)m / z;285.0[M+H] + .

[0558] Step 3: (1-(3-bromo-2-fluorophenyl)-1H-pyrazole-5-yl)-methane-d2-ol (I-20d): I-20d (4.3g) was synthesized using I-20c (6.2g, 21.7mmol) as the starting material, following the procedure described for the synthesis of I-19 (Step 2). LCM(ES)m / z;273.2[M+H] + .

[0559] Step 4: Using 1-(3-bromo-2-fluorophenyl)-1H-pyrazole-5-carbaldehyde-d(I-20e):I-20d (4.3g, 15.7 mmol) as the starting material, I-20e (2.1g) was synthesized according to the procedure described for the synthesis of I-5 (Step 6). LCM(ES)m / z;270.0[M+H] + .

[0560] Step 5: Using 1-(1-(3-bromo-2-fluorophenyl)-1H-pyrazole-5-yl)-N-methylmethane-d2-amine (I-20f):I-20e (2.1 g, 7.78 mmol) as a starting material, I-20f (2.0 g) was synthesized according to the procedure described for the synthesis of I-11 (Step 5). LCM(ES)m / z;286.1[M+H] + .

[0561] Step 6: Using 6-bromo-5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2(I-20g):I-20f (2.0g, 6.99 mmol) as a starting material, I-20g (1.7g) was synthesized according to the procedure described for the synthesis of I-16 (Step 5). LCM(ES)m / z;266.1[M+H] + .

[0562] Step 7: Using tert-butyl(5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2) carbamate (I-20h): I-20h (1.3g) was synthesized using I-20g (1.7g, 6.39 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;303.1[M+H] + .

[0563] Step 8: Using 5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-4,4-d2-6-amine (I-20): I-20h (1.3 g, 4.3 mmol) as a starting material, I-20 (0.8 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z;203.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.65(d,J=1.6Hz,1H);7.00(dd,J1=1.2Hz,J2=7.6Hz,1H);6.92(t,J=8.0Hz,1H);6 .54(dd,J1=1.2Hz,J2=8.0Hz,1H);6.28(d,J=1.6Hz,1H);5.13(s,2H);2.36(s,3H).

[0564] Example 21: Preparation of 5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-amine (I-21):

[0565] [ka]

[0566] Step 1: 1-(3-bromo-2-fluorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (I-21b) and 1-(3-bromo-2-fluorophenyl)-3-(furan-2-yl)-5-(trifluoromethyl)-1H-pyrazole (I-21c): To a solution of I-21a (15.1 g, 73.2 mmol) stirred in AcOH (150 mL), (3-bromo-2-fluorophenyl)hydrazine (10 g, 48.8 mmol) was added at room temperature, and the reaction mixture was stirred at 100 °C for 4 hours. After completion, volatile matter was removed under vacuum, and water (100 mL) was added to the residue. Extraction was performed using ELISA (70 mL three times). The combined extracts were washed with water and brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-20% butyl in heptane) to obtain an inseparable mixture (17 g) of 1-(3-bromo-2-fluorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole I-21b and 1-(3-bromo-2-fluorophenyl)-3-(furan-2-yl)-5-(trifluoromethyl)-1H-pyrazole I-21c as an orange liquid. LCM(ES)m / z;375.1[M+1] + .

[0567] Step 2: 1-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (I-21d) and 1-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (I-21e):I-41b+I-41c (17 g, 45.3 mmol) were stirred in acetone (200 mL) and water (200 mL). Potassium permanganate (50.1 g, 317 mmol) was added in small amounts at 0°C. The reaction mixture was then stirred at 60°C for 3 hours. After complete consumption of the starting materials, the reaction mixture was allowed to cool to room temperature, and IPA (100 mL) was added. This mixture was then stirred at room temperature for 16 hours. The reaction mixture was then filtered through a Celite bed and washed with ELISA (50 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was acidified with 1N HCl to pH 2. Extraction was performed using ethyl acetate (60 mL twice). The combined extract was washed with water and brine (50 mL), dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The residue was purified by Combi-Flash (using gradient elution of 0-70% ethyl acetate in heptane) to obtain the desired compound 1-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid I-21d (6.0 g) as a pale yellow solid. LCM(ES)m / z;353.0[M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) δ 14.14 (s, 1H); 7.93-7.90 (m, 1H); 7.70 (t, J=6.8 Hz, 1H); 7.58 (s, 1H); 7.34 (t, J=7.2 Hz, 1H), and 1-(3-bromo-2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid I-21e (2.3 g) was obtained as a yellow solid. LCM(ES) m / z; 353.0 [M+H] + .

