TYK2 inhibitors, their compositions, and methods

Abstract

The present invention provides a novel class of therapeutic agents that are safe and effective TYK2 inhibitors for various TYK2-mediated diseases and disorders, pharmaceutical compositions of these compounds, and methods for preparing and using them.

Description

[Technical Field]

[0001] (Priority claim and related patent applications)

[0002] This application claims priority to PCT / CN2023 / 100508, filed on 15 June 2023, the entirety of which is incorporated herein by reference for all purposes.

[0003] This invention relates, in general, to novel compounds and methods for their therapeutic use. More specifically, the invention provides a novel class of tyrosine kinase 2 inhibitors, as well as pharmaceutical compositions of these compounds, methods for their preparation, and methods for their use for various diseases and conditions. [Background technology]

[0004] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the Janus kinase-signaling and transcriptional activator (JAK-STAT) pathway. The human JAK family enzymes consist 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 regulates the function of JH1. (Non-patent document 1)

[0005] These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as the common gamma chain receptor and the glycoprotein 130 (gp130) transmembrane protein. (Non-Patent Literature 2) Approximately 40 cytokine receptors signal through combinations of these four JAKs and their downstream substrates, seven members of the STAT family. (Non-Patent Literature 3)

[0006] TYK2 is a key component of the JAK-STAT signaling pathway. TYK2 regulates INFα, IL12, and IL23. (Non-Patent Literature 4; Non-Patent Literature 5; Non-Patent Literature 6) Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, IFN-ζ) and interleukins (IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, pithyroid neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokines, and LIF). Activated TYK2 phosphorylates further signaling proteins, including members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. Selective inhibition of TYK2 can be used to treat various autoimmune inflammatory diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA), as well as cancer and diabetes.

[0007] Selectivity for other JAK family subtypes is considered important for enhancing intended pharmacological effects and reducing side effects. Identifying highly TYK2-selective kinase inhibitors has been a major challenge due to the high sequence homology of active sites among JAK family kinases. TYK2 specificity is important for the clinical application of TYK2 kinase inhibitors because Tyk2 knockout mice can survive with normal blood cell counts, while JAK3 deficiency causes severe combined immunodeficiency in mice, and JAK1 knockout or JAK2 knockout mice exhibit perinatal lethality. (Non-Patent Literature 7; Non-Patent Literature 8; Non-Patent Literature 9) Genetic evidence suggests that pharmacological inhibition of TYK2 should not cause acute toxicity in human patients, but careful monitoring for viral or tuberculosis infections may be necessary in patients receiving long-term treatment. (Non-Patent Literature 10) [Prior art documents] [Non-patent literature]

[0008] [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(1):273 - 287. [Non-Patent Document 4] Ihle, et al. 1995 Annu Rev Immunol. 13:369 - 398 [Non-Patent Document 5] Leonard, et al. 1998 Annu Rev Immunol. 16:293 - 322 [Non-Patent Document 6] Liu, et al. 1998 Curr Opin Immunol. 10:271 - 278. [Non-Patent Document 7] Ghoreschi, et al. 2009 Immunol Rev. 228:273 - 287 [Non-Patent Document 8] [[ID=^32]] Karaghiosoff, et al. 2000 Immunity. 13:549 - 560 [Non-Patent Document 9] Shimoda, et al. 2000 Immunity. 13:561 - 571. [Non-Patent Document 10] Akahane, et al. 2017 Br J Haematol. 177(2):271 - 282. [Summary of the Invention] [Problems to be Solved by the Invention]

[0009] There is an urgent need for TYK2 inhibitors with high selectivity, improved efficacy, and minimal side effects against other JAK family members in a broad therapeutic area, and problems remain.

Means for Solving the Problems

[0010] The present invention provides novel, highly selective, and potent compounds that can be administered orally. These therapeutic agents are safe and effective highly selective TYK2 inhibitors with reduced or lower 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.

[0011] In one aspect, the present invention generally relates to Structural Formula (I):

[0012]

Chemical Formula

[0013] In another embodiment, the present invention generally relates to structural formula (II):

[0014] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0015] In yet another embodiment, the present invention generally relates to structural formula (III):

[0016] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2is CH or N, Y 3 is NR, O, CH2, CF2 or O-NH, Y 4 is CH or N, R 41 is H, F, C1-C3 alkyl and CD3, provided that when Y 3 is NR, O or O-NH, R 41 is not F, R 42 is R 42’ (R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocycle, aryl and heteroaryl), an aryl group or heteroaryl group substituted with 0-2 R 42a each, or (C=O)R 42b , or (C=O)NHR 42b and R A and R B each is independently selected from H, D, halo, OR, and C 1-3 alkyl, provided that when both R A and R B are H, R C is not CH3 or F, R C is H, D, F, Cl, OR, C 42a alkyl substituted with 0-2 R 1-5 alkyl, C 3-5 cycloalkyl or heterocyclic group, each of R and R' is independently H or C1-C6 alkyl, C1-C6 acyl, or R and R' together with the nitrogen atom to which they are attached form a 4-7 membered ring containing 0-2 heteroatoms selected from O, NR, S and SO2, R 42aIn each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0017] In yet another embodiment, the present invention generally relates to structural formula (IV):

[0018] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not H or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0019] In yet another aspect, the present invention generally relates to structural formula (V):

[0020] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, (C=O)R 42b , or (C=O)NHR 42b And, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 46 This is a C1-C6 alkyl or C3-C6 cycloalkyl having H, CD3, 0-4 halogens, CN and OR. R 47C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group, R 48 [is H, halo, or C1-C3 alkyl] This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0021] In yet another aspect, the present invention relates generally to a method for preparing the compounds disclosed herein, as exemplified by the synthesis schemes and experimental procedures disclosed herein.

[0022] In yet another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0023] In yet another aspect, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0024] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (I):

[0025] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's.42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0026] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (II):

[0027] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0028] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (III):

[0029] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not CH3 or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42aC replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0030] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (IV):

[0031] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b, or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not H or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0032] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (V):

[0033] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, (C=O)R 42b , or (C=O)NHR 42b And, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 46 This is a C1-C6 alkyl or C3-C6 cycloalkyl having H, CD3, 0-4 halogens, CN and OR. R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group, R 48 [is H, halo, or C1-C3 alkyl] This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0034] In yet another aspect, the present invention relates in general to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders. definition

[0035] All technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art, unless otherwise defined. General principles of organic chemistry, and specific functional groups and reactivity, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 2006.

[0036] The following terms shall have the meanings set forth below, unless otherwise indicated by the context in which they are found.

[0037] The ranges provided herein are understood to be abbreviations for all values ​​within the 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.

[0038] As used herein, the term "at least" a particular value is understood to mean that value and all values ​​greater than that value.

[0039] As used herein, “more than one” 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.

[0040] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless otherwise explicitly indicated by the context.

[0041] Unless otherwise specified or the context makes clear, the term “about” as used herein is understood to mean within the normal range of acceptance in the art, e.g., within two standard deviations of the mean. “About” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise specified by the context, all numerical values ​​provided herein may be modified by the term “about.”

[0042] Unless otherwise specified or evident from the context, the term “or” as used herein is understood to be inclusive.

[0043] Any composition or method disclosed herein may be combined with one or more other compositions and methods provided herein.

[0044] In this specification, the enumeration of chemical groups in the definition of a variable part includes the definition of any single group or combination of the enumerated groups of that variable part. Details of embodiments of a variable part or aspect in this specification include that embodiment as a single embodiment or in combination with other embodiments or parts thereof.

[0045] The term "comprising," when used to define a composition and method, is intended to mean that the composition and method include the elements described but do not exclude other elements. The term "consisting essentially of," when used to define a composition and method, is intended to mean that the composition and method include the elements described but exclude other elements that have any essential significance to the composition and method. For example, "consisting essentially of" refers to the administration of an expressly described pharmacologically active agent, excluding pharmacologically active agents that are not expressly described. The term "consisting essentially of" does not exclude pharmacologically inactive or inactive agents, such as pharmaceutically acceptable excipients, carriers, and diluents. The term "consisting of," when used to define a composition and method, shall mean the exclusion of trace elements of other components and significant method steps. Embodiments defined by each of these transitional clauses are within the scope of the present invention.

[0046] Certain compounds of the present invention may exist in specific geometric forms or stereoisomers. The present invention considers all such compounds, including cis and trans isomers, atrop isomers, R-enantiomers and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, to be within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. The present invention is intended to include all such isomers, as well as mixtures thereof. In certain embodiments, each chiral atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess in either the R or S configuration. In the case of optically active compounds, it is often preferable to use only one enantiomer and substantially exclude the other enantiomer.

[0047] According to the present invention, isomer mixtures containing any of various isomer ratios may be used. For example, when combining only two isomers, mixtures containing 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 envisioned by the present invention. Those skilled in the art will readily understand that similar ratios can be considered for more complex isomer mixtures.

[0048] For example, if a specific enantiomer of the compound of the present invention is desired, it may be prepared by asymmetric synthesis or by induction with a chiral auxiliary group, in which case the resulting diastereomer mixture is separated and the auxiliary group is 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 is formed with a suitable optically active acid or base, and then the diastereomer thus formed is separated by fractional crystallization or chromatography, which are well known in the art, and then the pure enantiomer is recovered.

[0049] Mixtures of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of their components, for example, by chromatography and / or fractional crystallization.

[0050] Definitions of specific functional groups and chemical terms are explained in more detail below. When a range of values ​​is listed, it is intended that the range includes each value and its sub-ranges. For example, "C 1-6 "Alkyl" refers to 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 It is intended to include alkyl groups.

[0051] When substituents are specified in a conventional chemical formula written from left to right, they equally encompass chemically identical substituents that would result if the structure were written from right to left; for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0052] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Therefore, if a group can be substituted by one or more substituents, such substitutions are selected to give a compound that, according to the principles of chemical bonding, is not inherently unstable and / or is likely to be unstable under ambient conditions (e.g., aqueous, neutral, and some known physiological conditions), as is known to those skilled in the art.

[0053] Solvates and polymorphs of the compounds of the present invention are also envisioned in the present invention. Examples of solvates of the compounds of the present invention include hydrates.

[0054] As used herein, the term "alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, unsaturated, and having 1 to 10 carbon atoms (e.g., C 1-10 Alkyl). Whenever a numerical range such as "1 to 10" is used herein, it always refers to each integer within the specified range, 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 covers the use of the term "alkyl" when 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. Typical saturated linear alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl. On the other hand, 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, 2,3-dimethylbutyl, etc. 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 independently include 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, 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 can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0055] As used herein, the term "alkoxy" refers to a molecule with 1 to 10 carbon atoms (C) bonded to the parent molecule structure via oxygen. 1-10 This refers to -O-alkyl groups including linear, branched, saturated cyclic structures and combinations thereof. Unless otherwise specified herein, this term includes 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 include 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, each R aThese are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which may be optionally substituted as defined herein.

[0056] As used herein, the terms “aromatic” or “aryl” refer to 6 to 14 ring atoms (e.g., C) having at least one ring (e.g., phenyl, fluorenyl, naphthyl) that is a conjugated pi-electron system that is a carbocyclic group. 6-14 Aromatic or C 6-14 This refers to a radical having an aryl group. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted aryl groups. In some embodiments, the aryl group is C 6-10These are aryl groups. For example, a divalent radical formed from a substituted benzene derivative and having free valence on the ring atom is called a substituted phenylene radical. In other embodiments, divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in "-yl" by removing one hydrogen atom from a carbon atom with free valence are named by adding "-idene" to the name of the corresponding monovalent radical; for example, a naphthyl group with two bond sites is called naphthylidene. Whenever numerical ranges such as "6 to 14 aryls" are used herein, they refer to each integer within the specified range; for example, "6 to 14 ring atoms" means that an aryl group can consist of up to 14 ring atoms, such as 6 ring atoms or 7 ring atoms. This term includes monocyclic or fused polycyclic (i.e., rings sharing pairs of adjacent ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and others. In polycyclic groups, only one ring needs to be aromatic; therefore, groups such as indanyl are included in 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 moiety may be optionally substituted with one or more substituents, which may independently include 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(Ra )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, each R a These are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which may be optionally substituted as defined herein.

[0057] 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 are called “cycloalkenyl” if they contain at least one double bond in the carbocyclic ring, and “cycloalkynyl” if they contain at least one triple bond in the carbocyclic ring. Cycloalkyl groups are groups having 3 to 13 ring atoms (i.e., C 3-13This term includes cycloalkyl groups. Unless otherwise specified herein, this term is intended to include both substituted and unsubstituted cycloalkyl groups. Whenever numerical ranges such as "3 to 10" are used herein, each integer within the specified range refers to a group, for example, "3 to 13 carbon atoms" means that a cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., and may contain up to 13 carbon atoms. The term "cycloalkyl" also includes bridging cyclic and spiro-fused cyclic structures that do not contain heteroatoms. This term also includes monocyclic or fused polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, and so on. In some embodiments, "cycloalkyl" means C 3-8 It may be a cycloalkyl radical. In some embodiments, "cycloalkyl" is C 3-5 It may be a cycloalkyl radical. Specific examples of cycloalkyl groups, though not limited to them, 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 Examples of carbocyclyl groups include the aforementioned C 3-7 In addition to the carbocyclyl group, other examples include cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrielinyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl. 3-13 Examples of carbocyclyl groups include the aforementioned C 3-8In addition to the carbocyclyl group, other examples include octahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, etc. 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, each R aThese are independently hydrogen, alkyl, haloalkyl, carbocyl, carbocylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which may be optionally substituted as defined herein. The terms “cycloalkenyl” and “cycloalkynyl” reflect the above description of “cycloalkyl,” where the prefix “alk” is replaced with “alken” or “alkyn,” respectively, and the parent terms “alkenyl” or “alkynyl” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group may have 5 to 13 ring atoms.

[0058] 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” include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, where the halo is fluorine, and includes, but is 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 further optionally substituted as defined herein.

[0059] As used herein, the term “heteroatom” refers to oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0060] As used herein, the term “heteroalkyl” refers to an alkyl group 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 include both substituted and unsubstituted heteroalkyl groups. A numerical range may also be specified, for example, C 1-4 A heteroalkyl group refers to the total chain length, which in this example is the length of four atoms. For example, the -CH2OCH2CH3 radical is called a "C4" heteroalkyl group, and the description of its atomic chain length includes the heteroatom center. The connection to the parent molecular structure may be via either a heteroatom or carbon in the heteroalkyl chain. For example, a nitrogen-containing heteroalkyl moiety 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 can be optionally oxidized. One or more nitrogen atoms can also be optionally quaternized, if present. 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)).

[0061] 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 include both substituted and unsubstituted heterocycloalkyl groups. Specific 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, 3,4-dihydro-2H-[1,4]oxazine, etc.

[0062] As used herein, the terms “heteroaryl” or “heteroaromatic” refer 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 arrangement) radical having a ring carbon atom and 1 to 6 ring heteroatoms provided to the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). Unless otherwise stated herein, this term is intended to include both substituted and unsubstituted heteroaryl groups. A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or both rings. Whenever numerical ranges such as “5-18” are used herein, they refer to each integer within the specified range; for example, “5-18 ring atoms” means that a heteroaryl group can consist of up to 18 ring atoms, such as 5 ring atoms, 6 ring atoms, and so on. In some examples, heteroaryls can 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 having free valence, and the divalent radicals are named by adding "-ene" to the name of the corresponding monovalent radical, for example, a pyridyl group having two bond sites is pyridylene.

[0063] For example, a nitrogen-containing "heteroaromatic" 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 radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally 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).

[0064] "Heteroaryl" also includes a ring system in which the heteroaryl ring defined above is fused with one or more aryl groups, and the bond site to the parent molecule structure is either on the aryl ring or the heteroaryl ring, or a ring system in which the heteroaryl ring defined above is fused with one or more cycloalkyl or heterocyclyl groups, and the bond site to the parent molecule structure is on the heteroaryl ring. In the case of polycyclic heteroaryl groups that do not contain heteroatoms in one ring (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site to the parent molecule structure can be on either ring, i.e., the ring with heteroatoms (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, 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 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0065] Examples of heteroaryls 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, and benzofuranil. Nyl, benzopyranonil, benzoflazanil, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinil, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinil, carbazolyl, sinnolinil, cyclopenta[d]pyrimidinil, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinil, 5,6-dihydrobenzo[h]quinazolinil, 5,6-dihydrobenzo[h]sinnolinil, 6,7-dihydro-5H Benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranil, dibenzothiophenyl, furanil, furazanil, furanonil, furo[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, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl Lu, 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]thieno[2,3 Examples include, but are not limited to, [-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]pyrimidinyl, 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(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, each R a These are independently hydrogen, alkyl, haloalkyl, carbocykyl, carbocykylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which may be optionally substituted as defined herein.

