TYK2 inhibitors, their compositions, and methods

Abstract

This invention provides a class of therapeutic agents that are safe and effective TYK2 inhibitors, as well as pharmaceutical compositions of these compounds, methods for their preparation, and methods for their use for various diseases or disorders mediated by TYK2. The present invention provides novel, selective, and potent compounds that are available orally and / or topically, and / or are suitable for CNS permeable administration, gastrointestinal (GI) localized administration, and / or topical administration. These therapeutic agents are safe and effective TYK2 inhibitors and may exhibit fewer and / or less adverse effects than currently available drugs.

Description

[Technical Field]

[0001] Priority Claim and Related Patent Applications This application claims priority to PCT International Patent Application No. PCT / CN2023 / 100518 filed on 15 June 2023; No. PCT / CN2023 / 137938 filed on 11 December 2023; No. PCT / CN2024 / 075796 filed on 4 February 2024; and No. PCT / CN2024 / 081039 filed on 11 March 2024, the entire contents of each of these applications being incorporated herein by reference for all purposes.

[0002] The present invention generally relates to novel compounds and methods for their therapeutic use. More specifically, the present invention provides a novel class of tyrosine kinase 2 inhibitors and pharmaceutical compositions of these compounds, as well as methods for preparing them and for their use in relation to various diseases and conditions. [Background technology]

[0003] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the Janus kinase-transduction activator (JAK-STAT) pathway. In humans, the JAK family consists of four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). This family is defined by the presence of two adjacent kinase domains, JH1 and JH2, of which JH1 performs phosphorylation involved in pathway activation, while JH2 modulates JH1 function (Thomas, et al., 2015 British Journal of Cancer 113, 365-371).

[0004] These cytoplasmic tyrosine kinases associate with membrane cytokine receptors, such as the common gamma chain receptor and the glycoprotein 130 (gp130) transmembrane protein (Murray, et al. 2007 Immunol. 178(5):2623-2629). Approximately 40 cytokine receptors signal through combinations of these four JAKs and their seven downstream substrates, which are members of the STAT family (Ghoreschi et al. 2009 Immunol Rev. 228(l):273-287).

[0005] Selective inhibition of TYK2 may be used to treat various autoimmune inflammatory diseases, such as psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, inflammatory bowel disease (IBD), Crohn's disease (CD), rheumatoid arthritis (RA), diabetes mellitus, type 1 diabetes mellitus, renal fibrosis, chronic kidney diseases such as diabetic nephropathy, polycystic kidney disease, HIV-associated kidney injury, and cancers, such as T-cell acute lymphoblastic leukemia (T-ALL) and cutaneous T-cell lymphoma (CTCL) (Ellinghaus, D. et al. 2012 Am.J.Hum.Genet. 90:636-647, Graham, D. et al. 2007). Rheumatology(Oxford).46:927-930, Eyre,S.et al.2012 Nat.Genet.,44:1336-1340, Frank C.Brosius III.et al.2015 Curr Opin Nephrol Hypertens.24(1):88-95, Keiichiro Mine.et al.2024 Nature Communications.15:1337-1350, Calliope A.Dendrou.et al.2016 Sci Transl Med.8(363):149-180, Tao, JHet al.2011 Mol.Biol.Rep.38:4663-4672).

[0006] TYK2 plays a crucial role in the immune system, particularly in mediating inflammatory responses. While primarily studied in the context of immune-related disorders, new research indicates TYK2 involvement in various brain diseases. In patients with multiple sclerosis (MS), TYK2 regulates T cell activation and the production of cytokines, especially interleukin-12 (IL-12) and interferon-α (IFN-α), which are important for immune responses. Th17 cells have been identified in active brain lesions from MS patients. TYK2 dysregulation can exacerbate inflammation in MS, thereby contributing to central nervous system damage (Beecham, et al. 2013 Nature genetics. 45(11):1353-1360, Couturier, N. et al. 2011 Brain. 134:693-703, Murphy, CA et al. 2003 Nature, 421:744-748). TYK2 has been identified as a potential risk factor for Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline and neuronal loss. Studies have shown that TYK2 may modulate microglial activation and neuroinflammation, processes associated with the progression of AD pathology (Shi et al. 2019 J Exp Med. 216 (11):2546-2561). TYK2 has also been associated with Parkinson's disease (PD), a progressive neurodegenerative disorder primarily affecting motor function. Studies have suggested that TYK2 may influence neuroinflammation and dopaminergic neuronal degeneration, key processes in PD pathology (Qin, et al. 2016, Journal of Neuroscience 36(18):5144-5159).

[0007] Selectivity compared to other JAK family subtypes is considered important for enhancing the intended pharmacological effect and reducing side effects. Identifying kinase inhibitors with high TYK2 selectivity is a significant challenge, partly due to the high sequence homology of active sites among JAK family kinases. TYK2 specificity is crucial for the clinical application of TYK2 kinase inhibitors because Tyk2 knockout mice have normal blood cell counts and are viable, while JAK3 deficiency results in severe combined immunodeficiency in mice, and JAK1 or JAK2 knockout mice exhibit perinatal lethality (Ghoreschi, et al. 2009 Immunol Rev. 228:273-287, Karaghiosoff, et al. 2000 Immunity. 13:549-560, Shimoda, et al. 2000 Immunity. 13:561-571). Genetic evidence suggests that pharmacological inhibition of TYK2 should not result in acute toxicity in human patients, but careful monitoring for viral or mycobacterial infections is necessary in patients receiving long-term treatment (Akahane, et al. 2017 Br J Haematol. 177(2):271-282).

[0008] The ability of drugs to cross the blood-brain barrier (BBB) ​​is crucial for treating central nervous system (CNS) diseases. The BBB acts as a highly selective barrier that maintains brain homeostasis by regulating the movement of substances between the bloodstream and the brain. However, this barrier also presents significant challenges for drug delivery to the brain. For the effective treatment of CNS disorders, such as Alzheimer's disease, Parkinson's disease, and brain tumors, drugs must be able to cross the BBB and reach their targets in the brain. Compounds with low brain permeability may require high doses, leading to systemic side effects and reduced therapeutic efficacy. Developing drugs with enhanced brain permeability requires strategies such as optimizing molecular properties, utilizing drug delivery systems, and designing prodrugs that can be metabolically activated to increase BBB permeability. Furthermore, the discovery of transport mechanisms that facilitate the movement of specific molecules across the BBB has opened new avenues for drug delivery. In summary, the ability of drugs to cross the BBB is essential for the successful treatment of CNS diseases. Improving brain permeability can enhance drug efficacy, reduce side effects, and lead to the development of more effective treatments for difficult-to-treat neurological disorders.

[0009] Localized or intra-gastrointestinal Janus kinase (JAK) inhibitors represent a specialized class of drugs designed to specifically target the JAK-STAT signaling pathway within the gastrointestinal tract. These inhibitors offer several advantages in the treatment of inflammatory bowel disease (IBD) and Crohn's disease, including: Local action: By specifically targeting JAK inhibition in the gastrointestinal tract, these inhibitors minimize systemic exposure, thereby potentially reducing the risk of systemic side effects associated with broader JAK inhibitors. Enhanced potency: By concentrating the therapeutic effect within the gastrointestinal tract, localized or intra-gastrointestinal JAK inhibitors may offer enhanced efficacy in controlling inflammation and promoting mucosal healing in patients with IBD and Crohn's disease. Reduced systemic side effects: The local action of these inhibitors may result in a reduction in the incidence of systemic adverse effects associated with systemic JAK inhibitors, such as infections or hematological abnormalities. Possibility of dose reduction: Targeting the gastrointestinal tract with JAK inhibitors may allow for dose reduction of the drug to achieve therapeutic effects, thereby further reducing the risk of systemic side effects. Combination therapy: Localized or intra-gastrointestinal JAK inhibitors can be used alone or in combination with other therapies for IBD management, thereby providing flexibility in treatment while potentially minimizing systemic exposure to the drug.

[0010] Solubility is a critical factor in the development of small molecule drugs because it directly impacts their bioavailability, efficacy, and ultimately, their clinical success. Poor solubility can lead to insufficient drug absorption, unstable pharmacokinetics, and reduced therapeutic efficacy. Therefore, enhancing solubility is a primary focus in drug development to ensure proper drug delivery and optimal therapeutic outcomes. Several candidate drugs have faced setbacks or failures in clinical development due to solubility issues. These cases highlight the importance of addressing solubility early in the drug development process to mitigate risks and optimize the clinical potential of small molecule therapeutics. There is an urgent and unmet need for selective TYK2 inhibitors with improved efficacy and minimal side effects, and challenges remain regarding such selective TYK2 inhibitors across a wide range of therapeutic areas. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Thomas,et al.,2015 British Journal of Cancer 113,365-371 [Non-Patent Document 2] Murray,et al.2007 Immunol.178(5):2623-2629 [Non-Patent Document 3] Ghoreschi et al.2009 Immunol Rev.228(l):273-287 [Non-Patent Document 4] Ellinghaus,D.et al.2012 Am.J.Hum.Genet.90:636-647 [Non-Patent Document 5] Graham,D.et al.2007 Rheumatology(Oxford).46:927-930 [Non-Patent Document 6] Eyre,S.et al.2012 Nat.Genet.,44:1336-1340 [Non-Patent Document 7] Frank C.Brosius III.et al.2015 Curr Opin Nephrol Hypertens.24(1):88-95 [Non-Patent Document 8] Keiichiro Mine.et al.2024 Nature Communications.15:1337-1350 [Non-Patent Document 9] Calliope A.Dendrou.et al.2016 Sci Transl Med.8(363):149-180 [Non-Patent Document 10] Tao,JHet al.2011 Mol.Biol.Rep.38:4663-4672 [Non-Patent Document 11] Beecham,et al.2013 Nature genetics.45(11):1353-1360 [Non-Patent Document 12] Couturier, N. et al.2011 Brain.134:693-703, Murphy, CAet al.2003 Nature,421:744-748 [Non-Patent Document 13] Shi et al.2019 J Exp Med.216 (11):2546-2561 [Non-Patent Document 14] Qin,et al.2016,Journal of Neuroscience 36(18):5144-5159 [Overview of the Initiative] [Means for solving the problem]

[0012] The present invention provides novel, selective, and potent compounds that are available orally and / or topically, and / or are suitable for CNS permeable administration, gastrointestinal (GI) localized administration, and / or topical administration. These therapeutic agents are safe and effective TYK2 inhibitors and may exhibit fewer and / or fewer side effects than currently available drugs. The present invention also provides pharmaceutical compositions of these compounds, as well as methods for their preparation and use.

[0013] This specification discloses a series of novel TYK2 inhibitors specifically designed to fit into profiles that are potentially suitable for (I) CNS permeable administration, (II) oral administration, or (III) GI and / or topical use on the skin. For compounds designed for oral administration, they are potent against TYK2, exhibit various selectivity for other JAK kinases and JAK1 JH2 domains, and show a generally favorable drug profile. For compounds potentially suitable for GI-limited use, their properties, such as Caco-2 data, solubility, and PK, are suitable for limiting them to the intestinal site of action. For compounds potentially suitable for topical use, they are designed to have good skin permeability and high retention in the epidermis and dermis. The novel class of inhibitors exhibits an exceptional potency profile and has TYK2 IC50 values ​​in the low picomolar or nanomolar range. These therapeutic agents are safe and effective TYK2 inhibitors and exhibit fewer and / or fewer side effects than currently available drugs. The present invention also provides pharmaceutical compositions of these compounds, as well as methods for their preparation and use.

[0014] In one embodiment, the present invention generally relates to structural formula (I): [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Y 1 However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, t is 0 or 1, R 1 However, it is H, F, CD3, or C1-C3 alkyl, provided that Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 2 but, R2’ and wherein R 2’ is C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 spirocycloalkyl, or C3-C6 heterocycloalkyl, each being substituted with 0-2 R 2a ; R 2a is halogen, CN, OR, NRR', alkyl, cycloalkyl, heterocycle; aryl or heteroaryl group each substituted with 0-2 R 2a ; (C=O)R ; or 2b ; or (C=O)NHR 2b selected from the group consisting of, R 3 is

Chemical formula

[0015] In a particular embodiment of (I), t is 1, and the compound has the following structural formula: [ka] It holds.

[0016] In a particular embodiment of (I), t is 0, and the compound has the following structural formula: [ka] It holds.

[0017] In another embodiment, the present invention generally relates to structural formula (VIII): [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, X 6 However, CR 6 or N, X 7 However, CR 7 or N, X 8 However, it is C or N, X 9 However, CR 9 , O, S, N, or NR 9 And, X 10 However, CR 10 , O, S, N, or NR 10 And, Y 1 However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, Y 4 However, it is NR, CH2, or CF2, Y 5 However, these are NR, CH2, O, S, SO, or SO2. m is 0, 1, 2, and 3. n is 0, 1, 2, and 3. p is 0, 1, 2, and 3. Each of ring A and ring B is independently an aryl or heteroaryl group. The ring C is a 5-membered or 6-membered aryl or heteroaryl group, R 1 However, H, F, CD3, or C 1~3 It is alkyl, however, Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 4 However, 0 to 5 R 4a C replaced by 1~3 It is alkyl, and here, R 4a However, it is selected from D, F, and Cl, R 5 However, H, CN, Halo, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1~6 Alkyl, C 3~6 A cycloalkyl or heterocycle, where the alkyl, cycloalkyl, or heterocycle has 0 to 3 R 5a It is replaced by each R 5a However, it is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3, and OC(=O)CH3. R 6 , R 7 , R 9 , R 10 , and R 11 Each of these is H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C 1~3 Alkyl and C 3~5 A cycloalkyl group is independently selected, where the alkyl, cycloalkyl, R, and R' have 0 to 2 R's. 2a It has been replaced with, R 2a However, F, OCF3, CF3, CN, NO2, OR, NRR', and C 1~6 Selected from alkyl groups, The present invention relates to a compound or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of R and R' is independently H, C1-C6 alkyl, or acyl, or R and R', together with the nitrogen or carbon atom to which they are bonded, form a 3-6 membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2.

[0018] In further embodiments, the present invention generally relates to methods for preparing compounds disclosed herein, as exemplified by the synthetic schemes and experimental procedures disclosed herein.

[0019] In further embodiments, the present invention relates to pharmaceutical compositions comprising compounds disclosed herein that are generally effective in treating or reducing one or more diseases or disorders in mammals, including humans, and pharmaceutically acceptable excipients, carriers, or diluents.

[0020] In further embodiments, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0021] In further embodiments, the present invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering a therapeutically effective amount of a compound disclosed herein to a subject in need, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0022] In further embodiments, the present invention generally relates to the use of the compounds disclosed herein, and pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of agents for treating diseases or disorders. [Brief explanation of the drawing]

[0023] [Figure 1]This shows specific exemplary data regarding changes in mouse body weight (A) and DAI score (B). n = 10 mice per group; data are presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001 relative to the vehicle; two-way ANOVA, Dunnett's multiple comparison test.

[0024] [Figure 2] This shows specific exemplary data regarding changes in mouse body weight (A) and DAI score (B). n = 8 mice per group; data are shown as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001 relative to the vehicle; two-way ANOVA, Dunnett's multiple comparison test.

[0025] [Figure 3-1] This shows specific, exemplary data regarding immune cells in whole blood. n = 5 mice per group; data are presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001 relative to the vehicle; two-way ANOVA, Dunnett's multiple comparison test. [Figure 3-2] This shows specific, exemplary data regarding immune cells in whole blood. n = 5 mice per group; data are presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001 relative to the vehicle; two-way ANOVA, Dunnett's multiple comparison test.

[0026] [Figure 4] This shows specific exemplary data regarding CD4+ T cell count (A) and histological score (B) in the colon. n = 8 mice per group; data are shown as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.0001 relative to the vehicle; two-way ANOVA, Dunnett's multiple comparison test. [Modes for carrying out the invention]

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in which this invention pertains. General principles of organic chemistry, as well as specific functional parts and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006.

[0028] The following terms are intended to have the meanings set forth below, unless otherwise specified by the context in which they appear.

[0029] The ranges provided herein are understood to be abbreviated representations of all values ​​within a range. For example, the range 1–16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0030] As used herein, “at least” a particular value is understood to mean that value and all values ​​greater than that value.

[0031] As used herein, “2 or more” is understood to mean 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 100, etc., or any value in between.

[0032] In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural form unless the context clearly indicates otherwise.

[0033] Unless otherwise specified or evident from the context, the term “about” as used herein is understood to mean within the normal tolerances in the art, for example, within two standard deviations of the mean. “About” may be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the expressed value. Unless otherwise evident from the context, all numerical values ​​provided herein may be modified by the term “about.”

[0034] As used herein, the term “or” is understood to be inclusive unless otherwise specified or made clear from the context.

[0035] Any composition or method disclosed herein may be combined with one or more other compositions and methods provided herein.

[0036] Any description of an enumeration of chemical groups in any definition of a variable portion herein includes the definition of that variable portion as any single group or combination of the enumerated groups. Any description of an embodiment of a variable portion or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0037] The term "comprises," when used to define a composition and method, is intended to mean that the composition and method include the enumerated elements but do not exclude other elements. The term "consisting essentially of," when used to define a composition and method, means that the composition and method include the enumerated elements but exclude other elements of any essential importance to the composition and method. For example, "consisting essentially of" refers to the administration of pharmacologically active agents that are explicitly enumerated and excludes pharmacologically active agents that are not explicitly enumerated. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define a composition and method, also means excluding other components and minor elements of substantial method steps. Embodiments defined by each of these transitional clauses are within the scope of the present invention.

[0038] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention intends to include all such compounds, including cis and trans isomers, atrop isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the present invention. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention. In certain embodiments, each chiral atom has either an R configuration or an S configuration with an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. For optically active compounds, it is often preferable to use one enantiomer, substantially excluding other enantiomers.

[0039] Isomer mixtures having any of the following isomer ratios can be used in accordance with the present invention. For example, when only two isomers are combined, mixtures having isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are intended by the present invention. Those skilled in the art will readily understand that similar ratios are intended for more complex isomer mixtures.

[0040] For example, if a specific enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis or induction using a chiral auxiliary agent, where the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt may be formed using a suitable optically active acid or base, followed by separation of the diastereomer thus formed by fractional recrystallization or chromatography, which are well known in the art, and subsequent recovery of the pure enantiomer.

[0041] A mixture of isomers can be separated, for example, by chromatography and / or fractional recrystallization, based on the physicochemical differences of the components, into pure or substantially pure geometric isomers or optical isomers, diastereomers, racemic compounds.

[0042] Definitions of certain functional groups and chemical terms are described in more detail below. When a range of values is recited, the range is intended to include each value and sub-range within the range. For example, "C 1~6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1~6 、C 1~5 、C 1~4 、C 1~3 、C 1~2 、C 2~6 、C 2~5 、C 2~4 、C 2~3 、C 3~6 、C 3~5 、C 3~4 、C 4~6 、C 4~5 、and C 5~6 alkyl.

[0043] When substituents are specified by the conventional chemical formulas written from left to right, they similarly include chemically identical substituents obtained by writing their structure from right to left. For example, -C(=O)-O- is equivalent to -O-C(=O)-.

[0044] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted by one or more of a number of substituents, such substitution is selected to obtain compounds known to those skilled in the art that comply with the principles of chemical bonding and are not inherently unstable and / or likely to be unstable under ambient conditions (e.g., aqueous, neutral, and some known physiological conditions).

[0045] Solvates and polymorphs of the compounds of the present invention are also intended herein. Examples of solvates of the compounds of the present invention include hydrates.

[0046] As used herein, the term "alkyl" means a linear, branched, or cyclic hydrocarbon chain radical consisting only of carbon and hydrogen atoms, unsaturated, and having 1 to 10 carbon atoms (e.g., C 1~10 This refers to alkyl. Numerical ranges such as "1 to 10" always refer to each integer within a given range whenever they appear herein; for example, "1 to 10 carbon atoms" means that an alkyl group can consist of up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. However, this definition also includes the existence of the term "alkyl" for which no numerical range is specified. In some embodiments, "alkyl" means C 1~6It may be an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated linear alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl, while saturated branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, and 2,3-dimethylbutyl. The alkyl group is bonded to the parent molecule by a single bond. Unless otherwise specified herein, alkyl groups are optionally substituted with one or more substituents, which are independently acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(Ra )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a These are independently hydrogen, alkyl, haloalkyl, carbocyl, carbocylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be optionally substituted as defined herein. In non-limiting embodiments, the substituted alkyl may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0047] As used herein, the term "alkoxy" refers to linear, branched, saturated cyclic structures and combinations thereof containing 1 to 10 carbon atoms (C 1~10 This refers to an -O-alkyl group that contains ) and is bonded to the parent molecule structure via oxygen. Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted alkoxy groups. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, and cyclohexyloxy. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms. In some embodiments, C 1~3Alkoxy groups are alkoxy groups that include both linear and branched alkyl groups with 1 to 3 carbon atoms. Unless otherwise specified herein, alkoxy groups may be optionally substituted with one or more substituents, which may independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R aThese are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be optionally substituted as defined herein.

[0048] As used herein, the terms “aromatic” or “aryl” mean a group of 6 to 14 ring atoms (e.g., C) having at least one ring having a conjugated π-electron system that is a carbocyclic structure. 6~14 Aromatic or C 6~14 This refers to groups having an aryl group (e.g., phenyl, fluorenyl, and naphthyl). Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted aryl groups. In some embodiments, the aryl group is C 6~10These are aryl groups. For example, a divalent group formed from a substituted benzene derivative and having free valence on the ring atoms is named a substituted phenylene group. In other embodiments, a divalent radical derived from a monovalent polycyclic hydrocarbon radical, whose name ends in "-yl" by removing one hydrogen atom from a carbon atom with free valence, is named by adding "-idene" to the name of the corresponding monovalent radical; for example, a naphthyl group having two bond points is named naphthylidene. Numerical ranges such as "6-14 aryl" refer to each integer within a given range whenever they appear herein; for example, "6-14 ring atoms" means that an aryl group can consist of up to 14 ring atoms, such as 6 ring atoms, 7 ring atoms, etc. This term encompasses monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Examples of polycyclic aryl groups include bicyclic, tricyclic, and tetracyclic groups. In polycyclic groups, only one ring is required to be aromatic; therefore, groups such as indanyl are included by the definition of aryl. Non-restrictive examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenantrenyl, anthracenyl, fluorenyl, indolyl, and indanyl. Unless otherwise specified herein, the aryl portion may be optionally substituted with one or more substituents, which may independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a, -N(R a )2, -C(O)R a , -C(O)OR a、 -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a These are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be optionally substituted as defined herein.

[0049] As used herein, the terms “cycloalkyl” and “carbocykyl” refer to monocyclic or polycyclic radicals containing only carbon and hydrogen, which may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups may be named “cycloalkenyl” if the carbocyclic ring contains at least one double bond, or “cycloalkynyl” if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups encompass groups having 3 to 13 ring atoms (i.e., C 3~13Cycloalkyl). Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted cycloalkyl groups. Numerical ranges such as "3 to 10" refer to each integer within a given range whenever they appear herein; for example, "3 to 13 carbon atoms" means that a cycloalkyl group can consist of up to 13 carbon atoms, such as 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc. The term "cycloalkyl" also encompasses bridged cyclic and spiro-condensed cyclic structures that do not contain heteroatoms. The term also encompasses monocyclic or condensed polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Examples of polycyclic aryl groups include bicyclic, tricyclic, and tetracyclic groups. In some embodiments, "cycloalkyl" refers to C 3~8 It may be a cycloalkyl radical. In some embodiments, "cycloalkyl" is C 3~5 It may be a cycloalkyl radical. Examples of cycloalkyl groups, but not limited to, include the following: C 3~6 Examples of carbocyclyl groups, though not limited to them, include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~7 An example of a carbocyclyl group is norbornyl (C7). 3~8 An example of a carbocyclyl group is the C mentioned above. 3~7 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3~13 An example of a carbocyclyl group is the C mentioned above. 3~8Examples include carbocyl groups, and octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl. Unless otherwise specified herein, cycloalkyl groups may be optionally substituted with one or more substituents, which may independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R aThese are independently hydrogen, alkyl, haloalkyl, carbocyl, carbocylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be optionally substituted as defined herein. The terms “cycloalkenyl” and “cycloalkynyl” reflect the above description of “cycloalkyl,” where the prefix “alk” is replaced by “alken” or “alkyn,” respectively, and the original terms “alkenyl” or “alkynyl” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group may have 5 to 13 ring atoms.

[0050] As used herein, the terms “carbocyclic,” “carbocyclic formula,” and “carbocykyl” refer to monocyclic or polycyclic radicals that contain only carbon as ring atoms and may be saturated or partially unsaturated. Fully saturated carbocyclics are named cycloalkyl. Partially unsaturated cycloalkyl groups may be named “cycloalkenyl” if the carbocyclic contains at least one double bond, or “cycloalkynyl” if the carbocyclic contains at least one triple bond. Unless otherwise specified herein, these terms are intended to encompass both substituted and unsubstituted carbocyclic groups. The term “carbocyclic formula” also encompasses bridging cyclic structures and spiro-condensed cyclic structures that do not contain heterocyclic atoms. This term also encompasses monocyclic or condensed polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Examples of polycyclic groups include bicyclic, tricyclic, and tetracyclic groups. Unless otherwise specified herein, the carbocyclic group may be optionally substituted with one or more substituents.

[0051] As used herein, the terms “heterocyclic,” “heterocyclic,” or “heterocyclyl” refer to a fully saturated or partially unsaturated cyclic group having at least one heteroatom in at least one ring, e.g., a 3- to 7-membered monocyclic system, a 7- to 12-membered bicyclic system, or a 10- to 15-membered tricyclic system, where 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Each ring of a heterocyclic group containing heteroatoms may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur, where the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be bonded by any heteroatom or carbon atom of the ring or cyclic system.

[0052] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term "halide" or "halo" means fluoro, chloro, bromo, or iodine. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" encompass alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" encompass haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and 1-fluoromethyl-2-fluoroethyl. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may be optionally substituted as further described herein.

[0053] As used herein, the term “heteroatom” refers to oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0054] As used herein, the term “heteroalkyl” refers to an alkyl radical having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted heteroalkyl groups. A numerical range may be given to indicate the overall chain length, for example, C 1~4 A heteroalkyl group, in this example, has a length of four atoms. For example, the -CH2OCH2CH3 radical is referred to as a "C4" heteroalkyl group, which includes a heteroatom center in its atomic chain length description. Bonding to the parent molecular structure can be via either heteroatoms or carbon atoms of the heteroalkyl chain. For example, a nitrogen-containing heteroalkyl group refers to a group in which at least one of the skeletal atoms is a nitrogen atom. One or more heteroatoms in a heteroalkyl radical may optionally be oxidized. One or more nitrogen atoms, if present, may optionally be quaternized. For example, heteroalkyl groups also include skeletal chains substituted with one or more nitrogen oxide (-O-) substituents. Exemplary heteroalkyl groups include, but are not limited to, ethers such as methoxyethanyl (-CH2CH2OCH3), ethoxymethanyl (-CH2OCH2CH3), (methoxymethoxy)ethanyl (-CH2CH2OCH2OCH3), (methoxymethoxy)methanyl (-CH2OCH2OCH3), and (methoxyethoxy)methanyl (-CH2OCH2CH2OCH3); and amines such as (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, and -CH2N(CH2CH3)(CH3)).

[0055] As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted heterocycloalkyl groups. Examples of heterocycloalkyl groups include 2-hydroxyaziridine-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyltetrahydrofuran-3-yl, 3-carboxymorpholine-4-yl, 1-cyclopropyl-4-methylpiperazine-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, and 3,4-dihydro-2H-[1,4]oxazine.

[0056] As used herein, the term “heteroaryl” or alternatively “heterocyclic aromatic” refers to a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic configuration) having a ring carbon atom provided to the aromatic ring system and 1 to 6 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). Unless otherwise specified herein, this term is intended to encompass both substituted and unsubstituted heteroaryl groups. A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or both rings. Numerical ranges such as “5-18” always refer to each integer within a given range where they appear herein; for example, “5-18 ring atoms” means that a heteroaryl group may consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, etc. In some examples, heteroaryls may have 5 to 14 ring atoms. In some embodiments, heteroaryls have divalent radicals derived from monovalent heteroaryl radicals, whose names end in "-yl" by, for example, removing one hydrogen atom from an atom with free valence, and are named by adding "-ene" to the name of the corresponding monovalent radical; for example, a pyridyl group having two bond sites is pyridylene.

[0057] For example, the nitrogen-containing "heterocyclic aromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the ring's skeletal atoms is a nitrogen atom. One or more heteroatoms in a heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, may optionally be quaternized. Heteroaryls also include ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. Heteroaryls are bonded to the parent molecule structure via any atom of the ring(s).

[0058] "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, and the bond site to the parent molecule structure is located on either the aryl ring or the heteroaryl ring, or ring systems in which a heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site to the parent molecule structure is located on the heteroaryl ring. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site to the parent molecule structure may be located on either ring, i.e., the ring containing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 member aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 member aromatic ring system having a ring carbon atom provided to the aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 member heteroaryl"). In some embodiments, the 5-6 member heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 member heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 member heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0059] Examples of heteroaryls, though not limited to them, include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzoxazolyl, benzopyranil, benzopyranonil, benzofuranil, benzo Pyranoyl, benzoflazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinyl, carbazolyl, sinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]sinnolinyl, 6,7-dihydro-5Hbenzo[6,7]cyclohepta[1,2-c]pyrimidinyl Dadinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, flo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinol, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d] Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5] Examples include thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranil, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the heteroaryl moiety may be optionally substituted with one or more substituents, which may independently be acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R, a )3, -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(Ra )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a These are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of these parts may be optionally substituted as defined herein.

[0060] As used herein, the term “administer” refers to oral administration, suppository administration, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, focal administration, subarachnoid administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, such as a mini osmotic pump. The appropriate route of administration for a particular patient depends on the nature and severity of the disease or condition being treated or the nature of the treatment used, and the nature of the active compound.

[0061] Administration may be by any preferred route, including parenteral and transmucosal (e.g., oral, sublingual, palatal, gingival, intranasal, vaginal, rectal, or transdermal) administration. Parenteral administration includes, for example, intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods, but not limited to, include the use of liposomal formulations, intravenous injection, and transdermal patches.

[0062] "Simultaneous administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapeutic agents.

[0063] The compounds of the present invention may be administered to a patient alone or concurrently. Concurrent administration is intended to include administering the compounds individually or in combination (two or more compounds or drugs) simultaneously or sequentially. Accordingly, the preparations may be combined with other active agents as needed (for example, to reduce metabolic degradation).

[0064] The compositions of the present invention can be delivered transdermally via local routes and can be formulated as application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, topical preparations, powders, and aerosols. Oral preparations include tablets, pills, powders, sugars, capsules, liquids, licks, cachets, gels, syrups, slurries, and suspensions suitable for oral administration by patients. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid preparations include solutions, suspensions, emulsions, and gels, such as water or water / propylene glycol solutions.