[0568] Step 3: 1-(3-bromo-2-fluorophenyl)-N-methoxy-N-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (I-21f): I-21f (6.0 g, 17 mmol) was used as a starting material, and I-21f (6.0 g) was synthesized according to the procedure described for the synthesis of I-11 (Step 3). LCM(ES)m / z;396.0[M+H] + .

[0569] Step 4: Using 1-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carbaldehyde (I-21g): I-21f (6.0g, 15.1 mmol) as a starting material, I-21g (3.0g) was synthesized according to the procedure described for the synthesis of I-11 (Step 4). LCM(ES)m / z;337.0[M+H] + .

[0570] Step 5: Using 1-(1-(3-bromo-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl)-N-methylmethanamine (I-21h): I-21h (3.0g, 8.9 mmol) as a starting material, I-21h (3.0g) was synthesized according to the procedure described for the synthesis of I-8 (Step 2). LCM(ES)m / z;352.1[M+H] + .

[0571] Step 6: Using 6-bromo-5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline (I-21i): I-21i (2.0g) was synthesized using I-21g (3.0g, 8.52 mmol) as a starting material, following the procedure described for the synthesis of I-16 (Step 5). LCM(ES)m / z;332.1[M+H] + .

[0572] Step 7: Using tert-butyl(5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl) carbamate (I-21j): I-21j (1.5g) was synthesized using I-21i (2.0g, 6.02 mmol) as a starting material, following the procedure described for the synthesis of I-1 (Step 4). LCM(ES)m / z;369.2[M+H] + .

[0573] Step 8: Using 5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-amine (I-21): I-21j (1.5 g, 4.07 mmol) as a starting material, I-21 (0.7 g) was synthesized according to the procedure described for the synthesis of I-1 (Step 5). LCM(ES)m / z; 269.1[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.02-6.95(m,2H);6.77(s,1H);6.63(d,J=7.6Hz 1H);5.25(s,2H);4.23(s,2H);2.39(s,3H).

[0574] Example 22: Preparation of 4,6-dichloro-N-methylpyridazine-3-carboxamide (A-1):

[0575] [ka]

[0576] To a solution of A-1a (10.0 g, 50.3 mmol) stirred in anhydrous DCM (100 mL), a catalytic amount of DMF (2-3 drops) and oxalyl chloride (9.11 mL, 101.0 mmol) were added in small amounts at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 hours. After completion, 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 solution of methylamine hydrochloride (5.09 g, 75.4 mmol) and DIPEA (13.2 mL, 75.4 mmol) stirred in DCM (50 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. This was then washed with saturated NaOHCO3 solution (30 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Next, the residue was purified by Combi-Flash (using gradient elution of 0-40% ELISA in hexane) to obtain 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] + .

[0577] Example 23: Preparation of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (A-2):

[0578] [ka]

[0579] To a solution of A-1a (5.0 g, 25.1 mmol) stirred in anhydrous DCM (40 mL), a catalytic amount of DMF (2-3 drops) and oxalyl chloride (4.6 mL, 50.3 mmol) were added in small amounts at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 hours. After completion, volatile matter was removed under reduced pressure, and the residue was dried. The residue was then dissolved in anhydrous DCM (25 mL), and added to a solution of methane-d3-amine hydrochloride (2.13 g, 30.2 mmol) and DIPEA (13.2 mL, 75.4 mmol) stirred in anhydrous DCM (25 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. Next, the solution was washed with saturated NaOHCO3 solution (30 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by Combi-Flash (using gradient elution of 0-40% siRNA in hexane) to obtain 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] + .