[0066] As used herein, the term “administer” refers to oral administration, suppository administration, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, intrathecal, intracranial, intranasal, or subcutaneous administration, or implantation of a sustained-release device to the target, such as a mini osmotic pump. The preferred route of administration for a particular patient will vary depending 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.

[0067] Administration may be carried out by any preferred route, including parenteral and transmucosal (such as buccal, sublingual, palate, gingival, nasal cavity, vagina, rectum, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous injection, and transdermal patches.

[0068] "Concurrent administration" means that the compositions described herein are administered concurrently with, immediately before, or immediately after the administration of one or more additional therapeutic agents.

[0069] The compounds of the present invention may be administered to patients alone or concurrently. Concurrent administration means concurrent or consecutive administration of the compounds individually or in combination (two or more compounds or drugs). Therefore, the formulations may be combined with other active substances as needed (for example, to reduce metabolic degradation).

[0070] The compositions of the present invention can be formulated as application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and can be delivered transdermally via local routes. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, and suspensions suitable for ingestion by patients. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, emulsions, gels, such as aqueous solutions or water / propylene glycol solutions.

[0071] The compositions of the present invention may further contain components for providing 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 further detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference for any purpose. The compositions of the present invention can also be delivered as microspheres that are slowly released in the body. For example, microspheres can be administered by intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, 1995 J. Biomator Sci. Polym. Ed. 7:623-645; as a biodegradable, 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).

[0072] As used herein, the terms “disease,” “condition,” and “disorder” are interchangeable herein and refer to the state of existence or health condition of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0073] As used herein, the term “effective amount” of an activator refers to an amount sufficient to produce a desired biological response. As those skilled in the art will understand, the effective amount 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 method of administration, and the patient.

[0074] As used herein, terms such as “inhibition,” “inhibit,” and “inhibiting” in relation to biological target (e.g., TYK2) inhibitor interactions mean adversely affecting (e.g., reducing) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means adversely affecting (e.g., reducing) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition means mitigation of a disease or symptoms of a disease. In embodiments, inhibition means a decrease in the activity of a particular protein target. Inhibition may include, at least in part, 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 decrease in the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binding to the target protein). In this embodiment, inhibition refers to a decrease in the activity of the target protein due to an indirect interaction (for example, the inhibitor binds to a protein that activates the target protein, thereby preventing the activation of the target protein).

[0075] As used herein, the terms “isolated” or “purified” refer to materials that are substantially or essentially devoid of components normally present in their original state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0076] As used herein, the term “modulate” means directly or indirectly producing an increase or decrease, stimulation, inhibition, interference, or blockage of a measured activity compared to a preferred control. A “modulator” of a polypeptide or polynucleotide means a substance that affects, for example, increases, decreases, stimulates, inhibits, interferes with, or blocks the measured activity of a polypeptide or polynucleotide compared to a preferred control. For example, a “modulator” may bind to a target with measurable affinity and / or activate or inhibit the target, or directly or indirectly affect the normal regulation of receptor activity.

[0077] When 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 of the compound thereof. In some embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives of the compound thereof.

[0078] In certain embodiments, a pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with the target tissue without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with 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 salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or salts of amino groups formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. Examples include sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivaphosphates, propions, stearates, succinates, sulfates, tartrates, p-toluenesulfonates, undecanoates, and valersates.In some embodiments, organic acids that can be used to derive salts 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.

[0079] Salts may be prepared in situ during the isolation and purification of the disclosed compounds, or they may be prepared separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Examples of pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Examples include alkyl)4 salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Furthermore, 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 sulfonates, and aryl sulfonates. Examples of organic bases that can derive salts include primary amines, secondary amines, 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 can be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0080] 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 bound 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 molecules or water molecules. As used herein, the term “compound” will be understood to include the compound, the solvate of the compound, and mixtures thereof.

[0081] 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 a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug is inactive when administered to a subject but can be converted in vivo to an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by increasing absorption into the blood after oral administration) or can enhance delivery to a biological compartment of a subject (e.g., the brain or lymphatic system) compared to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound that have improved water solubility or active transport across the enteric membrane compared to the parent compound.

[0082] Prodrug compounds often offer advantages such as solubility, histocompatibility, or delayed release in mammals (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are found 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.

[0083] 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 commonly known in the art include, for example, 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 that react to form acylated base derivatives. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. Thus, those skilled in the art will understand that some of the compounds disclosed herein having a free amino group, amide group, hydroxyl group, or carboxyl group can 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.

[0084] Examples of the advantages of prodrugs include, but are not limited to, physical properties such as improved water solubility for parenteral administration at physiological pH compared to the parent compound, potentially improved absorption from the gastrointestinal tract, or potentially improved drug stability for long-term storage.

[0085] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in transporting or delivering the drug of interest from one organ or part of body to another. 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 materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as 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. The composition may also contain 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, fragrances, preservatives, and antioxidants.

[0086] 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, and rodents. Subjects for which administration is envisioned include humans (e.g., men or women of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or other non-human animals, including but not limited to non-human mammals (e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, cats, and / or dogs, and other commercially relevant mammals), and 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 stage of development. The non-human animal may be a transgenic animal. Generally, the terms “subject” and “patient” are used interchangeably herein with respect to human subjects.

[0087] As used herein, the terms “treatment” or “treating” a disease or disorder mean a method of reducing, delaying, or improving such a condition before or after it has occurred. Treatment may target one or more effects or symptoms of a disease and / or underlying condition. Treatment may be any reduction and may be the complete elimination of the disease or its symptoms. Therefore, treating or treating means any sign of success in treating or improving an injury, disease, condition or state, including objective or subjective parameters such as reduction, remission, symptom reduction, or making the injury, condition or state more tolerable to the patient, slowing the rate of degeneration or debilitation, mitigating debilitation in the final stages of degeneration, or improving the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters such as, for example, the results of a physical examination, neuropsychiatric examination, and / or 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%, as measured by any standard technique.

[0088] The treatment method involves administering a therapeutically effective amount of the compound described herein to a target. The administration step may be a single dose or may include a series of doses. The length of the treatment period will vary depending 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 for treatment, or a combination thereof. It will also be understood that the effective dose of the drug used for treatment may increase or decrease during the course of a particular treatment plan. Changes in dosage may be derived from and revealed by standard diagnostic assays known in the art. In some cases, long-term administration may be necessary. For example, the composition is administered to the target in an amount and for a duration sufficient to treat the patient. [Modes for carrying out the invention]

[0089] 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. These compounds are orally administered and have fewer and / or less side effects than currently available drugs.

[0090] The novel class of TYK2 inhibitors disclosed herein exhibits superior efficacy profiles and is useful for the treatment of one or more TYK2-mediated diseases and conditions, including allergic, autoimmune, inflammatory, metabolic, neurological, and proliferative diseases and conditions. While we do not wish to be bound by theory, the compounds of the present invention are regulators of interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-α) by inhibiting TYK2-mediated signaling.

[0091] These compounds are designed to exhibit good oral absorption and good in vivo stability, and to exert excellent efficacy against TYK2. 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 preferred pharmacokinetic profiles and pharmacokinetic properties suitable for their targeted indications.

[0092] In one embodiment, the present invention generally relates to structural formula (I):

[0093] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH,41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42cIn each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0094] In a specific embodiment of (I), Y 4 It is CH, and the compound has the structure:

[0095] [ka] It holds.

[0096] (I a In a specific embodiment of ), Y 1 CH is Y 2 It is CH, and its structure:

[0097] [ka] It holds.

[0098] (I a In a specific embodiment of ), Y 1 N is Y 2 It is CH, and its structure:

[0099] [ka] It holds.

[0100] (I a In a specific embodiment of ), Y1 CH is Y 2 It is N, and the structure:

[0101] [ka] It holds.

[0102] (I a In a specific embodiment of ), Y 1 N is Y 2 It is N, and the structure:

[0103] [ka] It holds.

[0104] In a specific embodiment of (I), Y 4 It is N, and the structure:

[0105] [ka] It holds.

[0106] (I f In a specific embodiment of ), Y 1 CH is Y 2 It is CH, and its structure:

[0107] [ka] It holds.

[0108] (I f In a specific embodiment of ), Y 1 N is Y 2 It is CH, and its structure:

[0109] [ka] It holds.

[0110] (If In a specific embodiment of ), Y 1 CH is Y 2 It is N, and the structure:

[0111] [ka] It holds.

[0112] (I f In a specific embodiment of ), Y 1 N is Y 2 It is N, and the structure:

[0113] [ka] It holds.

[0114] (I)~(I j In a specific embodiment of ), R A H is R B H is H.

[0115] (I)~(I j In a specific embodiment of ), R C This is CH3.

[0116] (I)~(I j In a specific embodiment of ), R C It is not CH3.

[0117] In another embodiment, the present invention generally relates to structural formula (II):

[0118] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0119] In a specific embodiment of (II), Y 4 It is CH, and its structure:

[0120] [ka] It holds.

[0121] (II a In a specific embodiment of ), Y 1 CH is Y 2 It is CH, and its structure:

[0122] [ka] It holds.

[0123] (II a In a specific embodiment of ), Y 1 CH is Y 2 It is N, and the structure:

[0124] [ka] It holds.

[0125] (II a In a specific embodiment of ), Y 1 N is Y 2 It is CH, and its structure:

[0126] [ka] It holds.

[0127] (II a In a specific embodiment of ), Y 1 N is Y 2 It is N, and the structure:

[0128] [ka] It holds.

[0129] In a specific embodiment of (II), Y 4 It is N, and the structure:

[0130] [ka] It holds.

[0131] (II f In a specific embodiment of ), Y 1 CH is Y 2 It is CH, and its structure:

[0132] [ka] It holds.

[0133] (II f In a specific embodiment of ), Y 1 N is Y 2 It is CH, and its structure:

[0134] [ka] It holds.

[0135] (II f In a specific embodiment of ), Y 1 CH is Y 2 It is N, and the structure:

[0136] [ka] It holds.

[0137] (II f In a specific embodiment of ), Y 1 N is Y 2 It is N, and the structure:

[0138] [ka] It holds.

[0139] (II)~(II j In a specific embodiment of ), R A H is R B H is H.

[0140] (II)~(II j In a specific embodiment of ), R C This is CH3.

[0141] (II)~(II j In a specific embodiment of ), R C It is not CH3.

[0142] In yet another embodiment, the present invention generally relates to structural formula (III):

[0143] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not CH3 or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42aIn each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0144] In a specific embodiment of (III), Y 1 CH is Y 2 It is CH, and its structure:

[0145] [ka] It holds.

[0146] In a specific embodiment of (III), Y 1 CH is Y 2 It is N, and the structure:

[0147] [ka] It holds.

[0148] In a specific embodiment of (III), Y 1 N is Y 2 It is CH, and its structure:

[0149] [ka] It holds.

[0150] In a specific embodiment of (III), Y 1 N is Y 2 It is N, and the structure:

[0151] [ka] It holds.

[0152] (III)~(III d In a specific embodiment of ), R A H is R B H is H.

[0153] (III)~(III d In a specific embodiment of ), R A and R B One of them is not H.

[0154] (III)~(III d In a specific embodiment of ), R C It is not CH3.

[0155] In yet another embodiment, the present invention generally relates to structural formula (IV):

[0156] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not H or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2)n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0157] In a specific embodiment of (IV), Y 1 CH is Y 2 It is CH, and its structure:

[0158] [ka] It holds.

[0159] In a specific embodiment of (IV), Y 1 N is Y 2 It is CH, and its structure:

[0160] [ka] It holds.

[0161] In a specific embodiment of (IV), Y 1 CH is Y 2 It is N, and the structure:

[0162] [ka] It holds.

[0163] In a specific embodiment of (IV), Y 1 N is Y 2 It is N, and the structure:

[0164] [ka] It holds.

[0165] (IV)~(IV d In a specific embodiment of ), R A H is R B H is H.

[0166] (IV)~(IV d In a specific embodiment of ), R C This is CH3.

[0167] (IV)~(IV d In a specific embodiment of ), R C It is not CH3.

[0168] In yet another aspect, the present invention generally relates to structural formula (V):

[0169] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, (C=O)R 42b , or (C=O)NHR 42b And, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 46 This is a C1-C6 alkyl or C3-C6 cycloalkyl having H, CD3, 0-4 halogens, CN and OR. R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group, R 48 [is H, halo, or C1-C3 alkyl] This relates to compounds having [a certain characteristic], or to pharmaceutically acceptable forms or isotopic derivatives thereof.

[0170] In a specific embodiment of (V), Y 1 CH is Y 2 It is CH, and its structure:

[0171] [ka] It holds.

[0172] In a specific embodiment of (V), Y 1 N is Y 2 It is CH, and its structure:

[0173] [ka] It holds.

[0174] In a specific embodiment of (V), Y 1 CH is Y 2 It is N, and the structure:

[0175] [ka] It holds.

[0176] In a specific embodiment of (V), Y 1 N is Y 2It is N, and the structure:

[0177] [ka] It holds.

[0178] In a specific embodiment of (V), the compound has the structure:

[0179] [ka] [In the formula, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It has a cycloalkyl or heterocyclic group.

[0180] (V)~(V e In a specific embodiment of ), Y 4 It is CH.

[0181] (V)~(V e In a specific embodiment of ), Y 4 It is N.

[0182] (V)~(V e In a specific embodiment of ), R 48 H is H.

[0183] (V)~(V e In a specific embodiment of ), R 48 It is a halo.

[0184] (V e In a specific embodiment of ), R A H is R B H is H.

[0185] (Ve In a specific embodiment of ), R C This is CH3.

[0186] (V e In a specific embodiment of ), R C It is not CH3.

[0187] (I)~(V e In a specific embodiment of ), R 47 These are C1-C3 alkoxy compounds.

[0188] (I)~(V e In a specific embodiment of ), R 47 This is OCH3.

[0189] (I)~(V e In a specific embodiment of ), R 47 This is OCD3.

[0190] (I)~(V e In a specific embodiment of ), Y 3 It is NR.

[0191] (I)~(V e In a specific embodiment of ), Y 3 It is NH.

[0192] (I)~(V e In a specific embodiment of ), Y 3 It is O.

[0193] (I)~(V e In a specific embodiment of ), Y 3 It is O-NH.

[0194] (I)~(V e In a specific embodiment of ), R 41 This is CH3.

[0195] (I)~(V e In a specific embodiment of ), R 41 This is CD3.

[0196] (I)~(V e In a specific embodiment of ), R 42 R 42’ That is the case.

[0197] (I)~(V e In a specific embodiment of ), R 42 is (C=O)R 42b And R 42b This is 0 to 2 R 42c Selected from C1-C6 alkyl, cyclopropyl, or cyclobutyl substituted with .

[0198] In a particular embodiment, R 42 is (C=O)R 42b And R 42b This is a cyclopropyl compound optionally substituted with one or more of F, Cl, CH3, CF3, and CN.

[0199] In a particular embodiment, R 42 is (C=O)R 42b And R 42b This is a bisspirocyclopropyl compound optionally substituted with one or more of F, Cl, CH3, CF3, and CN.

[0200] In a particular embodiment, R 42 is (C=O)R 42b And R 42b This is cyclobutyl in which one or more of F, Cl, CH3, CF3, and CN are optionally substituted.

[0201] In a particular embodiment, R 42 is (C=O)R 42b And R 42b This is a C1-C6 alkyl group that is optionally substituted with one or more of F, Cl, CH3, CF3, CN, NRR', and OR.

[0202] (I)~(V e In a specific embodiment of ), R 42 (C=O)NHR 42band R 42b is selected from C1-C6 alkyl, cyclopropyl or cyclobutyl substituted with 0 to 2 R 42c .

[0203] (I) to (V e ) In certain embodiments, R 42 is phenyl substituted with 0 to 2 R 42c .