[0065] The compositions of the present invention may further contain components that provide sustained release and / or comfort. Such components include high molecular weight anionic mucus-mimicking polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are described in more detail in U.S. Patents 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entirety of these patents is incorporated herein by reference for all purposes. The compositions of the present invention may be delivered as microspheres for sustained release within the body. For example, microspheres can be administered by intradermal injection of drug-containing microspheres released subcutaneously (see Rao, 1995 J. Biomator Sci. Polym. Ed. 7:623-645), as a biodegradable and injectable gel formulation (see, for example, Gao 1995 Pharm. Res. 12:857-863), or as microspheres for oral administration (see, for example, Eyles 1997 J. Pharm. Pharmacol. 49:669-674).

[0066] As used herein, the terms “disease,” “condition,” and “disorder” are interchangeable herein and refer to a physical condition or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0067] As used herein, the term “effective dose” of an active agent refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective dose of the compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

[0068] As used herein, with respect to biological target (e.g., TYK2)-inhibitor interactions, the terms “inhibit,” “inhibit,” and “to inhibit” mean to have a negative effect on the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor (e.g., to reduce the activity or function). In embodiments, inhibition means to have a negative effect on the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor (e.g., to reduce the concentration or level). In embodiments, inhibition means a reduction in disease or the symptoms of a disease. In embodiments, inhibition means a reduction in the activity of a particular protein target. Inhibition includes, at least partially, partially, or completely, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzyme activity or the amount of a protein. In embodiments, inhibition means a reduction in the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binds to the target protein). In this embodiment, inhibition refers to a reduction in the activity of the target protein through indirect interactions (for example, the inhibitor binds to a protein that activates the target protein, thereby preventing the activation of the target protein).

[0069] As used herein, the terms “isolated” or “purified” mean a substance that substantially or essentially contains no components that would normally be associated with it in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques, such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0070] As used herein, the term “modulate” means to result in an increase or decrease, stimulation, inhibition, interference, or blockage of a measured activity, directly or indirectly, compared to a preferred control. A “modulator” of a polypeptide or polynucleotide means a substance that, compared to a preferred control, affects the measured activity of the polypeptide or polynucleotide, for example, by increasing, decreasing, stimulating, inhibiting, interfering with, or blocking it. For example, a “modulator” may be able to bind to a target with measurable affinity and / or activate or inhibit it, or directly or indirectly affect the normal regulation of receptor activity.

[0071] As used herein, “pharmaceutically acceptable forms” of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0072] In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” means a salt that is appropriate for use in contact with the target tissue without excessive toxicity, irritation, allergic response, etc., within the bounds of sound medical judgment, and that corresponds to a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed by inorganic acids, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or by organic acids, e.g., acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, besilates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, and 2-hydroxy- Examples include tansulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, p-toluenesulfonates, undecanoates, and valersates.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0073] Salts can be prepared in situ during the isolation and purification of the compounds of this disclosure, or separately, by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Suitable pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C 1~4 Examples include alkyl)4 salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts may be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0074] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to a compound further comprising a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intermolecular forces. A solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” will be understood to encompass compounds, solvates of compounds, and mixtures thereof.

[0075] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to a compound that is converted in vivo to produce the disclosed compound or the pharmaceutically acceptable form of said compound. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In certain examples, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of the compound when administered to a subject (e.g., by enabling enhanced absorption into the blood after oral administration) or can enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound that have enhanced water solubility or active transport across the gastrointestinal membrane compared to the parent compound.

[0076] Prodrug compounds often offer advantages in mammalian organisms such as solubility, histocompatibility, or delayed release (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions on prodrugs are presented in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 (both of which are incorporated herein by reference in their entirety).

[0077] Prodrug forms often offer advantages in mammalian organisms such as solubility, tissue compatibility, or delayed release (see Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985, and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs generally known in the art include well-known acid derivatives, such as esters prepared by the reaction of a hydrophilic acid with a suitable alcohol, amides prepared by the reaction of a hydrophilic compound with an amine, and basic groups reacted to form acylated base derivatives. Other prodrug derivatives may be combined with other features disclosed herein to enhance their bioavailability. Thus, those skilled in the art will understand that certain compounds of this disclosure having free amino, amide, hydroxy, or carboxyl groups may be converted into prodrugs. Examples of prodrugs include compounds having a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the substituents disclosed herein.

[0078] Exemplary advantages of prodrugs include, but are not limited to, their physical properties, such as enhanced solubility at physiological pH for parenteral administration compared to the parent compound, or it may enhance absorption from the gastrointestinal tract, or it may enhance drug stability during long-term storage.

[0079] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in moving or transporting the drug of the subject from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include: sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, suitable substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer, as well as colorants, release agents, coating agents, sweeteners, flavorings, and fragrances, preservatives, and antioxidants may also be present in the composition.

[0080] As used herein, the term “subject” refers to any animal (e.g., mammal) that is a recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Subjects to which administration is intended include, but not limited to, humans (e.g., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, e.g., non-human mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques); commercially important mammals, e.g., cattle, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice). In certain embodiments, the non-human animal is a mammal. The non-human animal may be male or female at any developmental stage. The non-human animal may be a transgenic animal. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to human subjects.

[0081] As used herein, the term “treatment” or “treatment” of a disease or disorder means a method of reducing, delaying, or improving such a condition before or after its onset. Treatment may target one or more effects or symptoms of a disease and / or underlying pathology. Treatment may be any reduction, but not limited to, the complete disappearance of the disease or symptoms of the disease. Thus, treating or treatment means any sign of success in treating or improving a disease, disease, pathology, or condition, including any objective or subjective parameters such as remission; a tendency toward remission; a reduction in symptoms, or that the injury, pathology, or condition becomes more tolerable to the patient; a slowing of the rate of degeneration or debilitation; that the final stages of degeneration become less debilitating; or that the patient’s physical or mental health improves. Treatment or improvement of symptoms may be based on objective or subjective parameters, e.g., the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation. Compared to an equivalent untreated control, the degree of such reduction or improvement may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% when measured by any standard technique.

[0082] The treatment method involves administering a therapeutically effective dose of the compounds described herein to a subject. The administration step may be a single dose or may involve a series of doses. The length of the treatment period depends on various factors such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It will also be understood that the effective dose of the agent used in the treatment may increase or decrease throughout the course of a particular treatment regimen. Changes in dosage may occur and be revealed by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the composition is administered to the subject in an amount sufficient to treat the patient and for a period of time sufficient to treat the patient.

[0083] This invention is based on the unexpected discovery of novel, selective, and potent compounds that are TYK2 inhibitors. The invention also provides pharmaceutical compositions of these compounds, as well as methods for their preparation and use. The compounds of this invention are orally available and exhibit fewer and / or less severe side effects than currently available drugs.

[0084] The novel class of TYK2 inhibitors disclosed herein exhibits an exceptional potency profile and is useful for treating diseases and conditions mediated by one or more TYK2s, such as allergic diseases and conditions, autoimmune diseases and conditions, inflammatory diseases and conditions, metabolic diseases and conditions, neurological diseases and conditions, and proliferative diseases and conditions. While not wishing to be bound by theory, the compounds of the present invention are modulators of interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-α) by inhibiting TYK2-mediated signaling.

[0085] These compounds are designed to exhibit good efficacy against TYK2, along with good oral absorption and good in vivo stability. The present invention also provides pharmaceutical compositions of these compounds, as well as methods for their preparation and use. The TYK2 inhibitors disclosed herein exhibit favorable pharmacokinetic profiles and pharmacokinetic properties suitable for targeted indications.

[0086] In one embodiment, the present invention generally relates to structural formula (I): [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Y 1 However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, t is 0 or 1, R 1 However, it is H, F, CD3, or C1-C3 alkyl, provided that Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 2 but, R 2’ And here, R 2’ However, these are C1-C6 alkyl, C3-C6 cycloalkyl, C5-C7 spirocycloalkyl, or C3-C6 heterocycloalkyl, each containing 0-2 R 2a It is replaced with R 2a However, halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic; Each has 0 to 2 R 2a A substituted aryl or heteroaryl group; (C=O)R 2b ;or (C=O)NHR 2b Selected from the group consisting of, R 3 but, [ka] And, During the ceremony, X 6 However, CR 6 or N, X 7 However, CR 7 or N, X 8 However, it is C or N, X 9 However, CR 9 , O, S, N, or NR 9 And, X 10 However, CR 10 , O, S, N, or NR 10 And, Each of ring A and ring B is independently an aryl or heteroaryl group. R 2b However, C 1~6 Alkyl or C 3~6Cycloalkyl, C 5~7 Spirocycloalkyl, aryl, or heteroaryl, each containing 0 to 4 R 2c It has been replaced with, R 2c However, independently, in each appearance, Halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 It is an alkynyl, where the alkyl, haloalkyl, alkenyl, alkynyl, R, and R' have 0 to 3 R 2a It has been replaced with, R 4 However, 0 to 5 R 4a C replaced by 1~3 It is alkyl, and here, R 4a However, it is selected from D, F, and Cl, R 5 However, H, CN, Halo, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1~6 The alkyl, C3-C6 cycloalkyl, or heterocyclic group is characterized by having 0-3 R atoms. 5a It is replaced by each R 5a However, it is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3, and OC(=O)CH3. R 6 , R 7 , R 9 , and R 10 Each of these is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, and C3-C5 cycloalkyl, where the alkyl, cycloalkyl, R, and R' are 0-2 R 2a It has been replaced with, The present invention relates to a compound or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of R and R' is independently H or a C1-C6 alkyl or acyl, or R and R', together with the nitrogen atom to which they are bonded, form a 4-7 membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2.

[0087] In a particular embodiment of (I), t is 1, and the compound has the following structural formula: [ka] It holds.

[0088] In a particular embodiment of (I), t is 0, and the compound has the following structural formula: [ka] It holds.

[0089] In a particular embodiment of (II), ring A is a heteroaryl group.

[0090] In a particular embodiment of (II), X 6 CH is, X 7 CH is, R 3 The structure is as follows: [ka] It holds.

[0091] In a particular embodiment of (II), X 7 CH is, X 8 C is R 3 The structure is as follows: [ka] It holds.

[0092] In a particular embodiment of (II), X 6 CH is, X 8C is R 3 The structure is as follows: [ka] It holds.

[0093] In a particular embodiment of (II), X 7 CH is, X 10 CH is, R 3 The structure is as follows: [ka] It holds.

[0094] (II)~(II d In a particular embodiment of ), R 4 This is CH3.

[0095] (II)~(II d In a particular embodiment of ), R 4 This is CD3.

[0096] (III a )~(III b In a particular embodiment of ), R 3 teeth, [ka] Selected from.

[0097] In a particular embodiment, R 4 This is CD3.

[0098] In a particular embodiment, R 4 It is CH3, and R 3 teeth, [ka]

[0099] Selected from. (III a )~(III bIn a particular embodiment of ), R 3 teeth, [ka] That is the case.

[0100] R 3 In a particular embodiment, R 10 H is H.

[0101] (III a )~(III b In a particular embodiment of ), R 3 teeth, [ka] That is the case.

[0102] R 3 In a particular embodiment, R 9 C 1~3 They are alkyl or cyclopropyl, each being C 1~3 It is optionally substituted with alkoxy, CF3, or NRR'.

[0103] R 3 In a particular embodiment, R 9 C 1~3 It is alkyl.

[0104] R 3 In a particular embodiment, R 9 This is CH3.

[0105] R 3 In a particular embodiment, R 9 This is CD3.

[0106] R 3 In a particular embodiment, R 5 is a C substituted with OH. 1~4 It is alkyl.

[0107] R 3 In a particular embodiment, R 5teeth, [ka] And, During the ceremony, R 5’ This is C substituted with 0 to 5 F's. 1~3 Alkyl or cyclopropyl, R is H, C 1~3 It is alkyl or acyl.

[0108] R 3 In a particular embodiment, R 5 teeth, [ka] And, During the ceremony, R 5’ This is C substituted with 0 to 5 F's. 1~3 Alkyl or cyclopropyl, R is H, C 1~3 It is alkyl or acyl.

[0109] (II g )~(II h In a particular embodiment of ), R is CH3.

[0110] (II g )~(II h In a particular embodiment of ), R is CD3.

[0111] (II g )~(II h In a particular embodiment of ), R is C(=O)CH3.

[0112] (II g )~(II h In a particular embodiment of ), R is C(=O)CD3.

[0113] (II g )~(II h In a particular embodiment of ), R 5’This is CF3.

[0114] (II g )~(II h In a particular embodiment of ), R 5’ It is CHF2.

[0115] (I), (III a ), and (III b In a particular embodiment of ), Y 3 It is NH.

[0116] (III a In a particular embodiment of ), Y 1 CH is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0117] (III a In a particular embodiment of ), Y 1 CH is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0118] (III a In a particular embodiment of ), Y 1 N is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0119] (III a In a particular embodiment of ), Y 1 N is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0120] (I), (III a ), and (III b In a particular embodiment of ), Y 3 It is O.

[0121] (III a In a particular embodiment of ), Y 1 CH is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0122] (III a In a particular embodiment of ), Y 1 CH is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0123] (III a In a particular embodiment of ), Y 1 N is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0124] (III a In a particular embodiment of ), Y 1 N is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0125] (I), (III a), and (III b In a particular embodiment of ), Y 3 This is CH2.

[0126] (III a In a particular embodiment of ), Y 1 CH is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0127] (III a In a particular embodiment of ), Y 1 CH is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0128] (III a In a particular embodiment of ), Y 1 N is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0129] (III a In a particular embodiment of ), Y 1 N is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0130] In a particular embodiment of (I), in the formula t is 0, and the compound has the structural formula (III b ) has.

[0131] (III bIn a particular embodiment of ), Y 3 This is CD2.

[0132] (III b In a particular embodiment of ), Y 3 This is CF2.

[0133] (III b In a particular embodiment of ), Y 1 CH is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0134] (III b In a particular embodiment of ), Y 1 CH is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0135] (III b In a particular embodiment of ), Y 1 N is Y 2 CH is the compound, and its structural formula is as follows: [ka] It holds.

[0136] (III b In a particular embodiment of ), Y 1 N is Y 2 It is N, and the compound has the following structural formula: [ka] It holds.

[0137] R 3 In a particular embodiment, R 6and R 7 Each of these is H if it exists.

[0138] (II Ia )~(III b In a particular embodiment of ), R 2 R 2’ That is the case.

[0139] (III a )~(III b In a particular embodiment of ), R 2 is (C=O)R 2b That is the case.

[0140] In a particular embodiment, R 2b This is 0 to 3 R 2c Selected from C1-C6 alkyl groups substituted with [the appropriate compound].

[0141] In a particular embodiment, R 2 b is 0 to 3 R 2c C replaced by 3~6 It is a cycloalkyl group.

[0142] In a particular embodiment, R 2b It is cyclopropyl.

[0143] In a particular embodiment, R 2b It is a cyclopropyl compound substituted with F.

[0144] In a particular embodiment, R 2b This is 0 to 3 R 2c C replaced by 5~7 It is a spirocycloalkyl.

[0145] In a particular embodiment, R 2b This is C5 spiro[2.2]pentyl.

[0146] (III a )~(III b In a particular embodiment of ), R 2 (C=O)NHR2b That is the case.

[0147] (III a )~(III b In a particular embodiment of ), R 2 This is 0 to 2 R 2c It is a pyridinyl substituted with [a specific compound].

[0148] (III a )~(III b In a particular embodiment of ), R 2 This is 0 to 2 R 2b It is a phenyl compound substituted with [a specific compound].

[0149] (III a )~(III b In a particular embodiment of ), R 2 This is 0 to 2 R 2c It is pyrazolyl substituted with [the specified compound].

[0150] (III a )~(III b In a particular embodiment of ), R 2 This is 0 to 2 R 2c It is a pyrimidyl substituted with [another compound].

[0151] (III a )~(III b In a particular embodiment of ), R 1 This is CH3.

[0152] (III a )~(III b In a particular embodiment of ), R 1 This is CD3.

[0153] (III a In certain embodiments of the compound, the following structural formula is used: [ka] It has, In the formula, X 6 It is either N or CH.

[0154] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0155] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0156] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0157] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0158] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0159] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0160] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0161] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0162] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0163] (III a In certain embodiments of the compound, the following structural formula is used: [ka] It has, In the formula, X 6 It is either N or CH.

[0164] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0165] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0166] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0167] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0168] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0169] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0170] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0171] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0172] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, R is H, CD3, C 1~3 It is alkyl or acyl.

[0173] (III a In certain embodiments of the compound, the structural formula is selected from the following: [ka] It has, In the formula, X 6 It is either N or CH.

[0174] (III a In certain embodiments of the compound, the following structural formula is used: [ka] It has, In the formula, X 6 It is either N or CH.

[0175] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0176] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0177] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0178] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0179] (III a In certain embodiments of the compound, the compound has a structural formula selected from the following: [ka]

[0180] (III b In certain embodiments of the compound, the following structural formula is used: [ka] It has, In the formula, X 6 It is either N or CH.

[0181] (III b In certain embodiments of the compound, the following structural formula is used: [ka] It has, In the formula, X 6 It is either N or CH.

[0182] (IV 1 In certain embodiments of )~(VII), R 6 and R 7 Each of these is H if it exists.

[0183] (IV 1 In certain embodiments of )~(VII), in the formula, R 9 If it exists, C 1~3 They are alkyl or cyclopropyl, each optionally substituted with a C1-C3 alkoxy, CF3, or NRR'.

[0184] (IV 1 In certain embodiments of )~(VII), R 9 C 1~3 It is alkyl or cyclopropyl.

[0185] (IV 1 In certain embodiments of )~(VII), R 9 This is CH3.

[0186] (IV 1 In certain embodiments of )~(VII), R 9 This is CD3.

[0187] (IV 1 In certain embodiments of )~(VII), R 2b This is 0 to 2 R 2c It is a C1-C6 alkyl, cyclopropyl, or cyclobutyl substituted with [a specific compound].

[0188] (IV 1 In certain embodiments of )~(VII), R 2b It is cyclopropyl.

[0189] (IV 1In certain embodiments of )~(VII), R 5 teeth, [ka] And, During the ceremony, R 5’ This is C substituted with 0 to 5 F's. 1~3 Alkyl or cyclopropyl, R is H, C 1~3 It is alkyl or acyl.

[0190] (IV 1 In certain embodiments of )~(VII), R 5 teeth, [ka] And, During the ceremony, R 5’ This is C substituted with 0 to 5 F's. 1~3 Alkyl or cyclopropyl, R is H, C 1~3 It is alkyl or acyl.

[0191] In a particular embodiment, R is H.

[0192] In a particular embodiment, R is CH3.

[0193] In a particular embodiment, R is CD3.

[0194] In a particular embodiment, R 5’ This is CF3.

[0195] In a particular embodiment, R 5’ It is CHF2.

[0196] In a particular embodiment, R 5’ This is C substituted with 2 to 5 F's. 2~3 It is alkyl.

[0197] (IV 1 In certain embodiments of )~(VII), R 1 This is CH3.

[0198] (IV 1 In certain embodiments of )~(VII), R 1 This is CD3.

[0199] In another embodiment, the present invention generally relates to structural formula (VIII): [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, X 6 However, CR 6 or N, X 7 However, CR 7 or N, X 8 However, it is C or N, X 9 However, CR 9 , O, S, N, or NR 9 And, X 10 However, CR 10 , O, S, N, or NR 10 And, Y 1 However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, Y 4 However, it is NR, CH2, or CF2, Y 5 However, these are NR, CH2, O, S, SO, or SO2. m is 0, 1, 2, and 3. n is 0, 1, 2, and 3. p is 0, 1, 2, and 3. Each of ring A and ring B is independently an aryl or heteroaryl group. The ring C is a 5-membered or 6-membered aryl or heteroaryl group, R 1 However, H, F, CD3, or C 1~3 It is alkyl, however, Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 4 However, 0 to 5 R 4a C replaced by 1~3 It is alkyl, and here, R 4a However, it is selected from D, F, and Cl, R 5 However, H, CN, Halo, OCH3, C(=O)OR, NHC(=O)R, NRR', NO2, C 1~6 Alkyl, C 3~6 A cycloalkyl or heterocycle, where the alkyl, cycloalkyl, or heterocycle has 0 to 3 R 5a It is replaced by each R 5a However, it is independently selected from OH, D, F, Cl, CN, CH2F, CHF2, CF3, OCH3, OCD3, OCF3, and OC(=O)CH3. R 6 , R 7 , R 9 , R 10 , and R 11 Each of these is H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C 1~3 Alkyl and C 3~5 A cycloalkyl group is independently selected, where the alkyl, cycloalkyl, R, and R' have 0 to 2 R's. 2a It has been replaced with, R 2a However, F, OCF3, CF3, CN, NO2, OR, NRR', and C 1~6 Selected from alkyl groups, The present invention relates to a compound or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of R and R' is independently H, C1-C6 alkyl, or acyl, or R and R', together with the nitrogen or carbon atom to which they are bonded, form a 3-6 membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2.

[0200] In a particular embodiment of (VIII), Y 1 CH is Y 2 It is CH.

[0201] In a particular embodiment of (VIII), Y 1 N is Y 2 It is CH.

[0202] In a particular embodiment of (VIII), Y 1 CH is Y 2 It is N.

[0203] In a particular embodiment of (VIII), Y 1 N is Y 2 It is N.

[0204] In a particular embodiment of (VIII), Y 3 It is NH.

[0205] In a particular embodiment of (VIII), Y 3 It is O.

[0206] In a particular embodiment of (VIII), Y 3 This is CH2.

[0207] In a particular embodiment of (VIII), Y 3 This is CD2.

[0208] In a particular embodiment of (VIII), Y 4 It is NH.

[0209] In a particular embodiment of (VIII), Y 4 This is CH2.

[0210] In a particular embodiment of (VIII), R 1 This is CH3.

[0211] In a particular embodiment of (VIII), R 1 This is CD3.

[0212] In a particular embodiment of (VIII), R 4 This is CH3.

[0213] In a particular embodiment of (VIII), R 4 This is CD3.

[0214] Non-limiting examples of the compounds of the present invention are those listed in Table 1 of the Examples section herein.

[0215] In further embodiments, the present invention generally relates to methods for preparing compounds disclosed herein, as exemplified by the synthetic schemes and experimental procedures disclosed herein.

[0216] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed herein that is generally effective in treating or reducing one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0217] In yet another embodiment, the present invention generally provides an amount of structural formula (I) effective in treating or reducing one or more diseases or disorders in mammals, including humans: [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Y 1However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, R 1 However, these are H, F, C1-C3 alkyl, and CD3, where Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 2 but, R 2’ And here, R 2’ However, C1-C6 alkyl, C 3~6 Cycloalkyl, C 5~7 Spirocycloalkyl or C3-C6 heterocycloalkyl, each containing 0-2 R 2a It is replaced with R 2a However, halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic; Each has 0 to 2 R 2a A substituted aryl or heteroaryl group; (C=O)R 2b ;or (C=O)NHR 2b Selected from the group consisting of, R 3 but, [ka] And, During the ceremony, X 6 However, CR 6 or N, X 7 However, CR 7 or N, X 8 However, it is C or N, X 9 However, CR 9 , O, S, N, or NR 9 And, X 10 However, CR 10 , O, S, N, or NR 10And, Each of ring A and ring B is independently an aryl or heteroaryl group. R 2b However, C 1~6 Alkyl or C 3~6 Cycloalkyl, C 5~7 Spirocycloalkyl, aryl, or heteroaryl, each containing 0 to 2 R 2c It has been replaced with, R 2c However, independently, in each appearance, Halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 It is an alkynyl, where the alkyl, haloalkyl, alkenyl, alkynyl, R, and R' have 0 to 3 R 2a It has been replaced with, R 4 However, 0 to 5 R 4a C replaced by 1~3 It is alkyl, and here, R 4a However, it is selected from D, F, and Cl, R 5 However, H, CN, halo, OCH3, C(=O)OCH3, C 1~6 The alkyl, C3-C6 cycloalkyl, or heterocyclic group is characterized by having 0-3 R atoms. 5a It is replaced by each R 5a However, it is independently selected from OH, D, F, Cl, CN, OCH3, OCD3, OCF3, and OC(=O)CH3. R 6 , R 7 , R 9 , and R 10 Each of these is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, and C3-C5 cycloalkyl, where the alkyl, cycloalkyl, R, and R' are 0-2 R 2a It has been replaced with, The present invention relates to a compound or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent, wherein each of R and R' is independently H or a C1-C6 alkyl or acyl, or R and R', together with the nitrogen atom to which they are bonded, form a 4-7 membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0218] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0219] In certain embodiments, the pharmaceutical composition is suitable for topical administration.

[0220] In certain embodiments, the pharmaceutical composition is suitable for localized administration of the GI.

[0221] In certain embodiments, the pharmaceutical composition is useful for treating or reducing one or more of the following: inflammatory diseases, immune-mediated diseases, and cancer, or related diseases or disorders.

[0222] In a particular embodiment, the disease or disorder is an inflammatory disease.

[0223] In certain embodiments, the disease or disorder is an immune-mediated disease.

[0224] In a particular embodiment, the disease or disorder is cancer.

[0225] In certain embodiments, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes mellitus, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-associated kidney injury, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia eugenics (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0226] In further embodiments, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0227] In a particular embodiment, the unit dosage form is a tablet.

[0228] In certain embodiments, the unit dosage form is a capsule.

[0229] In certain embodiments, the unit dosage form is a topical formulation.

[0230] In further embodiments, the present invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering a therapeutically effective amount of a compound disclosed herein to a subject in need, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0231] In yet another aspect, the present invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising, to a subject in need, a therapeutically effective amount of the structural formula of (I): [ka] A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Y 1 However, it is CH, CF, or N, Y 2 However, it is CH or N, Y 3 However, it is NR, O, CH2, CD2, CF2, or O-NH, R 1 However, these are H, F, C1-C3 alkyl, and CD3, where Y 3 However, if it is N, O, or O-NH, then R 1 It is not F, R 2 but, R 2’ And here, R 2’ However, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 5~7 Spirocycloalkyl or C3-C6 heterocycloalkyl, each containing 0-2 R 2a It is replaced with R 2a However, halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic; Each has 0 to 2 R 2a A substituted aryl or heteroaryl group; (C=O)R 2b ;or (C=O)NHR 2b Selected from the group consisting of, R 3 but, [ka] And, During the ceremony, X 6 However, CR 6 or N, X 7 However, CR 7 or N, X 8 However, it is C or N, X 9 However, CR9 , O, S, N, or NR 9 And, X 10 However, CR 10 , O, S, N, or NR 10 And, Each of ring A and ring B is independently an aryl or heteroaryl group. R 2b However, C 1~6 Alkyl or C 3~6 Cycloalkyl, C 5~7 Spirocycloalkyl, aryl, or heteroaryl, each containing 0 to 2 R 2c It has been replaced with, R 2c However, independently, in each appearance, Halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 It is an alkynyl, where the alkyl, haloalkyl, alkenyl, alkynyl, R, and R' have 0 to 3 R 2a It has been replaced with, R 4 However, 0 to 5 R 4a C replaced by 1~3 It is alkyl, and here, R 4a However, it is selected from D, F, and Cl, R 5 However, H, CN, halo, OCH3, C(=O)OCH3, C 1~6 The alkyl, C3-C6 cycloalkyl, or heterocyclic group is characterized by having 0-3 R atoms. 5a It is replaced by each R 5a However, it is independently selected from OH, D, F, Cl, CN, OCH3, OCD3, OCF3, and OC(=O)CH3. R 6 , R 7 , R 9 , and R 10Each of these is independently selected from H, F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, and C3-C5 cycloalkyl, where the alkyl, cycloalkyl, R, and R' are 0-2 R 2a It has been replaced with, The procedure involves administering the compound or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of R and R' is independently H or a C1-C6 alkyl or acyl, or R and R', together with the nitrogen atom to which they are bonded, form a 4-7 membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2. The method relating to which the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0232] In a particular embodiment, the disease or disorder is an inflammatory disease.

[0233] In certain embodiments, the disease or disorder is an immune-mediated disease.

[0234] In a particular embodiment, the disease or disorder is cancer.

[0235] In certain embodiments, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes mellitus, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-associated kidney injury, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia eugenics (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0236] In certain embodiments, administration is by oral administration.

[0237] In certain embodiments, administration is performed by local administration.

[0238] In certain embodiments, administration is performed by localized administration of the GI.

[0239] In further embodiments, the present invention generally relates to the use of the compounds disclosed herein, and pharmaceutically acceptable excipients, carriers, or diluents, in the preparation of agents for treating diseases or disorders.

[0240] In certain embodiments of use, the disease or disorder is one or more of the following: inflammatory diseases, immune-mediated diseases, and cancer.

[0241] In a particular use case, the disease or disorder is an inflammatory disease.

[0242] In certain embodiments of use, the disease or disorder is an immune-mediated disease.

[0243] In a particular use case, the disease or disorder is cancer.

[0244] In certain embodiments of use, the drug is intended for oral administration.

[0245] In certain embodiments of use, the drug is intended for topical administration.

[0246] In certain embodiments of use, the drug is intended for localized administration to the GI (glycemic index).

[0247] As described herein, isotopic derivative compounds in which one or more hydrogen atoms (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc.) are replaced by deuterium atoms are intended in the present invention.

[0248] The term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, such as an increased level of inflammation compared to a control, such as a healthy person without the disease. Examples of inflammatory diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, and autoimmune diseases. These include thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are often closely related to other diseases, disorders, and conditions. For example, a non-exclusive list of inflammation-related diseases, disorders, and conditions that can be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., when inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Some of the aforementioned diseases, disorders, and conditions for which the compounds of this disclosure may be particularly effective (for example, due to limitations of current treatments) are described in more detail below.

[0249] The term "autoimmune disease" refers to a disease or condition in which the immune system of a subject exhibits an abnormal immune response to substances that do not normally elicit an immune response in healthy subjects. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acne vulgaris, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, Ecardi-Goutier syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, and autoimmune disorders. Inner ear disorders, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neurogenic neuropathy, Barlow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing polymyelitis, Churg-Straug S.S. syndrome, pemphigoid scarring / benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, Crest's disease, Cushing's disease, demyelinating neuropathy, depression, herpetiform dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler's syndrome, dry eye syndrome (DES - keratoconjunctivitis sicca), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrotic alveolitis Giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis, graft-versus-host disease (GVDH), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes zoster of pregnancy, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosing disease, inflammatory bowel disease (IBD), immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes mellitus),Juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosing, woody conjunctivitis, linear IgA disease, lupus, Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mohren's ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular scarring pemphigoid, optic neuritis, relapsing rheumatoid arthritis, streptococcal-associated childhood autologous cell carcinoma Immunotherapy neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, Personage-Turner syndrome, ciliary body squamous cellulitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), type I, II, and III polyglandular autoimmune syndromes, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone Psoriasis, psoriatic dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, plaque psoriasis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure erythropoiesis, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff person syndrome, and early childhood development These include interferon-stimulating factor (STING)-associated vascular disease (SAVI), subacute bacterial endocarditis, Suzak syndrome, sympathetic ophthalmitis, systemic lupus erythematosus (SLE), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transplant rejection (allogeneic transplant rejection), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous skin diseases, vitiligo, or Wegener's granulomatosis.

[0250] The term "immune-mediated disease" refers to chronic inflammatory diseases persisted by antibody and cellular immunity. Immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, xerophthalmos (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease). Examples include diseases such as Guillain-Barré syndrome, myasthenia gravis, and chronic idiopathic demyelinating diseases (CID), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, psoriasis vulgaris, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allogeneic transplant rejection), and graft-versus-host disease (GVDH).