[0580] Example 24: Preparation of 4,6-dichloro-N-(methyl-d3)nicotinamide (A-3):

[0581] [ka]

[0582] Using A-3a (3g) as the starting material, A-3 (2.6g) was synthesized as described for the synthesis of A-2. LCMS(ES)m / z 208.0[M+H] + .

[0583] Example 25: Preparation of 4,6-dichloropyridazine-3-carboxamide (A-4):

[0584] [ka]

[0585] To a solution of A-1a (2.5 g, 12.6 mmol) stirred in anhydrous DCM (50 mL), a catalytic amount of DMF (2-3 drops) and oxalyl chloride (2.5 mL, 25.1 mmol) were added in small amounts at 0°C. The reaction mixture was then gradually warmed to room temperature over 2 hours. After completion, volatiles were removed under reduced pressure, and the residue was dried. The residue was then dissolved in anhydrous DCM (25 mL) and added to a stirred solution of 0.5 M ammonia in dioxane (10.0 mL) and DIPEA (6.5 mL, 37.3 mmol) in anhydrous DCM (25 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was then stirred at room temperature for 2 hours. Water (50 mL) was then added to the reaction mixture, and the organic layer was separated. This was then washed with saturated NaOHCO3 solution (30 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Next, the residue was purified by Combi-Flash (using gradient elution of 0-60% ELISA in hexane) to obtain the desired compound 4,6-dichloropyridazine-3-carboxamide A-4 (4.2 g) as an off-white solid. LCM(ES)m / z;193.0[M+H] + .

[0586] Example 26: Preparation of 4,6-dichloro-N-methylnicotinamide (A-5):

[0587] [ka]

[0588] Using A-3a (3g) as the starting material, A-5 (2.5g) was synthesized as described for the synthesis of A-1. LCM(ES)m / z;204.9[M+H] + .

[0589] Example 27: Preparation of 4,6-dichloronicotin...