[0204] (I) to (V e ) In certain embodiments, R 42 is pyridinyl substituted with 0 to 2 R 42c .

[0205] (I) to (V e ) In certain embodiments, R 42 is pyrazolyl substituted with 0 to 2 R 42c .

[0206] (I) to (V e ) In certain embodiments, R 42 is pyrimidyl substituted with 0 to 2 R 42c .

[0207] In certain embodiments, R 42c is CH3 or CD3.

[0208] In certain embodiments, R 42c is F.

[0209] Non-limiting examples of the compounds of the present invention include the compounds listed in Table 1A in the Examples section of this specification, or pharmaceutically acceptable forms or isotope derivatives thereof.

[0210] In certain embodiments, the compound of the present invention is selected from the compounds listed in Table 1B, or pharmaceutically acceptable forms or isotope derivatives thereof.

[0211]

Table 1-1

[0212] [Table 1-2]

[0213] In yet another aspect, the present invention relates generally to a method for preparing the compounds disclosed herein, as exemplified by the synthesis schemes and experimental procedures disclosed herein.

[0214] In yet another aspect, the present invention generally relates to a pharmaceutical composition comprising a compound disclosed herein that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0215] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0216] In certain embodiments, the pharmaceutical composition is suitable for topical administration.

[0217] In certain embodiments, the pharmaceutical composition is suitable for gastrointestinal-restricted (GI-restricted) administration.

[0218] In certain embodiments, the pharmaceutical composition is useful for treating or alleviating one or more of the following conditions: inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders.

[0219] In certain embodiments, the disease or disorder is an inflammatory disease.

[0220] In certain embodiments, the disease or disorder is an immune-mediated disease.

[0221] In certain embodiments, the disease or disorder is cancer.

[0222] In certain embodiments, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0223] In yet another aspect, the present invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0224] In certain embodiments, the unit dosage form is a tablet.

[0225] In certain embodiments, the unit dosage form is a capsule.

[0226] In certain embodiments, the unit dosage form is a topical formulation.

[0227] In yet another aspect, the present invention generally relates to a method for treating, alleviating or preventing a disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of Structural Formula (I):

[0228] [wherein, [wherein, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2, CF2 or O-NH, Y 4 is CH or N, R 41 is H, F, C1-C3 alkyl and CD3, provided that when Y 3 is NR, O or O-NH, R 41 is not F, R 42 is R 42’ (R 42’These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0229] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (II):

[0230] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R42a an aryl or heteroaryl group substituted with, or (C=O)R 42b or (C=O)NHR 42b and R A and R B each independently is selected from H, D, halo, OR, and C 1-3 alkyl, R C is H, D, F, Cl, OR, C 42a alkyl substituted with 0 to 2 R 1-5 alkyl, C 3-5 cycloalkyl or heterocyclic group, each of R and R' independently is H or C1-C6 alkyl, C1-C6 acyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0 to 2 heteroatoms selected from O, NR, S, and SO2, R 42a is independently at each occurrence D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, R 42b each is C 42c alkyl or C 1-6 substituted with 0 to 2 R 3-6 alkyl or C 5-7 spirocycloalkyl, aryl or heteroaryl, R 42c is independently at each occurrence halo, CN, OR, NRR', OCF3, CF3, C 42a alkyl substituted with 0 to 3 R 1-6 alkyl, C 1-6 haloalkyl, C 42a alkenyl substituted with 0 to 3 R 2-6 alkynyl substituted with 0 to 3 R 42a alkyl, C 2-6 alkynyl, R 47C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method 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 relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (III):

[0232] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, RA and R B Each of these is independently H, D, Halo, OR, and C 1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not CH3 or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0233] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (IV):

[0234] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, or (C=O)R 42b , or (C=O)NHR 42b And, R A and R B Each of these is independently H, D, Halo, OR, and C1-3 Selected from alkyl groups, however R A and R B If both are H, then R C It is not H or F, R C These are H, D, F, Cl, OR, and 0 to 2 R 42a C replaced by 1-5 Alkyl, C 3-5 It is a cycloalkyl or heterocyclic group, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0235] In yet another aspect, the present invention relates to a method for treating, alleviating or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (V):

[0236] [ka] [In the formula, Y 1 is CH, CF, or N, Y 2 is CH or N, Y 3 These are NR, O, CH2, CF2, or O-NH. Y 4 is CH or N, R 41 These are H, F, C1-C3 alkyl and CD3, but Y 3 If R is NR, O, or O-NH, 41 It is not F, R 42 teeth, R 42’ (R 42’ These are C1-C6 alkyl, C3-C6 cycloalkyl, or heterocycloalkyl compounds, each substituted with 0-2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl atoms. Each has 0 to 2 R 42a A substituted aryl group or heteroaryl group, (C=O)R 42b , or (C=O)NHR 42b And, Each of R and R' is independently H or a C1-C6 alkyl or C1-C6 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. R 42a In each occurrence, independently, D, Halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R 42b Each of these has 0 to 2 R 42c C replaced by 1-6 Alkyl or C 3-6 Cycloalkyl, C 5-7 It is a spirocycloalkyl, aryl, or heteroaryl, R 42c In each occurrence, independently, there are Halo, CN, OR, NRR', OCF3, CF3, and 0-3 R's. 42a C replaced by 1-6 Alkyl, C 1-6 Haloalkyl, 0-3 R 42a C replaced by 2-6 Alkenyl, 0-3 R 42a C replaced by 2-6 It is alkinyl, R 46 This is a C1-C6 alkyl or C3-C6 cycloalkyl having H, CD3, 0-4 halogens, CN and OR. R 47 C is optionally replaced by 1 to 3 D or halos. 1-3 It is an alkoxy group, R 48 [is H, halo, or C1-C3 alkyl] This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is a method selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans.

[0237] In certain embodiments, the disease or disorder is an inflammatory disease.

[0238] In certain embodiments, the disease or disorder is an immune-mediated disease.

[0239] In certain embodiments, the disease or disorder is cancer.

[0240] In certain embodiments, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer. In certain embodiments, administration is via oral administration. In certain embodiments, administration is via local administration. In certain embodiments, administration is carried out via gastrointestinal restriction.

[0241] In yet another aspect, the present invention relates in general to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders.

[0242] In certain embodiments of use, the disease or disorder is one or more of the following: inflammatory diseases, immune-mediated diseases, and cancer.

[0243] In a particular embodiment of use, the disease or disorder is an inflammatory disease.

[0244] In certain embodiments of use, the disease or disorder is an immune-mediated disease.

[0245] In a particular embodiment of use, the disease or disorder is cancer.

[0246] In certain embodiments of use, the pharmaceutical product is intended for oral administration.

[0247] In certain embodiments of use, the pharmaceutical product is intended for topical administration.

[0248] In certain embodiments of use, the pharmaceutical product is intended for gastrointestinal restriction (GI restriction) administration.

[0249] As discussed herein, the present invention envisions isotopic derivative compounds having one or more hydrogen atoms (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc.) substituted for a deuterium atom.

[0250] The term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, such as elevated inflammation levels compared to a control group, 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-onset 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 adenitis, 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 intertwined with other diseases, disorders, and conditions. For example, a non-exclusive list of inflammation-related diseases, disorders, and conditions that may 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.

[0251] The term "autoimmune disease" refers to a disease or condition in which the immune system of a subject exhibits an abnormal immune response to a substance that does not normally elicit an immune response in a healthy subject. 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, Eicardi-Goutier syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, and autoimmune autonomic dysfunction. autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, Autoimmune urticaria, axonal or neurogenic neuropathies, Barro's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic atypical neutrophilic dermatosis with lipoatrophy and hyperthermia. atypical neutrophilic dermatosis with lipodystrophy and elevated Temperature, Candle), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, scarring pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, Cushing's disease, demyelinating neuropathy, depression, dermatomyositis herpetiformis, Devic's disease (neuromyelitis optica), lupus discoid, Dressler's syndrome, dry eye syndrome DES (keratoconjunctivitis sicca), endometriosis, Acidophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrous 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 illness, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mullen's syndrome ulcer, Mucha-Haberman disease, multiple sclerosis (MS), myocarditis gravis Asthenia, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular pemphigoid, optic neuritis, circadian rhythm rheumatoid arthritis, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria p, Parry-Romberg syndrome, Personage-Turner syndrome, squamous cellulitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenosis encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), type I, type II, and type III autoimmune polyglandular syndromes. Group, polymyalgia polyrheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, psoriasis vulgaris, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, 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 autologous These include immune disorders, Stiff Person syndrome, infant-onset interferon-stimulating factor (STING)-associated vasculopathy (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.

[0252] The term "immune-mediated disease" refers to chronic inflammatory diseases sustained by antibody and cellular immunity. Examples of immune-mediated diseases include 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, dry eye syndrome (DES), and Sjögren's disease. Examples of conditions that may be considered invasive include, but are not limited to, Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, myasthenia gravis, chronic idiopathic demyelinating disease (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). Other conditions that may be considered invasive include, but are not limited to, 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).

[0253] 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, leukemia, and solid tumors such as lymphoma, T-ALL, large B-cell lymphoma, carcinoma, and sarcoma. 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 thyroid cancers, endocrine cancers, brain cancers, breast cancers, uterine cancers, colon cancers, head and neck cancers, liver cancers, kidney cancers, lung cancers, non-small cell lung cancers, melanomas, mesotheliomas, ovarian cancers, sarcomas, stomach cancers, uterine cancers, medulloblastomas, colorectal cancers, and pancreatic cancers. Other examples include penile cancer, skin cancer - non-melanoma, anal cancer, hepatobiliary cancer, esophageal and gastric cancer, uterine sarcoma, gastrointestinal stromal tumor, salivary gland cancer, peripheral nervous system cancer, soft tissue sarcoma, bone cancer, kidney cancer, myeloproliferative neoplasm, 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 platelet cancer. Examples include hypercalcemia, primary macroglobulinemia, primary brain tumors, cancer, malignant islet cell tumors, malignant carcinoid tumors, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine tumors, 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.

[0254] In certain embodiments of use, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0255] Isotope-labeled compounds are also within the scope of this disclosure. As used herein, the term “isotope-labeled compound” means a compound disclosed herein (including its pharmaceutically acceptable salts and prodrugs) in which one or more atoms are replaced with atoms having atomic masses or mass numbers different from those commonly found in nature, as described herein. Examples of isotopes that can be incorporated into the compounds disclosed herein include, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as Cl.

[0256] By isotope labeling the compounds disclosed herein, they 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 because they are easy to prepare and detect. Furthermore, Deuterium ( 2 Substitution with heavier isotopes such as H) can improve metabolic stability, for example, by extending the half-life in the body or reducing the required dose, thereby providing certain therapeutic benefits, and may therefore be preferable in some situations. The isotope-labeled compounds disclosed herein (including their pharmaceutically acceptable salts, esters, and prodrugs) can be prepared by any means known in the art.

[0257] Furthermore, hydrogen, which is normally abundant ( 1 Substituting H) with a heavier isotope such as deutherium can yield specific therapeutic benefits, for example, through improved absorption, distribution, metabolism, and / or excretion (ADME) properties, and can produce drugs with improved efficacy, safety, and / or tolerability. 12C 13 Substitution with C may also yield benefits. (See International Publications 2007 / 005643, 2007 / 005644, 2007 / 016361, and 2007 / 016431.)

[0258] Stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R enantiomers and S enantiomers) of the compounds disclosed herein, as well as racemates, diastereomers and other mixtures of such isomers, are within the scope of this disclosure.

[0259] The compounds of the present invention are preferably isolated and purified after their preparation to obtain a composition containing 95% or more by weight ("substantially pure"), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention have a purity of more than 99%. Solvates and polymorphs of the compounds of the present invention are also envisioned in the present invention. Examples of solvates of the compounds of the present invention include hydrates.

[0260] Any appropriate route of administration may be used, such as parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intraperitoneal, rectal, or oral administration. The most suitable method of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the therapy and the active ingredient used.

[0261] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds or derivatives thereof described herein may be used with at least one inert, conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (i) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (iii) humectants, such as glycerol; and (iv) disintegrants, such as agar and calcium carbonate. Potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) a dissolution retarder, 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 adsorbent, e.g., kaolin and bentonite, 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 contain a buffer. Similar types of solid compositions can also be used as fillers for soft-filled and hard-filled gelatin capsules with excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and others known in the art.

[0262] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may also contain water or other solvents, solubilizers, and inert diluents commonly used in the art, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, 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 also contain additional agents such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and fragrances.

[0263] The materials, compositions, and components disclosed herein may be used in the disclosed methods and compositions, used in combination with the disclosed methods and compositions, used in the preparation of the disclosed methods and compositions, or are products of the disclosed methods and compositions. Where combinations, subsets, interactions, groups, etc., of these materials are disclosed, it is understood that each of the various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, but each is specifically considered and described herein. For example, where a method is disclosed and described, and a number of modifications that can be made to a number of molecules included in the method are described, all combinations and permutations of the method, as well as possible modifications, are specifically assumed unless otherwise indicated. Similarly, these subsets or combinations are also specifically assumed and disclosed. This concept applies to all aspects of this disclosure, including but not limited to the steps of a method using the disclosed compositions. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed in a particular step of the disclosed method or in combination of steps of the method, and that each of such combinations or subsets of combinations should be considered specifically assumed and disclosed. [Examples]

[0264] The following embodiments are illustrative of the invention and are not limiting in any way. Abbreviation

[0265] [Table 2]

[0266] Typical preparative HPLC method: Flow rate and gradient may be modified.

[0267] An example method of preparative HPLC is shown below.

[0268] Method A: NH4HCO3: Column: Gilson2-Xbridge C18 19×150mm, 5μm; Mobile phase: 20%~60% CH3CN in water (0.1% NH4HCO3), flow rate: 15mL / min.

[0269] Method B: TFA: Column: Waters-Xbridge C18 10×190mm, 5μm, Mobile phase: 15%~40% CH3CN in water (0.1% TFA), Flow rate: 15mL / min.

[0270] 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.

[0271] Method D: HCOOH: Column: Waters SunFire® Prep C18 OBD™ (5 μm, 19 × 150 mm); Mobile phase: 18-38% CH3CN in water (0.1% formic acid), flow rate: 20 mL / min.

[0272] Method E: NH4HCO3: Column: Waters Xbridge® Prep C18 OBD™ (5 μm, 19 x 150 mm); Mobile phase: 20%-60% CH3CN in water (10 mM NH4HCO3), flow rate: 20 mL / min.

[0273] Method F:HCOOH: Column: Waters Atlantis T3 19×150mm, 5μm, Mobile phase: 16%~30% CH3CN in H2O (0.1% formic acid), Flow rate: 20mL / min.

[0274] Typical methods of chiral preparative HPLC: Method G: Gilson 281, Daicel Chiralpak IB N, 10μm 30×250mm; Mobile phase: Hexane / EtOH=60 / 40, flow rate: 25mL / min.

[0275] Method H: Gilson 281, Daicel Chiralpak IB N, 10μm 30×250mm; Mobile phase: Hexane / EtOH=50 / 50, flow rate: 25mL / min.

[0276] Typical analytical HPLC methods: Method 1: Analysis was performed using an Agilent 1200 series HPLC-6120MS. A UHPLC long gradient equivalent was used, with 5% to 95% acetonitrile in water (containing 0.02% NH4OAc), flow rate 1.5 mL / min, and run time 6.5 minutes. A Waters Xbridge C18 column (18.5 μm, 4.6 × 50 mm) was used at a temperature of 40°C.

[0277] Method 2: Analysis was performed using an Agilent 1200 series HPLC-6120MS. A UHPLC long gradient equivalent was used, with 5% to 95% acetonitrile in water (containing 0.1% trifluoroacetic acid), flow rate 1.5 mL / min, and run time 6.5 minutes. A Waters Xbridge C18 column (18.5 μm, 4.6 × 50 mm) was used at a temperature of 40°C.

[0278] Method 3: Analysis was performed using an Agilent 1260 series HPLC-6120MS. A UHPLC long gradient equivalent was used, with 5% to 95% acetonitrile in water (containing 0.02% NH4OAc), flow rate 0.5 mL / min, and run time 2.5 minutes. A diamonsil Plus C18 column (18.5 μm, 4.6 × 30 mm) was used at a temperature of 40°C.