[0251] As used herein, the term “cancer” refers to all types of cancer, neoplasms, or malignant tumors found in mammals, such as humans, including hematological cancers, leukemias, and lymphomas, T-ALL, large B-cell lymphoma, solid tumors, such as carcinomas and sarcomas. Exemplary cancers include hematological cancers, brain cancers, gliomas, glioblastomas, neuroblastomas, prostate cancers, colorectal cancers, pancreatic cancers, cervical cancers, stomach cancers, ovarian cancers, lung cancers, and head cancers. Exemplary cancers include cancers of the thyroid, endocrine system, brain, breast, neck, colon, head and neck, liver, kidneys, lungs, non-small cell lung cancers, melanomas, mesotheliomas, ovarian cancers, sarcomas, stomach cancers, uterine cancers, medulloblastomas, colorectal cancers, and pancreatic cancers. Additional examples include penile tumors, skin tumors (non-melanoma), anal tumors, hepatobiliary tumors, esophageal and gastric tumors, uterine sarcoma, gastrointestinal stromal tumors, salivary gland neoplasms, peripheral nervous system neoplasms, soft tissue sarcoma, bone neoplasms, kidney neoplasms, myeloproliferative neoplasms, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, and primary cancers. Examples include thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the pancreatic endocrine or exocrine parts, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, metastatic leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, round cell liposarcoma, or prostate cancer.

[0252] In certain embodiments of use, the disease or disorder is selected from: inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes mellitus, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-associated kidney injury, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia eugenics (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0253] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, “isotope-labeled compound” means a compound of the disclosure in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature, including their pharmaceutically acceptable salts and prodrugs as described herein. Examples of isotopes that may be incorporated into the compounds of the disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is one example.

[0254] By isotope labeling the compounds of this disclosure, the compounds may be useful in tissue distribution assays of drugs and / or substrates. Tritium ( 3 H) Labeled compound and carbon 14 ( 14 C) Labeled compounds are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes, such as deuterium (2 Substitution at H) may result in certain therapeutic advantages due to higher metabolic stability, such as an increased in vivo half-life or a reduced required dose, and is therefore preferred in some situations. The isotope-labeled compounds of this disclosure, including their pharmaceutically acceptable salts, esters, and prodrugs, can be prepared by any means known in the art.

[0255] Furthermore, hydrogen is usually abundant 1 Substitution of H with heavier isotopes such as deuterium can result in certain therapeutic benefits, for example, due to improvements in absorption, distribution, metabolism, and / or excretion (ADME) properties, thereby creating drugs with improved efficacy, safety, and / or tolerability. The benefits are usually abundant. 12 C 13 This can also be obtained by substituting C (see WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0256] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemic mixtures, diastereomer mixtures, and other mixtures of such isomers, are within the scope of this disclosure.

[0257] The compounds of the present invention may, after their preparation, be preferably isolated and purified to obtain a composition containing 95% by weight or more ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure. Solvates and polymorphs of the compounds of the present invention are also intended herein. Examples of solvates of the compounds of the present invention include hydrates.

[0258] Any suitable route of administration, such as parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intraperitoneal, rectal, or oral administration, may be used. The most appropriate means of administration for a particular patient depends on the nature and severity of the disease or condition being treated, the nature of the treatment used, and the nature of the active compound.

[0259] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds or derivatives described herein may be accompanied by at least one conventional inert excipient (or carrier), for example, sodium citrate or dicalcium phosphate, or (i) fillers or bulking agents, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, for example, carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, for example, glycerol, and (iv) disintegrants, for example, agar, calcium carbonate, and jasper. The solids are mixed with (v) a solubility retardant, e.g., paraffin, (vi) an absorption enhancer, e.g., a quaternary ammonium compound, (vii) a wetting agent, e.g., cetyl alcohol and glycerol monostearate, (viii) an absorbent, e.g., kaolin and bentonite clay, and (ix) a lubricant, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffer. Similar types of solid compositions can also be used as fillers for soft and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugars, capsules, pills, and granules can be prepared using coatings and shells, e.g., enteric coatings and others known in the art.

[0260] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, or mixtures thereof. In addition to such inert diluents, the composition may contain additional agents, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or fragrances.

[0261] The materials, compositions, and components disclosed herein may be used for, in conjunction with, or in preparation for the methods and compositions disclosed herein, or are products thereof. Where combinations, subsets, interactions, groups, etc., of these materials are disclosed, specific references to each of the various individual and collective combinations and permutations of these compounds do not have to be expressly disclosed, but each is understood to be specifically intended and described herein. For example, where a method is disclosed and examined, and a number of possible modifications to a number of molecules contained in the method are examined, any combination and permutation of the method and possible modifications is specifically intended unless otherwise specified. Similarly, any subset or combination of these is also specifically intended and disclosed. This concept applies to all aspects of the disclosure, including, but not limited to, the steps of a method using the compositions of the disclosure. Accordingly, where various additional steps can be performed, each of these additional steps may be performed together with any specific step or combination of step steps of the method disclosed herein, and each of such combinations or subsets of combinations should be considered specifically intended and disclosed. [Examples]

[0262] The following examples are intended to be illustrative of the embodiment of the present invention and are not intended to limit it in any way. [Table A]

[0263] Typical preparative HPLC method: Flow rate and gradient may be changed.

[0264] An example of a preparative HPLC method is shown below.

[0265] Method A:NH4HCO3: Column: Gilson2-XbrigeC 18 19*150mm, 5μm; Mobile phase: 20%~60% CH3CN in water (0.1% NH4HCO3); Flow rate: 15ml / min.

[0266] Method B TFA: Column: Waters-Xbridge C18 10*190mm, 5μm; Mobile phase: 15%~40% CH3CN in water (0.1% TFA); Flow rate: 15ml / min.

[0267] Method C :HCOOH:Column:Waters-Xbridge C18 10*190mm, 5μm;Mobile phase:15%~40% CH3CN in water (0.1% formic acid);Flow rate:15ml / min.

[0268] Method D :HCOOH:Column:Waters SunFire(registered trademark) Prep C18 OBD™ (5 microns, 19*150 mm);Mobile phase: 18%~38% CH3CN in water (0.1% formic acid);Flow rate: 20 mL / min.

[0269] Method E :NH4HCO3:Column:Waters Xbridge(registered trademark) Prep C18 OBD TM (5 microns, 19*150 mm); mobile phase: 20%~60% CH3CN in water (10 mM NH4HCO3); flow rate: 20 mL / min.

[0270] Typical methods of chiral preparative HPLC: Method F: Gilson 281, Daicel Chiralpak IE, 10 μm, 30*250 mm; Mobile phase: Hexane / EtOH / Diethylamine = 70 / 30 / 0.3; Flow rate: 25 mL / min.

[0271] Method G: Gilson 281, Daicel Chiralpak IG, 10μm, 30*250mm; Mobile phase: Hexane / EtOH=70 / 30; Flow rate: 25mL / min.

[0272] Method H: Gilson 281, Daicel Chiralpak IB N, 10μm, 30*250mm; mobile phase: Hekisan / IPA / Jiechiru Amin=80 / 20 / 0.3; flow rate: 30ml / min.

[0273] Method I: Gilson 281, Daicel Chiralpak IA, 10μm, 30*250mm; Mobile phase: Hekisan / EtOH / Jetylaminn=30 / 70 / 0.3; Flow rate: 25mL / min.

[0274] Method J: Gilson 281, Daicel Chiralpak IB N-5, 10μm, 30*250mm; mobile phase: Hekisan / IPA / Jiechiru Amin=80 / 20 / 0.3; flow rate: 25mL / min.

[0275] Method K: Gilson 281, Daicel Chiralpak IE, 10μm 50*250mm; Mobile phase: Hekisan / EtOH=60 / 40; Flow rate: 60mL / min.

[0276] Method L: Gilson 281, Daicel Chiralpak IC, 10μm, 30*250mm; Mobile phase: Hekissin / IPA / DEA=60 / 40 / 0.3; Flow rate: 25mL / min.

[0277] Method M: Gilson 281, Daicel Chiralpak IH, 10 μm, 30*250 mm; Mobile phase: Hekissan / EtOH=90 / 10; Flow rate: 25 mL / min.

[0278] Method N: Gilson 281, Daicel Chiralpak IK, 10μm 50*250mm; Mobile phase: Hekissan / IPA=70 / 30; Flow rate: 60mL / min.

[0279] Method O:Gilson 281, Daicel Chiralpak ID, 10μm, 30*250mm; Mobile phase: Hexane / IPA / DEA=80 / 20 / 0.2; Flow rate: 25mL / min.

[0280] Typical methods of analytical HPLC Method 1 Analysis was performed using an Agilent 1200 series HPLC-6120MS. The setup was equivalent to a UHPLC long gradient, with 5% to 95% acetonitrile in water (containing 0.02% NH4OAc), a run time of 6.5 minutes, and a flow rate of 1.5 ml / min. A Waters Xbridge C18 column (18.5 microns, 4.6*50 mm) was used at 40°C.

[0281] Method 2 Analysis was performed using an Agilent 1200 series HPLC-6120MS. The setup was equivalent to a UHPLC long gradient, with 5% to 95% acetonitrile in water (containing 0.1% trifluoroacetic acid), a run time of 6.5 minutes, and a flow rate of 1.5 ml / min. A Waters Xbridge C18 column (18.5 microns, 4.6*50 mm) was used at a temperature of 40°C.

[0282] Method 3 Analysis was performed using an Agilent 1260 series HPLC-6120MS. The parameters were equivalent to a UHPLC long gradient, with 5% to 95% acetonitrile in water (containing 0.02% NH4OAc), a run time of 2.5 minutes, and a flow rate of 0.5 ml / min. A Diamonsil Plus C18 column (18.5 microns, 4.6*30 mm) was used at a temperature of 40°C.

[0283] Method 4Analysis was performed using either an Agilent 1260 series HPLC-6125C MS or an Agilent 1290 Infinity II HPLC-6125C MS. The HPLC long gradient equivalent was used, with 20%–100% acetonitrile in water (containing 0.1% FA), a run time of 1.3–4.5 minutes, and a flow rate of 0.7 mL / min or 1 mL / min. Agilent ZORBAX SB-C18 columns (1.8 micron, 2.1*50 mm) or Agilent Poroshell120 SB-C18 columns (1.9 micron, 2.1*50 mm) were used at a temperature of 40°C.

[0284] Method 5 Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to hexane / EtOH / DEA (70 / 30 / 0.2), with a run time of 20 minutes and a flow rate of 1 ml / min. A CHIRALPAK IE (5 μm, 4.6 x 250 mm) was used at a temperature of 30°C.

[0285] Method 6 Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to hexane / EtOH / DEA (30 / 70 / 0.2), with a run time of 30 minutes and a flow rate of 1 ml / min. A CHIRALPAK IA (5 μm, 4.6 x 250 mm) was used at a temperature of 30°C.

[0286] Method 7: Analysis was performed using a SHIMADZU 20A HPLC. Long gradient equivalent for HPLC, hexane / IPA / DEA (80 / 20 / 0.2), run time 30 minutes, flow rate 1 ml / min. A CHIRALPAK IB N-5 (5 μm, 4.6*250 mm) was used at a temperature of 30°C.

[0287] Method 8 Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to hexane / EtOH (70 / 30), with a run time of 30 minutes and a flow rate of 1 ml / min. A CHIRALPAK IG (5 μm, 4.6 x 250 mm) was used at a temperature of 30°C.

[0288] Method 9 Analysis was performed using a Shimadzu LC-20A HPLC. The HPLC long gradient was equivalent to 70 / 30 Hex / EtOH, with a run time of 7 minutes and a flow rate of 1 ml / min. A CHIRALPAK IE (5 μm, 4.6 x 150 mm) was used at 35°C.

[0289] Method 10 Analysis was performed using a Shimadzu LC-20A HPLC. The HPLC long gradient was equivalent to 60 / 40 hexane / EtOH, with a run time of 15 minutes and a flow rate of 1 ml / min. A CHIRALPAK IG (5 μm, 4.6 x 150 mm) was used at 30°C.

[0290] Method 11 Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to a hexane / EtOH (90 / 10) mixture, with a run time of 30 minutes and a flow rate of 1 ml / min. A CHIRALPAK IH (5 μm, 4.6 x 250 mm) was used at 30°C.

[0291] Method 12 Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to a hexane / IPA / DEA (50 / 50 / 0.2) mixture, with a run time of 25 minutes and a flow rate of 1 ml / min. A CHIRALPAK ID (5 μm, 4.6 x 250 mm) was used at 30°C.

[0292] Method 13 Analysis was performed using a SHIMADZU 20AT HPLC. The HPLC long gradient was equivalent to a hexane / IPA (70 / 30) mixture, with a run time of 30 minutes and a flow rate of 1 ml / min. A CHIRALPAK IK (5 μm, 4.6 x 250 mm) was used at a temperature of 35°C.

[0293] Method 14Analysis was performed using a SHIMADZU 20A HPLC. The HPLC long gradient was equivalent to a hexane / IPA (98 / 2) mixture, with a run time of 25 minutes and a flow rate of 1 ml / min. A CHIRALPAK IB N (5 μm, 4.6 x 250 mm) was used at a temperature of 30°C.

[0294] Intermediate A [ka] Step 1: 4-Chloro-6-(cyclopropanecarboxamide)methyl nicotinate (A2) A mixture of A1 (2.0 g, 9.71 mmol), cyclopropanecarboxamide (826 mg, 9.71 mmol), Pd(OAc)2 (109 mg, 0.49 mmol), dppf (538 mg, 0.97 mmol), and K3PO4 (4.12 g, 19.42 mmol) in dioxane (30 mL) was stirred at 90°C for 4 hours under N2. The mixture was diluted with H2O (100 mL), extracted with SiO2 (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain compound A2 (1.8 g, 73% yield) as a white solid. LC-MS (ESI, Method 4) t R = 3.33 min, m / z (M+H) + = 255.0.

[0295] Step 2: 4-Chloro-6-(cyclopropanecarboxamide)lithium nicotinate (A3) To a solution of A2 (500 mg, 1.96 mmol) in a cosolvent of MeOH (2 mL), THF (2 mL), and water (1 mL), LiOH·H2O (165 mg, 3.93 mmol) was added. The mixture was then stirred overnight at room temperature. The mixture was concentrated to dryness to obtain compound A3 (480 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 3.81 min, m / z (M+H) + = 241.1.

[0296] Step 3: 4-Chloro-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide (intermediate A) To a solution of A3 (480 mg, 1.95 mmol) in DCM (15 mL), methane-d3-amine hydrochloride (275 mg, 3.89 mmol), DIPEA (1.51 g, 11.68 mmol), and T3P (1.86 g, 2.92 mmol, 50% in ethyl acetate) were sequentially added at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The organic layer was washed with brine (50 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain intermediate A (300 mg, 60% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.25 min, m / z (M+H) + = 257.1.

[0297] Intermediate B [ka] Step 1: 4-chloro-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)methyl nicotinate (B1) A mixture of A1 (1.0 g, 4.85 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (751 mg, 7.28 mmol), K3PO4 (2.04 g, 9.67 mmol), dppf (269 mg, 0.49 mmol), and Pd(OAc)2 (109 mg, 0.49 mmol) in dioxane (8 mL) was stirred at 90°C for 12 hours under N2. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 30 / 1) to obtain B1 (220 mg, 17% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.16 min, m / z (M+H) + = 273.6.

[0298] Step 2: 4-Chloro-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)nicotinic acid (B2) To a solution of B1 (900 mg, 3.30 mmol) in MeOH / THF / H2O (15 mL, v / v / v=2 / 2 / 1), LiOH·2H2O (990 mg, 16.50 mmol) was added and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated to dryness and acidified to pH=2 with 1N HCl. The formed solid was filtered, and the filter cake was dried to obtain B2 (700 mg, 82% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.00 min, m / z (M+H) + = 258.9.

[0299] Step 3: 4-Chloro-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide (intermediate B) A mixture of B2 (700 mg, 2.71 mmol), DIPEA (2.10 g, 16.24 mmol, 2.83 mL), T3P (1.72 g, 5.41 mmol, 3.45 mL, 50% by weight in DMF), and methane-d3-amine hydrochloride (379 mg, 5.41 mmol) in DMF (4 mL) was stirred at 30°C for 48 hours. The mixture was diluted with H2O (10 mL) and extracted with DCM (10 * 3 mL). The organic layer was washed with brine (2 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain intermediate B (500 mg, 67% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 5.04-4.86 (m, 1H), 2.49-2.40 (m, 1H), 1.69-1.62 (m, 1H), 1.24-1.18 (m, 1H). LC-MS (ESI, Method 3) R = 0.91 min, m / z (M+H) + = 275.0.

[0300] Intermediate C [ka] Step 1: 4-Chloro-6-(cyclopropanecarboxamide)-N-methylnicotinamide (intermediate C) A mixture of A3 (338 mg, 1.37 mmol), DIPEA (1.06 g, 8.23 ​​mmol), methylamine hydrochloride (184 mg, 2.75 mmol), and T3P (1.75 g, 2.74 mmol, 50% by weight in DMF) in DMF (2 mL) was stirred at 50°C for 24 hours. The reaction mixture was poured into water (5 mL) and extracted with SiO2 (20 mL x 3). The separated organic layer was washed with water (5 mL) and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM / MeOH = 10 / 1) to obtain intermediate C (120 mg, 34% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 2.75 (d, J = 5.2 Hz, 3H), 2.02-1.99 (m, 1H), 0.85-0.82 (m, 4H). LC-MS (ESI, Method 3) R = 0.94 min, m / z (M+H) + = 254.2.

[0301] Intermediate D [ka] Step 1: 6-Chloro-4-((4-methoxybenzyl)amino)methyl nicotinate (D1) To a solution of A1 (5 g, 24.27 mmol) in ACN (8 mL), (4-methoxyphenyl)methaneamine (3.33 g, 24.27 mmol, 3.2 mL) and TEA (4.91 g, 48.54 mmol, 6.8 mL) were added. The mixture was then stirred at room temperature for 24 hours. The mixture was diluted with H2O (100 mL), extracted with EA (50 mL x 3), washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 20 / 1 to 5 / 1) to obtain compound D1 (6.5 g, 87% yield) as an off-white solid. LC-MS (ESI, Method 4) t R = 4.18 min, m / z (M+H) + = 307.1.

[0302] Step 2: 6-(cyclopropanecarboxamide)-4-((4-methoxybenzyl)amino)methyl nicotinate (D2) A mixture of D1 (2 g, 6.52 mmol), cyclopropanecarboxamide (1.11 g, 13.04 mmol), Xantphos (754 mg, 1.30 mmol), Pd2(dba)3 (597 mg, 0.65 mmol), and Cs2CO3 (5.31 g, 16.30 mmol) in 1,4-dioxane (30 mL) was stirred at 110°C for 2 hours. The mixture was then diluted with H2O (100 mL), extracted with EA (60 mL x 3), washed with brine, dried over Na2SO4, and concentrated to obtain compound D2 (2.3 g, 99% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.91 min, m / z (M+H) + = 356.2.

[0303] Step 3: 4-amino-6-(cyclopropanecarboxamide)methyl nicotinate 2,2,2-trifluoroacetate (intermediate D) A solution of D2 (2.1 g, 5.91 mmol) in TFA (10 mL) was stirred at 80°C for 16 hours. The mixture was then concentrated, diluted with EA (10 mL), filtered, and washed with EA (5 mL x 2). The solid was then dried to obtain compound intermediate D (1.8 g, 87% yield, TFA salt) as an off-white solid. LC-MS (ESI, Method 4) t R = 1.28 min, m / z (M+H) + = 236.2.

[0304] Intermediate E [ka] Step 1: 2,4-Dichloro-N-(methyl-d3)pyrimidine-5-carboxamide (Intermediate E) To a mixture of methane-d3-amine hydrochloride (1.40 g, 19.86 mmol) in DCM (200 mL), E1 (3.5 g, 16.55 mmol) was slowly added, followed by the addition of TEA (1.68 g, 16.55 mmol, 2.31 mL) at -78°C. After stirring at this temperature for 1 hour, the reaction mixture was quenched with water (30 mL). The organic layer was separated and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1) to obtain intermediate E (1.38 g, 35% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.85 (s, 1H). LC-MS (ESI, Method 3) R = 0.80 min, m / z (M+H) + = 208.9.

[0305] Intermediate F [ka] Step 1: 4-chloro-6-((5-fluoropyridine-2-yl)amino)methyl nicotinate (F1) A mixture of A1 (2.0 g, 9.71 mmol), 5-fluoropyridine-2-amine (1.31 g, 11.65 mmol), K3PO4 (4.12 g, 19.42 mmol), DPPF (807 mg, 1.46 mmol), and Pd(OAc)2 (327 mg, 1.46 mmol) in anhydrous dioxane (20 mL) was stirred at 90°C for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (PE / EA=7 / 1) to obtain F1 (2.0 g, 73% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.11 min, m / z (M+H) + = 282.4.

[0306] Step 2: 4-Chloro-6-((5-Fluoropyridine-2-yl)aminonicotinic acid (F2) To a solution of F1 (2.0 g, 7.10 mmol) in MeOH / THF / H2O (20 mL, v / v / v=2 / 2 / 1), LiOH·H2O (1.49 g, 35.50 mmol) was added. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to dryness and acidified to pH=2 with 1N HCl. The formed solid was collected by filtration, and the filtration cake was dried to obtain compound F2 (1.8 g, 95% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.88 min, m / z (M+H) + = 268.2.

[0307] Step 3: 4-Chloro-6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)nicotinamide (intermediate F) A mixture of F2 (400 mg, 1.50 mmol), methane-d3-amine hydrochloride (529 mg, 7.50 mmol), and DIPEA (1.16 g, 9.00 mmol) in T3P (2 mL, 50 wt% in DMF) was stirred at 50°C for 16 hours. After cooling to room temperature, the reaction mixture was poured into water (10 mL), and the resulting solid was collected by filtration. The filtered cake was slurryed with MeOH (5 mL) for 30 minutes. The solid was filtered and dried to obtain intermediate F (380 mg, 90% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.10 min, m / z (M+H) + = 284.1.

[0308] intermediate G [ka] Step 1: 4,6-Dichloronicotinate methyl-d3(G2) To a solution of G1 (2.00 g, 11 mmol) in DCM (20 mL), (COCl)2 (3.96 g, 31 mmol) and DMF (0.08 g, 1 mmol, 0.08 mL) were added at 0°C. The mixture was then stirred at 25°C for 2 hours and concentrated to obtain the residue. To a solution of the residue in DCM (20 mL), CD3OD (0.38 g, 0.011 mol, 0.43 mL) and TEA (2.10 g, 0.021 mol, 2.9 mL) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (20 mL) and then extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column (SiO in PE is 2-20%) to obtain G2 (1.5 g, 68% yield) as a white solid. LC-MS (ESI, Method 4) t R = 0.25 min, m / z [M+H] + = 208.9.

[0309] Step 2: 4-Chloro-6-(cyclopropanecarboxamide)methyl-d3 nicotinate (intermediate G) To a solution of G2 (1.5 g, 7 mmol) in dioxane (20 mL), cyclopropanecarboxamide (0.61 g, 7 mmol), Pd(OAc)2 (0.16 g, 0.7 mmol), dppf (1.20 g, 1.4 mmol), and K3PO4 (3.06 g, 14 mmol) were added under an N2 atmosphere. The mixture was stirred at 75°C for 16 hours. The reaction mixture was diluted with water (30 mL) and then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (PE / EA = 5 / 1) to obtain intermediate G (0.80 g, 44% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.92 min, m / z [M+H] + = 257.7.

[0310] Example 1 [ka] Step 1: 3-iodo-4-methoxy-1-methyl-1H-indole(1b) To a solution of 1a (2.78 g, 10.18 mmol) in DMF (15 mL), KOH (2.28 g, 40.72 mmol) and CH3I (4.34 g, 30.54 mmol) were added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (50 mL), and the resulting solid was filtered. The solid was dried to obtain compound 1b (2.8 g, 96% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.11-7.05 (m, 2H), 6.55 (dd, J = 7.6, 1.2 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H).

[0311] Step 2: (4-Methoxy-1-methyl-1H-indole-3-yl)carbamate tert-butyl(1c) A mixture of 1b (500 mg, 1.74 mmol), K3PO4 (738 mg, 3.48 mmol), BocNH2 (612 mg, 5.22 mmol), CuI (100 mg, 0.52 mmol), and N,N-dimethylethane-1,2-diamine (46 mg, 0.52 mmol) in toluene (5 mL) was stirred overnight at 110 °C. The mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 4 / 1) to obtain compound 1c (240 mg, 50% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.34 (s, 1H), 7.10-6.97 (m, 2H), 6.52 (d, J = 10.4 Hz, 1H), 3.90 (s, 3H), 3.71 (s, 3H), 1.50 (s, 9H).

[0312] Step 3: 4-Methoxy-1-methyl-1H-indole-3-amine hydrochloride (1d) To a solution of 1c (300 mg, 1.09 mmol) in siRNA (2 mL), HCl / EA (2 mL, 6 M) was added at room temperature. The mixture was stirred overnight at room temperature. The resulting solid was filtered, and the filter cake was dried to obtain compound 1d (158 mg, 68% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (brs, 3H), 7.37 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H).

[0313] Step 4: 6-Chloro-4-((4-methoxy-1-methyl-1H-indole-3-yl)amino)pyridazine-3-carboxylate methyl(1e) A mixture of 1d (90 mg, 0.42 mmol), methyl 4,6-dichloropyridazine-3-carboxylate (88 mg, 0.42 mmol), and DIPEA (273 mg, 2.12 mmol) in DMF (1 mL) was stirred at 80°C for 10 hours. The reaction product was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 4 / 1) to obtain compound 1e (80 mg, 55% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.45 min, m / z (M+H) + = 347.1.

[0314] Step 5: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-1H-indole-3-yl)amino)pyridazine-3-carboxylate methyl(1f) A mixture of 1e (98 mg, 0.28 mmol), cyclopropanecarboxamide (48 mg, 0.57 mmol), Cs2CO3 (276 mg, 0.85 mmol), BrettPhos (26 mg, 0.028 mmol), and BrettPhos Pd G3 (15 mg, 28 mmol) in anhydrous 1,4-dioxane (1 mL) was stirred at 80°C for 6 hours. The mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain compound 1f (65 mg, 58% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.49 min, m / z (M+H) + = 396.2.

[0315] Step 6: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-1H-indole-3-yl)amino)-N-methylpyridazine-3-carboxamide(1) A mixture of 1f (50 mg, 0.13 mmol) in methylamine (1.5 mL, 30% alcohol solution) was stirred at 80°C for 48 hours. The mixture was concentrated. The residue was purified by preparative HPLC (Method C) to obtain compound 1 (4 mg, 8% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 11.02 (s, 1H), 9.02-8.99 (m, 1H), 7.98 (s, 1H), 7.23 (s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 2.10-2.06 (m, 1H), 0.83-0.81 (m, 4H). LC-MS (ESI, Method 2) tR = 2.43 min, m / z (M+H) + = 395.2.

[0316] Example 2 [ka] Step 1: 5-bromo-4-methoxy-1-methyl-1H-indole-3-carbaldehyde (2b) 2a (1.5g, 6.3 mmol) in DMF (15mL) and t A mixture of BuOK (1.7 g, 15.6 mmol) was stirred at 0°C for 10 minutes. Then, iodomethane (3.5 g, 24.9 mmol) was added to the reaction mixture. After stirring at room temperature for 18 hours, the mixture was diluted with water (30 mL) and extracted with ELISA (30 mL x 3). The combined organic phase was washed with brine (40 mL), concentrated, and the residue was purified by silica gel flash chromatography (PE / DCM = 1 / 1) to obtain 2b (1.6 g, 96% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.25 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H).

[0317] Step 2: 5-Bromo-4-methoxy-1-methyl-1H-indole-3-carboxylic acid (2c) A mixture of 2b (1.2 g, 4.5 mmol) and KMnO4 (1.4 g, 8.9 mmol) in acetone / H2O (80 mL, v / v=1 / 1) was stirred at room temperature for 10 hours. The mixture was filtered, and the organic solvent was removed under reduced pressure. The aqueous layer was basicized to pH>10 with 1 M NaOH and washed with ELISA (20 mL). The separated aqueous layer was acidified to pH=5 with 2 M HCl and extracted with DCM / MeOH (40 mL x 3, v / v=10 / 1). The combined organic phases were washed with brine (40 mL), concentrated, and the crude product 2c (0.60 g, 50% yield) was obtained as a yellow solid. LC-MS (ESI, Method 3) t R = 1.11 min, m / z ( 79 Br, M+H) + = 284.0.

[0318] Step 3: (5-bromo-4-methoxy-1-methyl-1H-indole-3-yl)carbamate tert-butyl(2d) A mixture of 2c (417 mg, 1.5 mmol), DPPA (444 mg, 1.6 mmol), and Et3N (444 mg, 4.40 mmol) in toluene (4 mL) was stirred at 110°C for 1 hour. Then, t BuOH (217 mg, 2.9 mmol) was added to the mixture. After stirring at 110°C for 12 hours, the reaction mixture was cooled and concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 20 / 1) to obtain 2d (60 mg, 12% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.47 min, m / z ( 79 Br, M+H)+ = 355.2.

[0319] Step 4: 4-((5-bromo-4-methoxy-1-methyl-1H-indole-3-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide hydrochloride (2e) A mixture of 2d (55 mg, 0.15 mmol), intermediate A (40 mg, 0.14 mmol), and concentrated HCl catalyst in EtOH (1 mL) was stirred at 90°C for 18 hours. The reaction mixture was cooled, concentrated, and purified by preparative TLC (DCM / MeOH = 30 / 1) to obtain 2e (46 mg, 60% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.30 min, m / z ( 79 Br, M+H) + = 475.3.

[0320] Step 5: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-vinyl-1H-indole-3-yl)amino)-N-(methyl-d3)nicotinamide(2f) A mixture of 2e (56 mg, 0.11 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (19 mg, 0.13 mmol), CsF (48 mg, 0.315 mmol), and Pd(dppf)Cl2 (8 mg, 0.01 mmol) in dioxane / H2O (1.2 mL, v / v=3 / 1) was stirred at 150°C for 5 hours under microwave and N2. After cooling to room temperature, the mixture was filtered, and the residue was concentrated to obtain the crude product 2f (40 mg, 90% yield) as a black solid. LC-MS (ESI, Method 3) t R = 1.26 min, m / z (M+H) + = 423.4.

[0321] Step 6: 6-(cyclopropanecarboxamide)-4-((5-ethyl-4-methoxy-1-methyl-1H-indole-3-yl)amino)-N-(methyl-d3)nicotinamide(2) A mixture of 2f (40 mg, 0.095 mmol) and Pd / C (4 mg, 0.036 mmol, moistened with approximately 50% water) in MeOH was stirred at room temperature for 5 hours under H2 (0.1 MPa). The mixture was filtered and purified by preparative HPLC (Method A) to obtain 2 (11.4 mg, 28% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.33 (s, 1H), 8.44-8.46 (m, 2H), 7.74 (s, 1H), 7.27 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.97-1.91 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 0.73-0.69 (m, 4H). LC-MS (ESI, Method 2) R = 2.58 min, m / z (M+H) + = 425.2.