Claims

1. Equation (I): 【Chemistry 1】 A compound of, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein, Ring A is A １ and A ２ If ring A is independently an unsubstituted or substituted pyrazole which is N or C, then ring A is p examples of R ８ Replaced by, Each of said R ８ is independently hydrogen, halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ deuterated alkyl, unsubstituted or substituted C ２ -C ６ alkenyl, unsubstituted or substituted C ２ -C ６ alkynyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R １６ ) ２ , and when said R ８ is bonded to a nitrogen atom, said R ８ is hydrogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C １ -C ６ deuterated 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 groups, unsubstituted or substituted carbon rings, unsubstituted or substituted heterocycles, -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R) １６ ) ２ And, Z is -NR １０ -, -O-, -S-, -S(=O)-, or -SO ２ - and R １０ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ It is a cycloalkyl or monocyclic heterocycle, X １ , X ２ , and X ３ Each of them is independently CR １１ or N, R １１ each independently represent hydrogen, halogen, unsubstituted or substituted C １ -C ６ alkyl, unsubstituted or substituted C ２ -C ６ alkenyl, unsubstituted or substituted C ２ -C ６ alkynyl, unsubstituted or substituted C １ -C ６ fluoroalkyl, unsubstituted or substituted C １ -C ６ heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R １６ ) ２ , and B １ is N or CR １２ａ And, B ２ is N or CR １２ｂ And, R １２ａ and R １２ｂ These are, independently, hydrogen, halogen, and 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 carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ ,-SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R) １６ ) ２ And, R １ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ It is a fluoroalkyl, R ２ R is a ring B which is an unsubstituted or substituted heterocycle or an unsubstituted or substituted carbon ring, and if ring B is substituted, then ring B has q examples of R １３ Replaced by, The aforementioned R １３ These are, 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 carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ ,-SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R) １６ ) ２ And, Alternatively, two R atoms on adjacent atoms of ring B １３ The groups, by becoming one with the intervening atoms to which they are bonded, form an unsubstituted or substituted five-membered or six-membered monocyclic carbocyclic ring, or an unsubstituted or substituted five-membered or six-membered monocyclic heterocyclic ring. Alternatively, the aforementioned R ２ is -C(=O)R １４ , -C(=O)NR １４ R １５ , or -C (=O) OR １４ And, R １４ C is hydrogen, unsubstituted or substituted. １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, 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 It is a fluoroalkyl, Alternatively, the R １４ and R １５ These, by becoming one with the intervening atoms to which they are bonded, form unsubstituted or substituted five-membered or six-membered monocyclic heterocycles. Alternatively, the R １ and R １５ These, by becoming one with the intervening atoms to which they are bonded, form unsubstituted or substituted five-membered or six-membered monocyclic heterocycles. W is -NR ３ - or -O-, R ３ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ It is a cycloalkyl or monocyclic heterocycle, R ４ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ It is a cycloalkyl or monocyclic heterocycle, Alternatively, the R ３ and R ４ These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. Alternatively, the R ３ and R １２ａ These, by becoming one with the intervening atoms to which they are bonded, form substituted or unsubstituted five-membered or six-membered heterocycles. R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ It is a cycloalkyl or monocyclic heterocycle, R ６ and R ７ These are, independently, hydrogen, deuterium, halogen, and C. １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ Cycloalkyl, or monocyclic heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ ,-SR １６ , -S(=O)R １７ , -SO ２ R １７ , or -SO ２ N(R) １６ ) ２ And, Alternatively, one of the R atoms bonded to the same carbon atom ６ and one of the aforementioned R ７ They become one with the carbon atom to which they are bonded, resulting in C=O or C ３ -C ４ Forming a cycloalkyl group, R １６ These are, 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, Alternatively, two of the aforementioned R atoms on the same N atom １６ These atoms, by becoming one with the N atom to which they are bonded, form substituted or unsubstituted N-containing heterocycles. R １７ These are, independently, substitutional or non-substitutional 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, Here, unless otherwise specified, substituted alkyl, substituted fluoroalkyl, substituted deuteroalkyl, substituted alkoxy, substituted fluoroalkoxy, substituted heteroalkyl, substituted carbocyclic, and substituted heterocyclic are defined as deuterium, halogen, and C, respectively. １ -C ６ Alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -CH ２ CN, -OR １８ ien-CH ２ OR １８ , -CO ２ R １８ ien-CH ２ CO ２ R １８ , -C(=O)N(R １８ ) ２ ien-CH ２ C(=O)N(R) １８ ) ２ , -N(R １８ ) ２ ien-CH ２ N(R) １８ ) ２ , -NR １８ C(=O)R １８ ien-CH ２ NR １８ C(=O)R １８ , -NR １８ SO ２ R １９ ien-CH ２ NR １８ SO ２ R １９ ,-SR １８ ien-CH ２ SR １８ , -S(=O)R １９ ien-CH ２ S(=O)R １９ , -SO ２ R １９ ien-CH ２ SO ２ R １９ , -SO ２ N(R) １８ ) ２ , or -CH ２ SO ２ N(R) １８ ) ２ One or more R independently selected from the group consisting of ｓ Substituted with the base, R １８ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ６ Selected from heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl, Or, two of the aforementioned R １８ The groups, by becoming one with the N atom to which they are bonded, form an N-containing heterocycle. R １９ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ６ Selected from heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl, n is 1, 2, or 3. p is either 1 or 2, q is 1, 2, 3, or 4. The aforementioned compound may be 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, or 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, or 4-((2,5-dimethyl-4, A compound other than 5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylnicotinamide or 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-methylpyridazine-3-carboxamide, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

2. The aforementioned R １ However, hydrogen or C １ -C ４ It is alkyl, The aforementioned W is -NR ３ - and The aforementioned R ３ However, hydrogen, C １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, The aforementioned R ４ However, hydrogen, C １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, The aforementioned R ５ However, hydrogen or C １ -C ４ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

3. Formula (II): 【Chemistry 2】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

4. The aforementioned X １ CR １１ , the X ２ CR １１ , the X ３ CR １１ And, Or, the X １ CR １１ , the X ２ CR １１ , the X ３ N is, Or, the X １ CR １１ , the X ２ N, the aforementioned X ３ CR １１ And, Or, the X １ N, the aforementioned X ２ CR １１ , the X ３ CR １１ And, The aforementioned R １１ However, each is independent of hydrogen, halogen, and C. １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, -CN, -OH, -OR １７ , or -N(R １６ ) ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