[0279] Method 4: Analysis was performed using an Agilent 1260 series HPLC-6125C MS. An HPLC long gradient equivalent was used, with 20% to 100% acetonitrile in water (containing 0.1% formic acid), at a flow rate of 0.8 mL / min for a run time of 6 minutes. An Agilent ZORBAX SB-C18 column (1.8 μm, 2.1 × 50 mm) was used at a temperature of 30°C.

[0280] Method 5: Analysis was performed using a SHIMADZU 20A HPLC. An HPLC long gradient equivalent was used, with hexane / EtOH (60 / 40) and a flow rate of 1 mL / min for a run time of 20 minutes. A CHIRALPAK IB N-5 (5 μm, 4.6 × 250 mm) was used at a temperature of 30°C.

[0281] Method 6: Analysis was performed using a SHIMADZU 20A HPLC. An HPLC long gradient equivalent was used, with hexane / EtOH (50 / 50) and a flow rate of 1 mL / min for a run time of 20 minutes. A CHIRALPAK IB N-5 (5 μm, 4.6 × 250 mm) was used at a temperature of 30°C.

[0282] Intermediate A

[0283] [ka]

[0284] 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, yield 73%) as a white solid. LC-MS (ESI, method 4) t R =3.33 min, m / z(M+H) + =255.0.

[0285] Step 2. 4-Chloro-6-(cyclopropanecarboxamide)lithium nicotinate (A3) A solution of A2 (500 mg, 1.96 mmol) in MeOH (2 mL), THF (2 mL), and water (1 mL) was mixed with LiOH·H2O (165 mg, 3.93 mmol). 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.

[0286] Step 3. 4-Chloro-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide (Int.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 Â) 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 Int.A (300 mg, yield 60%) as a white solid. LC-MS (ESI, method 4) R =2.25 min, m / z(M+H) + = 257.1.

[0287] Intermediate B

[0288] [ka]

[0289] Step 1. 1,1,1-trifluoropropan-2-yl trifluoromethanesulfonic acid (Int.B) To a solution of B1 (1.24 g, 10.87 mmol) and pyridine (1.12 g, 14.13 mmol, 1.14 mL) in DCM (10 mL), trifluoromethanesulfonic anhydride (3.37 g, 11.96 mmol, 2.01 mL) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the filter cake was washed with DCM (17 mL) to obtain compound Int.B (27 mL, 10.87 mmol, 0.4 M in DCM, yield shown) as a solution, which was used directly in the next step.

[0290] Intermediate C

[0291] [ka]

[0292] Step 1. 2,2-difluoropropyl (Int.C) trifluoromethanesulfonic acid To a solution of C1 (1 g, 10.4 mmol) and triethylamine (1.5 g, 15.6 mmol) in DCM (15 mL), trifluoromethanesulfonic anhydride (4.4 g, 15.6 mmol) was added dropwise at -20°C. The reaction mixture was stirred at -20°C for 16 hours and then diluted with DCM (10 mL). The mixture was washed with ice water (10 mL). The separated organic layer was washed with 20% Na2CO3 aqueous solution (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain Int.C (2.3 g, yield 97%) as a black oil. 1 H NMR (400MHz, DMSO-d6) δ 5.08 (t, J = 13.6 Hz, 2H), 1.72 (t, J = 19.2 Hz, 3H).

[0293] Intermediate D

[0294] [ka]

[0295] Step 1. 6-Chloro-4-((4-methoxybenzyl)amino)nicotinate methyl(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, yield 87%) as an off-white solid. LC-MS (ESI, method 4) t R =4.18 min, m / z(M+H) + = 307.1.

[0296] 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.

[0297] Step 3. 4-amino-6-(cyclopropanecarboxamide)methyl nicotinate 2,2,2-trifluoroacetate (Int.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 Int.D (1.8 g, yield 87%, TFA salt) as an off-white solid. LC-MS (ESI, method 4) t R =1.28 min, m / z(M+H) + = 236.2.

[0298] Intermediate E

[0299] [ka]

[0300] Step 1. 2,4-Dichloro-N-(methyl-d3)pyrimidine-5-carboxamide (Int.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 at -78°C, followed by TEA (1.68 g, 16.55 mmol, 2.31 mL). After stirring at this temperature for 1 hour, the reaction was quenched with water (30 mL). The organic layer was separated and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA = 5 / 1) to obtain Int.E (1.38 g, yield 35%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 8.88 (s, 1H), 8.85 (s, 1H). LC-MS (ESI, Method 3) t R =0.80 min, m / z(M+H) + = 208.9.

[0301] Intermediate F

[0302] [ka]

[0303] Step 1. 4-Chloro-6-(cyclopropanecarboxamide)pyridazine-3-carboxylate methyl (F2) To a solution of F1 (500 mg, 2.4 mmol) and cyclopropanecarboxamide (408 mg, 4.8 mmol) in 1,4-dioxane (20 mL), Pd(OAc)2 (54 mg, 0.24 mmol), dppf (265 mg, 0.48 mmol), and K3PO4 (1.01 g, 4.8 mmol) were added, and the mixture was stirred at 90°C for 4 hours under an N2 atmosphere. The mixture was diluted with H2O (50 mL), extracted with siRNA (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain compound F2 (200 mg, yield 33%) as an off-white solid. LC-MS (ESI, method 4) t R =3.46 min, m / z(M+H) + = 270.1.

[0304] Step 2. 4-Chloro-6-(cyclopropanecarboxamide)pyridazine-3-carboxylate lithium (F3) To a solution of F2 (100 mg, 0.41 mmol) in MeOH (1 mL) and H2O (1 mL), LiOH·H2O (34 mg, 0.82 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain F3 (132 mg, crude product), which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R =1.44 min, m / z(M+H) + = 242.1.

[0305] Step 3. 4-Chloro-6-(cyclopropanecarboxamide)-N-(methyl-d3)pyridazine-3-carboxamide (Int.F) To a solution of F3 (132 mg, crude product) in DMF (1 mL), methane-d3-amine hydrochloride (58 mg, 0.82 mmol) and DIPEA (251 mg, 1.95 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Then, T3P (368 mg, 0.58 mmol, 50% in Â) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with H2O (50 mL), extracted with  (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to obtain compound Int.F (15 mg, yield 14%, produced in two steps) as an off-white solid. LC-MS (ESI, method 4) t R =2.24 min, m / z(M+H) + = 258.1.

[0306] intermediate G

[0307] [ka]

[0308] Step 1. N-(4-chloro-5-propionylpyridine-2-yl)cyclopropanecarboxamide (Int.G) A mixture of 1-(4,6-dichloropyridine-3-yl)propan-1-one (170 mg, 0.83 mmol, CAS 66525-49-1), cyclopropanecarboxamide (85 mg, 0.99 mmol), dppf (23 mg, 0.042 mmol), Pd(OAc)2 (19 mg, 0.042 mmol), and K3PO4 (265 mg, 1.25 mmol) in dioxane (3 mL) was stirred at 90°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (PE / EA = 3 / 1) to obtain Int.G (140 mg, yield 67%) as a white solid. 1H NMR(400MHz,CDCl3)δ 8.49(s,1H),8.34(s,1H),8.30(brs,1H),2.99(q,J=7.2Hz,2H),1.60-1 .53(m,1H),1.21(t,J=7.2Hz,3H),1.16-1.12(m,2H),0.98-0.93(m,2H).

[0309] Example 1

[0310] [ka]

[0311] Step 1. 2,4-Dichloro-3-methoxypyridine (1b) 2,2,6,6-tetramethylpiperidine (2.3 g, 16.72 mmol) was added at -78°C to a solution of n-BuLi (5.5 mL, 13.93 mmol, 2.5 M in THF) in THF (25 mL). The reaction mixture was stirred at -78°C for 15 minutes. Next, a solution of 1a (2.0 g, 13.93 mmol) in THF (25 mL) was added to the reaction mixture. The reaction mixture was stirred at -78°C for 4 hours. A solution of hexachloroethane (6.6 g, 27.86 mmol) in THF (50 mL) was added dropwise to the reactants, and the temperature was kept below -60°C. After stirring for a further 2 hours at -78°C, the reaction mixture was quenched with saturated NH4Cl (20 mL), diluted with water (40 mL), and extracted with ₹ (30 mL × 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA = 10 / 1) to obtain compound 1b (700 mg, yield 28%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 8.06 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H).

[0312] Step 2. 4,6-Dichloro-5-methoxynicotinaldehyde (1c) To a solution of n-BuLi (9.4 mL, 23.59 mmol, 2.5 M in THF) in THF (30 mL), compound 1b (2.8 g, 15.73 mmol) was added at -78°C. After stirring at -78°C for 30 minutes, anhydrous DMF (1.7 g, 23.59 mmol) was added to the reaction mixture at -78°C. After stirring at -78°C for 2 hours, the reaction was quenched with saturated NH4Cl (20 mL) and extracted with ₹ (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=5 / 1) to obtain compound 1c (2.0 g, yield 61%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 10.25 (s, 1H), 8.60 (s, 1H), 3.93 (s, 3H).

[0313] Step 3. 6-Chloro-7-methoxy-1H-pyrazolo[4,3-c]pyridine(1d) A mixture of 1c (1.5 g, 7.28 mmol) and hydrazine hydrate (3.6 g, 21.84 mmol, 30 wt% in water) in EtOH (20 mL) was stirred at 100°C for 8 hours. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain compound 1d (300 mg, yield 22%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 13.95 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 4.04 (s, 3H).

[0314] Step 4. 6-Chloro-7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine(1e) To a mixture of 1d (3g, 16.34 mmol) in DMF (50 mL), NaH (1.3g, 32.68 mmol, 60% of mineral oil) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and SEMCl (4g, 24.51 mmol) was added at 0°C. After stirring at 10°C for 1 hour, the reaction was quenched with H2O (50 mL) and extracted with siRNA (50 mL). The separated organic layer was washed with brine (50 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 1e (1.7g, yield 33%) as a yellow oil. LC-MS (ESI, method 3) t R =1.88 min, m / z(M+H) + =314.1.

[0315] Step 5. 7-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-6-amine(1f) 1e (1.7g, 5.42mmol), Pd2(dba)3 (248mg, 0.27mmol), BrettPhos (145mg, 0.27mmol), t A mixture of BuONa (780 mg, 8.12 mmol) and saturated NH3 / dioxane (20 mL) was stirred at 100°C for 12 hours under an N2 atmosphere. The mixture was cooled and concentrated. The residue was purified by preparative HPLC (Method A) to obtain 1f (550 mg, yield 34%) as a white solid. LC-MS (ESI, Method 3) t R =1.69 min, m / z(M+H) + = 295.2.

[0316] Step 6. 6-Chloro-4-((7-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide (1g) To a solution of 1f (500 mg, 1.70 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (389 mg, 1.87 mmol) in THF (5 mL), LiHMDS (6.79 mL, 6.79 mmol, 1 M in THF) was added at -10°C. The reaction mixture was stirred at -10°C to room temperature for 1 hour and quenched with ice water (20 mL). The resulting mixture was extracted with Âxa (30 mL x 2), and the combined organic layer was concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 97 / 3) to obtain 1 g (610 mg, yield 77%) as a brown solid. LC-MS (ESI, method 3) t R =1.45 min, m / z(M+H) + = 466.3.

[0317] Step 7. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(1) A mixture of 1 g (600 mg, 1.29 mmol), cyclopropanecarboxamide (548 mg, 6.44 mmol), BrettPhos Pd G3 (233 mg, 0.26 mmol), and Cs2CO3 (839 mg, 2.57 mmol) in 1,4-dioxane (6 mL) was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH = 20 / 1) to obtain 1 (200 mg, yield 30%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 11.79(s,1H), 10.79(s,1H), 9.37(s,1H), 8.76(s,1H), 8.73(s,1H), 8.65(s,1H), 8.38(s,1H), 5.86(s,2H), 4.00(s,3H), 3.69(t,J=8.4Hz,2H), 2.12-2.07(m,1H), 0.97-0.87(m,6H), 0.03(s,9H). LC-MS (ESI, Method 2) t R =4.13 min, m / z(M+H) + = 515.1.

[0318] Example 2

[0319] [ka]

[0320] Step 1. 2-Bromo-3-(dimethoxymethyl)phenol (2b) pTSA (172 mg, 1.00 mmol) was added to a solution of 2a (2 g, 9.95 mmol) and trimethoxymethane (5.28 g, 49.75 mmol, 5.45 mL) in MeOH (30 mL). The mixture was stirred at 100°C for 16 hours. The solvent was removed under vacuum, and crude product 2b (2.5 g, yield shown) was obtained as a yellow oily substance. LC-MS (ESI, method 4) t R =3.54 min, m / z( 79 Br,M+H-32) + = 215.0.

[0321] Step 2. 2,4-Dibromo-3-hydroxybenzaldehyde (2c) A solution of 2b (500 mg, 2.02 mmol) in CHCl3 (5 mL) was added to a solution of molecular bromine (323 mg, 2.02 mmol) in CHCl3 (5 mL) at 0°C. The reaction was stirred at 25°C for 16 hours. The reaction was quenched with an aqueous solution of Na2S2O3 (40 mL) and extracted with  (25 mL x 3). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA = 10 / 1 to 3 / 1) to obtain the title compound 2c (300 mg, yield 53%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 10.44 (s, 1H), 10.17 (d, J=0.8Hz, 1H), 7.83-7.65 (m, 1H), 7.27 (d, J=8.4Hz, 1H). LC-MS (ESI, Method 4) t R =2.92 min, m / z(M+H) + = 280.9.

[0322] Step 3. 2,4-Dibromo-3-methoxybenzaldehyde (2d) Iodomethane (228 mg, 1.61 mmol) was added to a solution of 2c (300 mg, 1.07 mmol) and K2CO3 (296 mg, 2.14 mmol) in DMF (3 mL). The mixture was stirred at 25°C for 2 hours, then poured into water (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title product 2d (300 mg, yield 95%) as a yellow solid. LC-MS (ESI, method 4) t R =4.00 min, m / z(M+H) + =294.9.

[0323] Step 4. (E)-1-(2,4-dibromo-3-methoxybenzylidene)-2-(4-methoxybenzyl)hydrazine hydrochloride (2e) Compound 2d (3.0 g, 10.21 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (2.12 g, 11.23 mmol) were dissolved in EtOH (30 mL). The resulting mixture was stirred at 25°C for 16 hours and then cooled to 0°C. The turbid mixture was filtered and washed with EtOH (5 mL) to obtain the title compound 2e (3.5 g, yield 74%) as a pale yellow solid. LC-MS (ESI, method 4) t R =5.22 min, m / z(M+H) + = 427.0.

[0324] Step 5. 6-Bromo-7-methoxy-1-(4-methoxybenzyl)-1H-indazole(2f) To a solution of 2e (3.5 g, 7.53 mmol) in DMF (50 mL), K2CO3 (2.6 g, 18.83 mmol) and CuI (143 mg, 0.75 mmol) were added. The mixture was stirred at 100°C for 16 hours. Water (200 mL) was added to the above mixture. The solution was extracted with  (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain crude compound 2f (2.4 g, yield 91%) as a yellow oil. LC-MS (ESI, method 4) tR =4.81 min, m / z( 79 Br, M+H) + =347.1.

[0325] Step 6. 6-bromo-7-methoxy-1H-indazole (2g) 2f (2.4g, 6.91 mmol) was dissolved in TFA (20 mL), and the mixture was stirred at 90°C for 4 hours. The mixture was then concentrated, diluted with H2O (50 mL), and the pH was adjusted to 7 with aqueous NaHCO3 solution. It was then extracted with SiO (50 mL x 3), washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 1 / 1 to 1 / 10) to obtain 2 g of the compound (1.4 g, yield 89%) as a yellow solid. LC-MS (ESI, method 4) t R =3.39 min, m / z( 79 Br, M+H) + = 226.9.

[0326] Step 7. 6-bromo-1-(2,2-difluoropropyl)-7-methoxy-1H-indazole(2h) To a solution of 2 g (400 mg, 1.76 mmol) in DMF (5 mL), Cs2CO3 (1.15 g, 3.52 mmol) and Int.C (804 mg, 3.52 mmol) were added. The mixture was then stirred at room temperature for 2 hours. The mixture was diluted with H2O (20 mL), extracted with siRNA (20 mL x 3), washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 20 / 1~1 / 1) to obtain compound 2h (100 mg, yield 19%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.34(d,J=6.8Hz,1H),7.27(d,J=6.8Hz,1H),4.95(t,J=13.2Hz,2H),4.05(s,3H),1.66(t,J=15.2Hz,3H). LC-MS (ESI, method 4) R =3.16 min, m / z( 79 Br, M+H) + = 305.1.