[0322] Example 3 [ka] Step 1: (3-methoxypyridine-4-yl)carbamate tert-butyl(3b) The solutions of 3a (800 mg, 6.44 mmol), Boc2O (1.83 g, 8.38 mmol, 1.9 mL), and DIPEA (1.67 g, 12.89 mmol, 2.24 mL) in DCM (15 mL) were stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was concentrated and purified by flash chromatography (EA in PE is 10-50%) to obtain compound 3b (1.45 g, given yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.92 min, m / z (M+H) + = 225.1.

[0323] Step 2: 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridine-1-ium-2,4-dinitrophenolate(3c) A mixture of 3b (1.45 g, 6.47 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (1.42 g, 7.11 mmol) in MeCN (50 mL) was stirred at 50°C for 16 hours. A yellow solution was formed. The reaction was concentrated to obtain 3c (2.73 g, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.66 min, m / z M + = 240.1.

[0324] Step 3: 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate ethyl(3d) A mixture of ethyl propioate (685 mg, 6.98 mmol, 0.71 mL), 3c (1.29 g, 5.37 mmol), and K2CO3 (1.48 g, 10.74 mmol) in DMF (15 mL) was stirred at 20°C for 2 hours. A black suspension was formed. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and then extracted with RINKAN (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 3d (428 mg, 22% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 4.16 min, m / z (M+H) + = 336.1.

[0325] Step 4: 5-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate ethyl(3e) To a mixture of 3d (330 mg, 0.98 mmol) in DCM (2 mL), HCl / dioxane (4 M, 2 mL) was added at 20°C. The resulting mixture was stirred at 20°C for 1 hour. A yellow solution was formed. The reaction mixture was concentrated to obtain 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate ethyl (231 mg, HCl salt, crude product) as a yellow solid. LC-MS (ESI, Method 4) tR = 0.48 min, m / z (M+H) + = 236.1.

[0326] To a mixture of ethyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (231 mg, HCl salt, crude product) in MeCN (5 mL), tert-butyl nitrite (152 mg, 1.47 mmol, 0.18 mL) was added at 0°C and the mixture was stirred for 10 minutes. Then, CuCl (145.8 mg, 1.47 mmol) was added to the mixture. The resulting mixture was stirred at 80°C for 12 hours. A yellow solution was formed. The reaction mixture was concentrated and purified by flash chromatography (EA in PE is 10-30%) to obtain 3e (100 mg, 40% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.44 min, m / z (M+H) + = 255.2.

[0327] Step 5: 5-chloro-4-methoxy-pyrazolo[1,5-a]pyridine(3f) A well-mixed solution of 3e (100 mg, 0.39 mmol) in 2 mL of 50% H2SO4 was heated at 110°C for 3 hours. A yellow solution was formed. This solution was cooled to room temperature. This solution was neutralized with 1.0 M aqueous NaOH solution. 40 mL of water was added to the above solution. The solution was extracted with  (30 mL x 3). The organic layers were combined. The organic layers were dried on anhydrous Na2SO4. The organic layers were filtered through a Celite pad. The organic layers were removed under reduced pressure to obtain 3f (33 mg, 46% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 2.4 Hz, 1.2 Hz, 1H), 4.06 (s, 3H). LC-MS (ESI, Method 4) R = 2.46 min, m / z (M+H) + = 183.1.

[0328] Step 6: 5-Chloro-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine (3g) A mixture of 3f (31 mg, 0.17 mmol) and NIS (38.2 mg, 0.17 mmol) in DMF (2 mL) was stirred at 20°C for 12 hours. A yellow suspension was formed. The reaction mixture was quenched with water (50 mL) and extracted with RINKAN (30 mL x 3). The combined organic layer was washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 3 g (50 mg, 95% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 3.12 min, m / z (M+H) + = 308.9.

[0329] Step 7: 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-(cyclopropanecarboxamide)methyl nicotinate (3h) A mixture of 3 g (50 mg, 0.16 mmol) of dioxane (1 mL), intermediate D (68 mg, 0.19 mmol, TFA salt), BrettPhos (17.4 mg, 0.032 mmol), Cs2CO3 (132 mg, 0.41 mmol), and BrettPhos Pd G3 (14.7 mg, 0.016 mmol) was subjected to three rounds of nitrogen degassing and purging. The resulting mixture was stirred at 100°C for 24 hours under an N2 atmosphere. A yellow suspension was formed. The reaction mixture was concentrated and purified by preparative TLC (PE / EA = 1 / 2) to obtain 3 h (60 mg, 89% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.58 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 1.98-1.90 (m, 1H), 0.78-0.70 (m, 4H). LC-MS (ESI, Method 4) R = 2.42 min, m / z (M+H) + = 416.2.

[0330] Step 8: 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-6-(cyclopropanecarboxamide)nicotinic acid (3i) A mixture of 3h (60 mg, 0.144 mmol) and LiOH·H2O (18 mg, 0.433 mmol) in THF (3 mL) and water (1 mL) as cosolvents was stirred at 40°C for 12 hours. A yellow solution was formed. The reaction mixture was concentrated and dried under reduced pressure to obtain 3i (58 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.01 min, m / z (M+H) + = 402.2.

[0331] Step 9: 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide(3) A mixture of CD3NH2·HCl (30.5 mg, 0.433 mmol), 3i (58 mg, crude product), DIPEA (93.3 mg, 0.721 mmol, 0.13 mL), and T3P (275.6 mg, 0.433 mmol, 50% purity in Â) in DMF (2 mL) was stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method E) to obtain 3 (3.6 mg, 6% yield) as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.35 (s, 1H), 8.55 (s, 1H), 8.51-8.43 (m, 2H), 8.11 (s, 1H), 7.65 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 3.79 (s, 3H), 1.98-1.90 (m, 1H), 0.76-0.71 (m, 4H). LC-MS (ESI, Method 4) R = 1.97 min, m / z (M+H) + = 418.2.

[0332] Example 4 [ka] Step 1: 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate methyl(4a) A mixture of methyl propioate (749 mg, 8.91 mmol, 7.93 mL), 3c (1.89 g, 4.45 mmol), and K2CO3 (1.23 g, 8.91 mmol) in DMF (5 mL) was stirred at 20°C for 2 hours. A black suspension was formed. The reaction mixture was concentrated, diluted with water (50 mL), and then extracted with RINKAN (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 4a (350 mg, 24% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.28 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.32 (brs, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.55 (s, 9H). LC-MS (ESI, Method 4) R = 4.13 min, m / z (M+H) + = 322.1.

[0333] Step 2: 5-chloro-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate methyl(4b) To a mixture of 4a (1.25 g, 3.89 mmol) in DCM (5 mL), TFA (2 mL) was added at 20°C. The resulting mixture was stirred at 20°C for 1 hour. A yellow solution was formed. The reaction mixture was concentrated to obtain 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate methyl (800 mg, TFA salt, crude product) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.46 min, m / z (M+H) + = 222.1.

[0334] To a mixture of methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (800 mg, TFA salt, crude product) in MeCN (10 mL), tert-butyl nitrite (559 mg, 5.42 mmol, 0.65 mL) was added at 0°C and the mixture was stirred for 10 minutes. Then, CuCl (716 mg, 7.23 mmol) was added to the mixture, and the resulting mixture was stirred at 80°C for 2 hours. A yellow solution was formed. The reaction mixture was concentrated and purified by flash chromatography (EA in PE is 10-30%) to obtain 4b (600 mg, 69% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.31 min, m / z (M+H) + = 241.2.

[0335] Step 3: 5-Chloro-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (4c) A mixture of 4b (300 mg, 1.25 mmol) and LiOH·H2O (157 mg, 3.74 mmol) in a cosolvent of THF (6 mL) and water (2 mL) was stirred at 70°C for 12 hours. A yellow solution was formed. The reaction mixture was diluted with water (30 mL) and extracted with HCl (20 mL). The aqueous layer was adjusted to pH=3 with HCl aqueous solution (2 M) and extracted with HCl (20 mL x 3). The organic layer was concentrated and dried under reduced pressure to obtain 4c (180 mg, 64% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.79 min, m / z (M+H) + = 227.0.

[0336] Step 4: (5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate tert-butyl(4d) A mixture of 4c (180 mg, 0.79 mmol), N,N-diethylethaneamine (161 mg, 1.59 mmol, 0.22 mL), and DPPA (284 mg, 1.03 mmol, 0.22 mL) in tBuOH (3 mL) was stirred at 110°C for 6 hours. A yellow suspension was formed. The reaction mixture was diluted with water (50 mL) and extracted with ethylethanol (50 mL x 3). The combined organic layer was washed with water (100 mL x 3) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 5-30%) to obtain 4d (100 mg, 42% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.31 min, m / z (M+H) + = 298.1.

[0337] Step 5: 5-Chloro-4-methoxypyrazolo[1,5-a]pyridine-3-amine(4e) To a mixture of 4d (100 mg, 0.34 mmol) in DCM (3 mL), TFA (1 mL) was added at 20°C. The resulting mixture was stirred at 20°C for 1 hour. A yellow solution was formed. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-60%) to obtain 4e (40 mg, 60% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.65 min, m / z (M+H) + = 198.1.

[0338] Step 6: 2-Chloro-4-((5-Chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide(4f) A mixture of 4e (40 mg, 0.20 mmol) and intermediate E (42 mg, 0.20 mmol) in DCM (5 mL) was mixed with DIPEA (52 mg, 0.40 mmol, 0.07 mL) at 0°C. The resulting mixture was stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was quenched with water (50 mL) and extracted with siRNA (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain 4f (74 mg, 98% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.88 min, m / z (M+H) + = 370.1.

[0339] Step 7: 2-Amino-4-((5-Chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (4g) A mixture of 4f (20 mg, 0.054 mmol) and TsOH (19 mg, 0.11 mmol) in NH3 / dioxane solution (3 mL, 0.4 M) was stirred at 80°C for 72 hours. A white suspension was formed. The reaction mixture was diluted with water (40 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with water (40 mL x 3) and brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 4 g (12 mg, 63% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.87 min, m / z (M+H) + = 351.2.

[0340] Step 8: 4-(N-(5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)cyclopropanecarboxamide)-2-(cyclopropanecarboxamide)-N-(methyl-d3)pyrimidine-5-carboxamide(4h) A mixture of 4 g (12 mg, 0.034 mmol) of cyclopropane carbonyl chloride (11 mg, 0.103 mmol) and DIPEA (17 mg, 0.171 mmol, 0.024 mL) in DCM (2 mL) was stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was concentrated and dried under reduced pressure to obtain 4 h (16 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 2.94 min, m / z (M+H) + = 487.3.

[0341] Step 9: 4-((5-chloro-4-methoxypyrazolo[1,5-a]pyridin-3-yl)amino)-2-(cyclopropanecarboxamide)-N-(methyl-d3)pyrimidine-5-carboxamide(4) A mixture of 4h (16 mg, crude product) and K2CO3 (9 mg, 0.066 mmol) in MeOH (3 mL) was stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was filtered, purified by preparative HPLC (Method D), and then lyophilized to obtain 4 (2.3 mg, 16.7% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 10.98 (s, 1H), 9.62 (s, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.39 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 4.09 (s, 3H), 2.15-2.06 (m, 1H), 0.93-0.80 (m, 4H). LC-MS (ESI, Method 4) R = 2.17 min, m / z (M+H) + = 419.2.

[0342] Example 5 [ka] Step 1: 3-Methoxy-4-methylpyridine (5b) To a mixture of 5a (2.50 g, 22.91 mmol) in DMF (20 mL), NaH (1.37 g, 34.36 mmol, 60% of mineral oil) and CH3I (3.58 g, 25.20 mmol, 1.57 mL) were added at 0°C. The resulting mixture was stirred at 20°C for 2 hours. A black suspension was formed. The reaction mixture was diluted with water (100 mL) and then extracted with  (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 5b (230 mg, 8% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.10 (d, J = 4.8 Hz, 1H), 6.72 (m, 1H), 3.90 (s, 3H), 2.21 (s, 3H). LC-MS (ESI, Method 4) R = 0.56 min, m / z (M+H) + = 124.0.

[0343] Step 2: 1-amino-3-methoxy-4-methylpyridine-1-ium-2,4-dinitrophenolate (5c) A mixture of 5b (230 mg, 1.87 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (409 mg, 2.05 mmol) in MeCN (3 mL) was stirred at 50°C for 16 hours. A yellow solution was formed. The reaction was concentrated to obtain 5c (260 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, method 4) t R = 1.16 min, m / z M + = 140.1.

[0344] Step 3: 4-Methoxy-5-methylpyrazolo[1,5-a]pyridine-3-carboxylate methyl(5d) A mixture of methyl propioate (236 mg, 2.80 mmol, 0.25 mL), 5c (260 mg, 1.87 mmol), and K2CO3 (516 mg, 3.74 mmol) in DMF (3 mL) was stirred at 20°C for 2 hours. A black suspension was formed. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and then extracted with  (50 mL x 2). The combined organic layer was washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 5d (140 mg, 34% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.60 min, m / z (M+H) + = 221.0.

[0345] Step 4: 4-methoxy-5-methylpyrazolo[1,5-a]pyridine(5e) A well-mixed solution of 5d (140 mg, 0.636 mmol) in 2 mL of 50% H2SO4 was heated at 110°C for 3 hours. A yellow solution was formed. This solution was cooled to room temperature. The solution was neutralized with 1.0 M aqueous NaOH solution using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with  (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered through a Celite pad, and removed by distillation to obtain 5e (50 mg, 48% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 2.28 (s, 3H). LC-MS (ESI, Method 4) R = 2.29 min, m / z (M+H) + = 163.1.

[0346] Step 5: 3-iodo-4-methoxy-5-methylpyrazolo[1,5-a]pyridine(5f) A mixture of 5e (50 mg, 0.308 mmol) and NIS (73 mg, 0.324 mmol) in DMF (1 mL) was stirred at 20°C for 24 hours. A yellow suspension was formed. The reaction mixture was quenched with water (50 mL) and extracted with  (30 mL x 3). The combined organic layer was washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 5f (70 mg, 79% yield) as a yellow solid. LCMS (ESI, Method 4) t R = 2.93 min, m / z (M+H) + = 289.0. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 6.59 (d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.32 (s, 3H).

[0347] Step 6: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridine-3-yl)amino)methyl nicotinate (5g) A mixture of 5f (70 mg, 0.243 mmol), intermediate D (102 mg, 0.29 mmol, TFA salt), BrettPhos (26 mg, 0.049 mmol), Cs2CO3 (198 mg, 0.607 mmol), and BrettPhos Pd G3 (22 mg, 0.024 mmol) in dioxane (3 mL) was subjected to three rounds of nitrogen degassing and purging. The resulting mixture was stirred at 100°C for 72 hours under an N2 atmosphere. A yellow suspension was formed. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 5 g (60 mg, 62% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.18 min, m / z (M+H) + = 396.3.

[0348] Step 7: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridine-3-yl)aminonicotinic acid (5h) A mixture of 5 g (60 mg, 0.152 mmol) and LiOH·H2O (19 mg, 0.455 mmol) in THF (3 mL) and water (1 mL) was stirred at 40°C for 12 hours. A yellow solution was formed. The reaction mixture was concentrated and dried under reduced pressure to obtain 5h (58 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.78 min, m / z (M+H) + = 382.2.

[0349] Step 8: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-methylpyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(5) A mixture of CD3NH2·HCl (32 mg, 0.456 mmol), 5h (58 mg, crude product), DIPEA (118 mg, 0.912 mmol, 0.158 mL), and T3P (290 mg, 0.456 mmol, 50% purity in ethyl acetate) in DMF (2 mL) was stirred at 20°C for 12 hours. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method D) to obtain 5 (5.2 mg, 9% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 10.28 (s, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 6.73 (d, J = 6.8 Hz, 1H), 3.66 (s, 3H), 2.22 (s, 3H), 1.98-1.90 (m, 1H), 0.74-0.70 (m, 4H). LC-MS (ESI, Method 4) R = 1.82 min, m / z (M+H) + = 398.3.

[0350] Example 6 [ka] Step 1: 1-amino-3-methoxy-4-(methoxycarbonyl)pyridine-1-ium-2,4-dinitrophenolate (6b) A mixture of 6a (6.8 g, 40.68 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (9.72 g, 48.82 mmol) in ACN (60 mL) was stirred overnight at 50°C. The mixture was concentrated to obtain 6b (14.9 g, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 0.46 min, m / z M+ = 183.0.

[0351] Step 2: 4-methoxypyrazolo[1,5-a]pyridine-3,5-dicarboxylate dimethyl(6c) A mixture of 6b (14.9 g, 40.68 mmol), methyl propa-2-ioate (3.53 g, 42.03 mmol), and K2CO3 (10.56 g, 76.43 mmol) in DMF (60 mL) was stirred at 30°C for 2 hours. The reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with brine (100 mL x 2) and concentrated. The residue was purified by silica gel flash chromatography (PE / ethyl acetate = 5 / 1) to obtain 6c (6.62 g, 62% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.10 min, m / z (M+H) + = 265.2.

[0352] Step 3: 4-methoxypyrazolo[1,5-a]pyridine-5-carboxylic acid (6d) A mixture of 6c (7 g, 26.49 mmol) in an aqueous H2SO4 solution (130 mL, 50 wt% water) was stirred at 85°C for 4 hours. After cooling to room temperature, the mixture was diluted with water (200 mL) and neutralized to pH=3 with aqueous NaOH solution (1 N). The mixture was extracted with ELISA (200 mL x 3). The organic layer of the compound was washed with brine (100 mL) and concentrated to obtain 6d (4.4 g, 86% yield) as a brown solid. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 193.1.

[0353] Step 4: 4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate methyl(6e) To a solution of 6d (4.4 g, 22.90 mmol) in MeOH (250 mL), concentrated HCl (3.75 mL, 46 mmol) was added. After stirring at 80°C for 18 hours, the mixture was concentrated, and the residue was diluted with DCM (20 mL). This solution was washed with saturated NaHCO3 (20 mL), and the aqueous layer was extracted with DCM (20 mL x 2). The combined organic layers were concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 4 / 1) to obtain 6e (2.76 g, 58% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.14 min, m / z (M+H) + = 207.1.

[0354] Step 5: 4-Methoxy-3-nitropyrazolo[1,5-a]pyridine-5-carboxylate methyl(6f) To a solution of 6e (500 mg, 2.42 mmol) in TFA (5 mL), KNO3 (245 mg, 2.42 mmol) was added at room temperature, and the mixture was stirred at 35 °C for 3 hours. The solvent was removed by pumping with N2. The mixture was basicized to pH > 8 with saturated Na2CO3 and extracted with RINKAN (5 mL x 3). The organic layer was concentrated and purified by flash chromatography (PE / EA = 3 / 1) to obtain the crude product. The crude product was triturated with RINKAN (3 mL). The resulting solid was filtered and dried to obtain 6f (300 mg, 49% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.06 min, m / z (M+H) + = 252.2.

[0355] Step 6: 3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate methyl hydrochloride (6g) SnCl2·2H2O (359 mg, 1.59 mmol) was added at 0°C to a 6 f (200 mg, 0.79 mmol) solution in concentrated HCl (4 mL), and the mixture was stirred at 0°C for 2 hours. The resulting solid was filtered and dried to obtain 6 g (150 mg, 73% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.53 min, m / z (M+H)+ = 222.0.

[0356] Step 7: 3-((2-(cyclopropanecarboxamide)-5-((methyl-d3)carbamoyl)pyridine-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridine-5-carboxylate methyl(6) To a solution of 6 g (150 mg, 0.58 mmol) and intermediate A (149 mg, 0.58 mmol) in dioxane (2 mL), TsOH·H2O (22 mg, 0.12 mmol) was added and the mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated and purified by silica gel flash chromatography (DCM / MeOH = 10 / 1) to obtain 6 (110 mg, 43% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.68 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.44 (d, J = 7.2 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.87 (s, 3H), 2.03-1.92 (m, 1H), 0.80-0.70 (m, 4H). LC-MS (ESI, Method 3) R = 1.05 min, m / z (M+H) + = 442.1.

[0357] Example 7 [ka] Step 1: (4-methoxypyrazolo[1,5-a]pyridine-5-yl)methanol (7a) LiAlH4 (455 mg, 11.98 mmol) was added to a solution of 6e (1.3 g, 6.30 mmol) in THF (15 mL) at 0°C. After stirring at 0°C for 1 hour, the reaction product was quenched with an aqueous solution of Seniet salt (10 mL) and extracted with ELISA (15 mL x 2). The combined organic layer was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 2 / 1) to obtain 7a (1.07 g, 95% yield) as a white solid. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 179.0.

[0358] Step 2: 4-methoxypyrazolo[1,5-a]pyridine-5-carbaldehyde(7b) To a solution of 7a (1.0 g, 5.62 mmol) in siRNA (10 mL), MnO2 (2.92 g, 33.68 mmol) was added at room temperature. After stirring at 80°C for 4 hours, the mixture was filtered, and the filtrate was concentrated to obtain 7b (800 mg, 81% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.02 min, m / z (M+H) + = 177.3.

[0359] Step 3: 2,2,2-trifluoro-1-(4-methoxypyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol(7c) To a solution of 7b (620 mg, 3.52 mmol) and trimethyl(trifluoromethyl)silane (1.10 g, 7.74 mmol) in THF (10 mL), TBAF (0.2 mL, 0.2 mmol, 1.0 M in THF) was added at 0°C. The mixture was stirred at 0°C for 1 hour and at 25°C for 16 hours. Then, a 1 M HCl solution was added, and the reaction was stirred at 25°C for 2 hours. The mixture was adjusted to pH=8 with an aqueous NaOH solution (1 M). The mixture was extracted with RINKAN (5 mL x 3). The organic layer was concentrated, and the residue was purified by flash chromatography (PE / EA = 3 / 1) to obtain 7c (834 mg, 96% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 6.8 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 6.97-6.88 (m, 3H), 5.48-5.45 (m, 1H), 4.03 (s, 3H). LC-MS (ESI, Method 3) R = 1.09 min, m / z (M+H) + = 247.2.

[0360] Step 4: 2,2,2-trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol (7d) A mixture of 7c (210 mg, 0.85 mmol) and KNO3 (95 mg, 0.94 mmol) in TFA (3 mL) was stirred at 30°C for 2 hours. The solvent was removed by pumping with N2. The residue was dissolved in ethyl acetate (5 mL) and basicized to pH=9 with saturated Na2CO3 solution (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phase was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH=19 / 1) to obtain 7d (150 mg, 60% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 5.62-5.55 (m, 1H), 3.80 (s, 3H). LC-MS (ESI, Method 3) R = 1.12 min, m / z (M+H) + = 292.1.

[0361] Step 5: 1-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethane-1-ol hydrochloride (7e) SnCl2·2H2O (620 mg, 2.75 mmol) was added at 0°C to a mixture of 7d (200 mg, 0.69 mmol) in concentrated HCl (4 mL). After stirring at 10°C for 1 hour, the reaction mixture was filtered. The filtered cake was dried under reduced pressure to obtain 7e (150 mg, 66% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.85 min, m / z (M+H) + = 262.0.

[0362] Step 6: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(7) A mixture of 7e (193 mg, 0.59 mmol), intermediate A (151 mg, 0.59 mmol), and TsOH·H2O (45 mg, 0.24 mmol) in 1,4-dioxane (3 mL) was stirred in a shielded tube at 100°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 9 / 1) to obtain the crude product. The crude product was purified by preparative HPLC (Method A) to obtain 7 (250 mg, 88% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.36 (s, 1H), 8.55 (s, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 5.43-5.36 (m, 1H), 3.72 (s, 3H), 1.99-1.90 (m, 1H), 0.76-0.67 (m, 4H). LC-MS (ESI, Method 2) R = 3.15 min, m / z (M+H) + = 482.0.

[0363] Step 7: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (7A) and (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (7B) Compound 7 (520 mg, 1.08 mmol) was separated by chiral preparative HPLC (Method F) to obtain 7A (204.2 mg, 39% yield) as a white solid and 7B (206.1 mg, 40% yield) as a white solid.

[0364] 7A: 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.36 (s, 1H), 8.54 (s, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.01 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.45-5.32 (m, 1H), 3.72 (s, 3H), 1.97-1.90 (m, 1H), 0.74-0.71 (m, 4H). LC-MS (ESI, Method 2) R = 2.39 min, m / z (M+H) + = 482.1. HPLC (Method 5) R = 10.03 minutes.

[0365] 7B: 11H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.36 (s, 1H), 8.54 (s, 1H), 8.51 - 8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.01 (d, J = 6.0 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.41 - 5.30 (m, 1H), 3.72 (s, 3H), 1.97 - 1.90 (m, 1H), 0.74 - 0.71 (m, 4H). LC-MS (ESI, method 2) t R = 2.40 minutes, m / z (M+H) + = 482.1. HPLC (method 5) t R = 12.27 minutes.

[0366] Example 8 [Chemical formula] Step 1: 1-(3-((2-(Cyclopropanecarboxamido)-5-((methyl-d3)carbamoyl)pyridin-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoroethyl methanesulfonate (8a) MsCl (29 mg, 0.50 mmol) was added to a solution of 7 (80 mg, 0.17 mmol) and TEA (100 mg, 1.00 mmol, 0.14 mL) in DCM (1 mL) at 0 °C. Then the mixture was stirred at 14 °C for 30 minutes. The reaction was quenched with ice water (3 mL) and extracted with DCM (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated to give 8a (90 mg, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, method 3) t R = 1.12 minutes, m / z (M+H) + = 560.2.

[0367] Step 2: 6-(Cyclopropanecarboxamido)-4-((4-methoxy-5-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)nicotinamide (8) To a solution of 8a (90 mg, 0.16 mmol) in EtOH (1 mL) was added NaBH4 (9 mg, 0.24 mmol) at 0 °C, and then the mixture was stirred at 15 °C for 18 h. The reaction mixture was quenched with ice water (3 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were concentrated, and the residue was purified by preparative HPLC (Method A) to give 8 (3.5 mg, 5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.35 (s, 1H), 8.55 (s, 1H), 8.51 - 8.48 (m, 2H), 8.10 (s, 1H), 7.69 (s, 1H), 6.83 (d, J = 6.8 Hz, 1H), 3.71 (s, 3H), 3.74 - 3.65 (m, 2H), 1.96 - 1.93 (m, 1H), 0.75 - 0.72 (m, 4H). LC-MS (ESI, Method 2) t R = 2.91 min, m / z (M+H) + = 466.1.

[0368] Example 9

Chemical Structure

[0369] To a mixture of methyl 5-amino-4-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylate (1.51 mg, TFA salt, crude product) in MeCN (10 mL), tert-butyl nitrite (1.06 g, 10.24 mmol, 1.22 mL) was added at 0°C and the mixture was stirred for 10 minutes. Then, CuBr (1.96 g, 13.65 mmol) was added to the mixture, and the resulting mixture was stirred at 80°C for 2 hours. A yellow solution was formed. The reaction mixture was concentrated and purified by flash chromatography (EA in PE is 10-30%) to obtain 9a (300 mg, 15% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.53 min, m / z ( 79 Br, M+H) + = 285.0.

[0370] Step 2: 4-Methoxy-5-(3,3,3-trifluoropropane-1-en-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate methyl(9b) A mixture of 9a (80 mg, 0.281 mmol), 4,4,6-trimethyl-2-(3,3,3-trifluoropropane-1-en-2-yl)-1,3,2-dioxaborinane (86 mg, 0.365 mmol), Na2CO3 (89 mg, 0.842 mmol), and Pd(dppf)Cl2 (46 mg, 0.056 mmol) in dioxane (2 mL) and water (0.2 mL) was subjected to three rounds of nitrogen degassing and purging. The resulting mixture was stirred at 100°C for 1 hour under an N2 atmosphere. A yellow suspension was formed. The reaction mixture was diluted with water (30 mL) and extracted with Â(30 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 0-20%) to obtain 9b (84 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.91 min, m / z (M+H) + = 301.1.

[0371] Step 3: 4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate methyl(9c) To a solution of 9b (84 mg, 0.28 mmol) in MeOH (5 mL), Pd / C (8 mg, 10% by weight, 10% Pd (dry basis), moistened with 55% H2O) was added. The reaction mixture was degassed and purged with hydrogen three times. The resulting mixture was stirred at 40°C for 24 hours under an H2 atmosphere. A black suspension was formed. The reaction mixture was filtered and concentrated to obtain 9c (80 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.93 min, m / z (M+H) + = 303.2.

[0372] Step 4: 4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (9d) A mixture of 9c (80 mg, 0.26 mmol) and LiOH·H2O (89 mg, 2.12 mmol) in a cosolvent of THF (3 mL) and water (1 mL) was stirred at 70°C for 24 hours. A yellow solution was formed. The reaction mixture was diluted with water (30 mL), extracted with siRNA (20 mL), and the organic layer was discarded. The aqueous layer was adjusted to pH=3 with aqueous HCl (2 M), and then extracted with siRNA (20 mL x 3). The organic layer was concentrated and dried under reduced pressure to obtain 9d (76 mg, 99% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.35 min, m / z (M+H) + = 289.1.

[0373] Step 5: (4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyridine-3-yl) tert-butyl(9e) carbamate A mixture of 9d (80 mg, 0.28 mmol), N,N-diethylethaneamine (56 mg, 0.56 mmol, 0.08 mL), and DPPA (99 mg, 0.36 mmol, 0.08 mL) in tBuOH (1 mL) was stirred at 110°C for 6 hours. A yellow suspension was formed. The reaction mixture was diluted with water (30 mL) and extracted with  (30 mL x 3). The combined organic layer was washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 5-30%) to obtain 9e (20 mg, 20% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 3.20 min, m / z (M+H) + = 360.2.

[0374] Step 6: 4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyridine-3-amine(9f) To a mixture of 9e (20 mg, 0.056 mmol) in DCM (3 mL), TFA (1 mL) was added at 20°C. The resulting mixture was stirred at 20°C for 1 hour. A yellow solution was formed. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (50 mL) and extracted with  (30 mL x 3). The combined organic layers were washed with water (60 mL x 3) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-60%) to obtain 9f (12 mg, 83% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.87 min, m / z (M+H) + = 260.2.

[0375] Step 7: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(9) A mixture of 9f (10 mg, 0.039 mmol), intermediate A (10 mg, 0.039 mmol), and TsOH (7 mg, 0.041 mmol) in dioxane (1 mL) was stirred at 100°C for 2 hours. A yellow solution was formed. The reaction mixture was filtered and purified by preparative HPLC (Method E) to obtain 9 (3.7 mg, 20% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.36 (s, 1H), 8.55 (s, 1H), 8.52-8.49 (m, 2H), 8.10 (s, 1H), 7.69 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.16-4.07 (m, 1H), 3.68 (s, 3H), 1.98-1.90 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H), 0.74-0.70 (m, 4H). LC-MS (ESI, Method 4) R = 2.27 min, m / z (M+H) + = 480.3.

[0376] Step 8: (R*)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (9A) and (S*)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (9B) Compound 9 (24 mg, 0.05 mmol) was separated by chiral preparative HPLC (Method I) to obtain 9A (9.5 mg, 40% yield) as a white solid and 9B (9.1 mg, 38% yield) as a white solid.

[0377] 9A:LC-MS (ESI, Method 4) t R = 2.26 min, m / z (M+H) + = 480.2. HPLC (Method 6) R = 6.42 minutes.