5. Formula (IV): 【Transformation 3】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

6. Equation (VI): 【Chemistry 4】 It has the structure, and in the formula, A １ and A ２ However, each is independently N or C, A ３ A ４ , and A ５ However, N and NR are independent of each other. ８ , or CR ８ And, Here, A １ , A ２ , A ３ , A ４ , and the A ５ Two adjacent ring atoms selected from are N or NR ８ And the remaining atoms are C or CR ８ The compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

7. Formula (VIa-1), formula (VIc-1), or formula (VIf-1): 【Transformation 5】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

8. The aforementioned R ８ However, each is independent of hydrogen, halogen, and unsubstituted or substituted C. １ -C ６ Alkyl, unsubstituted, or substituted C １ -C ６ Juteroalkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -CO ２ R １６ , or -C(=O)N(R １６ ) ２ And the R ８ When bonded to a nitrogen atom, the R ８ However, hydrogen, unsubstituted or substituted C １ -C ６ Alkyl, unsubstituted, or substituted C １ -C ６ Juteroalkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -C(=O)R １６ , -CO ２ R １６ , or -C(=O)N(R １６ ) ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

9. The aforementioned R ８ However, each is independent of hydrogen, -Cl, -F, methyl, ethyl, isopropyl, and -CD. ３ ien-CH ２ OH, -CF ３ Cyclopropyl, oxetanyl, azetidinyl, -CN, -OH, -CO ２ H, or -CO ２ CH ３ And the R ８ When bonded to a nitrogen atom, the R ８ However, hydrogen, methyl, ethyl, isopropyl, -CD ３ ien-CH ２ OH, -CF ３ Cyclopropyl, oxetanyl, azetidinyl, -CO ２ H, or -CO ２ CH ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

10. The aforementioned R ６ and R ７ However, each is independent of hydrogen, deuterium, halogen, and C. １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, The aforementioned Z is -NR １０ - or -O-, The aforementioned R １０ However, hydrogen, C １ -C ４ Alkyl, C １ -C ４ A compound according to any one of claims 1 to 9, which is a duteroalkyl or cyclopropyl compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

11. The aforementioned R ２ but, 【Transformation 6】 And the above q is 0, 1, 2, 3, or 4, The aforementioned R １３ However, each is independent of halogen, unsubstituted, or substituted C １ -C ６ Alkyl, unsubstituted, or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted carbon ring, 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 The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

12. The aforementioned R ２ However, -C(=O)R １４ , -C(=O)NR １４ R １５ , or -C (=O) OR １４ And, The aforementioned R １４ However, non-substitutive or substituted C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, unsubstituted or substituted C ３ -C ６ Cycloalkyl, or unsubstituted or substituted 4-6 member heterocycloalkyl, wherein substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl may contain deuterium, halogen, C １ -C ６ Alkyl, -CN, -OR １８ , and -N(R １８ ) ２ One or more R independently selected from the group consisting of ｓ Substituted with the base, The aforementioned R １５ However, hydrogen, C １ -C ６ Alkyl, or C １ -C ６ It is a fluoroalkyl, Alternatively, the R １４ and R １５ The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein they integrate with intervening atoms to which they are bonded, thereby forming an unsubstituted or substituted five-membered or six-membered monocyclic heterocycle.

13. The aforementioned R ２ ga-C(=O)R １４ And, The aforementioned R １４ However, non-substitutive or substituted C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, unsubstituted or substituted C ３ -C ４ A cycloalkyl, or an unsubstituted or substituted four-membered heterocycloalkyl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, or substituted heterocycloalkyl is deuterium, halogen, -CN, -NH ２ , -OH, -NH(CH ３ ), -N(CH ３ ) ２ ien-CH ３ ien-CH ２ CH ３ ,-CHF ２ , -CF ３ , -OCH ３ , -OCHF ２ , and -OCF ３ One or more R independently selected from the group consisting of ｓ A compound according to claim 12, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, substituted with a group.