[0327] Step 8. (1-(2,2-difluoropropyl)-7-methoxy-1H-indazole-6-yl)carbamate tert-butyl(2i) A mixture of 2h (100 mg, 0.33 mmol), tert-butyl carbamate (77 mg, 0.66 mmol), Cs2CO3 (267 mg, 0.82 mmol), and BrettPhos Pd G3 (30 mg, 0.033 mmol) in dioxane (2 mL) was stirred at 100°C for 16 hours. The mixture was then concentrated, diluted with siRNA, filtered, and the filtrate was concentrated to obtain crude compound 2i (110 mg, yield 98%) as a yellow solid. LC-MS (ESI, method 4) t R =3.14 min, m / z(M+H) + = 342.2.

[0328] Step 9. 1-(2,2-difluoropropyl)-7-methoxy-1H-indazole-6-amine(2j) To a solution of 2i (110 mg, 0.32 mmol) in DCM (2 mL), TFA (1 mL) was added at room temperature. The mixture was then concentrated, diluted with H2O (20 mL), basicized to pH > 7 with aqueous Na2CO3 solution, and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (EA in PE 0%~45%) to obtain compound 2j (70 mg, yield 90%) as a yellow oil. LC-MS (ESI, method 4) t R =2.05 min, m / z(M+H) + = 242.1.

[0329] Step 4. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)nicotinamide(2) pTSA (29 mg, 0.17 mmol) was added to a solution of 2j (40 mg, 0.17 mmol) and Int.A (47 mg, 0.18 mmol) in dioxane (1.5 mL), and the mixture was then stirred at room temperature for 16 hours. The mixture was concentrated and purified by preparative HPLC (Method E) to obtain compound 2 (43.3 mg, yield 57%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),10.55(s,1H),8.63(s,1H),8.53(s,1H),8.15(s,1H),7.83(s,1H),7.54(d,J=8.4Hz,1 H),7.15(d,J=8.4Hz,1H),4.97(t,J=13.2Hz,2H),3.78(s,3H),1.96-1.91(m,1H),1.65(t,J=19.2Hz,3H),0.74-0.71(m,4H). LC-MS (ESI, method 4) R =2.12 min, m / z(M+H) + = 462.3.

[0330] Example 3

[0331] [ka]

[0332] Step 1. 6-Chloro-7-methoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridine (3a) Int.B (27 mL, 10.87 mmol, 0.4 M in DCM) was added to a solution of 1d (1 g, 5.45 mmol) and Cs2CO3 (5.32 g, 16.34 mmol) in DMF (10 mL). The mixture was then stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain compound 3a (160 mg, yield 10%) as a yellow solid. 1¹H NMR (400MHz, CDCl3) δ 8.64 (s, 1H), 8.20 (s, 1H), 5.77-5.66 (m, 1H), 4.09 (s, 3H), 1.89 (d, J=7.2Hz, 3H). LC-MS (ESI, Method 4) t R =2.91 min, m / z(M+H) + = 280.1.

[0333] Step 2. 7-Methoxy-N-(4-Methoxybenzyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-amine(3b) 3a (160 mg, 0.57 mmol), (4-methoxyphenyl)methanamine (157 mg, 1.14 mmol), t A mixture of BuONa (110 mg, 1.14 mmol), BrettPhos (61 mg, 0.11 mmol), and BrettPhos Pd G3 (52 mg, 0.057 mmol) in dioxane (2 mL) was stirred at 120°C for 24 hours. The mixture was diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash chromatography (DCM / MeOH = 100 / 1 to 30 / 1) to obtain compound 3b (140 mg, yield 64%) as a yellow oil. LC-MS (ESI, method 4) t R =3.11 min, m / z(M+H) + = 381.2.

[0334] Step 3. 7-Methoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-amine(3c) A solution of 3b (140 mg, 0.37 mmol) in TFA (2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, diluted with H2O (10 mL), basicized to pH > 7 with aqueous Na2CO3 solution, extracted with ₹ (10 mL × 3), washed with brine (15 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1~5 / 1) to obtain compound 3c (70 mg, yield 73%) as a yellow solid. LC-MS (ESI, method 4) t R =0.81 min, m / z(M+H) + = 261.1.

[0335] Step 4. 6-Chloro-4-((7-Methoxy-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(3d) To a solution of 4,6-dichloro-N-(methyl-d3)nicotinamide (29 mg, 0.14 mmol) and 3c (30 mg, 0.115 mmol) in DMF (2 mL), NaH (23 mg, 0.58 mmol, 60% purity in mineral oil) was added at 0°C. The mixture was then stirred at 0°C for 2 hours and then stirred at room temperature for 16 hours. The mixture was diluted with H2O (10 mL), extracted with  (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash chromatography (MeOH in DCM was 0-6%) to obtain compound 3d (25 mg, 50% yield) as a yellow solid. LC-MS (ESI, method 4) t R =3.15 min, m / z(M+H) + = 432.2.

[0336] Step 5. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(3) A mixture of 3d (25 mg, 0.058 mmol), cyclopropanecarboxamide (99 mg, 1.16 mmol), BrettPhos Pd G3 (5 mg, 0.006 mmol), BrettPhos (3 mg, 0.006 mmol), and Cs2CO3 (47 mg, 0.14 mmol) in dioxane (0.5 mL) was stirred under microwave at 120°C for 1 hour. The mixture was diluted with H2O (10 mL), extracted with  (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by preparative HPLC (Method E) to obtain compound 3 (8 mg, yield 29%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.71(s,1H),10.74(s,1H),9.25(s,1H),8.71(s,1H),8.69(s,1H),8.57(s,1H),8.40(s,1H) ,5.69-5.65(m,1H),3.91(s,3H),2.04-2.00(m,1H),1.85(d,J=6.8Hz,3H),0.81-0.78(m,4H). LC-MS (ESI, method 4) R =2.26 min, m / z(M+H) + = 481.3.

[0337] Step 6. (R * )-6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide (3A) and (S * )-6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(3B) 3 (8 mg, 0.017 mmol) was separated by chiral preparative HPLC (Method G), and 3A (2.5 mg, yield 31%) was obtained as a white solid, and 3B (2.4 mg, yield 30%) was obtained as a white solid. 3A:LC-MS (ESI, Method 4) R=2.25 min, m / z(M+H) + =481.2. HPLC (Method 5) t R =5.92 minutes. 3B:LC-MS (ESI, Method 4) R =2.26 min, m / z(M+H) + =481.3. HPLC (Method 5) t R =7.89 minutes.

[0338] Example 4

[0339] [ka]

[0340] Step 1. 6-Chloro-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)nicotinamide (4a) To a solution of 2j (30 mg, 0.12 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (25.9 mg, 0.12 mmol) in THF (1 mL), LiHMDS (0.87 mL, 0.87 mmol, 1 M in THF) was added at 0°C. The mixture was then stirred at room temperature for 2 hours. The mixture was diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by flash chromatography (DCM / MeOH = 100 / 1 to 30 / 1) to obtain compound 4a (50 mg, yield 97%) as a yellow solid. LC-MS (ESI, method 4) t R =2.74 min, m / z(M+H) + = 413.2.

[0341] Step 2. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)-6-((5-morpholinopyridine-2-yl)amino)nicotinamide(4) Compound 4a (50 mg, 0.12 mmol), 5-morpholinopyridine-2-amine (65 mg, 0.36 mmol), XantPhos (14 mg, 0.024 mmol), Cs2CO3 (99 mg, 0.30 mmol), and Pd2(dba)3 (11 mg, 0.012 mmol) were dissolved in DMA (1 mL). The resulting mixture was stirred at 145°C for 2 hours. The mixture was concentrated to dryness and purified by preparative HPLC (Method D) to obtain the title compound 4 (11.4 mg, yield 17%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.59(s,1H),9.43(s,1H),8.47(s,1H),8.45(s,1H),8.16(s,1H),7.77 (d,J=3.2Hz,1H),7.59(d,J=8.8Hz,1H),7.52-7.50(m,2H),7.37(dd,J= 9.2Hz,J=2.8Hz,1H),7.32(d,J=8.8Hz,1H),4.98(t,J=13.2Hz,2H),3.81(s,3H),3.73-3.71(m,4H),3.03-3.01(m,4H),1.67(t,J=19.2Hz,3H). LC-MS (ESI, Method 4) R =2.27 min, m / z(M+H) + = 556.4.

[0342] Example 5

[0343] [ka]

[0344] Step 1. 2-(6-chloro-5-methoxypyrimidine-4-yl)malonic acid = 1-tert-butyl = 3-methyl(5b) A solution of tert-butyl methyl malonate (53.52 g, 307 mmol) in THF (600 mL) was mixed with NaH (22.35 g, 559 mmol, 60% purity in mineral oil) at 0°C. The mixture was stirred at 0°C for 30 minutes. Next, a solution of 5a (50 g, 279 mmol) in THF (100 mL) was added to the mixture at 0°C. The mixture was stirred at 80°C for 2 hours and poured into ice water (400 mL). The mixture was acidified with 2N HCl to adjust the pH to 2 and extracted with  (500 mL x 2). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to obtain 5b (88 g, 100% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) R =1.33 min, m / z(M+H) + = 317.2.

[0345] Step 2. 2-(6-chloro-5-methoxypyrimidine-4-yl)methyl acetate (5c) The mixture of 5b (70 g, 177 mmol) in HCl / siRNA (2 M, 400 mL) was stirred overnight at 30°C. The reaction mixture was concentrated. The residue was diluted with siRNA (100 mL) and adjusted to pH=10 with saturated Na₂CO₃ (150 mL). The mixture was extracted with siRNA (200 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to obtain 5c (38 g, 100% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R =1.05 min, m / z(M+H) + = 217.2.

[0346] Step 3. 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)methyl acetate (5d) A mixture of 5c (54 g, 199 mmol), TEA (40 g, 399 mmol), and DMBNH2 (37 g, 219 mol) in EtOH (300 mL) was stirred at 80°C for 5 hours. After cooling to 5°C, the formed solid was collected by filtration and dried to obtain 5d (1.33 g, yield 83%) as a white solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) R =1.05 min, m / z(M+H) + = 348.2.

[0347] Step 4. 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)-3-(dimethylamino)acrylate methyl(5e) A mixture of 5d (17.5 g, 50.38 mmol) and DMF-DMA (18.05 g, 151 mmol) was stirred at 130°C for 6 hours. The mixture was concentrated to obtain crude 5e (20.27 g, yield shown) as a brown oily substance, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) R =1.38 min, m / z(M+H) + = 403.3.

[0348] Step 5. 5-((2,4-dimethoxybenzyl)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-methylcarboxylate(5f) To a mixture of 5e (crude product 21.5 g, 48.1 mmol) in DCM (200 mL), a solution of O-(mesitylsulfonyl)hydroxylamine (28.75 g, 80.14 mmol, 60 wt% in H2O) in DCM (100 mL) was added dropwise at 0°C. After stirring at 0°C for 2 hours, the reaction mixture was poured into ice-saturated NaHCO3 (70 mL) and extracted with DCM (150 mL x 2). The combined organic layer was concentrated, and the residue was purified by silica gel flash chromatography (DCM / Ã=5 / 1) to obtain 5f (11.25 g, yield 63%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 8.85(s,1H),8.27(s,1H),7.21(d,J=8.4Hz,1H),6.46(d,J=2.4Hz,1H),6.41(dd,J=8.4,2.4Hz,1H) ,5.64(t,J=6.0Hz,1H),4.64(d,J=6.0Hz,2H),3.86(s,3H),3.85(s,3H),3.80(s,3H),3.79(s,3H).

[0349] Step 6. 5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl (5g) A solution of 5 f (17.7 g, 47.53 mmol) in DCM (40 mL) was mixed with HCl / siRNA (120 mL, 2 M). The mixture was stirred at 30°C for 1 hour. The mixture was concentrated, and the residue was diluted with H2O (100 mL). The suspension was basicized to pH=13 with 2 M NaOH aqueous solution. The solid was filtered, and the filter cake was refluxed in DCM / MeOH (200 mL) for 1 hour. The solid was filtered off, and the filtrate was concentrated to obtain 5 g (8.2 g, yield 78%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.81 (s, 1H), 8.32 (s, 1H), 4.91 (s, 2H), 3.88 (s, 6H).

[0350] Step 7. 5-[bis(tert-butoxycarbonyl)amino]-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl(5h) A mixture of 5 g (8.2 g, 36.94 mmol), Boc2O (20.15 g, 92.34 mmol), and DMAP (901 mg, 7.29 mmol) in DCM (125 mL) was stirred at 30°C for 6 hours. The solvent was removed under vacuum, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain 5 h (14.4 g, yield 92%) as a yellow oily substance. 1 H NMR (400MHz, CDCl3) δ 9.05 (s, 1H), 8.50 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 1.46 (s, 18H).

[0351] Step 8. 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylic acid (5i) To a mixture of 5h (13.5 g, 31.96 mmol) in MeOH (200 mL) and H2O (100 mL), NaOH (1.92 g, 47.94 mmol) was added at room temperature. The mixture was stirred at 40°C for 10 hours. After cooling to room temperature, the organic layer was removed under reduced pressure, and the aqueous layer was acidified to pH=1 with 2N HCl aqueous solution. The resulting solid was filtered and dried to obtain a white solid. The obtained white solid, K2CO3 (12.17 g, 88.03 mmol), and MeOH (80 mL) were stirred at 70°C for 3 hours. The mixture was then concentrated, and the residue was acidified to pH=1 with 2N HCl aqueous solution. The resulting solid was filtered and dried to obtain 5i (7.42 g, yield 71%) as a white solid. 1 H NMR (400MHz, CDCl3) δ 9.12 (s, 1H), 8.52 (s, 1H), 7.33 (s, 1H), 3.97 (s, 3H), 1.57 (s, 9H).

[0352] Step 9. (3-iodo-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)carbamate tert-butyl(5j) A mixture of 5i (3.3 g, 10.70 mmol) and NIS (4.82 g, 21.41 mmol) in DMF (45 mL) was mixed with NaHCO3 (2.70 g, 32.11 mmol) at 0°C. After stirring at 10°C for 2 hours, the reaction mixture was diluted with an aqueous solution of Na2S2O3 (350 mL) and extracted with SiO3 (100 mL x 3). The organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain 5j (2.97 g, yield 71%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 9.28 (s, 1H), 9.19 (s, 1H), 8.21 (s, 1H), 3.83 (s, 3H), 1.49 (s, 9H).

[0353] Step 10. (4-Methoxy-3-(3,3,3-trifluoropropane-1-en-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)carbamate tert-butyl(5k) A mixture of 5j (145 mg, 0.37 mmol), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (165 mg, 0.74 mmol), Na2CO3 (79 mg, 0.74 mmol), and Pd(dppf)Cl2 (27 mg, 0.04 mmol) in 1,4-dioxane / H2O (0.5 mL / 0.1 mL) was stirred at 70°C for 6 hours and at 90°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with  (10 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to obtain 5k (130 mg, crude product) as a yellow oily substance, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R =1.28 min, m / z(M- t Bu+H) + = 303.1.

[0354] Step 11. (4-Methoxy-3-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)carbamate tert-butyl (5L) A mixture of 5k (130 mg, 0.36 mmol), Pd / C (150 mg, 50 wt%, wetted with water), and Pd(OH)2 (150 mg, 20% Pd on carbon, wetted with water, 50% water) in MeOH (2 mL) was stirred at 50°C for 3 days under an H2 (50 Psi) atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain 5 L (130 mg, crude product) as a yellow oily substance, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R =1.35 min, m / z(M- t Bu+H) + =305.0.

[0355] Step 12. 4-Methoxy-3-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-5-amine(5m) A mixture of 5 L (125 mg, 0.35 mmol) and TFA / DCM (2 mL / 6 mL) was stirred at 0°C for 1 hour. The solvent was removed by pumping a nitrogen stream. The residue was diluted with DCM (3 mL) and adjusted to pH > 7 with NH3 / 1,4-dioxane (2 M). The mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / Â=10 / 1) to obtain 5 m (59 mg, yield 65%) as a yellow oil. LC-MS (ESI, method 3) t R =1.17 min, m / z(M+H) + = 261.0.