[0378] 9B:LC-MS (ESI, Method 4) t R = 2.27 min, m / z (M+H) + = 480.3. HPLC (Method 6) R = 11.56 minutes.

[0379] Example 10 [ka] Step 1: 5-bromo-4-methoxy-pyrazolo[1,5-a]pyridine (10a) A well-mixed solution of 9a (285 mg, 1.00 mmol) in 5 mL of 50% H2SO4 was heated at 110°C for 3 hours. A yellow solution was formed. This solution was cooled to room temperature. The solution was neutralized with 1.0 M aqueous NaOH solution using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with  (30 mL x 3). The organic layers were combined. The organic layers were dried on anhydrous Na2SO4. The organic layers were filtered through a Celite pad. The solvent was evaporated under reduced pressure to obtain 10a (220 mg, 97% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 7.2 Hz, 1.2 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.63 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 4.05 (s, 3H). LC-MS (ESI, Method 4) R = 2.54 min, m / z ( 79 Br, M+H) + = 227.0.

[0380] Step 2: 5-bromo-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (10b) A mixture of 10a (100 mg, 0.44 mmol) and KNO3 (40 mg, 0.40 mmol) in TFA (3 mL) was stirred at 30°C for 2 hours. A yellow solution was formed. The reaction mixture was diluted with  (30 mL), quenched with aqueous NaHCO3 solution (50 mL), and separated and extracted with  (30 mL x 3). The combined organic layer was washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 5-30%) to obtain 10b (100 mg, 83% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.53 min, m / z ( 79 Br, M+H) + = 272.0.

[0381] Step 3: 4-Methoxy-3-nitro-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine(10c) A mixture of 10b (80 mg, 0.29 mmol), CuI (67 mg, 0.35 mmol), and MDFA (85 mg, 0.44 mmol) in DMF (1 mL) was stirred at 100°C for 12 hours. A yellow suspension was formed. The reaction mixture was diluted with water (30 mL) and extracted with  (30 mL x 3). The combined organic layer was washed with water (50 mL x 3) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 5-30%) to obtain 10c (60 mg, 78% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H). LC-MS (ESI, Method 4) R = 2.75 min, m / z (M+H) + = 262.1.

[0382] Step 4: 4-Methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-amine(10d) To a solution of 10c (60 mg, 0.23 mmol) in MeOH (5 mL), Pd / C (6 mg, 10% by weight, 10% Pd (dry basis), moistened with 55% H2O) was added. The apparatus was degassed and purged with hydrogen three times. The resulting mixture was stirred at 40°C for 24 hours under an H2 atmosphere. A black suspension was formed. The reaction mixture was filtered and concentrated to obtain 10d (27 mg, 51% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.92 min, m / z (M+H) + = 232.1.

[0383] Step 5: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(10) A mixture of 10d (27 mg, 0.12 mmol), intermediate A (29 mg, 0.12 mmol), and TsOH (24 mg, 0.14 mmol) in dioxane (1 mL) was stirred at 100°C for 2 hours. A yellow solution was formed. The reaction mixture was filtered and purified by flash chromatography (MeOH in DCM is 0-10%), and further triturated with MeCN to obtain 10 (9.7 mg, 18% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.48 (s, 1H), 8.63-8.59 (m, 2H), 8.52 (s, 1H), 8.25 (s, 1H), 7.73 (s, 1H), 7.01 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H), 1.98-1.90 (m, 1H), 0.76-0.71 (m, 4H). LC-MS (ESI, Method 4) R = 2.15 min, m / z (M+H) + = 452.3.

[0384] Example 11 [ka] Step 1: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(11) A mixture of 10d (16 mg, 0.068 mmol), intermediate B (15 mg, 0.055 mmol), and TsOH (14 mg, 0.082 mmol) in dioxane (1 mL) was stirred at 100°C for 6 hours. A yellow suspension was formed. The reaction mixture was diluted with aqueous NaHCO3 (30 mL) and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (60 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM is 0-10%) and tritulated in MeCN to obtain 11 (17.4 mg, 66% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.46 (s, 1H), 8.59-8.55 (m, 2H), 8.49 (s, 1H), 8.23 ​​(s, 1H), 7.69 (s, 1H), 6.97 (d, J = 7.2 Hz, 1H), 4.93-4.72 (m, 1H), 3.78 (s, 3H), 2.14-2.06 (m, 1H), 1.56-1.43 (m, 1H), 1.11-1.02 (m, 1H). LC-MS (ESI, Method 4) R = 2.22 min, m / z (M+H) + = 470.2.

[0385] Example 12 [ka] Step 1: 1-amino-4-cyano-3-methoxypyridine-1-ium-2,4-dinitrophenolate (12b) A mixture of 12a (500 mg, 3.73 mmol) and O-(2,4-dinitrophenyl)hydroxylamine (816 mg, 4.10 mmol) in MeCN (10 mL) was stirred at 50°C for 16 hours. A yellow solution was formed. The reaction was concentrated to obtain 12b (559 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.64 min, m / z M + = 150.1.

[0386] Step 2: 5-Cyano-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate methyl(12c) A mixture of methyl propioate (626 mg, 7.45 mmol, 0.66 mL), 12b (559 mg, 3.72 mmol), and K2CO3 (1.03 g, 7.45 mmol) in DMF (10 mL) was stirred at 20°C for 2 hours. A black suspension was formed. The reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and then extracted with  (50 mL x 2). The combined organic layers were washed with water (50 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 12c (400 mg, 46% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.32 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.29 (s, 3H), 3.92 (s, 3H). LC-MS (ESI, Method 4) R = 2.18 min, m / z (M+H) + = 232.1.

[0387] Step 3: 4-methoxypyrazolo[1,5-a]pyridine-5-carbonitrile (12d) A well-mixed solution of 12c (50 mg, 0.216 mmol) in 1 mL of 50% H2SO4 was heated at 100°C for 1 hour. A brown solution was formed. This solution was cooled to room temperature. The solution was neutralized with 1.0 M NaOH aqueous solution using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted with  (30 mL x 3). The organic layers were combined. The organic layers were dried on anhydrous Na2SO4. The organic layers were filtered through a Celite pad. The organic layers were removed under reduced pressure to obtain 12d (20 mg, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 7.2 Hz, 0.8 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 2.4 Hz, 0.8 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 4.40 (s, 3H). LC-MS (ESI, Method 4) R = 2.07 min, m / z (M+H) + = 174.2.

[0388] Step 4: 4-Methoxy-3-nitro-pyrazolo[1,5-a]pyridine-5-carbonitrile(12e) To a mixture of 12d (20 mg, 0.115 mmol) in TFA (1 mL), KNO3 (11 mg, 0.11 mmol) was added at 20°C. The resulting mixture was stirred at 30°C for 2 hours. A yellow solution was formed. The reaction mixture was quenched with aqueous NaHCO3 solution (50 mL) and extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 10-30%) to obtain 12e (20 mg, 79% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.19 min, m / z (M+H) + = 219.1.

[0389] Step 5: 3-amino-4-methoxy-pyrazolo[1,5-a]pyridine-5-carbonitrile(12f) A mixture of 12e (20 mg, 0.092 mmol) and Pd / C (5 mg, 10% Pd (dry basis), moistened with 55% H2O) in MeOH (3 mL) was subjected to hydrogen degassing and purging three times. The resulting mixture was stirred at 40°C for 12 hours under an H2 atmosphere. A black suspension was formed. The reaction mixture was filtered and concentrated to obtain 12f (12 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.62 min, m / z (M+H) + = 189.1. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 1H), 7.50 (s, 1H), 6.40 (d, J = 7.2 Hz, 1H), 4.41 (s, 3H).

[0390] Step 6: 4-((5-cyano-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide(12) A mixture of 12f (12 mg, 0.064 mmol), intermediate A (13 mg, 0.051 mmol), and TsOH (13 mg, 0.076 mmol) in dioxane (2 mL) was stirred at 100°C for 6 hours. A yellow suspension was formed. The reaction mixture was diluted with aqueous NaHCO3 (30 mL) and extracted with RINKAN (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM is 0-10%) and triturated in MeOH to obtain 12 (9.0 mg, 34% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 10.81 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.25 (s, 3H), 2.01-1.94 (m, 1H), 0.80-0.77 (m, 4H). LC-MS (ESI, Method 4) R = 1.87 min, m / z (M+H) + = 409.3.

[0391] Example 13 [ka] Step 1: 4-((5-cyano-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide(13) A mixture of 12f (18 mg, 0.096 mmol), intermediate B (21 mg, 0.076 mmol), and TsOH (20 mg, 0.115 mmol) in dioxane (2 mL) was stirred at 100°C for 6 hours. A yellow suspension was formed. The reaction mixture was diluted with aqueous NaHCO3 (30 mL) and extracted with siRNA (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM is 0-10%) and tritulated in MeCN to obtain 13 (23.4 mg, 72% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.85 (s, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.00-4.79 (m, 1H), 4.25 (s, 3H), 2.22-2.14 (m, 1H), 1.66-1.55 (m, 1H), 1.18-1.09 (m, 1H). LC-MS (ESI, Method 4) R = 1.85 min, m / z (M+H) + = 427.2.

[0392] Example 14 [ka] Step 1: 6-(cyclopropanecarboxamide)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-5-yl)amino)-N-methylnicotinamide(14) A solution of 7e (150 mg, 0.46 mmol), intermediate C (116 mg, 0.46 mmol), and TsOH·H2O (38 mg, 0.20 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by silica gel chromatography column (DCM / MeOH = 20 / 1) to obtain 14 (136 mg, 62% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.08 min, m / z (M+H) + = 479.2.

[0393] Step 2: (S)-6-(Cyclopropanecarboxamido)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-5-yl)amino)-N-methylnicotinamide (14A) and (R)-6-(cyclopropanecarboxamido)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-5-yl)amino)-N-methylnicotinamide (14B) Compound 14 (136 mg, 0.28 mmol) was separated by chiral preparative HPLC (Method F) to give 14A (43 mg, 32% yield) as a white solid and 14B (39 mg, 29% yield) as a white solid.

[0394] 14A: 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.34 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 8.51 - 8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.02 (d, J = 5.6 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.41 - 5.37 (m, 1H), 3.72 (s, 3H), 2.80 (d, J = 4.4 Hz, 3H), 1.94 - 1.92 (m, 1H), 0.73 - 0.71 (m, 4H). LC-MS (ESI, Method 2) t R = 2.39 min, m / z (M+H) + = 479.2. HPLC (Method 5) t R = 8.98 min.

[0395] 14B: 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.35 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 8.51-8.49 (m, 2H), 8.11 (s, 1H), 7.68 (s, 1H), 7.03 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.41-5.38 (m, 1H), 3.72 (s, 3H), 2.80 (d, J = 4.4 Hz, 3H), 1.95-1.92 (m, 1H), 0.74-0.72 (m, 4H). LC-MS (ESI, Method 2) R = 2.39 min, m / z (M+H) + = 479.2. HPLC (Method 5) R = 10.89 minutes.

[0396] Example 15 [ka] Step 1: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(15) A mixture of 7e (252 mg, 0.77 mmol), intermediate B (210 mg, 0.77 mmol), and TsOH·H2O (58 mg, 0.31 mmol) in 1,4-dioxane (2 mL) was stirred at 100°C for 12 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 15 (170 mg, 45% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.06 min, m / z (M+H) + = 500.2.

[0397] Step 2: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-((S*)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (15A) and 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-((R*)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (15B) Compound 15 (170 mg, 0.34 mmol) was separated by chiral preparative HPLC (Method F) to obtain 15A (66 mg, 17% yield) as a white solid and 15B (73 mg, 19% yield) as a white solid.

[0398] 15A: 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.37 (s, 1H), 8.55 (s, 1H), 8.52-8.50 (m, 2H), 8.13 (s, 1H), 7.68 (s, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 5.42-5.38 (m, 1H), 4.96-4.75 (m, 1H), 3.73 (s, 3H), 2.16-2.12 (m, 1H), 1.58-1.51 (m, 1H), 1.12-1.06 (m, 1H). LC-MS (ESI, Method 2) R = 2.36 min, m / z (M+H) + = 500.2. HPLC (Method 5) R = 9.59 minutes.

[0399] 15B: 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.38 (s, 1H), 8.55 (s, 1H), 8.52-8.50 (m, 2H), 8.12 (s, 1H), 7.69 (s, 1H), 7.01 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.42-5.38 (m, 1H), 4.96-4.76 (m, 1H), 3.72 (s, 3H), 2.17-2.10 (m, 1H), 1.57-1.49 (m, 1H), 1.13-1.05 (m, 1H). LC-MS (ESI, Method 2) R = 2.34 min, m / z (M+H) + = 500.2. HPLC (Method 5) R = 11.56 minutes.

[0400] Example 16 [ka] Step 1: 4-Methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine (16a) To a solution of 7a (200 mg, 1.12 mmol) in THF (2 mL), NaH (67 mg, 1.68 mmol, 60% purity in mineral oil) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (191 mg, 1.35 mmol) was added to the mixture and stirred at room temperature for 5 hours. The mixture was diluted with H2O (30 mL), extracted with siRNA (15 mL x 3), washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain compound 16a (181 mg, 84% yield) as yellow oil. LC-MS (ESI, Method 4) t R = 2.08 min, m / z (M+H) + = 193.1.

[0401] Step 2: 4-Methoxy-5-(methoxymethyl)-3-nitropyrazolo[1,5-a]pyridine(16b) To a solution of 16a (180 mg, 0.94 mmol) in TFA (2 mL), KNO3 (95 mg, 0.94 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with H2O (20 mL) and extracted with siRNA (10 mL x 3). The combined organic layers were washed with aqueous Na2CO3 solution and brine, dried over Na2SO4, and concentrated to obtain compound 16b (150 mg, 67% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 2.16 min, m / z (M+H) + = 238.1.

[0402] Step 3: 4-Methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-amine(16c) To a solution of 16b (150 mg, 0.63 mmol) in EtOH (3 mL) and H2O (1 mL), Fe powder (177 mg, 3.16 mmol) and NH4Cl (169 mg, 3.16 mmol) were added. The mixture was then stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated, diluted with H2O (10 mL), extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL), dried on Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1~5 / 1) to obtain compound 16c (75 mg, 57% yield) as yellow oil. LC-MS (ESI, Method 4) t R = 0.44 min, m / z (M+H) + = 208.1.

[0403] Step 4: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(16) A mixture of 16c (20 mg, 0.96 mmol), intermediate A (25 mg, 0.096 mmol), and pTSA (17 mg, 0.096 mmol) in dioxane (1 mL) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 16 (11.4 mg, 28% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.05 (s, 1H), 7.87 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.39 (s, 1H), 4.51 (s, 2H), 3.80 (s, 3H), 3.39 (s, 3H), 1.52-1.47 (m, 1H), 1.05-1.01 (m, 2H), 0.89-82 (m, 2H). LC-MS (ESI, Method 4) R = 1.72 min, m / z (M+H) + = 428.4.

[0404] Example 17 [ka] Step 1: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(methoxymethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(17) A mixture of 16c (15 mg, 0.72 mmol), intermediate B (16 mg, 0.058 mmol), and pTSA (12 mg, 0.072 mmol) in dioxane (1 mL) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 17 (10.7 mg, 33% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.33 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 6.8 Hz, 1H), 8.03 (s, 1H), 7.64 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.92-4.72 (m, 1H), 4.41 (s, 2H), 3.67 (s, 3H), 3.26 (s, 3H), 2.11-2.08 (m, 1H), 1.55-1.45 (m, 1H), 1.08-1.03 (m, 1H). LC-MS (ESI, Method 4) R = 1.68 min, m / z (M+H) + = 446.3.

[0405] Example 18 [ka] Step 1: 2-(4-methoxypyrazolo[1,5-a]pyridin-5-yl)acetonitrile (18a) To a suspension of t-BuOK (127 mg, 1.14 mmol) in THF (2 mL), TosMIC (111 mg, 0.57 mmol) in THF (2 mL) was added at -60°C, and the mixture was then stirred at -60°C for 15 minutes. A solution of 7b (50 mg, 0.28 mmol) in THF (1 mL) was added dropwise to the mixture at -60°C, and the mixture was stirred for a further 1.5 hours at -60°C. MeOH (5 mL) was added to the mixture, and the mixture was stirred at 70°C for 20 minutes. The mixture was then concentrated, diluted with H2O (20 mL), extracted with ELISA (10 mL x 3), washed with brine (15 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 10 / 1~1 / 2) to obtain compound 18a (10 mg, 19% yield) as a yellow solid. LC-MS (ESI, Method 4) R = 1.82 min, m / z (M+H) + = 188.1.

[0406] Step 2: 2-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)acetonitrile (18b) To a solution of 18a (10 mg, 0.053 mmol) in TFA (1 mL), KNO3 (5 mg, 0.053 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with H2O (20 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were washed with aqueous Na2CO3 solution and brine, dried over Na2SO4, and concentrated to obtain compound 18b (10 mg, 81% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.94 min, m / z (M+H) + = 233.1.

[0407] Step 3: 2-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)acetonitrile (18c) To a solution of 18b (10 mg, 0.043 mmol) in EtOH (1 mL) and H2O (0.2 mL), Fe powder (12 mg, 0.22 mmol) and NH4Cl (12 mg, 0.22 mmol) were added. The mixture was then stirred at 80°C for 2 hours. The mixture was filtered, and the filter cake was washed with SiO (10 mL). The filtrate was concentrated, diluted with H2O (10 mL), extracted with SiO (10 mL x 3), washed with brine (10 mL), dried on Na2SO4, and concentrated to obtain compound 18c (5 mg, 57% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.45 min, m / z (M+H) + = 203.2.

[0408] Step 4: 4-((5-(cyanomethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide(18) A solution of 18c (5 mg, 0.025 mmol), intermediate A (6 mg, 0.025 mmol), and pTSA (4 mg, 0.025 mmol) in dioxane (0.5 mL) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 18 (2 mg, 19% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 10.31 (s, 1H), 8.51 (s, 1H), 8.48-8.46 (m, 2H), 8.06 (s, 1H), 7.62 (s, 1H), 6.83 (d, J = 7.2 Hz, 1H), 3.98 (s, 2H), 3.70 (s, 3H), 1.93-1.87 (m, 1H), 0.70-0.68 (m, 4H). LC-MS (ESI, Method 4) R = 1.48 min, m / z (M+H) + = 423.3.

[0409] Example 19 [ka] Step 1: (S)-2,2,2-trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol(7d-A) 7d (5.9 g, 20 mmol) was separated by chiral preparative HPLC (Method G) to obtain 7d-A (2.6 g, 44% yield) as a green solid.

[0410] 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 7.33 (d, J = 6.8 Hz, 1H), 5.70-7.67 (m, 1H), 3.92 (s, 3H). HPLC (Method 8) R = 6.06 minutes.

[0411] Step 2: (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethane-1-ol hydrochloride (7e-A) SnCl2·2H2O (1.7g, 7.56 mmol) was added at 0°C to a mixture of 7d-A (1.1g, 3.78 mmol) in concentrated HCl (15 mL). After stirring at 10°C for 1 hour, the reaction mixture was filtered. The filtered cake was dried under reduced pressure to obtain 7e-A (1g, 89% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.81 min, m / z (M+H) + = 262.0.

[0412] Step 3: (S)-6-chloro-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(19a) A mixture of 7e-A (55 mg, 0.21 mmol), 4,6-dichloro-N-(methyl-d3)nicotinamide (48 mg, 0.23 mmol), and TsOH·H2O (16 mg, 0.084 mmol) in 1,4-dioxane (0.3 mL) was stirred at 100°C for 18 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 19 / 1) to obtain 19a (50 mg, 55% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.16 min, m / z (M+H) + = 433.0.

[0413] Step 4: (S)-6-(1-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(19) A mixture of 19a (50.0 mg, 0.12 mmol), 1-fluorocyclopropane-1-carboxamide (60.0 mg, 0.58 mmol), Cs2CO3 (113 mg, 0.35 mmol), and BrettPhos Pd G3 (21 mg, 0.023 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 19 (5.2 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.97 (s, 1H), 8.63 (s, 1H), 8.61-8.51 (m, 2H), 8.15 (s, 1H), 7.61 (s, 1H), 7.03 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 6.4 Hz, 1H), 5.43-5.38 (m, 1H), 3.73 (s, 3H), 1.47-1.35 (m, 4H). LC-MS (ESI, Method 2) R = 2.48 min, m / z (M+H) + = 500.1.

[0414] Example 20 [ka] Step 1: 4-Methoxy-5-(2-oxopropyl)pyrazolo[1,5-a]pyridine-3-carboxylate methyl(20a) A mixture of 9a (500 mg, 1.7 mmol), propa-1-en-2-ylacetate (263 mg, 2.6 mmol), tri-o-tolylphosphine (32 mg, 0.105 mmol), and tributylmethoxystannan (844 mg, 2.6 mmol) in toluene (5 mL) was stirred at 100°C for 15 minutes. PdCl2 (9 mg, 0.052 mmol) was added to the mixture and stirred at 100°C for 3 hours. The mixture was concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain compound 20a (130 mg, 28% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.2 Hz, 1H), 8.42 (s, 1H), 6.96 (d, J = 7.2 Hz, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 2.24 (s, 3H). LC-MS (ESI, Method 3) R = 1.36 min, m / z (M+H) + = 263.1.

[0415] Step 2: 1-(4-methoxypyrazolo[1,5-a]pyridine-5-yl)propan-2-one(20b) A mixture of 20a (270 mg, 1 mmol) in 50% H2SO4 (3 mL) was stirred at 85°C for 4 hours. After cooling, the reaction mixture was diluted with ice water (5 mL) and basicized to pH=3 with 1 N NaOH. The mixture was extracted with ELISA (5 mL x 3). The organic layer was washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel flash chromatography (PE / EA=3 / 1) to obtain 20b (200 mg, 95% yield) as yellow oil. LC-MS (ESI, Method 3) t R = 1.29 min, m / z (M+H) + = 205.2.

[0416] Step 3: 1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)propan-2-one(20c) To a solution of 20b (200 mg, 0.98 mmol) in TFA (2 mL), KNO3 (99 mg, 0.98 mmol) was added at 0°C. The mixture was stirred at 30°C for 2 hours. The solvent was removed by pumping with N2. The residue was dissolved in ELISA (15 mL) and basicized to pH=9 with saturated Na2CO3. The mixture was extracted with ELISA (20 mL x 2). The combined organic phase was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA=3 / 1) to obtain 20c (153 mg, 62% yield) as a yellow solid. LC-MS (ESI, Method 3) t R= 1.34 min, m / z (M+H) + = 250.1.

[0417] Step 4: 5-(2,2-difluoropropyl)-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (20d) DAST (355 mg, 2 mmol) was added at 0°C to a solution of 20c (110 mg, 0.44 mmol) in DCM (2 mL). The mixture was then stirred at 25°C for 10 hours. The mixture was diluted with DCM (5 mL) and washed with saturated NaHCO3 (5 mL). The organic layer was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain 20d (84 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.55 min, m / z (M+H) + = 272.2.

[0418] Step 5: 5-(2,2-difluoropropyl)-4-methoxypyrazolo[1,5-a]pyridine-3-amine(20e) To a solution of 20d (74 mg, 0.27 mmol) and 4,4'-bipyridine (2 mg, 0.013 mmol) in DMF (1 mL), tetrahydroxydiborone (73 mg, 0.82 mmol) was added at 0°C. After stirring at 10°C for 10 minutes, the mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 20e (50 mg, yield 75%) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.42 min, m / z (M+H) + = 242.2.

[0419] Step 6: 6-(cyclopropanecarboxamide)-4-((5-(2,2-difluoropropyl)-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(20) A mixture of 20e (40 mg, 0.16 mmol), intermediate A (46 mg, 0.18 mmol), and TsOH·H2O (15 mg, 0.08 mmol) in 1 mL of 1,4-dioxane was stirred at 90°C for 7 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 20 (63 mg, 82% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.31 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 6.76 (d, J = 7.2 Hz, 1H), 3.66 (s, 3H), 3.26 (t, J = 16.4 Hz, 2H), 1.94-1.91 (m, 1H), 1.61 (t, J = 18.8 Hz, 3H), 0.73-0.70 (m, 4H). LC-MS (ESI, Method 2) R = 2.94 min, m / z (M+H) + = 462.1.

[0420] Example 21 [ka] Step 1: (S)-4-((4-Methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazole-3-yl)amino)nicotinamide(21) A mixture of 19a (44 mg, 0.10 mmol), 1-methyl-1H-pyrazole-3-amine (49 mg, 0.51 mmol), Cs2CO3 (66 mg, 0.20 mmol), and BrettPhos Pd G3 (18 mg, 0.02 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 21 (23 mg, 47% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.14 (s, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.45 (s, 1H), 7.03-7.01 (m, 2H), 6.89 (d, J = 6.8 Hz, 1H), 6.08 (s, 1H), 5.44-5.39 (m, 1H), 3.77 (s, 3H), 3.63 (s, 3H). LC-MS (ESI, Method 2) R = 0.94 min, m / z (M+H) + = 494.1.

[0421] Example 22 [ka] Step 1: 6-(cyclopropanecarboxamide)-4-((5-(hydroxymethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(22) LiAlH4 (51 mg, 1.50 mmol) was slowly added at 0°C to a solution of 6 (110 mg, 0.25 mmol) in THF (5 mL), and the mixture was stirred at 0°C for 2 hours. The mixture was sequentially quenched at 0°C with H2O (0.05 mL), 15% NaOH aqueous solution (0.05 mL), and H2O (0.1 mL). 。 Next, the mixture was stirred at room temperature for 15 minutes, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel flash chromatography (DCM / MeOH=8 / 1) to obtain 22 (70 mg, 68% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 11.31 (s, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.91 (d, J = 7.2 Hz, 1H), 5.29-5.26 (m, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.69 (s, 3H), 1.97-1.91 (m, 1H), 0.73-0.72 (m, 4H). LC-MS (ESI, Method 2) R = 2.73 min, m / z (M+H) + = 414.0.

[0422] Example 23 [ka] Step 1: 1-(4-methoxypyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol (23a) To a stirred solution of 7b (755 mg, 4.29 mmol) in anhydrous DCM (10 mL), methylmagnesium bromide (2.89 mL, 8.67 mmol, 3 M in Et2O) was added dropwise at 0°C. The reaction mixture was then stirred at 0°C for 0.5 hours. This was then quenched with saturated NH4Cl (5 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with water (15 mL) and brine (10 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (MeOH / DCM = 3 / 100) to obtain compound 23a (787 mg, 96% yield) as a pale yellow oil. LC-MS (ESI, Method 4) t R = 1.49 min, m / z (M+H) + = 193.1.

[0423] Step 2: 1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol(23b) To a stirred solution of 23a (740 mg, 3.85 mmol) in TFA (7 mL), KNO3 (385 mg, 3.77 mmol) was added at 0°C. The mixture was then stirred at 25°C for 0.5 hours. The solvent was evaporated under reduced pressure to obtain a residue, which was purified by flash chromatography (PE / EA = 2 / 1) to obtain compound 23b (830 mg, 91% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.75 min, m / z (M+H) + = 238.0.

[0424] Step 3: 1-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol hydrochloride (23c) SnCl2·H2O (3.28 g, 12.83 mmol) was added to a suspension of 23b (830 mg, 3.50 mmol) in concentrated HCl (10 mL) at 0°C. The mixture was then stirred at 25°C for 0.5 hours. After filtration, the solid was dried under reduced pressure to obtain 23c (802 mg, 94% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 0.34 min, m / z (M+H) + = 208.2.

[0425] Step 4: 5-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-amine(23d) To a solution of 23c (710 mg, 2.91 mmol), imidazole (992 mg, 14.57 mmol), and DMAP (36 mg, 0.29 mmol) in THF (10 mL), tert-butylchlorodiphenylsilane (1.04 g, 3.79 mmol) was added. The mixture was then stirred at 50°C for 2 hours. The mixture was diluted with H2O (20 mL), extracted with siRNA (15 mL x 3), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain compound 23d (70 mg, 5.4% yield) as a yellow oil. LC-MS (ESI, Method 4) t R= 4.10 min, m / z (M+H) + = 446.3.

[0426] Step 5: 4-((5-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide(23e) A mixture of 23d (60 mg, 0.13 mmol), intermediate A (21 mg, 0.081 mmol), and pTSA (23 mg, 0.13 mmol) in dioxane (1 mL) was stirred at 70°C for 6 hours. The mixture was diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain compound 23e (20 mg, 22% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 3.87 min, m / z (M+H) + = 666.5.

[0427] Step 6: 6-(cyclopropanecarboxamide)-4-((5-(1-hydroxyethyl)-4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(23) Compound 23e (20 mg, 0.03 mmol) was dissolved in TBAF solution (1 M in THF, 0.5 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (10 mL), extracted with Âxy (10 mL x 3), washed with NH4Cl aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to obtain the crude product. The crude product was then purified by preparative HPLC (Method E) to obtain compound 23 (4.0 mg, 35% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.29 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 6.93 (d, J = 7.2 Hz, 1H), 5.26 (d, J = 4.4 Hz, 1H), 5.10-5.04 (m, 1H), 3.68 (s, 3H), 1.96-1.90 (m, 1H), 1.31 (d, J = 6.4 Hz, 3H), 0.74-0.71 (m, 4H). LC-MS (ESI, Method 4) R = 1.00 min, m / z (M+H) + = 428.3.

[0428] Example 24 [ka] Step 1: (S)-6-((5-fluoropyridine-2-yl)amino)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(24) A mixture of 7e-A (35 mg, 0.12 mmol), intermediate F (33 mg, 0.12 mmol), and TsOH·H2O (2 mg, 0.012 mmol) in NMP (0.1 mL) and 1,4-dioxane (0.3 mL) was stirred at 100°C for 12 hours. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain 24 (14 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.64 (s, 1H), 8.52 (d, J = 7.2 Hz, 1H), 8.47-8.44 (m, 2H), 8.20 (s, 1H), 8.00 (s, 1H), 7.82-7.79 (m, 1H), 7.62-7.58 (m, 1H), 7.17 (s, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 5.43-5.39 (m, 1H), 3.77 (s, 3H). LC-MS (ESI, Method 2) R = 2.87 min, m / z (M+H) + = 509.0.

[0429] Example 25 [ka] Step 1: (S)-6-((2,6-dimethylpyrimidine-4-yl)amino)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(25) A mixture of 19a (50 mg, 0.11 mmol) and 2,6-dimethylpyrimidine-4-amine (28 mg, 0.23 mmol) in dioxane (2 mL) was mixed with BrettPhos Pd G3 (41 mg, 0.05 mmol) and Cs2CO3 (75 mg, 0.23 mmol). The mixture was stirred at 100°C for 3 hours under an N2 atmosphere. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 25 (7.3 mg, 12% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.90 (s, 1H), 8.54-8.49 (m, 3H), 8.24 (s, 1H), 7.73 (s, 1H), 7.06-7.02 (m, 2H), 6.90 (d, J = 6.8 Hz, 1H), 5.42-5.39 (m, 1H), 3.76 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H). LC-MS (ESI, Method 2) R = 0.88 min, m / z (M+H) + = 520.2.