14. B １ CR １２ａ , the above B ２ CR １２ｂ And, Or, the above B １ N, the aforementioned B ２ CR １２ｂ And, Or, the above B １ CR １２ａ , the above B ２ N is, Or, the above B １ N, the aforementioned B ２ N is, The aforementioned R １２ａ and R １２ｂ However, each is independent of hydrogen, halogen, and C. １ -C ４ Alkyl, C １ -C ４ A compound according to any one of claims 1 to 13, which is a fluoroalkyl or -CN compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

15. B １ CH, the aforementioned B ２ CH is, Or, the above B １ N, the aforementioned B ２ CH is A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

16. Formula (XVII): 【Transformation 7】 It has the structure, and in the formula, Z is -NR １０ - or -O-, X １ CR １１ or N, X ２ CR １１ or N, X ３ CR １１ or N, B １ is N or CR １２ａ And, B ２ is N or CR １２ｂ And, R ２ R is an unsubstituted or substituted phenyl, an unsubstituted or substituted six-membered monocyclic heteroaryl, or an unsubstituted or substituted five-membered monocyclic heteroaryl, wherein if ring B is substituted, ring B has q examples of R １３ Replaced by, Alternatively, R ２ is -C(=O)R １４ , -C(=O)NR １４ R １５ , or -C (=O) OR １４ And, R ４ is hydrogen, C １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, R ６ These are, independently, hydrogen, deuterium, halogen, and C. １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, R ７ These are, independently, hydrogen, deuterium, halogen, and C. １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, Alternatively, one of the R atoms bonded to the same carbon atom ６ and one of the aforementioned R ７ These become one with the carbon atom to which they are bonded, resulting in -C=O- or C ３ -C ４ Forming a cycloalkyl group, R ８ These are, independently, hydrogen, halogen, and unsubstituted or substituted C. １ -C ６ Alkyl, unsubstituted, or substituted C １ -C ６ Juteroalkyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted heterocyclic, -CN, -OH, -OR １７ , -C(=O)R １６ , -C (=O) OR １６ , or -C(=O)N(R １６ ) ２ And the R ８ When bonded to a nitrogen atom, the R ８ C is hydrogen, unsubstituted or substituted. １ -C ６ Alkyl, unsubstituted, or substituted C １ -C ６ Juteroalkyl, unsubstituted or substituted C １ -C ６ Fluoroalkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -C(=O)R １６ , -C (=O) OR １６ , or -C(=O)N(R １６ ) ２ And, R １０ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Juteroalkyl, C １ -C ６ Fluoroalkyl, C ３ -C ６ It is a cycloalkyl or monocyclic heterocycle, R １１ These are, independently, hydrogen, halogen, and C. １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, -CN, -OH, -OR １７ , or -N(R １６ ) ２ And, R １２ａ is hydrogen, halogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, or -CN, R １２ｂ is hydrogen, halogen, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, or -CN, The aforementioned R １３ These are, independently, halogen, unsubstituted, or substituted C １ -C ６ Alkyl, unsubstituted or substituted carbon ring, unsubstituted or substituted heterocycle, -CN, -OH, -OR １７ , -C(=O)R １６ , -C (=O) OR １６ , -C(=O)N(R １６ ) ２ , -N(R １６ ) ２ , -NR １６ C(=O)R １７ , -S (=O) ２ R １７ , or -S (=O) ２ (R １６ ) ２ And, R １４ C is either non-substituted or substituted. １ -C ６ Alkyl, unsubstituted, or substituted C ３ -C ４ A cycloalkyl, or an unsubstituted or substituted four-membered heterocycloalkyl, R １５ is hydrogen, C １ -C ６ Alkyl, or C １ -C ６ It is a fluoroalkyl, R １６ These are, independently, hydrogen and C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ Heteroalkyl, C ３ -C ７ It is a cycloalkyl or monocyclic 3- to 8-membered heterocycloalkyl, Alternatively, two of the aforementioned R atoms on the same N atom １６ These combine with the nitrogen atom to which they are bonded to form a 4-6 member nitrogen-containing heterocycloalkyl group. R １７ Each of them is independent of C １ -C ６ Alkyl, C １ -C ６ Fluoroalkyl, C １ -C ６ Heteroalkyl, C ３ -C ７ It is a cycloalkyl or monocyclic 3- to 8-membered heterocycloalkyl, n is either 1 or 2, q is either 1 or 2. The compound of formula (XVII) is not 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylpyridazine-3-carboxamide, 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylnicotinamide, or 4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyridine-4-yl)amino)-N-methylnicotinamide), but the compound according to claim 1, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