[0356] Step 13. 6-Chloro-4-((4-Methoxy-3-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide(5n) A solution of 5m (50 mg, 0.19 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (120 mg, 0.58 mmol) in DMF (1 mL) was mixed with NaH (23 mg, 0.58 mmol, 60% in mineral oil) at 0°C. The mixture was then stirred at 15°C for 3 hours. The reaction mixture was quenched with ice water (3 mL) and extracted with  (5 mL x 3). The organic layer was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 5n (10 mg, yield 12%) as a white solid. LC-MS (ESI, Method 3) t R =1.26 min, m / z(M+H) + = 432.3.

[0357] Step 14. 6-(cyclopropanecarboxamide)-4-((4-methoxy-3-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide(5) A mixture of 5n (10.0 mg, 0.023 mmol), cyclopropanecarboxamide (10.0 mg, 0.12 mmol), Cs2CO3 (15 mg, 0.046 mmol), and BrettPhos Pd G3 (4 mg, 0.005 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 10 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 5 (3 mg, yield 27%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.54(s,1H),10.76(s,1H),9.33(s,1H),8.86(s,1H),8.69(s,1H),8.58(s,1H),8.26(s,1H) ,4.11-4.05(m,1H),3.87(s,3H),2.02-1.96(m,1H),1.55(d,J=7.2Hz,3H),0.81-0.79(m,4H). LC-MS (ESI, method 2) R =3.25 min, m / z(M+H) + = 481.1.

[0358] Step 15. (R * )-6-(cyclopropanecarboxamide)-4-((4-methoxy-3-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide (5A) and (S * )-6-(cyclopropanecarboxamide)-4-((4-methoxy-3-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide(5B) Compound 5 (10 mg, 0.021 mmol) was separated by chiral preparative HPLC (Method H), yielding 5A (3 mg, 27% yield) as a white solid and 5B (3 mg, 27% yield) as a white solid. 5A: 1H NMR(400MHz,DMSO-d6)δ 11.54(s,1H),10.76(s,1H),9.33(s,1H),8.85(s,1H),8.70(s,1H),8.58(s,1H),8.26(s,1H) ,4.11-4.07(m,1H),3.87(s,3H),2.02-1.97(m,1H),1.55(d,J=7.2Hz,3H),0.81-0.79(m,4H). LC-MS (ESI, method 2) R =3.23 min, m / z(M+H) + =481.0. HPLC (Method 6) t R =5.00 minutes.

[0359] 5B: 1 H NMR(400MHz,DMSO-d6)δ 11.54(s,1H),10.76(s,1H),9.33(s,1H),8.85(s,1H),8.69(s,1H),8.58(s,1H),8.26(s,1H) ,4.11-4.07(m,1H),3.87(s,3H),2.02-1.97(m,1H),1.55(d,J=7.2Hz,3H),0.81-0.79(m,4H). LC-MS (ESI, method 2) R =3.24 min, m / z(M+H) + =481.0. HPLC (Method 6) t R =7.03 minutes.

[0360] Example 6

[0361] [ka]

[0362] Step 1. (3-methoxypyridine-4-yl)carbamate tert-butyl(6b) The solutions of 6a (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 (10-50% siRNA in PE) to obtain 6b (1.45 g, yield shown) as a white solid. LC-MS (ESI, method 4) t R =1.92 min, m / z(M+H) + = 225.1.

[0363] Step 2. 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridine-1-ium=2,4-dinitrophenolate(6c) A mixture of 6b (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 6c (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.

[0364] Step 3. (3-cyano-4-methoxypyrazolo[1,5-a]pyridine-5-yl)carbamate tert-butyl(6d) A mixture of 6c (88 mg, 0.208 mmol), acrylonitrile (27 mg, 0.312 mmol), TEMPO (40 mg, 0.25 mmol), and DIPEA (54 mg, 0.416 mmol, 73 μL) in toluene (1 mL) was stirred at 40°C for 12 hours. A black solution was formed. The reaction mixture was diluted with water (30 mL) and extracted with  (30 mL x 2). The combined organic layer was washed with brine (40 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (10-50%  in PE) to obtain 6d (30 mg, 50% yield in two steps) as a yellow solid.1 H NMR(400MHz, CDCl3)δ 8.30(d,J=7.2Hz,1H),8.14(s,1H),8.08(d,J=7.6Hz,1H),7.22(brs,1H),4.04(s,3H),1.56(s,9H). LC-MS (ESI, method 4) R =4.02 min, m / z(M+H) + = 289.1.

[0365] Step 4. 5-amino-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile(6e) To a mixture of 6d (30 mg, 0.104 mmol) in DCM (3 mL), TFA (1.49 g, 13.1 mmol, 1 mL) was added at 0°C. The resulting mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated, diluted with H2O (10 mL), adjusted to pH > 7 with Na2CO3 aqueous solution, extracted with ELISA (10 mL x 3), washed with brine, and dried under vacuum to obtain 6e (18 mg, yield 92%) as a yellow solid. LC-MS (ESI, method 4) t R =1.97 min, m / z(M+H) + = 189.0.

[0366] Step 5. 6-Chloro-4-((3-cyano-4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino)-N-(methyl-d3)nicotinamide(6f) A solution of 6e (18 mg, 0.096 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (20 mg, 0.096 mmol) in THF (0.5 mL) was mixed with LiHMDS (0.67 mL, 0.67 mmol, 1 M in THF) at 0°C. The resulting mixture was stirred at 10°C for 2 hours. The reaction mixture was diluted with H2O (10 mL), extracted with  (10 mL x 3), washed with brine (10 mL), and dried under vacuum to obtain 6f (30 mg, yield 88%) as a yellow solid. LC-MS (ESI, method 4) t R =2.41 min, m / z(M+H) + =360.1.

[0367] Step 6. 4-((3-cyano-4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino)-N-(methyl-d3)-6-((5-morpholinopyridine-2-yl)amino)nicotinamide(6) To a solution of 6f (30 mg, 0.083 mmol) and 5-morpholinopyridine-2-amine (30 mg, 0.17 mmol) in dioxane (0.5 mL), XantPhos (10 mg, 0.017 mmol), Cs2CO3 (54 mg, 0.17 mmol), and Pd(OAc)2 (2 mg, 0.008 mmol) were added at 25°C. The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The mixture was diluted with H2O (2 mL), extracted with  (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC (Method E) to obtain compound 6 (6.5 mg, yield 16%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ 11.10(s,1H),9.71(s,1H),8.55(s,1H),8.49(s,1H),8.14(s,1H),7.95-7.93(m,2H),7.75(d,J=6.4Hz,1H),7.48(d,J=9. 2Hz,1H), 7.41(dd,J=9.2Hz,2.8Hz,1H),6.95(d,J=6.4Hz,1H),3.74(t,J=4.8Hz,4H),3.66(s,3H),3.03(t,J=4.8Hz,4H). LC-MS (ESI, method 4) R =1.72 min, m / z(M+H) + = 503.3.

[0368] Example 7

[0369] [ka]

[0370] Step 1. 2-Chloro-4-((3-cyano-4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide(7a) A mixture of Int.E (45 mg, 0.212 mmol) and 6e (40 mg, 0.212 mmol) in DMF (3 mL) was mixed with NaH (60 mg, 1.49 mmol, 60% of mineral oil) at 0°C. The resulting mixture was stirred at 0-20°C for 2 hours. The reaction mixture was quenched with water (30 mL) and extracted with  (30 mL x 3). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 7a (30 mg, yield 39%) as a yellow solid. LC-MS (ESI, method 4), t R =2.53 min, m / z(M+H) + = 361.2.

[0371] Step 2 4-((3-cyano-4-methoxypyrazolo[1,5-a]pyridin-5-yl)amino)-N-(methyl-d3)-2-((5-morpholinopyridine-2-yl)amino)pyrimidine-5-carboxamide(7) A mixture of 7a (30 mg, 0.083 mmol), 5-morpholinopyridine-2-amine (18 mg, 0.10 mmol), BrettPhos (10 mg, 0.017 mmol), Cs2CO3 (81 mg, 0.25 mmol), and BrettPhos Pd G3 (8 mg, 0.008 mmol) in dioxane (1 mL) was degassed and purged three times with nitrogen. The resulting mixture was stirred at 100°C for 1 hour under an N2 atmosphere. A yellow suspension was formed. The reaction mixture was concentrated and purified by preparative HPLC (Method E) to obtain compound 7 (1.6 mg, yield 3.8%) as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ 12.29(s,1H),10.14(s,1H),9.03(d,J=6.8Hz,1H),8.76(s,1H),8.67(d,J=7.6Hz,1H),8.62(s,1H),8.56(s,1H),8.10(d,J =2.8Hz,1H),7.84(d,J=6.8Hz,1H),7.46(dd,J=9.2,3.2Hz,1H),3.98(s,3H),3.77(t,J=4.8Hz,4H),3.15(t,J=4.8Hz,4H). LC-MS (ESI, method 4) R =2.43 min, m / z(M+H) + = 504.3.

[0372] Example 8

[0373] [ka]

[0374] Step 1. 6-Chloro-1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine (8a) A mixture of 1d (400 mg, 2.18 mmol), Int.C (1.6 g, 7.01 mmol), and Cs2CO3 (1.42 g, 4.36 mmol) in DMF (5 mL) was stirred at 30°C for 1 hour. The reaction mixture was diluted with H2O (15 mL) and extracted with SiO2 (15 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to obtain 8a (120 mg, yield 21%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.73(s,1H),8.45(s,1H),4.98(t,J=13.6Hz,2H),4.02(s,3H),1.71(t,J=19.2Hz,3H).

[0375] Step 2. 1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-amine(8b) 8a (266 mg, 1 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), BrettPhos (27 mg, 0.050 mmol) and t A mixture of BuONa (147 mg, 1.52 mmol) in saturated NH3 / dioxane (4 mL) was stirred under N2 at 100°C for 12 hours. The mixture was cooled and concentrated. The residue was purified by preparative HPLC (Method A) to obtain 8b (100 mg, yield 41%) as a white solid. LC-MS (ESI, Method 3) t R =1.27 min, m / z(M+H) + = 243.2.

[0376] Step 3. 6-Chloro-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(8c) To a solution of 8b (90 mg, 0.37 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (93 mg, 0.45 mmol) in THF (0.8 mL), LiHMDS (1.5 mL, 1.5 mmol, 1 M in THF) was added at -40°C. The reaction mixture was stirred from -40°C to room temperature for 1 hour and quenched with H2O (1 mL). The organic solvent was evaporated under reduced pressure. The formed solid was collected by filtration and dried to obtain 8c (50 mg, yield 38%) as a red solid. LC-MS (ESI, method 3) t R =1.60 min, m / z(M+H) + = 414.2.

[0377] Step 4. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide(8) A mixture of 8c (32 mg, 0.08 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (40 mg, 0.40 mmol), BrettPhos Pd G3 (14 mg, 0.015 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in 1,4-dioxane (0.5 mL) was stirred overnight at 90°C under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain compound 8 (5.8 mg, yield 16%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.66(s,1H),10.76(s,1H),9.23(s,1H),8.71(s,1H),8.68(s,1H),8.58(s,1H),8.33(s,1H),5.00-4.8 2(m,3H),3.90(s,3H),2.23-2.20(m,1H),1.69(t,J=19.2Hz,3H),1.65-1.60(m,1H),1.18-1.23(m,1H). LC-MS (ESI, method 2) R =3.46 min, m / z(M+H) + = 481.2.

[0378] Example 9

[0379] [ka]

[0380] Step 1. 6-Chloro-7-methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine (9a) A mixture of 1d (1 g, 5.4 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (2.5 g, 11 mmol), and Cs2CO3 (3.5 g, 11 mmol) in DMF (10 mL) was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with SiO (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA=3 / 1) to obtain compound 9a (254 mg, yield 18%) as a yellow solid. LC-MS (ESI, method 3) t R =1.23 min, m / z(M+H) + =266.0.

[0381] Step 2. 7-Methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-amine(9b) 9a (254 mg, 0.96 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), BrettPhos (25 mg, 0.047 mmol), t A mixture of BuONa (137 mg, 1.4 mmol) and saturated NH3 / dioxane (4 mL) was stirred at 100°C for 12 hours. The mixture was cooled, concentrated, and the residue was purified by preparative HPLC (Method A) to obtain compound 9b (59 mg, yield 25%) as a white solid. LC-MS (ESI, Method 3) R =1.34 min, m / z(M+H) + = 247.2.

[0382] Step 3. 6-Chloro-4-((7-Methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(9c) To a solution of 9b (45 mg, 0.18 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (46 mg, 0.22 mmol) in THF (0.5 mL), LiHMDS (0.7 mL, 0.7 mmol, 1 M in THF) was added at -40°C. The reaction mixture was stirred from -40°C to room temperature for 1 hour and quenched with H2O (2 mL). The organic solvent was evaporated under reduced pressure. The formed solid was collected by filtration and dried to obtain compound 9c (12 mg, yield 16%) as a white solid. LC-MS (ESI, method 3) t R =1.63 min, m / z(M+H) + = 418.2.

[0383] Step 4. 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(9) A mixture of 9c (50 mg, 0.12 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (62 mg, 0.60 mmol), BrettPhos Pd G3 (22 mg, 0.024 mmol), and Cs2CO3 (78 mg, 0.24 mmol) in 1,4-dioxane (0.5 mL) was stirred overnight at 90°C under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain compound 9 (3.3 mg, yield 6%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.73(s,1H),10.78(s,1H),9.27(s,1H),8.73(s,1H),8.70(s,1H),8.59(s,1H),8.39(s,1H),5.34(q, J=8.0Hz,2H),5.01-4.83(m,1H),3.93(s,3H),2.22-2.18(m,1H),1.68-1.61(m,1H),1.24-1.14(m,1H). LC-MS (ESI, method 2) R =3.33 min, m / z(M+H) + = 485.2.

[0384] Example 10

[0385] [ka]

[0386] Step 1. 6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(10) A mixture of 9c (30 mg, 0.07 mmol), (1R,2R)-2-fluorocyclopropane-1-carboxamide (37 mg, 0.36 mmol), BrettPhos Pd G3 (13 mg, 0.014 mmol), and Cs2CO3 (47 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) was stirred overnight at 90°C under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain 10 (10 mg, yield 29%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.73(s,1H),10.78(s,1H),9.27(s,1H),8.74(s,1H),8.70(s,1H),8.60(s,1H),8.39(s,1H),5.34(d, J=8.4Hz,2H),5.01-4.83(m,1H),3.93(s,3H),2.24-2.19(m,1H),1.68-1.61(m,1H),1.17-1.14(m,1H). LC-MS (ESI, method 2) R =3.32 min, m / z(M+H) + = 485.2.

[0387] Example 11

[0388] [ka]

[0389] Step 1. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-6-((1R,2R)-2-fluorocyclopropane-1-carboxamide)-N-(methyl-d3)nicotinamide(11) A mixture of 8c (50 mg, 0.12 mmol), (1R,2R)-2-fluorocyclopropane-1-carboxamide (62 mg, 0.60 mmol), BrettPhos Pd G3 (22 mg, 0.024 mmol), and Cs2CO3 (78 mg, 0.24 mmol) in 1,4-dioxane (0.5 mL) was stirred at 90°C for 2 hours under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain 11 (13 mg, yield 22%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.66(s,1H),10.75(s,1H),9.23(s,1H),8.71(s,1H),8.67(s,1H),8.58(s,1H),8.33(s,1H),5.01-4.8 0(m,3H),3.90(s,3H),2.22-2.17(m,1H),1.69(t,J=19.2Hz,3H),1.60-1.58(m,1H),1.17-1.12(m,1H). LC-MS (ESI, method 2) R =2.56 min, m / z(M+H) + = 481.2.

[0390] Example 12

[0391] [ka]

[0392] Step 1. 6-bromo-7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (12a) TsOH·H2O (38 mg, 0.2 mmol) was added to a solution of 2 g (450 mg, 1.98 mmol) and 3,4-dihydro-2H-pyran (500 mg, 5.95 mmol, 0.54 mL) in DCM (5 mL). After stirring at 5°C for 12 hours, the reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA=6 / 1) to obtain 12a (450 mg, yield 73%) as a yellow solid. LC-MS (ESI, method 3) t R =1.41 min, m / z( 79 Br, M+H) + = 311.1.