[0430] Example 26 [ka] Step 1: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)methyl nicotinate (26) A mixture of 7e-A (30 mg, 0.10 mmol), A2 (23 mg, 0.090 mmol), and TsOH·H2O (7.0 mg, 0.036 mmol) in dioxane (0.5 mL) was stirred at 100°C for 18 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 26 (12.2 mg, 25% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), δ 9.57 (s, 1H) , 8.67 (s, 1H), 8.54 (d, J = 6.8 Hz, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.93 (d, J = 6.8 Hz, 1H), 5.46-5.33 (m, 1H), 3.89 (s, 3H), 3.70 (s, 3H), 2.03-1.86 (m, 1H), 0.79-0.65 (m, 4H). LC-MS (ESI, Method 2) R = 2.64 min, m / z (M+H) += 480.1.

[0431] Example 27 [ka] Step 1: (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine(27a) To a solution of 7d-A (100 mg, 0.34 mmol) in THF (5 mL), NaH (21 mg, 0.52 mmol, 60% in mineral oil) was added at 0°C. The mixture was stirred for 20 minutes, and then CH3I (73 mg, 0.52 mmol, 0.032 mL) was slowly added. The mixture was transferred to room temperature and stirred for 4 hours. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with  (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (EA in PE is 25%) to obtain 27a (52 mg, 49% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.23 (q, J = 6.4 Hz, 1H), 3.92 (s, 3H), 3.45 (s, 3H). LC-MS (ESI, Method 4) R = 2.94 min, m / z (M+H) + = 306.1.

[0432] Step 2: (S)-4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine-3-amine(27b) To a solution of 27a (52 mg, 0.17 mmol) in MeOH (2 mL), Pd / C (5 mg, 0.05 mmol, 10% palladium-carbon) was added under an H2 atmosphere, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 27b (45 mg, 96% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.92 min, m / z (M+H) + = 276.1.

[0433] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(27) TsOH (31 mg, 0.18 mmol) was added to a solution of 27b (45 mg, 0.16 mmol) and intermediate A (34 mg, 0.13 mmol) in dioxane (2 mL). The mixture was stirred at 85°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Method E) to obtain 27 (18 mg, 22% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.37 (s, 1H), 8.53 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.30 (s, 3H), 1.97-1.82 (m, 1H), 0.73-0.61 (m, 4H). LC-MS (ESI, Method 4) R = 2.29 min, m / z (M+H) + = 496.4.

[0434] Example 28 [ka] Step 1: (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine(28a) To a solution of 7d-A (100 mg, 0.34 mmol) in THF (5 mL), NaH (21 mg, 0.52 mmol, 60% in mineral oil) was added at 0°C. The mixture was stirred for 20 minutes, and then CD3I (75 mg, 0.52 mmol, 0.032 mL) was slowly added. The mixture was transferred to room temperature and stirred for 4 hours. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with  (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried on anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (EA in PE is 25%) to obtain 28a (55 mg, 52% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.91 min, m / z (M+H) + = 309.1.

[0435] Step 2: (S)-4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-amine(28b) To a solution of 28a (55 mg, 0.17 mmol) in MeOH (2 mL), Pd / C (5 mg, 0.05 mmol, 10% palladium-carbon) was added under an H2 atmosphere. The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 28b (45 mg, 91% yield) as a brown solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 1.89 min, m / z (M+H) + = 279.1.

[0436] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(28) To a solution of 28b (45 mg, 0.16 mmol) and intermediate A (34 mg, 0.13 mmol) in dioxane (2 mL), TsOH (31 mg, 0.18 mmol) was added, and the mixture was stirred at 85 °C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Method E) to obtain 28 (23 mg, 28% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.37 (s, 1H), 8.53 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 6.73 (d, J = 7.2 Hz, 1H), 5.24 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 1.95-1.85 (m, 1H), 0.74-0.61 (m, 4H). LC-MS (ESI, Method 4) R = 2.27 min, m / z (M+H) + = 499.4.

[0437] Example 29 [ka] Step 1: 4-Methoxy-5-((Methoxy-d3)methyl)pyrazolo[1,5-a]pyridine (29a) To a solution of 7a (80 mg, 0.45 mmol) in THF (1 mL), NaH (23 mg, 0.58 mmol, 60% purity in mineral oil) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Iodomethane-d3 (78 mg, 0.54 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O (30 mL), extracted with siRNA (15 mL x 3), washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain compound 29a (80 mg, 91% yield) as yellow oil. LC-MS (ESI, Method 4) t R = 2.05 min, m / z (M+H) + = 196.1.

[0438] Step 2: 4-Methoxy-5-((Methoxy-d3)methyl)-3-nitropyrazolo[1,5-a]pyridine(29b) To a solution of 29a (80 mg, 0.41 mmol) in TFA (1 mL), KNO3 (41 mg, 0.41 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with H2O (20 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was washed with aqueous Na2CO3 solution and saturated brine, dried over Na2SO4, and concentrated to obtain compound 29b (90 mg, 91% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 2.16 min, m / z (M+H) + = 241.1.

[0439] Step 3: 4-Methoxy-5-((Methoxy-d3)methyl)pyrazolo[1,5-a]pyridine-3-amine(29c) To a solution of 29b (90 mg, 0.37 mmol) in MeOH (2 mL) and H2O (0.5 mL), Fe powder (105 mg, 1.87 mmol) and NH4Cl (100 mg, 1.87 mmol) were added. The mixture was then stirred at 70°C for 2 hours. The mixture was filtered and washed with siRNA (10 mL). The filtrate was concentrated, diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with brine (10 mL), dried on Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1~5 / 1) to obtain compound 29c (70 mg, 89% yield) as a yellow oil. LC-MS (ESI, Method 4) t R = 0.45 min, m / z (M+H) + = 211.3.

[0440] Step 4: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-((methoxy-d3)methyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(29) A mixture of 29c (33 mg, 0.16 mmol), intermediate A (40 mg, 0.16 mmol), and pTSA (27 mg, 0.16 mmol) in dioxane (1 mL) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 29 (18.4 mg, 27% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.34 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.68 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.70 (s, 3H), 1.96-1.90 (m, 1H), 0.74-0.71 (m, 4H). LC-MS (ESI, Method 4) R = 1.68 min, m / z (M+H) + = 431.4.

[0441] Example 30 [ka] Step 1: (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethane-1-ol(30a) To a solution of 7d-A (100 mg, 0.34 mmol) and 4,4'-bipyridine (2 mg, 0.013 mmol) in DMF (1 mL), tetrahydroxydiborone (92 mg, 1.032 mmol) was added at 0°C. After stirring at 10°C for 10 minutes, the mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 30a (45 mg, 50% yield) as a green solid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J = 7.2 Hz, 1H), 7.49 (s, 1H), 6.83 (d, J = 6.0 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 5.36-5.29 (m, 1H), 4.31 (s, 2H), 3.87 (3, 3H).

[0442] Step 2: (S)-6-chloro-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(30b) To a solution of 30a (45 mg, 0.17 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (47 mg, 0.22 mmol) in EtOH (0.5 mL), concentrated HCl (7 mg, 0.17 mmol) was added and the mixture was stirred at 80°C for 12 hours. The reaction mixture was purified by preparative HPLC (Method A) to obtain 30b (60 mg, 80% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.14 min, m / z (M+H) + = 434.1.

[0443] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(30) A mixture of 30b (60 mg, 0.14 mmol), cyclopropanecarboxamide (35 mg, 0.41 mmol), BrettPhos (15 mg, 0.03 mmol), and BrettPhos Pd G3 (25.08 mg, 0.03 mmol) in dioxane (0.5 mL) was stirred at 100°C for 12 hours under N2. The reaction mixture was concentrated to dryness and purified by silica gel flash chromatography (DCM / MeOH = 10 / 1) to obtain compound 30 (15 mg, 22% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.55 (s, 1H), 9.09 (s, 1H), 8.54 (d, J = 7.2 Hz, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.04 (d, J = 5.6Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 5.40-5.37 (m, 1H), 3.72 (s, 3H), 2.01-1.99 (m, 1H), 0.79-0.75 (m, 4H). LC-MS (ESI, Method 2) R = 0.98 min, m / z (M+H) + = 483.1.

[0444] Example 31 [ka] 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoroacetyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide and 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide (31) To a solution of 7 (50 mg, 0.10 mmol) in  (0.5 mL), 2-iodoxybenzoic acid (116 mg, 0.40 mmol) was added. After stirring at 95°C for 12 hours, the reaction mixture was concentrated to dryness and purified by flash chromatography (DCM / MeOH = 10 / 1) to obtain mixture 31 as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 0.2H), 10.79 (s, 0.2H), 10.69 (s, 0.8H), 10.37 (s, 0.8H), 8.62 (s, 0.2H), 8.56 (s, 0.2H), 8.55 (s, 0.8H), 8.54 (d, J = 8.0 Hz, 0.2H), 8.53 (s, 0.8H), 8.42 (d, J = 7.6 Hz, 0.8H), 8.28 (s, 0.2H), 8.10 (s, 0.8H), 7.93 (s, 0.2H), 7.75 (s, 0.8H), 7.71 (s, 1.6H), 7.04 (d, J = 7.2 Hz, 0.2H), 6.98 (d, J = 7.6 Hz, 0.8H), 3.90 (s, 0.6H), 3.70 (s, 2.4H), 1.97-1.93 (m, 1H), 0.77-0.73 (m, 4H). LC-MS (ESI, Method 2) R = 1.99 min, m / z (M+H) + = 480.2, 498.2.

[0445] Example 32 [ka] Step 1: 4-((4-Methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)-6-(spiro[2.2]pentan-1-carboxamide)nicotinamide(32) A mixture of 19a (30.0 mg, 0.07 mmol) in 1,4-dioxane (0.4 mL), spiro[2.2]pentane-1-carboxamide (39.0 mg, 0.35 mmol), Xantphos (8 mg, 0.014 mmol), XPhos Pd G2 (11 mg, 0.014 mmol), and Cs2CO3 (45 mg, 0.14 mmol) was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 32 (7 mg, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 10.40 (d, J = 6.4 Hz, 1H), 8.56-8.49 (m, 3H), 8.14 (s, 1H), 7.74-7.71 (m, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.72 (s, 3H), 2.31-2.28 (m, 1H), 1.35-1.30 (m, 1H), 1.26-1.23 (m, 1H), 0.85-0.79 (m, 3H), 0.68-0.67 (m, 1H). LC-MS (ESI, Method 2) R = 1.11 min, m / z (M+H) + = 508.0.

[0446] Step 2: 4-((4-methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)-6-((S*)-spiro[2.2]pentan-1-carboxamide)nicotinamide (32A) and 4-((4-methoxy-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)-6-((R*)-spiro[2.2]pentan-1-carboxamide)nicotinamide (32B) Compound 32 (23 mg, 0.05 mmol) was separated by chiral preparative HPLC (Method H) to obtain 32A (5 mg, 22% yield) as a white solid and 32B (6.5 mg, 28% yield) as a white solid. 32A: 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.40 (s, 1H), 8.54-8.49 (m, 3H), 8.14 (s, 1H), 7.74 (s, 1H), 7.04 (d, J = 4.4 Hz, 1H), 6.91 (d, J = 6.8 Hz, 1H), 5.42-5.38 (m, 1H), 3.73 (s, 3H), 2.31-2.28 (m, 1H), 1.30-1.26 (m, 2H), 0.83-0.82 (m, 3H), 0.68-0.65 (m, 1H). LC-MS (ESI, method 2) t R = 1.11 minutes, m / z (M+H) + = 508.0. HPLC (Method 7) t R = 8.14 points.

[0447] 32B: 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.38 (s, 1H), 8.56-8.49 (m, 3H), 8.14 (s, 1H), 7.71 (s, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 5.42-5.39 (m, 1H), 3.73 (s, 3H), 2.31-2.28 (m, 1H), 1.30-1.25 (m, 2H), 0.84-0.81 (m, 3H), 0.69-0.66 (m, 1H). LC-MS (ESI, method 2) t R = 1.11 minutes, m / z (M+H) + = 508.0. HPLC (Method 7) t R = 10.48 points.

[0448] Example 33

change

[0449] Step 2: (S)-2-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridin-3-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide(33) A mixture of 33a (60 mg, 0.07 mmol), cyclopropanecarboxamide (31 mg, 0.37 mmol), BrettPhos Pd G3 (13 mg, 0.015 mmol), and Cs2CO3 (48 mg, 0.15 mmol) in dioxane (0.4 mL) was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 33 (8 mg, 22% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.96 (s, 1H), 9.61 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 5.47-5.44 (m, 1H), 3.95 (s, 3H), 2.14-2.11 (m, 1H), 0.93-0.86 (m, 4H). LC-MS (ESI, Method 2) R = 1.11 min, m / z (M+H) + = 483.0.

[0450] Example 34 [ka] Step 1: 6-(cyclopropanecarboxamide)-4-((5-(2-hydroxypropan-2-yl)-4-methylpyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(34) To a solution of 6 (5 mg, 0.01 mmol) in THF (1 mL), CH3MgBr (0.041 mL, 0.12 mmol, 3 M in Et2O) was slowly added at 0°C under an N2 atmosphere. The mixture was stirred for 10 minutes, then heated to 50°C and stirred for 12 hours. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method A) to obtain 34 (1.8 mg, 37% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.96 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.37 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H), 7.24 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.14 (s, 1H), 2.55 (s, 3H), 1.91-1.82 (m, 1H), 1.47 (s, 6H), 0.69-0.59 (m, 4H). LC-MS (ESI, Method 4) R = 1.46 min, m / z (M+H) + = 426.3.

[0451] Example 35 [ka] Step 1: 2-(6-chloro-5-methoxypyrimidine-4-yl)dimethyl(35b) malonate To a solution of dimethyl malonate (7.38 g, 55.86 mmol, 6.36 mL) in DMF (100 mL), Cs₂CO₃ (36.40 g, 111.73 mmol) and 4,6-dichloro-5-methoxypyrimidine (10 g, 55.86 mmol) were added, and the mixture was stirred at 100°C for 2 hours. The mixture was concentrated under reduced pressure, diluted with H₂O (100 mL), the pH was adjusted to 2 with 2N HCl, extracted with siRNA (100 mL x 3), washed with brine (100 mL x 2), dried over Na₂SO₄, and concentrated to obtain crude compound 35b (15 g, 98% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.23 min, m / z (M+H) + = 275.1.

[0452] Step 2: 2-(5,6-dimethoxypyrimidine-4-yl)methyl acetate (35c) To a solution of 35b (12 g, 43.69 mmol) in MeOH (50 mL), NaOMe (16.2 mL, 87.38 mmol, 5.4 M in MeOH) was added, and the mixture was stirred at 60°C for 2 hours. The mixture was concentrated, diluted with H2O (100 mL), the pH was adjusted to 2 with 2N HCl, extracted with ELISA (100 mL x 3), washed with brine (100 mL), dried on Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 20 / 1~1 / 1) to obtain compound 35c (9 g, 97% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.79 min, m / z (M+H) + = 213.1.

[0453] Step 3: 2-(5,6-dimethoxypyrimidine-4-yl)-3-(dimethylamino)acrylate methyl(35d) A solution of 35c (1 g, 4.71 mmol) in DMF-DMA (1 mL) was stirred at 120°C for 6 hours. The mixture was concentrated to obtain compound 35d (1.26 g, crude product) as a yellow oil. LC-MS (ESI, Method 4) t R = 1.23 min, m / z (M+H) + = 268.1.

[0454] Step 4: 4,5-Dimethoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(35e) To a solution of 35d (1.26 g, 4.71 mmol) in DCM (10 mL), O-(mesitylsulfonyl)hydroxylamine (2.90 g, 9.43 mmol) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated, the solid was triturated with H2O (10 mL), filtered, and the filter cake was washed with DCM (2 mL x 2). The solid was dried under reduced pressure to obtain compound 35e (600 mg, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.45 (s, 1H), 3.99 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H). LC-MS (ESI, Method 4) R = 2.04 min, m / z (M+H) + = 238.1.

[0455] Step 5: 4,5-dimethoxypyrazolo[1,5-c]pyrimidine-3-carboxylic acid (35f) A suspension of 35e (550 mg, 2.32 mmol) in MeOH (11 mL) was slowly added with a solution of NaOH (4.64 mL, 4.64 mmol, 1 M in H2O), and the mixture was stirred at 40°C for 16 hours. The mixture was concentrated and then treated with H2O (5 mL) to adjust the pH to 1 with 2N HCl. The mixture was then filtered, and the filter cake was washed with Et2O (2 mL). The solid was dried under reduced pressure to obtain compound 35f (90 mg, 17% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.20 min, m / z (M+H) + = 224.1.

[0456] Step 6: (4,5-dimethoxypyrazolo[1,5-c]pyrimidine-3-yl) tert-butyl carbamate (35g) To a solution of 35f (30 mg, 0.134 mmol) in toluene (1 mL), DPPA (74 mg, 0.27 mmol) and TEA (54 mg, 0.54 mmol) were added, and the mixture was then stirred at 80°C for 1 hour, cooled to room temperature, and then... t BuOH (0.5 mL) was added to the mixture. The mixture was stirred at 110°C for 4 hours, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1 to 15 / 1) to obtain 35 g (25 mg, 63% yield) of the compound as a yellow solid. LC-MS (ESI, Method 4) t R = 2.64 min, m / z (M+H) + = 295.2.

[0457] Step 7: 6-(cyclopropanecarboxamide)-4-((4,5-dimethoxypyrazolo[1,5-c]pyrimidine-3-yl)amino)-N-(methyl-d3)nicotinamide(35) A mixture of 35 g (25 mg, 0.085 mmol) of dioxane (1 mL), intermediate A (22 mg, 0.085 mmol), and pTSA (15 mg, 0.085 mmol) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 35 (10.7 mg, 30% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.13(s, 1H), 9.22 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.13 (s, 1H), 7.49 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H), 1.92-1.86 (m, 1H), 0.70-0.67 (m, 4H). LC-MS (ESI, Method 4) R = 1.71 min, m / z (M+H) + = 415.3.

[0458] Example 36 [ka] Step 1: 4-((4,5-dimethoxypyrazolo[1,5-c]pyrimidine-3-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide(36) A mixture of 35 g (18 mg, 0.061 mmol) of dioxane (1 mL), intermediate B (17 mg, 0.061 mmol), and pTSA (11 mg, 0.061 mmol) was stirred at 100°C for 2 hours. The mixture was then concentrated and purified by preparative HPLC (Method E) to obtain compound 36 (6.5 mg, 24% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.79 (s, 1H), 8.25 (s, 1H), 8.23 ​​(s, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 6.22 (s, 1H), 4.86-4.65 (m, 1H), 4.02 (s, 3H), 3.84 (s, 3H), 1.85-1.82 (m, 1H), 1.64-1.60 (m, 1H), 1.21-1.13 (m, 1H). LC-MS (ESI, Method 4) R = 1.65 min, m / z (M+H) + = 433.3.

[0459] Example 37 [ka] Step 1: 2-(6-chloro-5-methoxypyrimidine-4-yl)malonate 1-tert-butyl 3-methyl(37a) To a solution of tert-butylmethyl malonate (13.08 g, 75.08 mmol) in THF (200 mL), NaH (6.01 g, 150.16 mmol, 60% of mineral oil) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Next, a solution of 35a (11.2 g, 62.57 mmol) in THF (20 mL) was added to the mixture at 0°C. The mixture was stirred at 80°C for 3 hours and poured into ice water (150 mL). The mixture was acidified to pH=2 with 2N HCl and extracted with RINKAN (300 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to obtain 37a (19.8 g, crude product) as yellow oil. LC-MS (ESI, Method 3) t R = 1.26 min, m / z (M+H-56) + = 261.2.

[0460] Step 2: 2-(6-chloro-5-methoxypyrimidine-4-yl)methyl acetate (37b) To a mixture of 37a (18.0 g, 56.83 mmol) in DCM (150 mL), TFA (75 mL) was added at 0°C. After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was diluted with HCl (500 mL) and washed with saturated NaHCO3 (150 mL) and brine (100 mL). The organic layer was concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 10 / 1) to obtain 37b (10.5 g, 85% yield) as yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 3.95 (s, 3H), 3.91 (s, 2H), 3.75 (s, 3H).

[0461] Step 3: 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)methyl acetate (37c) A mixture of 37b (1.0 g, 4.62 mmol), TEA (934 mg, 9.23 mmol), and DMBNH2 (1.00 g, 6.00 mmol) in EtOH (10 mL) was stirred at 80°C for 5 hours. The mixture was diluted with H2O (20 mL) and extracted with SiO2 (40 mL x 2). The organic layer was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 1 / 1) to obtain 37c (1.33 g, 83% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.07 min, m / z (M+H) + = 348.2.

[0462] Step 4: 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)-3-(dimethylamino)acrylate(Z)-methyl(37d) A mixture of 37c (1.33 g, 3.83 mmol) in DMF-DMA (10 mL) was stirred at 120°C for 18 hours. The mixture was concentrated to obtain 37d (1.54 g, crude product) as brown oil. LC-MS (ESI, Method 3) t R = 1.07 min, m / z (M+H) + = 403.3.

[0463] Step 5: 5-((2,4-dimethoxybenzyl)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-methylcarboxylate(37e) A mixture of 37d (1.61 g, 4.00 mmol) in DCM (30 mL) was dropwise added to a solution of O-(mesitylsulfonyl)hydroxylamine (1.03 g, 4.80 mmol) in DCM (5 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. An additional amount of O-(mesitylsulfonyl)hydroxylamine (515 mg, 2.40 mmol) in DCM (5 mL) was added to the mixture at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated and purified by silica gel flash chromatography (DCM / MeOH = 50 / 1) to obtain 37e (788 mg, 53% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.27 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.41 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 5.64 (t, J = 6.0 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H).

[0464] Step 6: 5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(37f) To a mixture of 37e (4.26 g, 11.44 mmol) in DCM (15 mL), TFA (15 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure at 30°C. The residue was dissolved in DCM (80 mL), and this solution was basicized to pH=12 with 1 M NaOH. The mixture was extracted with DCM (80 mL). The organic layer was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 10 / 1) to obtain 37f (1.94 g, 76% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.27 (s, 1H), 6.68 (brs, 2H), 3.77 (s, 3H), 3.71 (s, 3H).

[0465] Step 7: 5-iodo-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl (37g) To a mixture of 37f (1.1g, 4.95 mmol) in ACN (12 mL), tert-butyl nitrite (766 mg, 7.43 mmol, 0.88 mL) was added at 0°C. The mixture was stirred at 15°C for 10 minutes. CuI (1.41 g, 7.43 mmol) was added to the mixture and stirred at 70°C for 2 hours. After cooling to room temperature, the reaction product was quenched with 40 mL of 25% NH3·H2O aqueous solution and extracted with ELISA (60 mL x 2). The combined organic layer was concentrated, and the residue was purified by flash chromatography (PE / EA=2 / 1) to obtain 37 g (410 mg, 25% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.24 min, m / z (M+H) + = 333.9.

[0466] Step 8: 4-Methoxy-5-(3,3,3-trifluoropropane-1-en-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(37h) A mixture of 37 g (450 mg, 1.35 mmol) of 1,4-dioxane / H2O (4.5 mL / 1.5 mL), 4,4,6-trimethyl-2-(3,3,3-trifluoropropane-1-en-2-yl)-1,3,2-dioxaborinane (600 mg, 2.70 mmol), Na2CO3 (287 mg, 2.70 mmol), and Pd(dppf)Cl2 (99 mg, 0.14 mmol) was stirred at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with HCl (15 mL) and washed with water (7 mL) and brine (7 mL). The organic layer was concentrated to obtain 37 h (400 mg, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R= 1.25 min, m / z (M+H) + = 302.0.

[0467] Step 9: 4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(37i) A mixture of 37h (400 mg, 1.33 mmol), Pd(OH)2 / C (200 mg, 20% palladium-carbon moistened with water), and Pd / C (200 mg, 10% by weight, moistened with water) in MeOH (4 mL) was stirred at 50°C for 18 hours under an H2 (50 psi) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated to obtain 37i (400 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.27 min, m / z (M+H) + = 304.2.

[0468] Step 10: 4-Methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (37j) A mixture of 37i (400 mg, 1.32 mmol) and NaOH (106 mg, 2.64 mmol) in MeOH (8 mL) and H2O (4 mL) was stirred at 40°C for 10 hours. The reaction mixture was concentrated and added to water (8 mL). The aqueous solution was acidified to pH=1 with 2N HCl. The resulting mixture was extracted with ELISA (20 mL x 2), and the combined organic phase was concentrated. The residue was purified by preparative HPLC (Method A) to obtain 37j (180 mg, 51% yield) as a white solid. LC-MS (ESI, Method 3) t R = 0.47 min, m / z (M+H) + = 290.1.

[0469] Step 11: 3-iodo-4-methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine (37k) A mixture of 37j (92 mg, 0.32 mmol) and NaHCO3 (80 mg, 0.95 mmol) in DMF (2 mL) was mixed with NIS (215 mg, 0.95 mmol) at 0°C. The mixture was stirred at 40°C for 10 hours. After cooling to room temperature, the reaction mixture was diluted at 0°C with saturated Na2S2O3 (5 mL). The mixture was then extracted with RINKAN (8 mL x 2). The combined organic layer was washed with brine (5 mL x 2), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain 37k (115 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.38 min, m / z (M+H) + = 371.9.

[0470] Step 12: N-(4-methoxy-5-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-3-yl)-1,1-diphenylmethanymine (37l) A mixture of 37k (115 mg, 0.31 mmol), diphenylmethanymine (112 mg, 0.62 mmol, 0.1 mL), Xantphos (18 mg, 0.031 mmol), Pd2(dba)3 (28 mg, 0.031 mmol), and Cs2CO3 (202 mg, 0.62 mmol) in 1,4-dioxane (1 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with  (8 mL x 3). The combined organic layer was concentrated, and the residue was purified by flash chromatography (PE / EA = 5 / 1) to obtain 37 L (20 mg, 15% yield) as yellow oil. LC-MS (ESI, Method 3) t R = 1.62 min, m / z (M+H) + = 425.2.

[0471] Step 13: 6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-3-yl)amino)-N-(methyl-d3)nicotinamide(37) A mixture of 37L (20mg, 0.047 mmol) of 1,4-dioxane (0.5 mL), intermediate A (12 mg, 0.047 mmol), and TsOH·H2O (2 mg, 0.01 mmol) was stirred at 60°C for 16 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 37 (7.2 mg, 32% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.36 (s, 1H), 9.37 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.63 (s, 1H), 4.20-4.03 (m, 1H), 3.74 (s, 3H), 2.02-1.87 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 0.80-0.66 (m, 4H). LC-MS (ESI, Method 2) R = 2.75 min, m / z (M+H) + = 481.2.

[0472] Example 38 [ka] Step 1: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-3-yl)amino)-N-(methyl-d3)nicotinamide(38) A mixture of 37L (20mg, 0.047 mmol) of 1,4-dioxane (0.5mL), intermediate B (13mg, 0.047 mmol), and TsOH·H2O (3mg, 0.016 mmol) was stirred at 80°C for 8 hours. After cooling to room temperature, the mixture was diluted with SiO (6mL) and washed with water (2mL) and brine (2mL). The organic layer was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 38 (10.2mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.40-10.38 (m, 1H), 9.38 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 7.64-7.63 (m, 1H), 4.94-4.77 (m, 1H), 4.13-4.11 (m, 1H), 3.75-3.74 (m, 3H), 2.14-2.12 (m, 1H), 1.56-1.44 (m, 4H), 1.13-1.10 (m, 1H). LC-MS (ESI, Method 2) R = 2.73 min, m / z (M+H) + = 499.2.

[0473] Example 39 [ka] Step 1: 2-(5-methoxy-6-vinylpyrimidine-4-yl)methyl acetate (39a) To a mixture of 37b (12.1 g, 55.86 mmol) in dioxane (64 mL) and water (16 mL), Pd(dppf)Cl2 (2.0 g, 2.79 mmol), XPhos Pd G3 (472 mg, 0.56 mmol), and Na2CO3 (11.8 g, 111.72 mmol) were added. The reaction mixture was stirred at 90°C for 28 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with siRNA (70 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain 39a (7 g, 60% yield) as yellow oil. LC-MS (ESI, Method 3) t R = 1.02 min, m / z (M+H) + = 209.3.

[0474] Step 2: 3-(dimethylamino)-2-(5-methoxy-6-vinylpyrimidine-4-yl)methyl acrylate (39b) A mixture of 39a (7 g, 33.61 mmol) in DMF-DMA (13.4 mL, 100.83 mmol) was stirred at 60°C for 4 hours. The mixture was concentrated to obtain 39b (8.7 g, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 264.3.

[0475] Step 3: 4-Methoxy-5-vinylpyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(39c) A mixture of 39b (8.7 g, 33.04 mmol) in DCM (30 mL) was mixed with a solution of 2,4,6-trimethylbenzenesulfonic acid amino (14.23 g, 66.09 mmol) in DCM (30 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was basicized to pH=9 with saturated Na2CO3. The separated aqueous layer was extracted with DCM (200 mL x 3). The combined organic layer was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA=1 / 1) to obtain 39c (2.1 g, 27% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.17 min, m / z (M+H) + = 234.2.

[0476] Step 4: 5-Formyl-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(39d) To a mixture of 39c (2.0 g, 8.58 mmol) in acetone (10 mL), K2OsO4·2H2O (158 mg, 0.43 mmol) was added. A solution of NaIO4 (3.67 g, 17.15 mmol) in water (10 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 1 hour and filtered. The filtrate was concentrated and purified by silica gel flash chromatography (PE / EA = 1 / 1) to obtain 39d (1.2 g, 59% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.94 min, m / z (M+H) + = 236.0.

[0477] Step 5: 4-Methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(39e) To a mixture of 39d (1.20 g, 5.10 mmol) in THF (10 mL), TMSCF3 (1.60 g, 11.22 mmol) was added dropwise, followed by TBAF (1.0 M in THF, 0.25 mL). After stirring at 0°C for 10 minutes, the reaction mixture was diluted with THF (10 mL) and aqueous HCl (10 mL, 1 M). The mixture was stirred at 25°C for 1 hour. The mixture was basicized to pH=8 with aqueous NaOH (1 M) and extracted with SiO2 (50 mL x 3). The combined organic layer was concentrated to obtain 39e (1 g, 64% yield) as a brown oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.12 min, m / z (M+H) + = 306.0.

[0478] Step 6: 4-Methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (39f) A mixture of 39e (600 mg, 1.97 mmol) in methanol (4 mL) and water (2 mL) was mixed with NaOH (157.3 mg, 3.93 mmol), and the mixture was stirred at 45°C for 8 hours. The mixture was adjusted to pH=1 with HCl aqueous solution (2 M) and extracted with ELISA (20 mL x 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 39f (130 mg, 23% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 0.92 min, m / z (M+H) + = 292.0.

[0479] Step 7: 2,2,2-trifluoro-1-(3-iodo-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)ethane-1-ol (39g) NIS (255 mg, 1.13 mmol) was added at 0°C to a solution of 39f (110 mg, 0.38 mmol) and NaHCO3 (95 mg, 1.13 mmol) in DMF (1.2 mL). The mixture was stirred at 15°C for 18 hours. The reaction product was quenched with saturated Na2S2O3 (10 mL) in an ice bath and extracted with Depositphotos (15 mL x 2). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method A) to obtain 39 g (16 mg, 11% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.19 min, m / z (M+H) + = 373.9.