17. The aforementioned Z is -NR １０ - and The aforementioned X １ CR １１ And, The aforementioned X ２ CR １１ And, The aforementioned X ３ CR １１ And, The aforementioned R ２ ga-C(=O)R １４ And, The aforementioned R ６ However, each is independent of hydrogen, deuterium, halogen, and C. １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, The aforementioned R ７ However, each is independent of hydrogen, deuterium, halogen, and C. １ -C ４ Alkyl, or C １ -C ４ It is a juteroalkyl, The aforementioned R ８ However, each is independent of hydrogen and -CH ３ , -CD ３ , -OH, -CH ２ OH, -CF ３ , oxetanyl, -CN, or -C(=O)OCH ３ And the R ８ When bonded to a nitrogen atom, the R ８ is hydrogen, -CH ３ , -CD ３ ien-CH ２ OH, oxetanyl, or -C(=O)OCH ３ And, The aforementioned R １０ However, hydrogen, C １ -C ４ Alkyl, C １ -C ４ It is a duteroalkyl or cyclopropyl, The aforementioned R １１ The compound according to claim 16, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein each is independently hydrogen or fluoro.

18. 1:6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 2:6-(cyclopropanecarboxamide)-N-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 3:6-[(5-fluoropyridine-2-yl)amino]-N-methyl-4-{[2-(oxetan-3-yl)-2H,4H-clomeno[4,3-c]pyrazole-6-yl]amino}pyridazine-3-carboxamide, 4:6-(cyclopropanecarboxamide)-N-methyl-4-((2-(oxetan-3-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 5:6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 6:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 7:6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 8:6-((5-fluoropyridine-2-yl)amino)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 9:6-((2,6-dimethylpyrimidine-4-yl)amino)-N-(methyl-d3)-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)nicotinamide, 10:6-(cyclopropanecarboxamide)-4-((2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-N-methylpyridazine-3-carboxamide, 11:4-((2,4-dimethyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylpyridazine-3-carboxamide, 12: (4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-methylpyridazine-3-carboxamide), 13:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)nicotinamide, 14: [6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide], 15:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 16:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-(methyl-d3)nicotinamide, 17:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 18:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-methylnicotinamide, 19:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 20:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 21:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(1-hydroxycyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 22: 2-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide, 23:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 24:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(oxetan-3-carboxamide)nicotinamide, 25:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide, 26:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 27: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 28: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)pyridazine-3-carboxamide, 29: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(oxetan-3-yl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 30: (S)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 31: (R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 32:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2R)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 33:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 34:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((2,6-dimethylpyrimidine-4-yl)amino)-N-methylpyridazine-3-carboxamide, 35:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 36: rel-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-((1R,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide, 37: 6-(cyclopropanecarboxamide)-4-((2-isopropyl-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 38: 6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((2-methyl-4,5-dihydro-2H-benzo[2,3]oxepino[4,5-c]pyrazole-7-yl)amino)pyridazine-3-carboxamide, 39:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(2-hydroxy-2-methylpropanamide)-N-(methyl-d3)nicotinamide, 40:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-6-(1-methylazetidine-3-carboxamide)nicotinamide, 41: Methyl (4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-5-((methyl-d3)carbamoyl)pyridine-2-yl)carbamate, 42:3-(cyclopropanecarboxamide)-5-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)-1,2,4-triazine-6-carboxamide, 43:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)nicotinamide, 44:6-(cyclopropanecarboxamide)-4-((4,5-dimethyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 45:4-((2,5-bis(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide, 46: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)nicotinamide, 47: 6-(cyclopropanecarboxamide)-4-((4,4-difluoro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 48:6-(cyclopropanecarboxamide)-4-((4,4-difluoro-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 49: 6-((5-fluoropyridine-2-yl)amino)-N-methyl-4-((1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 