[0393] Step 2. (7-Methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)carbamate tert-butyl(12b) A mixture of 12a (400 mg, 1.29 mmol), Cs2CO3 (838 mg, 2.57 mmol), Pd2(dba)3 (118 mg, 0.13 mmol), BocNH2 (301 mg, 2.57 mmol), and XantPhos (74 mg, 0.13 mmol) in 1,4-dioxane (3 mL) was stirred under N2 at 100°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA=4 / 1) to obtain 12b (400 mg, yield 90%) as a yellow solid. LC-MS (ESI, method 3) t R =1.39 min, m / z(M-84+H) + = 264.2.

[0394] Step 3. 7-Methoxy-1H-indazole-6-amine hydrochloride (12c) A solution of 12b (400 mg, 1.15 mmol) in HCl / siRNA (4 mL, 2 M) was stirred at 35°C for 2 hours. The formed solid was collected by filtration and dried to obtain 12c (200 mg, yield 87%) as a yellow solid. LC-MS (ESI, method 3) t R =0.36 min, m / z(M+H) + = 163.9.

[0395] Step 4. 6-Chloro-4-((7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)nicotinamide(12d) Solutions of 12c (200 mg, 1.00 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (271 mg, 1.30 mmol) in EtOH (2 mL) were stirred at 80°C for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 20 / 1) to obtain 12d (200 mg, yield 60%) as a yellow solid. LC-MS (ESI, method 3) t R =1.06 min, m / z(M+H) + =335.0.

[0396] Step 5. 6-Chloro-4-((1-(cyanomethyl)-7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)nicotinamide(12e) To a solution of 12d (130 mg, 0.39 mmol) in DMF (1.5 mL), NaH (47 mg, 1.16 mmol, 60% in mineral oil) was slowly added at 0°C and the mixture was stirred at 0°C for 30 minutes. Then, 2-bromoacetonitrile (70 mg, 0.58 mmol, 0.04 mL) was added to the mixture at 0°C. After stirring at 25°C for 12 hours, the reaction solution was poured into ice water (5 mL) and extracted with  (10 mL × 2). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH = 30 / 1) to obtain 12e (85 mg, yield 59%) as a yellow solid. LC-MS (ESI, method 3) R =1.15 min, m / z(M+H) + = 374.2.

[0397] Step 6. 4-((1-(cyanomethyl)-7-methoxy-1H-indazole-6-yl)amino)-N-(methyl-d3)-6-((1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-yl)amino)nicotinamide(12) A mixture of 12e (50 mg, 0.13 mmol), 1-methyl-5-(morpholinomethyl)pyrazole-3-amine (32 mg, 0.16 mmol, CAS: 1328640-42-1), Cs2CO3 (87 mg, 0.27 mmol), and BrettPhos Pd G3 (24 mg, 0.027 mmol) in 1,4-dioxane (0.5 mL) was stirred at 110°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH = 10 / 1) to obtain 12 (17.5 mg, yield 25%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.65(s,1H),9.20(s,1H),8.43(s,1H),8.41(s,1H),8.20(s,1H),7.61(d,J=8.8Hz,1H),7.37(d,J=8.4Hz,1H),7. 25(s,1H),6.04(s,1H),5.75(s,2H),3.87(s,3H),3.61(s,3H),3.55-3.53(m,4H),3.42(s,2H),2.34-2.32(m,4H). LC-MS (ESI, method 2) R =1.99 min, m / z(M+H) + = 534.3.

[0398] Example 13

[0399] [ka]

[0400] Step 1. 6-((1S,2S)-2-fluorocyclopropane-1-carboxamide)-4-((4-methoxy-3-(1,1,1-trifluoropropane-2-yl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide(13) A mixture of 5n (10 mg, 0.023 mmol), (1S,2S)-2-fluorocyclopropane-1-carboxamide (12 mg, 0.12 mmol), BrettPhos Pd G3 (4 mg, 0.005 mmol), and Cs2CO3 (15 mg, 0.05 mmol) in 1,4-dioxane (0.5 mL) was stirred overnight at 90°C under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by preparative HPLC (Method A) to obtain 13 (0.6 mg, yield 5%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),10.83(s,1H),9.37(s,1H),8.89(s,1H),8.73(s,1H),8.61(s,1H),8.28(s,1H),5.01-4.83(m,1H) ,4.13-4.11(m,1H),3.90(s,3H),2.21-2.18(m,1H),1.56(d,J=6.4Hz,3H),1.18-1.16(m,1H),1.09-1.05(m,1H). LC-MS (ESI, method 2) R =3.24 min, m / z(M+H) + = 499.0.

[0401] Example 14

[0402] [ka]

[0403] Step 1. 2-Chloro-3-methoxy-5-nitropyridine-4-amine (14b) To a solution of 14a (1.0 g, 6.31 mmol) in concentrated H2SO4 (10 mL), KNO3 (701 mg, 6.94 mmol) was added at 0°C, and the mixture was stirred at room temperature for 4 hours. The mixture was poured into ice water, basicized to pH=13 with NH3·H2O, extracted with SiO4 (50 mL x 5), washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain compound 14b (800 mg, yield 62%) as a pale yellow solid. LC-MS (ESI, method 4) t R=1.88 min, m / z(M+H) + = 204.1.

[0404] Step 2. 6-Chloro-5-methoxypyridine-3,4-diamine(14c) To a solution of 14b (350 mg, 1.72 mmol) in MeOH (4 mL) and H2O (1 mL), Fe powder (480 mg, 8.60 mmol) and NH4Cl (460 mg, 8.6 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 then concentrated, diluted with H2O (10 mL), extracted with siRNA (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 50 / 1~5 / 1) to obtain compound 14c (290 mg, yield 97%) as a yellow oil. LC-MS (ESI, method 4) t R =0.46 min, m / z(M+H) + = 174.1.

[0405] Step 3. 6-Chloro-7-methoxy-1H-imidazo[4,5-c]pyridine (14d) To a solution of 14c (290 mg, 1.67 mmol) in trimethoxymethane (1.77 g, 16.71 mmol, 1.83 mL), formic acid (80 mg, 1.67 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The mixture was concentrated, diluted with H2O (20 mL), extracted with siRNA (15 mL x 3), washed with brine (15 mL), dried over Na2SO4, and concentrated to obtain compound 14d (300 mg, yield 98%) as a yellow solid. LC-MS (ESI, method 4) t R =0.88 min, m / z(M+H) + = 184.1.

[0406] Step 4. 6-Chloro-1-(2,2-difluoropropyl)-7-methoxy-1H-imidazo[4,5-c]pyridine(14e) To a solution of 14d (300 mg, 1.63 mmol) in DMF (5 mL), Cs2CO3 (1.60 g, 4.90 mmol) and Int.C (559 mg, 2.45 mmol) were added. The mixture was then stirred at room temperature for 4 hours. The mixture was then diluted with H2O (30 mL), extracted with EA (20 mL x 3), washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by preparative TLC (DCM / MeOH = 30 / 1) to obtain compound 14e (120 mg, yield 28%) as a yellow solid. 1 ¹H NMR (400MHz, CDCl3) δ 8.68 (s, 1H), 7.94 (s, 1H), 4.74 (t, J=13.2Hz, 2H), 4.07 (s, 3H), 1.71 (t, J=18.4Hz, 3H). LC-MS (ESI, Method 4) t R =2.16 min, m / z(M+H) + = 262.1.

[0407] Step 5. 1-(2,2-difluoropropyl)-7-methoxy-N-(4-methoxybenzyl)-1H-imidazo[4,5-c]pyridine-6-amine(14f) A mixture of 14e (120 mg, 0.46 mmol), (4-methoxyphenyl)methaneamine (126 mg, 0.92 mmol), BrettPhos Pd G3 (83 mg, 0.091 mmol), and tBuONa (88 mg, 0.92 mmol) in THF (1.5 mL) was stirred at 90°C for 2 hours. The mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain compound 14f (150 mg, 90% yield) as a yellow oily substance. LC-MS (ESI, method 4) t R =1.98 min, m / z(M+H) + = 363.2.

[0408] Step 6. 1-(2,2-difluoropropyl)-7-methoxy-1H-imidazo[4,5-c]pyridine-6-amine (14g) A solution of 14f (150 mg, 0.41 mmol) in TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with H2O (20 mL), adjusted to pH > 7 with aqueous Na2CO3 solution, and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1~5 / 1) to obtain 14 g of the compound (90 mg, 90% yield) as a yellow solid. LC-MS (ESI, method 4) t R =0.50 min, m / z(M+H) + = 243.1.

[0409] Step 7. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-imidazo[4,5-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(14) A mixture of 14 g (2 mg, 0.008 mmol), Int.A (2 mg, 0.008 mmol), Pd(OAc)2 (0.9 mg, 0.004 mmol), dppf (4 mg, 0.008 mmol), and K3PO4 (4 mg, 17 mmol) in dioxane (0.5 mL) was stirred at 100°C for 16 hours. The mixture was concentrated and purified by preparative HPLC (Method E) to obtain compound 14 (1.0 mg, yield 26%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),10.65(s,1H),9.09(s,1H),8.61(s,1H),8.51(s,1H),8.48(s,1H),8.18(s,1H),4. 82(t,J=14.4Hz,2H),3.84(s,3H),1.97-1.95(m,1H),1.71(t,J=19.2Hz,3H),0.77-0.73(m,4H). LC-MS (ESI, method 4) R =2.01 min, m / z(M+H) + = 463.3.

[0410] Example 15

[0411] [ka]

[0412] Step 1. 6-Bromo-7-methoxy-1H-indole(15b) To a solution of 15a (17g, 219.9 mmol) in THF (100 mL), magnesium vinyl bromide (220 mL, 220 mmol, 1 M in THF) was added under an N2 atmosphere at -40°C. The resulting mixture was stirred at -20°C for 30 minutes, then the reaction was quenched with aqueous NH4Cl solution (300 mL), and extracted with EA (300 mL x 3). The combined organic layer was washed with brine (300 mL x 2), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by flash chromatography (EA in PE was 5-10%) to obtain 15b (4.78 g, yield 20%) as a yellow oil. LC-MS (ESI, Method 2), t R =1.88 min, m / z( 79 Br, M+H) + = 225.9.

[0413] Step 2. 6-Bromo-7-methoxy-1-(methyl-d3)-1H-indole(15c) To a solution of 15b (4.5 g, 19.9 mmol) in DMF (50 mL), NaH (1.19 g, 29.85 mmol, 60% of mineral oil) was added at 0°C under an N2 atmosphere. The resulting mixture was stirred at 0°C for 30 minutes, and iodomethane-d3 (3.17 g, 21.89 mmol) was added. The resulting mixture was stirred at 25°C for 16 hours. The reaction was then quenched with aqueous NH4Cl solution (50 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by flash chromatography (EA in PE was 5-15%) to obtain 15c (4.57 g, yield 68%) as a yellow oil. LC-MS (ESI, method 2), t R =2.19 min, m / z( 79 Br, M+H) + =243.0.

[0414] Step 3. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(methyl-d3)-1H-indole-6-yl)amino)methyl nicotinate (15d) To a solution of 15c (400 mg, 1.64 mmol) in dioxane (6 mL), Int.D (402 mg, 1.15 mmol), Cs2CO3 (1.61 g, 4.94 mmol), EPhos (87.9 mg, 0.164 mmol), and EPhos Pd G4 (221.4 mg, 0.25 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours under an N2 atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EA (30 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, evaporated under vacuum, and purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 15d (120 mg, yield 11%) as a yellow solid. LC-MS (ESI, method 2), t R =1.76 min, m / z(M+H) + = 398.2.

[0415] Step 4. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(methyl-d3)-1H-indole-6-yl)aminonicotinic acid (15e) To a solution of 15d (110 mg, 0.28 mmol) in THF / MeOH / H2O=3 / 2 / 1 (6 mL), LiOH·H2O (23.2 mg, 0.55 mmol) was added and stirred at 40°C for 16 hours under an N2 atmosphere. The mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over sodium sulfate, evaporated under vacuum, and purified by preparative TLC (DCM / MeOH=10 / 1) to obtain 15e (85 mg, yield 69%) as a yellow solid. LC-MS (ESI, method 2), t R =1.49 min, m / z(M+H) + =384.0.

[0416] Step 5. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(methyl-d3)-1H-indole-6-yl)amino)-N-(methyl-d3)nicotinamide(15) To a solution of 15e (85 mg, 0.22 mmol) in DMF (2 mL), CD3NH2·HCl (23.5 mg, 0.33 mmol), EDCl (51.1 mg, 0.266 mmol), HOBt (36 mg, 0.266 mmol), and TEA (112 mg, 1.11 mmol, 0.15 mL) were added. The reaction mixture was stirred under an N2 atmosphere at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with EA (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, evaporated under vacuum, and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 15 as the crude product (26 mg). The crude product was then purified by preparative HPLC (Method F) to obtain 15 (5.6 mg, yield 6%) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 10.59 (s,1H), 10.34 (s,1H), 8.52-8.48 (m,2H), 7.71 (s,1H), 7.27-7.25 (m,2H), 6.95 (d,J=8.4Hz,1H), 6.40 (s,1H), 3.73 (s,3H), 1.94-1.92 (m,1H), 0.72-0.69 (m,4H). LC-MS (ESI, Method 4), t R =2.49 min, m / z(M+H) + = 400.1.

[0417] Example 16

[0418] [ka]

[0419] Step 1. 2-Bromo-4-fluoro-5-methylphenol (16b) To a solution of 16a (10 g, 79.3 mmol) in DCM (140 mL), Br2 (15.21 g, 95.1 mmol, 4.89 mL) was added under nitrogen at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with water (100 mL), extracted with EA (100 mL x 2), washed with water (100 mL x 2) and brine (100 mL x 2), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by flash chromatography (PE) to obtain 16b (14 g, yield 73%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.12 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 6.8 Hz, 1H), 2.20 (s, 3H).

[0420] Step 2. 6-Bromo-4-fluoro-3-methyl-2-nitrophenol(16c) To a solution of 16b (14 g, 68.3 mmol) in DCM (150 mL), nitric acid (3.2 mL, 81.9 mmol, 68%) was added under nitrogen at -20°C. The reaction mixture was stirred at -20°C for 2 hours. The reaction was quenched with H2O (50 mL) and extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash chromatography (PE) to obtain 16c (9.5 g, yield 55%) as a yellow solid. 1 ¹H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 2.48 (s, 3H). LC-MS (ESI, Method 2), t R =2.58 min, m / z( 79 Br, M+H) + = 250.0.

[0421] Step 3. 1-Bromo-5-fluoro-2-methoxy-4-methyl-3-nitrobenzene (16d) A solution of 16c (5g, 20.0 mmol) in DCM (50 mL) was stirred under nitrogen at 25°C, and solutions of CH3I (3.41 g, 0.024 mol, 1.49 mL) and K2CO3 (8.29 g, 60.0 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours. The reaction was then quenched with water (100 mL), extracted with ethyl acetate (100 mL), washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (EA in PE was 10-30%) to obtain 16d (4.9 g, yield 92%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.39(d,J=8.4Hz,1H),3.93(s,3H),2.18(s,3H).

[0422] Step 4. 2-(4-bromo-6-fluoro-3-methoxy-2-nitrophenyl)-N,N-dimethylethene-1-amine(16e) To a solution of 16d (2 g, 7.6 mmol) in DMF (9 mL), DMF-DMA (20 mL, 22.8 mmol) was added at 25°C under a nitrogen atmosphere. The resulting solution was stirred at 110°C for 3 hours under a nitrogen atmosphere. The solvent was evaporated under vacuum to obtain 16e (2.1 g, crude product) as a yellow oily substance, which was used directly in the next step without further purification.

[0423] Step 5. 6-Bromo-4-fluoro-7-methoxy-1H-indole(16f) To a solution of 16e (2 g, 6.3 mmol) in EtOH / HOAc = 1 / 1 (40 mL), Fe powder (1.06 g, 18.9 mmol) was added under nitrogen at 25°C. The reaction mixture was stirred at 80°C for 2 hours. The reaction was then quenched with water (50 mL), extracted with  (100 mL x 2), washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (EA in PE was 10-40%) to obtain 16f (550 mg, yield 33%) as a yellow oil. LC-MS (ESI, method 4), tR =2.75 min, m / z( 79 Br,MH) - = 242.0.