[0480] Step 8: 1-(3-((diphenylmethylene)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)-2,2,2-trifluoroethane-1-ol(39h) A mixture of 39 g (17 mg, 0.045 mmol) of 1,4-dioxane (0.5 mL), diphenylmethanymine (17 mg, 0.091 mmol), Xantphos (3 mg, 0.0046 mmol), Pd2(dba)3 (4 mg, 0.0046 mmol), and Cs2CO3 (30 mg, 0.091 mmol) was stirred at 90°C for 8 hours under an N2 atmosphere. The mixture was diluted with water (3 mL) and extracted with ELISA (5 mL x 3). The combined organic layer was concentrated, and the residue was purified by preparative TLC (PE / EA = 5 / 1) to obtain 39 h (8 mg, 41% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.44 min, m / z (M+H) + = 427.2.

[0481] Step 9: 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-3-yl)amino)-N-(methyl-d3)nicotinamide(39) A mixture of 39h (16 mg, 0.038 mmol), intermediate B (12 mg, 0.045 mmol), and TsOH·H2O (3 mg, 0.015 mmol) in 1,4-dioxane (0.5 mL) was stirred at 80°C for 8 hours. The mixture was filtered and washed with DCM (2 mL). The filtered cake was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 39 (5.8 mg, 31% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.43 (s, 1H), 9.38 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 7.64 (s, 1H), 5.39-5.27 (m, 1H), 4.95-4.74 (m, 1H), 3.78 (s, 3H), 2.20-2.07 (m, 1H), 2.05-1.94 (m, 1H), 1.59-1.41 (m, 1H), 1.15-1.03 (m, 1H). LC-MS (ESI, Method 2) R = 2.45 min, m / z (M+H) + = 501.0.

[0482] Example 40 [ka] Step 1: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-(pyrazolo[1,5-a]pyridine-3-ylamino)nicotinamide (40) Intermediate A (20 mg, 0.078 mmol) and pTSA (13 mg, 0.078 mmol) were dissolved in dioxane (7 mL), to which 40a (21 mg, 0.16 mmol) was added at room temperature. The mixture was stirred at 100 °C for 3 hours. This was added to H₂O (10 mL) and extracted with EA (20 mL). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method E) to obtain 40 (16.5 mg, 60% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.06 (s, 1H), 8.68-8.65 (m, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 7.42-7.39 (m, 1H), 7.38 (s, 1H), 7.23-7.18 (m, 1H), 6.95-6.90 (m, 1H), 1.95-1.86 (m, 1H), 0.72-0.63 (m, 4H). LC-MS (ESI, Method 4) R = 4.44 min, m / z (M+H) + = 354.3.

[0483] Example 41 [ka] Step 1: (Isobutyl carbonate) pyrazolo[1,5-a]pyridine-5-carboxylic acid anhydride (41b) To a solution of 41a (1 g, 6.17 mmol) in THF (20 mL), NMM (749 mg, 7.40 mmol) was added under nitrogen at 0°C. Isobutyl chloroformate (1.01 g, 7.40 mmol) was added dropwise after 5 minutes. The reaction mixture was stirred at 0°C to room temperature for 2 hours. The resulting solution was added to H2O (30 mL) and extracted with EA (50 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain 41b (1.8 g, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 3.14 min, m / z (M+H) + = 263.1.

[0484] Step 2: Pyrazolo[1,5-a]pyridine-5-ylmethanol(41c) To a solution of 41b (1.8 g, crude product) in methanol (20 mL), NaBH4 (662 mg, 17.5 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The resulting solution was added to NH4Cl solution (30 mL) and extracted with EA (40 mL). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 41c (1 g, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.72 min, m / z (M+H) + = 149.1.

[0485] Step 3: Pyrazolo[1,5-a]pyridine-5-carbaldehyde (41d) Dess-Martin periodinane (3.44 g, 8.10 mmol) was added to a solution of 41c (1 g, 5.40 mmol) in DCM (15 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The resulting solution was filtered, and the combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography (EA in PE is 10-40%) to obtain 41d (600 mg, 76% yield) as a white solid. LC-MS (ESI, Method 4) t R = 1.34 min, m / z (M+H) + = 147.1.

[0486] Step 4: 2,2,2-trifluoro-1-(pyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol(41e) To a solution of 41d (300 mg, 2.05 mmol) and TMSCF3 (409 mg, 2.87 mmol) in THF (15 mL), TBAF (1.0 M in THF, 107 mg, 0.41 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour and at 25°C for 12 hours. Then, a 1 M HCl solution was added, and the reaction was stirred at 25°C for 2 hours. The mixture was adjusted to pH=8 with 1 M NaOH aqueous solution. The mixture was extracted with EA (15 mL x 3). The organic layer was concentrated, and the residue was purified by flash chromatography (PE / EA = 2 / 1) to obtain 41e (238 mg, 54% yield) as a white solid. LC-MS (ESI, Method 4) t R = 2.00 min, m / z (M+H) + = 217.1.

[0487] Step 5: 2,2,2-trifluoro-1-(3-nitropyrazolo[1,5-a]pyridine-5-yl)ethane-1-ol(41f) To a solution of 41e (100 mg, 0.46 mmol) in TFA (5 mL), KNO3 (56 mg, 0.56 mmol) was added at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. The resulting solution was added to H2O (10 mL), and the pH was adjusted to 8-9 with saturated Na2CO3 solution. The mixture was extracted with EA (20 mL x 2). The combined organic phase was concentrated, and the residue was purified by flash chromatography (PE / EA = 1 / 1) to obtain 41f (100 mg, 83% yield) as yellow oil. LC-MS (ESI, Method 4) t R = 2.33 min, m / z (M+H) + = 262.0.

[0488] Step 6: 1-(3-aminopyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethane-1-ol (41g) To a solution of 41f (100 mg, 0.38 mmol) in methanol (10 mL), Pd / C (10% palladium-carbon moistened with approximately 55% water) (8 mg) was added under an H2 atmosphere. The mixture was stirred at 25°C for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 41 g (100 mg, crude product) as a brown solid, which was used in the next step without further purification. LC-MS (ESI, Method 4) t R = 0.38 min, m / z (M+H) + = 232.0.

[0489] Step 7: 6-(cyclopropanecarboxamide)-N-(methyl-d3)-4-((5-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)nicotinamide(41) 41 g (27 mg, 0.12 mmol) of intermediate A (15 mg, 0.058 mmol) and 4-methylbenzenesulfonic acid (10 mg, 0.058 mmol) were added to a solution in dioxane (4 mL) at room temperature. The mixture was stirred at 100 °C for 3 hours. The resulting solution was added to H₂O (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography and then by preparative HPLC (Method E) to obtain 41 (6.4 mg, 24% yield) as a pale pink solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.09 (s, 1H), 8.71 (d, J = 7.2 Hz, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.09 (s, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.43 (s, 1H), 7.06 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 5.36-5.27 (m, 1H), 1.94-1.85 (m, 1H), 0.73-0.62 (m, 4H). LC-MS (ESI, Method 4) R= 1.47 min, m / z (M+H) + = 452.2.

[0490] Example 42 [ka] Step 1: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)methyl nicotinate (42) To a solution of 27b (70 mg, 0.25 mmol) and A2 (45 mg, 0.18 mmol) in dioxane (2 mL), TsOH (48 mg, 0.28 mmol) was added, and the mixture was stirred at 85 °C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Method E) to obtain 42 (30 mg, 24% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.57 (s, 1H), 8.64 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.14 (s, 1H), 7.64 (s, 1H), 6.76 (d, J = 7.2 Hz, 1H), 5.25 (q, J = 6.8 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 3.30 (s, 3H), 1.95-1.84 (m, 1H), 0.75-0.57 (m, 4H). LC-MS (ESI, Method 4) R = 2.82 min, m / z (M+H) + = 494.3.

[0491] Example 43 [ka] Step 1: Acetate (S)-2,2,2-trifluoro-1-(4-methoxy-3-nitropyrazolo[1,5-a]pyridine-5-yl)ethyl(43a) To a solution of 7d-A (150 mg, 0.52 mmol), TEA (261 mg, 2.58 mmol, 0.36 mL), and DMAP (6 mg, 0.052 mmol) in THF (5 mL), Ac2O (526 mg, 5.15 mmol, 0.49 mL) was added, and the mixture was stirred at 55°C for 2 hours. The mixture was quenched with saturated NaHCO3 (20 mL) and extracted with ₹ (30 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried, and concentrated under reduced pressure. The residue was purified by flash chromatography (₹20%) to obtain 43a (149 mg, 87% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 2.95 min, m / z (M+H) + = 334.1.

[0492] Step 2: Acetate (S)-1-(3-amino-4-methoxypyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethyl(43b) To a solution of 43a (90 mg, 0.27 mmol) in MeOH (4 mL), Pd / C (9 mg, 0.081 mmol, 10% palladium-carbon moistened with approximately 55% water) was added under an H2 atmosphere. The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain 43b (70 mg, 85% yield) as a brown oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R = 2.18 min, m / z (M+H) + = 304.1.

[0493] Step 3: Acetate (S)-1-(3-((2-(cyclopropanecarboxamide)-5-((methyl-d3)carbamoyl)pyridine-4-yl)amino)-4-methoxypyrazolo[1,5-a]pyridine-5-yl)-2,2,2-trifluoroethyl(43) TsOH (44 mg, 0.25 mmol) was added to a solution of 43b (70 mg, 0.23 mmol) and intermediate A (41 mg, 0.16 mmol) in dioxane (4 mL). The mixture was stirred at 85 °C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Method E) to obtain 43 (45 mg, 37% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.41 (s, 1H), 8.58 (s, 1H), 8.55 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.59 (q, J = 7.2 Hz, 1H), 3.78 (s, 3H), 2.20 (s, 3H), 1.97-1.89 (m, 1H), 0.78-0.66 (m, 4H). LC-MS (ESI, Method 4) R = 2.34 min, m / z (M+H) + = 524.4.

[0494] Example 44 [ka] Step 1: 4-methoxypyrazolo[1,5-a]pyridine (44b) A well-mixed solution of 44a (200 mg, 1.04 mmol) in 1 mL of 50% H2SO4 was heated at 100°C for 1 hour. A brown solution was formed. This solution was cooled to room temperature. The solution was neutralized with 1.0 M NaOH aqueous solution using litmus paper as an indicator. 40 mL of water was added to the above solution. The solution was extracted using siRNA (30 mL x 3). The organic layers were combined. The organic layers were dried on anhydrous Na2SO4. The organic layers were filtered through a Celite pad. The organic layers were removed under reduced pressure to obtain 44b (45 mg, 94% yield) as a colorless oil. LC-MS (ESI, Method 4) t R = 2.01 min, m / z (M+H) + = 149.1.

[0495] Step 2: 4-methoxy-3-nitro-pyrazolo[1,5-a]pyridine (44c) A mixture of 44b (145 mg, 0.98 mmol) in TFA (2 mL) was added to KNO3 (89 mg, 0.88 mmol) at 20°C. The resulting mixture was stirred at 30°C for 1 hour. A yellow solution was formed. The reaction mixture was quenched with aqueous NaHCO3 solution (50 mL) and extracted with ELISA (30 mL x 3). The combined organic layer was washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE is 20-60%) to obtain 44c (80 mg, 42% yield) as a yellow solid. LC-MS (ESI, Method 4) t R = 1.78 min, m / z (M+H) + = 194.1.

[0496] Step 3: 4-methoxypyrazolo[1,5-a]pyridine-3-amine (44d) A mixture of 44c (50 mg, 0.26 mmol) and Pd / C (5 mg, 10% Pd (dry basis), moistened with 55% H2O) in MeOH (3 mL) was subjected to hydrogen degassing and purging three times. The resulting mixture was stirred at 40°C for 12 hours under an H2 atmosphere. A black suspension was formed. The reaction mixture was filtered and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 44d (20 mg, 47% yield) as a red solid. 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.2 Hz, 1H), 7.46 (s, 1H), 6.43 (t, J = 7.2 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 3.92 (s, 3H), 3.56 (brs, 2H). LC-MS (ESI, Method 4) R = 0.43 min, m / z (M+H) + = 164.1.

[0497] Step 4: 6-(cyclopropanecarboxamide)-4-((4-methoxypyrazolo[1,5-a]pyridine-3-yl)amino)-N-(methyl-d3)nicotinamide(44) A mixture of 44d (20 mg, 0.12 mmol), intermediate A (31 mg, 0.12 mmol), and pTSA (42 mg, 0.24 mmol) in dioxane (2 mL) was stirred at 100°C for 12 hours. A yellow suspension was formed. The reaction mixture was diluted with aqueous NaHCO3 (30 mL) and extracted with siRNA (30 mL x 3). The combined organic layers were washed with water (60 mL x 2) and brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM is 0-10%) and tritulated in MeCN to obtain 44 (26.5 mg, 56% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.58 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.19 (d, J = 6.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 6.78 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 3.86 (s, 3H), 2.00-1.93 (m, 1H), 0.78-0.73 (m, 4H). LC-MS (ESI, Method 4) R = 4.92 min, m / z (M+H) + = 384.3.

[0498] Example 45 [ka] Step 1: 2,2,2-trifluoro-1-(4-fluoro-2-methoxyphenyl)ethane-1-ol (45b) To a solution of 45a (5g, 32.44 mmol) and CsF (98 mg, 0.65 mmol) in THF (50 ml), TMSCF3 (9.23 g, 64.88 mmol) was slowly added at 0°C. After stirring at 30°C for 3 hours, the reaction was quenched with aqueous HCl (1 mL, 2 M) and stirred at 20°C for 1 hour. The mixture was diluted with saturated NaHCO3 (10 mL) and extracted with HCl (10 mL). The organic layer was washed with brine (10 mL), dried on anhydrous Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by silica gel flash chromatography (PE / HCl = 20 / 1) to obtain 45b (7.2 g, 99% yield) as yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (t, J = 8.0 Hz, 1H), 6.97 (dd, J = 11.6, 2.8 Hz, 1H), 6.87-6.82 (m, 1H), 6.72 (d, J = 6.0 Hz, 1H), 5.37-5.32 (m, 1H), 3.82 (s, 3H).

[0499] Step 2: 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-methoxyethyl)benzene(45c) To a solution of 45b (4.8 g, 21.41 mmol) in THF (48 mL), NaH (1.03 g, 25.70 mmol, 60% of the mineral oil) was added at 0°C. After stirring at 0°C for 30 minutes, CH3I (9.12 g, 64.24 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour, then at 30°C for 3 hours. This solution was poured into ice water (30 mL) and extracted with siRNA (40 mL x 2). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography (PE / siRNA = 30 / 1) to obtain 45c (4.5 g, 88% yield) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.6 Hz, 1H), 6.97 (dd, J = 11.6, 2.4 Hz, 1H), 6.91-6.85 (m, 1H), 5.18-5.15 (m, 1H), 3.85 (s, 3H), 3.31 (s, 3H).

[0500] Step 3: 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-methoxyethyl)benzaldehyde (45d) To a solution of 45c (1.28 g, 5.37 mmol) in THF (13 mL), LDA (4.03 mL, 2 M in THF) was added dropwise at -50°C. The mixture was stirred at -50°C for 1 hour. Then, DMF (8.06 mmol, 0.62 mL) was added to the mixture at -50°C, and the reaction was stirred at -50°C for 1 hour. The reaction was quenched with saturated NH4Cl (25 mL) and extracted with ₹ (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 45d (1.43 g, crude product) as a yellow oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.77-7.73 (m, 1H), 7.31-7.26 (m, 1H), 5.26-5.23(m, 1H), 3.85 (s, 3H), 3.31 (s, 3H).

[0501] Step 4: 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-methoxyethyl)benzonitrile (45e) To a solution of 45d (1.43 g, 5.37 mmol) in NH3·H2O (7 mL) and 1,4-dioxane (7 mL), 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (2.04 g, 5.37 mmol) was added at 0°C. The mixture was then stirred at 33°C for 16 hours. TLC showed that the starting material had disappeared. The mixture was diluted with water (15 mL) and extracted with siRNA (20 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain 45e (1.4 g, crude product) as a yellow solid, which was used directly in the next step without further purification.

[0502] Step 5: 4-Methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine(45f) A mixture of 45e (1.2 g, 4.56 mmol) in EtOH (5 mL) and a 40% aqueous methylhydrazine solution (7 mL) was stirred at 90°C for 4 hours. After cooling to room temperature, the mixture was diluted with water (25 mL) and extracted with Depositphotos (30 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel flash chromatography (PE / Depositphotos = 5 / 1) to obtain 45f (390 mg, 36% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.19 min, m / z (M+H) + = 290.4.

[0503] Step 6: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (45) A mixture of 45f (200 mg, 0.69 mmol), A2 (194 mg, 0.76 mmol), Pd2(dba)3 (127 mg, 0.14 mmol), Xantphos (80 mg, 0.14 mmol), and Cs2CO3 (451 mg, 1.38 mmol) in 1,4-dioxane (2 mL) was stirred at 90°C for 5 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH=49 / 1) to obtain 45 (298 mg, 85% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.29 min, m / z (M+H) + = 508.5.

[0504] Step 7: (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (45A) and (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (45B) Compound 45 (290 mg, 0.57 mmol) was separated by chiral preparative HPLC (Method J) to obtain 45A (77.5 mg, 27% yield) as a white solid and 45B (77.5 mg, 27% yield) as a white solid.

[0505] 45A:LC-MS (ESI, method 2): t R = 0.98 min, m / z (M+H) + = 508.1. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.29 (q, J = 6.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.32 (s, 3H), 2.06-2.01 (m, 1H), 0.84-0.80 (m, 4H). Chiral HPLC (Method 7) t R = 13.97 minutes.

[0506] 45B:LC-MS (ESI, method 2): t R = 0.98 min, m / z (M+H) + = 508.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 5.29 (q, J = 7.2 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.07-2.01 (m, 1H), 0.86-0.79 (m, 4H). Chiral HPLC (Method 7) t R = 17.26 minutes.

[0507] Step 8: (S)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (45f-A) and (R)-4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (45f-B) 45f (5.8g, 20.05 mmol) was separated by chiral preparative HPLC (Method G, hexane / EtOH = 90 / 10) to obtain 45f-A (1.84g, 32% yield) (chiral HPLC (Method 8, hexane / EtOH = 90 / 10) t R = 8.64 min) was observed as a white solid, and 45f-B (2.23 g, 38% yield) (chiral HPLC (Method 8, hexane / EtOH = 90 / 10) t R (= 10.30 min) was obtained as a white solid.

[0508] Example 46 [ka] Step 1: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)aminonicotinic acid (46a) A solution of 45 (80 mg, 0.16 mmol) in THF (6 mL) and MeOH (2 mL) was mixed with an aqueous solution of LiOH (0.5 mL, 2 M in water) at 10°C. The mixture was then stirred at 30°C for 3 hours. The mixture was adjusted to pH < 7 with 2 N HCl and extracted with siRNA (8 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 46a (77 mg, crude product) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.21 min, m / z (M+H) + = 494.4.

[0509] Step 2: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide(46) To a solution of 46a (70 mg, 0.14 mmol), methyl-d3-amine hydrochloride (20 mg, 0.28 mmol), and DIPEA (73 mg, 0.57 mmol) in DMF (0.5 mL), BOP (125 mg, 0.28 mmol) was added at 0°C. The mixture was then stirred at 0°C for 2 hours. The mixture was quenched with ice water (3 mL) and extracted with RINKAN (6 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method C) to obtain 46 (8.8 mg, 12% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.93 min, m / z (M+H) + = 510.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.70 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 5.32-5.24 (m, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.08-2.00 (m, 1H), 0.85-0.77 (m, 4H).

[0510] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide (46A) and (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide (46B) 46 (220 mg, 0.41 mmol) was separated by chiral preparative HPLC (Method K) to obtain 46A (102 mg, 46% yield) as a white solid and 46B (102 mg, 46% yield) as a white solid.

[0511] 46A:LC-MS (ESI, method 2): t R = 1.09 min, m / z (M+H) + = 510.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 10.73 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 7.45-7.38 (m, 2H), 5.32-5.26 (m, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.32 (s, 3H), 2.05-2.00 (m, 1H), 0.85-0.78 (m, 4H). Chiral HPLC (Method 9) t R = 5.39 minutes.

[0512] 46B:LC-MS (ESI, method 2): t R = 1.09 min, m / z (M+H) + = 510.0. 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 10.72 (s, 1H), 9.14 (s, 1H), 8.64 (s, 1H), 8.58 (s, 1H), 7.45-7.38 (m, 2H), 5.31-5.26 (m, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.04-1.99 (m, 1H), 0.87-0.79 (m, 4H). Chiral HPLC (Method 9) t R = 5.94 minutes.

[0513] Example 47 [ka] Step 1: (S)-4-methoxy-3-nitro-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine(47a) To a solution of 7d-A (200 mg, 0.69 mmol) and CD3I (498 mg, 3.43 mmol) in anhydrous DMF (2 mL), NaH (33 mg, 0.82 mmol, 60% in mineral oil) was slowly added at 0°C and stirred for 30 minutes at 0°C. This solution was poured into ice water (5 mL) and extracted with siRNA (5 mL x 2). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / siRNA = 20 / 1) to obtain 47a (200 mg, 94% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.27 min, m / z (M+H) + = 309.3.

[0514] Step 2: (S)-4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-amine(47b) To a solution of 47a (200 mg, 0.65 mmol) and 4,4'-bipyridine (4.05 mg, 0.026 mmol) in DMF (2 mL), B2(OH)4 (175 mg, 1.95 mmol) was slowly added at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was directly purified by preparative HPLC (Method A) to obtain 47b (130 mg, 72% yield) as a brown solid. LC-MS (ESI, Method 3) t R = 1.01 min, m / z (M+H) + = 279.2.

[0515] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)pyrazolo[1,5-a]pyridine-3-yl)amino)methyl nicotinate (47) A mixture of 47b (30 mg, 0.11 mmol), A2 (33 mg, 0.13 mmol), Cs2CO3 (70 mg, 0.22 mmol), Xantphos (12 mg, 0.022 mmol), and Pd2(dba)3 (20 mg, 0.022 mmol) in dioxane (0.4 mL) was stirred at 100°C for 5 hours under N2. The reaction mixture was cooled, concentrated, and purified by silica gel flash chromatography (PE / siRNA=3 / 1) to obtain 47 (21.5 mg, 40% yield) as a yellow solid. LC-MS (ESI, Method 2) t R = 0.90min, m / z (M+H) + = 497.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.61 (s, 1H), 8.68 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.67(s, 1H), 6.81 (d, J = 7.2 Hz, 1H), 5.29-5.26 (m, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 1.95-1.92 (m, 1H), 0.75-0.67 (m, 4H).

[0516] Example 48 [ka] Step 1: tert-butyldimethyl(2,2,2-trifluoro-1-(4-fluoro-2-methoxyphenyl)ethoxy)silane(48a) To a solution of 45b (3 g, 13.38 mmol) and imidazole (1.37 g, 20.08 mmol) in DMF (3 mL), TBSCl (3.03 g, 20.08 mmol) was added at room temperature. After stirring at 30 °C for 3 hours, the reaction product was diluted with 0.2 M HCl (20 mL) and extracted with HCl (20 mL x 2). The organic layer was washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel flash chromatography (PE / HCl = 50 / 1) to obtain 48a (3.5 g, 77% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 11.2, 2.4 Hz, 1H), 7.08 (td, J = 8.4, 2.4 Hz, 1H), 5.53 (q, J = 6.8 Hz, 1H), 3.91 (s, 3H), 0.91 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).

[0517] Step 2: 3-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-6-fluoro-2-methoxybenzaldehyde(48b) To a solution of 48a (1 g, 2.95 mmol) in THF (10 mL), LDA (6 mL, 12 mmol, 2 M in THF) was added dropwise over 30 minutes at -60°C. The reaction mixture was stirred at the same temperature for 1 hour. Then, DMF (0.65 g, 8.86 mmol) was added dropwise to this solution at -60°C. The reaction mixture was stirred for a further 2 hours at -60°C and quenched with aqueous HCl (10 mL, 2 M). The mixture was extracted with siRNA (10 mL x 2), the combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 48b (1 g, 92% yield) as a yellow oil, which was used directly in the next step without further purification.

[0518] Step 3: 3-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-6-fluoro-2-methoxybenzonitrile(48c) To a solution of 48b (200 mg, 0.55 mol) in 1,4-dioxane (1 mL) and NH3·H2O (1 mL), 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (207 mg, 0.55 mmol) was added in an ice bath. The mixture was then stirred at room temperature for 16 hours. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (8 mL). The separated organic layer was dried over anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure at 35°C to obtain 48c (198 mg, crude product) as a yellow oil, which was used directly in the next step without further purification.

[0519] Step 4: 5-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-methoxy-1-methyl-1H-indazole-3-amine(48d) A mixture of 48c (198 mg, 0.55 mmol), 40% aqueous methylhydrazine (2 mL), and EtOH (2 mL) was stirred at 90°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (8 mL) and extracted with RINKAN (10 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / RINKAN = 5 / 1 to 2 / 1) to obtain 48d (70 mg, 33% yield) as yellow oil. LC-MS (ESI, Method 3) t R = 1.57 min, m / z (M+H) + = 390.5.

[0520] Step 5: 4-((5-(1-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-4-methoxy-1-methyl-1H-indazole-3-yl)amino)-6-(cyclopropanecarboxamide)methyl nicotinate (48e) A mixture of 48d (75 mg, 0.19 mmol), A2 (54 mg, 0.21 mmol), Pd2(dba)3 (35 mg, 0.039 mmol), Xantphos (22 mg, 0.039 mol), and Cs2CO3 (125 mg, 0.39 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 3 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain 48e (85 mg, 73% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.56 min, m / z (M+H) + = 608.7.

[0521] Step 6: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (48) To a solution of 48e (70 mg, 0.12 mmol) in THF (1 mL), TBAF (1 mL, 1 M in THF) was added at 0°C. The mixture was then stirred at 30°C for 1 hour. The reaction mixture was diluted with water (3 mL) and extracted with siRNA (6 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 97 / 3) to obtain 48 (40 mg, 70% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.17 min, m / z (M+H) + = 494.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 6.87 (brs, 1H), 5.48-5.42 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 2.10-1.96 (m, 1H), 0.93-0.76 (m, 4H).

[0522] Step 7: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (48A) and (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (48B) 48 (15 mg, 0.03 mmol) was separated by chiral preparative HPLC (Method G, hexane / EtOH = 60 / 40) to obtain 48A (5.3 mg, 36% yield) as a white solid and 48B (5.6 mg, 38% yield) as a white solid.

[0523] 48A:LC-MS (ESI, method 2): t R = 0.89 min, m / z (M+H) + = 494.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 5.2 Hz, 1H), 5.52-5.39 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 2.07-2.01 (m, 1H), 0.87-0.79 (m, 4H). Chiral HPLC (Method 8, Hexane / EtOH = 60 / 40) t R = 5.08 minutes.

[0524] 48B:LC-MS (ESI, method 2): t R = 0.88 min, m / z (M+H) + = 494.1. 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.88 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 5.6 Hz, 1H), 5.51-5.38 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 2.07-2.01 (m, 1H), 0.87-0.79 (m, 4H). Chiral HPLC (Method 8, Hexane / EtOH = 60 / 40) t R = 6.87 minutes.

[0525] Example 49 [ka] Step 1: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)aminonicotinic acid (49a) To a solution of 48 (38 mg, 0.077 mmol) in THF (0.5 mL) and MeOH (0.5 mL), LiOH (0.25 mL, 2 M) in water was added under ice bath conditions. The mixture was then stirred at 30°C for 2 hours. The mixture was adjusted to pH < 7 with 2 N HCl and extracted with siRNA (8 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 49a (36 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R = 1.12 min, m / z (M+H) + = 480.4.

[0526] Step 2: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide(49) A solution of 49a (35 mg, 0.073 mmol), triduteriomethanamine hydrochloride (10 mg, 0.15 mmol), and DIPEA (38 mg, 0.29 mmol) in DMF (0.5 mL) was prepared by adding BOP (65 mg, 0.15 mmol) at 0°C. The mixture was then stirred at 0°C for 2 hours. The mixture was quenched with ice water (4 mL) and extracted with RINKAN (7 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method A) to obtain 49 (7.3 mg, 20% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.84 min, m / z (M+H) + = 496.1.1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 5.46-5.41 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.06-1.95 (m, 1H), 0.92-0.69 (m, 4H).

[0527] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide (49A) and (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)nicotinamide (49B) 49 (135 mg, 0.27 mol) was separated by chiral preparative HPLC (Method I, hexane / IPA / DEA = 60 / 40 / 0.3) to obtain 49A (40 mg, 30% yield) as a white solid and 49B (45.4 mg, 34% yield) as a white solid.

[0528] 49A: LC-MS (Method 2) R = 0.83 min, m / z (M+H) + = 496.1. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.46-5.41 (m, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 2.07-1.97 (m, 1H), 0.89-0.75 (m, 4H). Chiral HPLC (Method 6, Hexane / IPA / DEA = 60 / 40 / 0.2) R = 9.08 minutes.

[0529] 49B: LC-MS (Method 2) R = 0.84 min, m / z (M+H) + = 496.1. 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.69 (s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 5.57-5.31 (m, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 2.12-1.91 (m, 1H), 0.99-0.72 (m, 4H). Chiral HPLC (Method 6, Hexane / IPA / DEA = 60 / 40 / 0.2) R = 12.84 minutes.

[0530] Example 50 [ka] Step 1: 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene (50a) To a solution of 45b (5g, 22.31 mmol) in THF (50 ml), NaH (1.07 g, 26.77 mmol, 60% of the mineral oil) was added at 0°C. After stirring at 0°C for 30 minutes, CD3I (9.70 g, 66.92 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour and then at 30°C for 3 hours. This solution was poured into ice water (30 mL) and extracted with siRNA (40 mL x 2). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / siRNA = 30 / 1) to obtain 50a (5g, 93% yield) as yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 1H), 6.7-6.73 (m, 1H), 6.69-6.65 (m, 1H), 5.12-5.07 (m, 1H), 3.86 (s, 3H).

[0531] Step 2: 4-Fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene(50b) To a solution of 50a (2.5 g, 10.36 mmol) in THF (20 mL), LDA (15 mL, 30 mmol, 2 M in THF) was added dropwise at -50°C. The mixture was stirred at -50°C for 1 hour. Then, DMF (2.41 mL, 31.09 mmol) was added to the mixture at -50°C and stirred at -50°C for 1 hour. The reaction product was quenched with saturated NH4Cl (25 mL) and extracted with ₹ (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35°C to obtain 50b (2 g, crude product) as a yellow oil, which was used directly in the next step without further purification.

[0532] Step 3: 6-Fluoro-2-methoxy-3-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzonitrile (50c) To a solution of 50b (400 mg, 1.49 mmol) in NH3·H2O (2 mL) and 1,4-dioxane (2 mL), 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (567 mg, 1.49 mmol) was added in an ice bath. The mixture was then stirred at 30°C for 12 hours. TLC showed that the starting material had disappeared. The mixture was diluted with water (3 mL) and extracted with siRNA (10 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35°C to obtain 50c (1.6 g, crude product) as a yellow liquid, which was used directly in the next step without further purification.