50:6-(cyclopropanecarboxamide)-N-methyl-4-((1-methyl-1,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)pyridazine-3-carboxamide, 51:6-(cyclopropanecarboxamide)-4-((1,5-dimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 52: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 53:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)-N-(methyl-d3)nicotinamide, 54: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)pyridazine-3-carboxamide, 55:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(trifluoromethyl)-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl)amino)nicotinamide, 56: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 57: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 58: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)pyridazine-3-carboxamide, 59: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-4,5-dihydropyrazolo[1,5-a]quinoxaline-6-yl-4,4-d2)amino)nicotinamide, 60: Methyl 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)aminonicotinate, 61:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-6-(3-isopropyl-2-oxoimidazolidine-1-yl)-N-(methyl-d3)nicotinamide, 62:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(N-methylcyclopropanecarboxamide)pyridazine-3-carboxamide, 63:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl-4,4-d2)amino)-6-(3-isopropyl-2-oxoimidazolidine-1-yl)-N-(methyl-d3)nicotinamide, 64:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)-N-(methyl-d3)nicotinamide, 65:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 66:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)nicotinamide, 67: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2-methyl-5-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 68: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 69: (S)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 70: (R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 71:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)nicotinamide, 72: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 73: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl-4,4-d2)amino)-N-(methyl-d3)pyridazine-3-carboxamide, 74:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 75:4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-6-(3,3-dimethylureido)-N-(methyl-d3)pyridazine-3-carboxamide, 76:6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 77: 6-(cyclopropanecarboxamide)-4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl-4,4-d2)amino)-N-(methyl-d3)nicotinamide, 78: (R)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 79: 4-((2,5-dimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)pyridazine-3-carboxamide, 80: (S)-N-(methyl-d3)-6-(3-methylureido)-4-((2,4,5-trimethyl-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 81: (R)-6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydropyrazolo[1,5-a]pyrido[3,4-e]pyrazine-6-yl)amino)pyridazine-3-carboxamide, 82:6-(cyclopropanecarboxamide)-4-((8-fluoro-2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 83:6-(cyclopropanecarboxamide)-4-((8-fluoro-5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)nicotinamide, 84:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,6]naphthyridine-6-yl)amino)nicotinamide, 85: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,6]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 86:6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)nicotinamide, 87: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-methyl-2-(methyl-d3)-4,5-dihydro-2H-pyrazolo[4,3-c][1,7]naphthyridine-6-yl)amino)pyridazine-3-carboxamide, 88: N-(2-methyl-4-((2-methyl-2,4-dihydrochromeno[4,3-c]pyrazole-6-yl)amino)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide, 89: N-(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide, 90: N-(4-((2,5-dimethyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-2-(methyl-d3)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-b]pyridine-6-yl)cyclopropanecarboxamide, and 91:6-(cyclopropanecarboxamide)-4-((2-isopropyl-5-methyl-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide A compound selected from, or a pharmaceutically acceptable salt, tautomer, or solvate thereof.

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

20. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a pharmaceutical for treating a TYK2-mediated disease or illness in a patient requiring treatment for such disease or illness, wherein the treatment comprises administering the compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, to the patient in a therapeutically effective amount.

21. Use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, in the manufacture of a pharmaceutical product for treating an inflammatory disease or illness, or an autoimmune disease or illness, in a patient requiring treatment for such an inflammatory disease or illness, or an autoimmune disease or illness, wherein the treatment comprises administering the compound, or a pharmaceutically acceptable salt, tautomer, or solvate thereof, to the patient in a therapeutically effective amount.

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

23. The use according to any one of claims 20 to 22, wherein the pharmaceutical product is administered locally to the patient.

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