[0533] Step 4: 4-Methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-amine(50d) A mixture of 50c (300 mg, 1.13 mmol) and 40% aqueous methylhydrazine solution (1.5 mL) in EtOH (1.5 mL) was stirred at 90°C for 12 hours. After cooling to room temperature, the mixture was diluted with water (3 mL) and extracted with HCl (10 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / HCl = 5 / 1) to obtain 50d (150 mg, 46% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.20 min, m / z (M+H) + = 293.4.

[0534] Step 5: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl)-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (50) A mixture of 50d (150 mg, 0.51 mmol), A2 (131 mg, 0.51 mmol), Pd2(dba)3 (94 mg, 0.10 mmol), Xantphos (60 mg, 0.10 mmol), and Cs2CO3 (335 mg, 1.03 mmol) in 1,4-dioxane (2 mL) was stirred at 90°C for 12 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / Â=2 / 1) to obtain 50 (70 mg, 27% yield) as a yellow solid. LC-MS (ESI, Method 3) t R = 1.28 min, m / z (M+H) + = 511.5.

[0535] Step 6: (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (50A) and (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (50B) 50 (70 mg, 0.14 mmol) was separated by chiral preparative HPLC (Method G, hexane / EtOH = 80 / 20) to obtain 50A (26 mg, 37% yield) as a white solid and 50B (25 mg, 36% yield) as a white solid.

[0536] 50A:LC-MS (ESI, method 2): t R = 1.13 min, m / z (M+H) + = 511.0. 1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.91 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.30-5.27 (m, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 2.05-1.98 (m, 1H), 0.84-0.80 (m, 4H). Chiral HPLC (Method 8, Hexane / IPA = 80 / 20) t R = 12.51 minutes.

[0537] 50B:LC-MS (ESI, method 2): t R = 1.13 min, m / z (M+H) + = 511.0. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 10.91 (s, 1H), 9.18 (s, 1H), 8.77 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.30-5.27 (m, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 2.05-2.02 (m, 1H), 0.84-0.80 (m, 4H). Chiral HPLC (Method 8, Hexane / IPA = 80 / 20) t R = 16.16 minutes.

[0538] Example 51 [ka] Step 1: 6-Chloro-4-((4-Methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(51a) To a solution of 45f (100 mg, 0.35 mmol) and 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (87 mg, 0.41 mmol) in THF (0.8 mL), LiHMDS (1.4 mL, 1.40 mmol, 1 M in THF) was added at -40°C. The reaction mixture was stirred at -40°C to 25°C for 2 hours. The mixture was quenched with H2O (2 mL) and the organic solvent was evaporated. The formed solid was filtered, and the filter cake was dried to obtain 51a (100 mg, 63% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.48 min, m / z (M+H) + = 462.3.

[0539] Step 2: 6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(51) A mixture of 51a (100 mg, 0.22 mmol), cyclopropanecarboxamide (91 mg, 1.08 mmol), BrettPhos Pd G3 (39 mg, 0.043 mmol), and Cs2CO3 (141 mg, 0.43 mol) in 1,4-dioxane (1.2 mL) was stirred at 90°C for 5 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH=20 / 1) to obtain 51 (80 mg, 72% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.31 min, m / z (M+H) + = 511.5.

[0540] Step 3: (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (51A) and (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-methyl-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (51B) 51 (80 mg, 0.16 mmol) was separated by chiral preparative HPLC (Method L) to obtain 51A (20 mg, 25% yield) as a white solid and 51B (12 mg, 15% yield) as a white solid.

[0541] 51A:LC-MS (ESI, method 2): t R = 1.16 min, m / z (M+H) + = 511.0. 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.30 (s, 1H), 9.44 (s, 1H), 9.20 (s, 1H), 7.48-7.41 (m, 2H), 5.32-5.29 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.32 (s, 3H), 2.14-2.10 (m, 1H), 0.90-0.87 (m, 4H). Chiral HPLC (Method 8, Hexane / EtOH = 90 / 10) t R = 8.65 minutes.

[0542] 51B:LC-MS (ESI, method 2): t R = 1.00 min, m / z (M+H) + = 511.2. 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.30 (s, 1H), 9.44 (s, 1H), 9.21 (s, 1H), 7.48-7.41 (m, 2H), 5.33-5.27 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.34 (s, 3H), 2.17-2.11 (m, 1H), 0.92-0.84 (m, 4H). Chiral HPLC (Method 8, Hexane / EtOH = 90 / 10) t R = 10.33 minutes.

[0543] Example 52 [ka] Step 1: 4-Methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine(52a) To a mixture of methyl-d3-hydrazine hydrochloride (1:2) (1.50 g, 12.30 mmol) in EtOH / H2O (0.5 mL / 0.1 mL), KOH (1.34 g, 23.94 mmol) was added in an ice bath. The reaction mixture was stirred at 30°C for 30 minutes. The solid was removed by filtration. The filtrate was added to 45e (175 mg, 0.66 mmol) and stirred in a shielded tube at 90°C for 2 hours. After cooling to room temperature, the mixture was purified by preparative HPLC (Method C, HCOOH) to obtain compound 52a (58 mg, 29.8% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.22 (s, 2H), 5.21-5.15 (m, 1H), 3.87 (s, 3H), 3.28 (s, 3H).

[0544] Step 2: (S)-4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (52a-A) and (R)-4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-amine (52a-B) 52a (150 mg, 0.51 mmol) was separated by chiral preparative HPLC (Method G, hexane / EtOH = 90 / 10, 20 mL / min) to obtain 52a-A (64 mg, 43% yield) as a white solid and 52a-B (65 mg, 43% yield) as a white solid.

[0545] 52a-A: Chiral HPLC (Method 8, Hexane / EtOH = 90 / 10) t R = 8.63 minutes.

[0546] 52a-B: Chiral HPLC (Method 8, Hexane / EtOH = 90 / 10) t R = 10.32 minutes.

[0547] Step 3: (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (52A) and (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-methoxyethyl)-1H-indazole-3-yl)amino)methyl nicotinate (52B) A mixture of 52a-A (30 mg, 0.10 mmol), A2 (26 mg, 0.10 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (67 mg, 0.21 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 4 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain the crude product. The crude compound was then re-purified by preparative HPLC (Method A) to obtain 52A (24.2 mg, 46% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.97 min, m / z (M+H) + = 511.1. 1 ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.78 (s, 1H), 7.49-7.40 (m, 2H), 5.32-5.27 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.31 (s, 3H), 2.09-1.99 (m, 1H), 0.88-0.76 (m, 4H). Chiral HPLC (Method 7, Hexane / IPA = 85 / 15, Run time 40 minutes) t R = 21.74 minutes.

[0548] A mixture of 52a-B (30 mg, 0.10 mmol), A2 (29 mg, 0.11 mmol), Pd2(dba)3 (19 mg, 0.021 mmol), Xantphos (12 mg, 0.021 mmol), and Cs2CO3 (67 mg, 0.21 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 4 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain the crude product. The crude compound was then re-purified by preparative HPLC (Method A) to obtain 52B (13.5 mg, 26% yield) as a white solid. LC-MS (ESI, Method 2) t R = 0.97 min, m / z (M+H) += 511.1. 1 ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.90 (s, 1H), 9.18 (s, 1H), 8.78 (s, 1H), 7.49-7.40 (m, 2H), 5.33-5.27 (m, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.33 (s, 3H), 2.04-1.98 (m, 1H), 0.83-0.76 (m, 4H). Chiral HPLC (Method 7, Hexane / IPA = 85 / 15, Run time 40 minutes) t R = 16.91 minutes.

[0549] Example 53 [ka] Step 1: 4-(methoxy-d3)-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3))-1H-indazole-3-amine 4-fluoro-2-methoxy-1-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)benzene (53a) To a solution of CD3NHNH2·HCl (700 mg, 5.74 mmol) in EtOH / H2O (0.5 mL / 0.1 mL), KOH (600 mg, 10.69 mmol) was added under ice bath conditions, and the solution was stirred at 30°C for 30 minutes. The formed solid was removed by filtration. The filtrate was added to 50b (500 mg, 1.88 mmol). The reaction mixture was stirred in a shielded tube at 90°C for 6 hours. The mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / Ã=2 / 1) to obtain the crude compound. The crude compound was re-purified by preparative HPLC (Method C) to obtain 53a (80 mg, 15% yield) as yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.13-5.08 (m, 1H), 3.99 (s, 3H).

[0550] Step 2: 6-(cyclopropanecarboxamide)-4-((4-(methoxy-d3)-1-methyl-5-(2,2,2-trifluoro-1-(methoxy-d3))-1H-indazole-3-yl)amino)methyl nicotinate (53) A mixture of 53a (35 mg, 0.12 mmol), A2 (36 mg, 0.14 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), Xantphos (14 mg, 0.02 mmol), and Cs2CO3 (77 mg, 0.23 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 4 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 19 / 1) to obtain the crude product. The crude product was re-purified by preparative HPLC (Method C) to obtain 53 (39 mg, 57% yield) as a white solid. LC-MS (ESI, Method 3) t R = 1.30 min, m / z (M+H) + = 514.4.

[0551] Step 3: (R)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (53A) and (S)-6-(cyclopropanecarboxamide)-4-((4-methoxy-1-(methyl-d3)-5-(2,2,2-trifluoro-1-(methoxy-d3)ethyl)-1H-indazole-3-yl)amino)methyl nicotinate (53B) 53 (39 mg, 0.07 mmol) was separated by chiral preparative HPLC (Method G, hexane / IPA = 80 / 20) to obtain 53A (13.2 mg, 34% yield) as a white solid and 53B (11.6 mg, 30% yield) as a white solid. 53A:LC-MS (ESI, method 2): t R = 0.96 min, m / z (M+H) + = 514.2. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.89 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.31-5.26 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.08-1.99 (m, 1H), 0.87-0.79 (m, 4H). Chiral HPLC (Method 8, Hexane / IPA = 80 / 20) t R = 12.46 minutes.

[0552] 53B:LC-MS (ESI, method 2): t R = 0.96 min, m / z (M+H) + = 514.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.94 (s, 1H), 9.12 (...

Claims

1. Structural formula (I): 【Chemistry 278】 A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, Y １ However, it is CH, CF, or N, Y ２ However, it is CH or N, Y ３ However, NR, O, CH ２ CD ２ CF ２ , or O-NH, t is 0 or 1, R １ is H, F, CD ３ or C １～３ alkyl, provided that when Y ３ is N, O, or O-NH, R １ is not F, R ２ but, R ２’ And here, R ２’ However, C １ ~C ６ Alkyl, C ３～６ Cycloalkyl, C ５～７ Spirocycloalkyl, or C ３～６ It is a heterocycloalkyl group, with each having 0 to 2 R atoms. ２ａ It is replaced with R ２ａ However, halogens, CN, OR, NRR', alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R ２ａ A aryl or heteroaryl group substituted with; (C=O)R ２ｂ ;or (C=O)NHR ２ｂ Selected from the group consisting of, R ３ but, 【Chemistry 279】 And, During the ceremony, X ６ However, CR ６ or N, X ７ However, CR ７ or N, X ８ However, it is C or N, X ９ However, CR ９ O, S, N, or NR ９ And, X １０ However, CR １０ O, S, N, or NR １０ And, Each of rings A and B is independently an aryl or heteroaryl group. R ２ｂ However, C １～６ Alkyl, C ３～６ Cycloalkyl, C ５～７ Spirocycloalkyl, aryl, or heteroaryl, each containing 0 to 4 R ２ｃ It has been replaced with, R ２ｃ However, independently, in each occurrence, Halo, CN, OR, NRR', OCF ３ CF ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenil, C ２～６ It is an alkynyl, where the alkyl, haloalkyl, alkenyl, alkynyl, R, and R' have 0 to 3 R ２ａ It has been replaced with, R ４ However, there are 0 to 5 R ４ａ C replaced by １～３ It is alkyl, and here, R ４ａ However, it is selected from D, F, and Cl, R ５ However, H, CN, Halo, OCH ３ , C(=O)OR, NHC(=O)R, NRR', NO ２ , C １～６ Alkyl, C ３～６ A cycloalkyl or heterocyclic ring, wherein the alkyl, cycloalkyl, or heterocyclic ring has 0 to 3 R atoms. ５ａ It is replaced by each R ５ａ However, OH, D, F, Cl, CN, CH ２ F, CHF ２ CF ３ , OCH ３ OCD ３ OCF ３ , and OC(=O)CH ３ Selected independently from, R ６ , R ７ , R ９ , and R １０ Each of these is H, F, Cl, CN, CD ３ ,CH ２ CF ３ CF ３ , OR, NRR', C １～３ Alkyl and C ３～５ A cycloalkyl group is independently selected, where the alkyl, cycloalkyl, R, and R' are 0 to 2 R's. ２ａ It has been replaced with, R and R' can independently be H or C １ ~C ６ It is either alkyl or acyl, or R and R' together with the nitrogen atom to which they are bonded, O, NR, S, and SO ２ The compound or a pharmaceutically acceptable form or isotopic derivative thereof, forming a 4-7 membered ring containing 0-2 heteroatoms selected from the above.

2. When t is 1, the following structural formula: 【Chemistry 280】 The compound according to claim 1, having the following characteristics.

3. When t is 0, the following structural formula: 【Chemistry 281】 The compound according to claim 1, having the following characteristics.

4. The compound according to any one of claims 1 to 3, wherein ring A is a heteroaryl group.

5. X ６ However, it is CH, and X ７ However, it is CH, and R ３ However, the structure is as follows: 【Chemistry 282】 A compound according to any one of claims 1 to 3, having the following characteristics.

6. X ７ However, it is CH, and X ８ However, C is R ３ However, the structure is as follows: 【Chemistry 283】 A compound according to any one of claims 1 to 3, having the following characteristics.

7. X ６ is CH, and X ８ is C, and R ３ has the following structure: 【Chemistry 284】 A compound according to any one of claims 1 to 3, having the following characteristics.

8. X ７ However, it is CH, and X １０ However, it is CH, and R ３ However, the structure is as follows: 【Chemical 285】 A compound according to any one of claims 1 to 3, having the following characteristics.

9. R ３ but, 【Chemistry 286】 A compound selected from any one of claims 1 to 8.

10. R ４ However, CH ３ The compound according to claim 9.

11. R ４ is CD ３ The compound according to claim 9, wherein

12. R ３ but, 【Chemistry 287】 The compound according to claim 9.

13. R １０ The compound according to any one of claims 1 to 12, wherein if present, it is H.

14. R ３ but, 【Chemical 288】 The compound according to claim 9.

15. R ９ However, if C exists, １～３ They are alkyl or cyclopropyl, each being C １～３ Alkoxy, CF ３ The compound according to any one of claims 1 to 14, which is optionally substituted with NRR'.

16. R ９ However, C １～３ The compound according to claim 15, wherein it is alkyl.

17. R ９ However, CH ３ The compound according to claim 16.

18. R ９ However, CD ３ The compound according to claim 16.

19. R ５ However, C substituted with OH １～４ A compound according to any one of claims 1 to 18, wherein it is alkyl.

20. R ５ but, 【Chemistry 289】 And, During the ceremony, R ５’ However, C is substituted with 0 to 5 F's. １～３ Alkyl or cyclopropyl, R is H, C １～３ The compound according to any one of claims 1 to 18, wherein it is alkyl or acyl.

21. R is CH ３ The compound according to claim 20.

22. R is CD ３ The compound according to claim 20.

23. R ５ but, 【Chemistry 290】 And, During the ceremony, R ５’ However, C is substituted with 0 to 5 F's. １～３ Alkyl or cyclopropyl, R is H, C １～３ The compound according to any one of claims 1 to 18, wherein it is alkyl or acyl.

24. R is CH ３ The compound according to claim 23.

25. R is CD ３ The compound according to claim 23.

26. R is C(=O)CH ３ Or C(=O)CD ３ The compound according to claim 20 or 23.

27. R ５’ However, CF ３ The compound according to any one of claims 20 to 26.

28. R ５’ However, CHF ２ The compound according to any one of claims 20 to 26.

29. Y ３ The compound according to any one of claims 1 to 28, wherein the compound is NH.

30. Y １ However, it is CH and Y ２ However, it is CH, 【Chemistry 291】 The compound according to claim 29.

31. Y １ However, it is CH and Y ２ However, N is, 【Chemistry 292】 The compound according to claim 29.

32. Y １ However, N is Y ２ However, it is CH, 【Chemistry 293】 The compound according to claim 29.

33. Y １ However, N is Y ２ However, N is, 【Chemistry 294】 The compound according to claim 29.

34. Y ３ The compound according to any one of claims 1 to 28, wherein the compound is O.

35. Y １ However, it is CH and Y ２ However, it is CH, 【Chemistry 295】 The compound according to claim 34.

36. Y １ However, it is CH and Y ２ However, N is, 【Chemistry 296】 The compound according to claim 34.

37. Y １ However, N is Y ２ However, it is CH, 【Chemistry 297】 The compound according to claim 34.

38. Y １ However, N is Y ２ However, N is, 【Chemistry 298】 The compound according to claim 34.

39. Y ３ However, CH ２ The compound according to any one of claims 1 to 28.

40. Y １ However, it is CH and Y ２ However, it is CH, 【Chemistry 299】 The compound according to claim 39.

41. Y １ However, it is CH and Y ２ However, N is, [Chemical 300] The compound according to claim 39.

42. Y １ However, N is Y ２ However, it is CH, 【Chemical 301】 The compound according to claim 39.

43. Y １ However, N is Y ２ However, N is, 【Chemical 302】 The compound according to claim 39.

44. Y ３ However, CD ２ The compound according to any one of claims 1 to 28.

45. Y ３ However, CF ２ The compound according to any one of claims 1 to 28, wherein t is 0.

46. Y １ However, it is CH and Y ２ However, it is CH, 【Chemical 303】 The compound according to claim 45.

47. Y １ However, it is CH and Y ２ However, N is, 【Chemical 304】 The compound according to claim 45.

48. Y １ However, N is Y ２ However, it is CH, 【Chemical 305】 The compound according to claim 45.

49. Y １ However, N is Y ２ However, N is, 【Chemical 306】 The compound according to claim 45.

50. R ６ and R ７ The compound according to any one of claims 1 to 49, wherein if present, it is H.

51. R ２ However, R ２’ The compound according to any one of claims 1 to 50.

52. R ２ However, (C=O)R ２ｂ The compound according to any one of claims 1 to 50.

53. R ２ｂ However, there are 0 to 3 R ２ｃ C replaced by １ ~C ６ A compound according to claim 52, selected from alkyl groups.

54. R ２ｂ However, there are 0 to 3 R ２ｃ C replaced by ３～６ The compound according to claim 52, wherein it is a cycloalkyl compound.

55. R ２ｂ The compound according to claim 54, wherein the compound is cyclopropyl.

56. R ２ｂ The compound according to claim 54, wherein the compound is a cyclopropyl substituted with F.

57. R ２ｂ However, there are 0 to 3 R ２ｃ C replaced by ５～７ The compound according to claim 52, wherein it is a spirocycloalkyl.

58. R ２ｂ However, C ５ The compound according to claim 57, wherein spiro[2,2]pentyl.

59. R ２ However, (C=O)NHR ２ｂ The compound according to any one of claims 1 to 49.

60. R ２ However, there are 0 to 2 R ２ｃ The compound according to any one of claims 1 to 49, wherein the compound is a pyridinyl substituted with [a specific compound].

61. R ２ However, there are 0 to 2 R ２ｃ The compound according to any one of claims 1 to 49, wherein the compound is a phenyl substituted with .

62. R ２ However, there are 0 to 2 R ２ｃ The compound according to any one of claims 1 to 49, wherein the compound is pyrazolyl substituted with [the specified compound].

63. R ２ However, there are 0 to 2 R ２ｃ The compound according to any one of claims 1 to 49, wherein the pyrimidyl is substituted with [the specified compound].

64. R １ However, CH ３ The compound according to any one of claims 1 to 63.

65. R １ However, CD ３ The compound according to any one of claims 1 to 63.

66. The following structural formula: 【Chemical 307】 It has, In the formula, X ６ The compound according to claim 1, wherein the compound is N or CH.

67. Select the following structural formula: 【Chemical 308】 The compound according to claim 1, having the following characteristics.

68. Select the following structural formula: 【Chemical 309】 The compound according to claim 1, having the following characteristics.

69. Select the following structural formula: 【Chemical 310】 The compound according to claim 1, having the following characteristics.

70. Select the following structural formula: 【Chemical 311】 The compound according to claim 1, having the following characteristics.

71. Select the following structural formula: 【Chemical 312】 The compound according to claim 1, having the following characteristics.

72. The following structural formula: 【Chemistry 313】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

73. The following structural formula: 【Chemical 314】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

74. The following structural formula: 【Chemical Industry 315】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

75. The following structural formula: 【Chemical 316】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

76. The following structural formula: 【Chemical 317】 It has, In the formula, X ６ The compound according to claim 1, wherein the compound is N or CH.

77. Select the following structural formula: 【Chemical 318】 The compound according to claim 1, having the following characteristics.

78. Select the following structural formula: 【Chemical 319】 The compound according to claim 1, having the following characteristics.

79. Select the following structural formula: 【Chem.320】 The compound according to claim 1, having the following characteristics.

80. Select the following structural formula: 【Chemistry 321】 The compound according to claim 1, having the following characteristics.

81. Select the following structural formula: 【Chemistry 322】 The compound according to claim 1, having the following characteristics.

82. The following structural formula: 【Chemical 323】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

83. The following structural formula: 【Chemical 324】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

84. The following structural formula: 【Chemical 325】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

85. The following structural formula: 【Chemistry 326】 It has, In the formula, R is H, CD ３ , C １～３ The compound according to claim 1, wherein it is alkyl or acyl.

86. The following structural formula: 【Chemistry 327】 It has, In the formula, X ６ The compound according to claim 1, wherein the compound is N or CH.

87. Select the following structural formula: 【Chemical 328】 The compound according to claim 1, having the following characteristics.

88. Select the following structural formula: 【Chemistry 329】 The compound according to claim 1, having the following characteristics.

89. Select the following structural formula: 【Chemistry 330】 The compound according to claim 1, having the following characteristics.

90. Select the following structural formula: 【Chemistry 331】 The compound according to claim 1, having the following characteristics.

91. Select the following structural formula: 【Chemistry 332】 The compound according to claim 1, having the following characteristics.

92. The following structural formula: 【Chemical 333】 It has, In the formula, X ６ The compound according to claim 1, wherein the compound is N or CH.

93. The following structural formula: 【Chemistry 334】 It has, In the formula, X ６ The compound according to claim 1, wherein the compound is N or CH.

94. R ６ and R ７ The compound according to any one of claims 66 to 93, wherein if present, it is H.

95. R ９ However, if C exists, １～３ They are alkyl or cyclopropyl, each being C １～３ Alkoxy, CF ３ The compound according to any one of claims 1 to 94, which is optionally substituted with NRR'.

96. R ９ However, C １～３ The compound according to claim 95, wherein it is alkyl or cyclopropyl.

97. R ９ However, CH ３ The compound according to claim 96.

98. R ９ However, CD ３ The compound according to claim 96.

99. R ２ｂ However, there are 0 to 2 R ２ｃ C replaced by １ ~C ６ The compound according to any one of claims 66 to 98, wherein the compound is alkyl, cyclopropyl, or cyclobutyl.

100. R ２ｂ The compound according to claim 99, wherein the compound is cyclopropyl.

101. R ５ but, 【Chemistry 335】 And, During the ceremony, R ５’ However, C is substituted with 0 to 5 F's. １～３ Alkyl or cyclopropyl, R is H, C １～３ The compound according to any one of claims 66 to 100, wherein it is alkyl or acyl.

102. The compound according to claim 101, wherein R is H.

103. R is CH ３ The compound according to claim 101.

104. R is CD ３ The compound according to claim 101.

105. R ５ but, 【Chemistry 336】 And, During the ceremony, R ５’ However, C is substituted with 0 to 5 F's. １～３ Alkyl or cyclopropyl, R is H, C １～３ The compound according to any one of claims 66 to 100, wherein it is alkyl or acyl.

106. The compound according to claim 105, wherein R is H.

107. R is CH ３ The compound according to claim 105.

108. R is CD ３ The compound according to claim 105.

109. R ５’ However, CF ３ The compound according to any one of claims 101 to 108.

110. R ５’ However, CHF ２ The compound according to any one of claims 101 to 108.

111. R ５’ However, C is replaced by 2 to 5 Fs. ２～３ A compound according to any one of claims 101 to 108, wherein it is alkyl.

112. R １ However, CH ３ The compound according to any one of claims 66 to 111.

113. R １ However, CD ３ The compound according to any one of claims 66 to 111.

114. Structural formula (VIII): 【Chemistry 337】 A compound having or a pharmaceutically acceptable form or isotopic derivative thereof, During the ceremony, X ６ However, CR ６ or N, X ７ However, CR ７ or N, X ８ However, it is C or N, X ９ However, CR ９ O, S, N, or NR ９ And, X １０ However, CR １０ O, S, N, or NR １０ And, Y １ However, it is CH, CF, or N, Y ２ However, it is CH or N, Y ３ However, NR, O, CH ２ CD ２ CF ２ , or O-NH, Y ４ However, NR, CH ２ , or CF ２ And, Y ５ However, NR, CH ２ O, S, SO, or SO ２ And, m is 0, 1, 2, and 3. n is 0, 1, 2, and 3. p is 0, 1, 2, and 3, Each of rings A and B is independently an aryl or heteroaryl group. The ring C is a 5-membered or 6-membered aryl or heteroaryl group. R １ However, H, F, CD ３ , or C １～３ It is alkyl, however, Y ３ However, if N, O, or O-NH, then R １ It is not F, R ４ However, there are 0 to 5 R ４ａ C replaced by １～３ It is alkyl, and here, R ４ａ However, it is selected from D, F, and Cl, R ５ However, H, CN, Halo, OCH ３ , C(=O)OR, NHC(=O)R, NRR', NO ２ , C １～６ Alkyl, C ３～６ A cycloalkyl or heterocyclic ring, wherein the alkyl, cycloalkyl, or heterocyclic ring has 0 to 3 R atoms. ５ａ It is replaced by each R ５ａ However, OH, D, F, Cl, CN, CH ２ F, CHF ２ CF ３ , OCH ３ OCD ３ OCF ３ , and OC(=O)CH ３ Selected independently from, R ６ , R ７ , R ９ , R １０ , and R １１ Each of these is H, F, Cl, CN, CD ３ ,CH ２ CF ３ CF ３ , OR, NRR', C １～３ Alkyl and C ３～５ A cycloalkyl group is independently selected, where the alkyl, cycloalkyl, R, and R' are 0 to 2 R's. ２ａ It has been replaced with, R ２ａ However, F, OCF ３ CF ３ , CN, NO ２ , OR, NRR', and C １～６ Selected from alkyl groups, R and R' are independently H and C １ ~C ６ It is either alkyl or acyl, or R and R' together with the nitrogen or carbon atom to which they are bonded, O, NR, S, and SO ２ The compound or a pharmaceutically acceptable form thereof or an isotopic derivative thereof, forming a 3-6 membered ring containing 0-2 heteroatoms selected from the above.

115. Y １ However, it is CH and Y ２ The compound according to claim 114, wherein the compound is CH.

116. Y １ However, N is Y ２ The compound according to claim 114, wherein the compound is CH.

117. Y １ However, it is CH and Y ２ The compound according to claim 114, wherein N is present.

118. Y １ However, N is Y ２ The compound according to claim 114, wherein N is present.

119. Y ３ The compound according to any one of claims 114 to 118, wherein the compound is NH.

120. Y ３ The compound according to any one of claims 114 to 118, wherein the compound is O.

121. Y ３ However, CH ２ The compound according to any one of claims 114 to 118.

122. Y ３ However, CD ２ The compound according to any one of claims 114 to 118.

123. Y ４ The compound according to any one of claims 114 to 122, wherein the compound is NH.

124. Y ４ However, CH ２ The compound according to any one of claims 114 to 122.

125. R １ However, CH ３ The compound according to any one of claims 114 to 122.

126. R １ However, CD ３ The compound according to any one of claims 114 to 122.

127. R ４ However, CH ３ The compound according to any one of claims 114 to 126.

128. R ４ However, CD ３ The compound according to any one of claims 114 to 126.

129. A compound selected from Table 1, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

130. A pharmaceutical composition comprising a compound according to any one of claims 1 to 129, effective for treating or reducing one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

131. The pharmaceutical composition according to claim 130, which is suitable for oral administration.

132. The pharmaceutical composition according to claim 130, which is suitable for topical administration.

133. The pharmaceutical composition according to claim 130, which is suitable for localized administration of GI.

134. A pharmaceutical composition according to any one of claims 130 to 133, useful for treating or reducing one or more of inflammatory diseases, immune-mediated diseases, and cancer or related diseases or disorders.

135. The pharmaceutical composition according to claim 134, wherein the disease or disorder is an inflammatory disease.

136. The pharmaceutical composition according to claim 134, wherein the disease or disorder is an immune-mediated disease.

137. The pharmaceutical composition according to claim 134, wherein the disease or disorder is a neuroinflammatory disease.

138. The pharmaceutical composition according to claim 134, wherein the disease or disorder is cancer.

139. The pharmaceutical composition according to claim 134, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes mellitus, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-related kidney injury, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia eugenics (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

140. A unit dosage form comprising the pharmaceutical composition according to any one of claims 130 to 139.

141. The unit dosage form according to claim 140, which is a tablet.

142. The unit dosage form according to claim 140, which is a capsule.

143. The unit dosage form according to claim 140, which is a topical preparation.

144. A method for treating, reducing or preventing a disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 129 to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

145. The method according to claim 144, wherein the disease or disorder is an inflammatory disease.

146. The method according to claim 144, wherein the disease or disorder is an immune-mediated disease.

147. The method according to claim 144, wherein the disease or disorder is a neuroinflammatory disease.

148. The method according to claim 144, wherein the disease or disorder is cancer.

149. The method according to claim 144, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, ankylosing spondylitis (AS), vitiligo, atopic dermatitis, discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, Crohn's disease (CD), rheumatoid arthritis (RA), T-cell acute lymphoblastic leukemia (T-ALL), cutaneous T-cell lymphoma (CTCL), multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), type 1 diabetes mellitus, asthma, renal fibrosis, diabetic nephropathy, polycystic kidney disease, HIV-related kidney injury, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia eugenics (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

150. The method according to any one of claims 144 to 149, wherein the administration is by oral administration.

151. The method according to any one of claims 144 to 149, wherein the administration is by local administration.

152. The method according to any one of claims 144 to 149, wherein the administration is by localized administration of GI.

153. The use of a compound according to any one of claims 1 to 129, and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a drug for treating a disease or disorder.

154. The use according to claim 153, wherein the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases, and cancer.

155. The use according to claim 154, wherein the disease or disorder is an inflammatory disease.

156. The use according to claim 154, wherein the disease or disorder is an immune-mediated disease.

157. The use according to claim 154, wherein the disease or disorder is cancer.

158. The use according to any one of claims 153 to 157, wherein the drug is for oral administration.

159. The use according to any one of claims 153 to 157, wherein the drug is for local administration.

160. The use according to any one of claims 153 to 157, wherein the drug is for localized administration to the GI.

161. A method for preparing the compound according to any one of claims 1 to 129.

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