[0424] Step 6. 6-Bromo-1-ethyl-4-fluoro-7-methoxy-1H-indole (16g) To a stirred solution of 16f (700 mg, 2.88 mmol) in DMF (10 mL) under nitrogen at 0°C, NaH (127 mg, 3.17 mmol, 60% of mineral oil) was added. The reaction mixture was stirred at 0°C for 0.5 hours. C2H5I (494 mg, 3.17 mmol, 2.5 mL) was added to the mixture. The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction was quenched with water (50 mL), extracted with EA (100 mL x 2), washed with water (100 mL x 2) and brine (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (EA in PE was 10-30%) to obtain 16 g (500 mg, yield 64%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.46(d,J=3.2Hz,1H),7.04(d,J=9.2Hz,1H),6.53(d,J=3.2Hz,1H),4.35(q,J=7.2Hz,2H),3.86(s,3H),1.35(t,J=7.2Hz,3H).

[0425] Step 7. 6-(cyclopropanecarboxamide)-4-((1-ethyl-4-fluoro-7-methoxy-1H-indole-6-yl)amino)methyl nicotinate (16h) To a solution of 16 g (500 mg, 1.84 mmol) of dioxane (5 mL), Cs2CO3 (599 mg, 5.52 mmol), EPhos Pd G4 (169 mg, 0.18 mmol), EPhos (196 mg, 0.37 mmol), and Int.D (642 mg, 1.84 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was cooled to room temperature, diluted with water (10 mL), and extracted with  (15 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 16 h (180 mg, yield 22%) as a yellow solid. LC-MS (ESI, method 2), t R =1.74 min, m / z(M+H) + = 427.1.

[0426] Step 8. 6-(cyclopropanecarboxamide)-4-((1-ethyl-4-fluoro-7-methoxy-1H-indole-6-yl)aminonicotinic acid (16i) To a solution of 180 mg (0.42 mmol) of LiOH·H2O in 1.2 mL of THF, 0.6 mL of MeOH, and 0.4 mL of H2O, LiOH·H2O (36 mg, 0.846 mmol) was added and stirred at 40°C for 16 hours under an N2 atmosphere. The mixture was diluted with water (5 mL), adjusted to pH=2 with 2N HCl, and extracted with ₹ (5 mL × 3). The combined organic layer was washed with brine (5 mL × 2), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain ¹⁶i (150 mg, yield 86%) as a yellow solid. LC-MS (ESI, method 2), t R =1.61 min, m / z(M+H) + = 413.1.

[0427] Step 9. 6-(cyclopropanecarboxamide)-4-((1-ethyl-4-fluoro-7-methoxy-1H-indole-6-yl)amino)-N-(methyl-d3)nicotinamide(16) To a solution of 16i (150 mg, 0.35 mmol) in DMF (2 mL), CD3NH2·HCl (39 mg, 0.53 mmol), EDCl (82 mg, 0.42 mmol), HOBt (60 mg, 0.42 mmol), and TEA (221 mg, 2.1 mmol, 0.3 mL) were added. The reaction mixture was stirred at 25°C for 16 hours under an N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with  (5 mL × 3). The combined organic layer was washed with brine (5 mL × 2), dried over sodium sulfate, evaporated under vacuum, and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain the crude product (30 mg). The crude product was then purified by preparative HPLC (Method F) to obtain 16 (10 mg, yield 6%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.66(s,1H),10.42(s,1H),8.56(s,1H),8.50(s,1H),7.77(s,1H),7.40(d,J=3.2Hz,1H),6.78(d,J=10.8Hz,1H),6. 48(d,J=3.2Hz,1H),4.35(q,J=7.2Hz,2H),3.71(s,3H),1.94-1.93(m,1H),1.35(t,J=7.2Hz,3H),0.73-0.71(m,4H). LC-MS (ESI, method 4), t R =3.07 min, m / z(M+H) + = 429.1.

[0428] Example 17

[0429] [ka]

[0430] Step 1. 6-Bromo-1-(2,2-difluoropropyl)-7-methoxy-1H-indole (17a) To a solution of 15b (1.5 g, 6.6 mmol) in DMF (15 mL), NaH (400 mg, 9.9 mmol, 60% in mineral oil) and Int.C (700 mg, 9.9 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 3 hours under an N2 atmosphere. The reaction mixture was diluted with water (100 mL) and then extracted with  (50 mL × 2). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography (EA in PE was 10-30%) to obtain 17a (830 mg, yield 37%) as a yellow solid. LC-MS (ESI, Method 2), t R =2.24 min, m / z( 79 Br, M+H) + = 303.8.

[0431] Step 2. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indole-6-yl)amino)methyl nicotinate (17b) To a solution of 17a (800 mg, 2.63 mmol) in dioxane (6 mL), Int.D (918 mg, 2.63 mmol), Cs2CO3 (2.57 g, 7.89 mmol), EPhos (280.9 mg, 0.526 mmol), and EPhos Pd G4 (241.6 mg, 0.263 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours under an N2 atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 17b (120 mg, yield 6%) as a yellow solid. LC-MS (ESI, method 2), t R =1.65 min, m / z(M+H) + = 459.1.

[0432] Step 3. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indole-6-yl)aminonicotinic acid (17c) LiOH·H2O (20.1 mg, 0.479 mmol) was added to a solution of 17b (110 mg, 0.239 mmol) in THF / MeOH / H2O=3 / 2 / 1 (2 mL). The resulting mixture was stirred at 40°C for 16 hours under an N2 atmosphere. The mixture was diluted with water (20 mL) and extracted with EA (2 mL x 3). The combined organic layers were washed with brine (2 mL x 2), dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash chromatography (MeOH in DCM was 10-50%) to obtain 17c (55 mg, yield 41%) as a yellow solid. LC-MS (ESI, method 2), t R =1.59 min, m / z(M+H) + = 445.0.

[0433] Step 4. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-indole-6-yl)amino)-N-(methyl-d3)nicotinamide(17) A mixture of CD3NH2·HCl (16.4 mg, 0.234 mmol), 7 (35 mg, 0.078 mmol), DIPEA (30.5 mg, 0.236 mmol, 0.158 mL), and T3P (148.8 mg, 0.234 mmol, 50% purity in GaN) in DMF (2 mL) was stirred at 70°C for 12 hours. A yellow solution was formed. The reaction mixture was diluted with water (10 mL) and then extracted with GaN (1 mL × 2). The combined organic layers were washed with water (1 mL) and brine (1 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method E) to obtain 17 (3.1 mg, yield 8%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 10.62(s,1H),10.34(s,1H),8.55(s,1H),8.49(s,1H),7.69(s,1H),7.32(d,J=8.0Hz,1H),7.27(d,J=3.2Hz,1H),6.98(d,J=8.4H) z,1H),6.53(d,J=3.2Hz,1H),4.81(q,J=14.4Hz,2H),3.72(s,3H),1.92-1.90(m,1H),1.58(t,J=18.8Hz,3H),0.70-0.72(m,4H). LC-MS (ESI, method 4), t R =2.79 min, m / z(M+H) + = 461.1.

[0434] Example 18

[0435] [ka]

[0436] Step 1. 2-Chloro-5-iodo-3-methoxypyridine-4-amine (18a) To a solution of 14a (2 g, 12.6 mmol) in DMF (10 mL), NIS (4.25 g, 18.9 mmol) and TsOH·H2O (240 mg, 1.2 mmol) were added. The mixture was stirred at 70°C for 12 hours. The mixture was quenched with water (50 mL), extracted with EA (50 mL x 3), dried over Na2SO4, and concentrated to obtain crude product 18a. The residue was purified by flash chromatography (EA in PE was 5-15%) to obtain 18a (3.4 g, yield 85%) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 8.06 (s,1H), 6.33 (s,2H), 3.70 (s,3H). LC-MS (ESI, Method 2), t R =1.52 min, m / z(M+H) + = 284.9.

[0437] Step 2. (E)-2-chloro-5-(2-ethoxyvinyl)-3-methoxypyridine-4-amine(18b) To a solution of 18a (3.4 g, 12 mmol) in dioxane / H2O=4 / 1 (14 mL), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.85 g, 14.4 mmol), K2CO3 (4.98 g, 3.6 mmol), and Pd(dppf)Cl2 (1.76 g, 2.4 mmol) were added. The mixture was stirred at 60°C for 16 hours. The mixture was quenched with water (50 mL), extracted with siRNA (50 mL x 3), dried over Na2SO4, and concentrated to obtain crude product 18b. The residue was purified by flash chromatography (EA in PE was 10-20%) to obtain 18b (2.56 g, yield 88%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.74(s,1H),6.75(d,J=12.8Hz,1H),5.51(d,J=12.8Hz,1H),4.44(s,2H),3.92(q,J=7.2Hz,3H),3.85(s,3H),1.35(t,J=7.2Hz,3H). LC-MS (ESI, method 2), t R =1.27 min, m / z(M+H) + = 229.1.

[0438] Step 3. 6-Chloro-7-methoxy-1H-pyrrolo[3,2-c]pyridine(18c) To a solution of 18b (2.56 g, 11.2 mmol) in DCM (20 mL), TFA (5 mL) was added. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated. The residue was dissolved in water, adjusted to pH=7 with aqueous NaHCO3 solution, extracted with DCM (10 mL x 3), dried over Na2SO4, and concentrated to obtain 18c (2 g, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 2), t R =0.20 min, m / z(M+H) + = 183.0.

[0439] Step 4. 6-Chloro-1-ethyl-7-methoxy-1H-pyrrolo[3,2-c]pyridine(18d) Cs2CO3 (1.52 g, 11 mmol) was added to a stirred solution of 18c (1 g, 5.50 mmol) and iodoethane (1.29 g, 8.25 mmol) in DMF (10 mL) at 25°C. The reaction mixture was stirred at 70°C for 16 hours. 30 mL of water was added to the mixture. The mixture was extracted with  (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (EA in PE was 10-30%) to obtain 18d (650 mg, crude product), which was used directly in the next step without further purification. LC-MS (ESI, Method 2), t R =1.54 min, m / z(M+H) + = 211.0.

[0440] Step 5. N-(1-ethyl-7-methoxy-1H-pyrrolo[3,2-c]pyridine-6-yl)-1,1-diphenylmethaneimine(18e) Pd2(dba)3 (522.1 mg, 0.57 mmol) and t-BuONa (821.1 mg, 8.54 mmol) were added to a stirred solution of 18d (600 mg, 2.85 mmol), diphenylmethaneimine (1.55 g, 8.54 mmol), and BINAP (709.4 mg, 1.14 mmol) in toluene (15 mL) at 25°C. The reaction mixture was stirred at 110°C for 16 hours. Water (40 mL) was added to the mixture. The mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (PE / EA = 3 / 1) to obtain 18e (500 mg, yield 46%) as a yellow solid. LC-MS (ESI, method 2), t R =1.65min m / z(M+H) + = 356.1.

[0441] Step 6. 1-Ethyl-7-methoxy-1H-pyrrolo[3,2-c]pyridine-6-amine(18f) To a stirred solution of 18e (500 mg, 1.41 mmol) in DCM (10 mL) at 25°C, TFA (3 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction was quenched with NaHCO3 aqueous solution (15 mL) and extracted with DCM (30 mL x 3). The combined organic layer was washed with brine (5 mL), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by preparative TLC using (DCM / MeOH = 10 / 1) to obtain 18f (170 mg, yield 61%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.06(s,1H),7.16(d,J=3.2Hz,1H),6.39(d,J=3.2Hz,1H),4.25(q,J=7.2Hz,2H),3.75(s,3H),1.33(t,J=7.2Hz,3H). LC-MS (ESI, method 2), t R =1.13 min, m / z(M+H) + = 192.1.

[0442] Step 7. 6-Chloro-4-((1-ethyl-7-methoxy-1H-pyrrolo[3,2-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide (18g) A solution of 18f (70 mg, 0.37 mmol) and 4,6-dichloro-N-(methyl-d3)nicotinamide (152.3 mg, 0.73 mmol) in THF (7 mL) was stirred at 0°C, and LiHMDS (1.84 mL, 1 mol / L in THF) was added dropwise. The reaction mixture was stirred at 0°C for 4 hours. A saturated NH4Cl solution (2 mL) was added to the mixture. The reaction products were extracted with DCM (15 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 18 g (100 mg, yield 75%) as a yellow solid. LC-MS (ESI, method 2), t R =1.36 min, m / z(M+H) + =363.0.

[0443] Step 8. 6-(cyclopropanecarboxamide)-4-((1-ethyl-7-methoxy-1H-pyrrolo[3,2-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(18) A mixture of 18 g (100 mg, 0.28 mmol), cyclopropanecarboxamide (117.3 mg, 1.38 mmol), and Cs2CO3 (179.6 mg, 0.55 mmol) in dioxane (10 mL) was stirred under nitrogen at 25°C, and BrettPhos (29.6 mg, 0.055 mmol) and BrettPhos Pd G3 (25.0 mg, 0.027 mmol) were added. The reaction mixture was stirred at 90°C for 16 hours. Water (20 mL) was added to the mixture. The mixture was extracted with EA (30 mL x 2). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain 18 (30 mg, crude product). The crude product was purified by preparative HPLC (Method E) to obtain 18 (9.5 mg, yield 8%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.30(s,1H),10.62(s,1H),9.02(s,1H),8.58(s,1H),8.51(s,1H),8.36(s,1H),7.38(d,J=3.2Hz,1H),6.55(d,J= 3.2Hz,1H), 4.38-4.31(q,J=7.2Hz,2H),3.83(s,3H),2.02-1.95(m,1H),1.37(t,J=7.2Hz,3H),0.80-0.74(m,4H). LC-MS (ESI, method 4), t R =2.45 min, m / z(M+H) + = 412.2.

[0444] Example 19

[0445] [ka]

[0446] Step 1. 2-(6-chloro-5-methoxypyrimidine-4-yl)-2-cyanoacetate tert-butyl (19a) To a solution of tert-butyl 2-cyanoacetate (9.46 g, 67.04 mmol) in THF (200 mL), NaH (5.36 g, 134.08 mmol, 60% in mineral oil) was added at 0°C. After stirring at 0°C for 30 minutes, a solution of 5a (10 g, 55.86 mmol) in THF (20 mL) was added. The mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (150 mL) and acidified to pH=2 with 2N HCl. The mixture was extracted with  (300 mL × 2). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure to obtain 19a (15 g, yield 95%) as a yellow solid. LC-MS (ESI, method 3) R =1.13 min, m / z(M+H-56) + = 228.2.

[0447] Step 2. 2-(6-chloro-5-methoxypyrimidine-4-yl)acetonitrile (19b) To a mixture of 19a (7.5 g, 26.44 mmol) in DCM (100 mL), TFA (50 mL) was added at 0°C. The mixture was stirred at room temperature for 4 hours. The solvent was concentrated. The residue was diluted with H2O (100 mL), adjusted to pH=9 with saturated Na2CO3 solution, and extracted with ELISA (100 mL x 3). The combined organic layers were concentrated under reduced pressure to obtain 19b (4.8 g, 99% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 8.72 (s, 1H), 4.05 (s, 3H), 3.97 (s, 2H).

[0448] Step 3. 2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)acetonitrile(19c) A mixture of 19b (4.8 g, 26.14 mmol), TEA (7.3 mL, 52.3 mmol), and DMBNH2 (5.68 g, 33.99 mmol) in EtOH (30 mL) was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was diluted with H2O (40 mL) and extracted with SiO2 (80 mL x 2). The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE / EA = 1 / 1) to obtain 19c (5.35 g, yield 65%) as a yellow oil. LC-MS (ESI, method 3) t R =0.99 min, m / z(M+H) + = 315.3.

[0449] Step 4. (Z)-2-(6-((2,4-dimethoxybenzyl)amino)-5-methoxypyrimidine-4-yl)-3-(dimethylamino)acrylonitrile(19d) The mixture of 19c (5.35 g, 17.02 mmol) in DMF-DMA (35 mL) was stirred at 130°C for 10 hours. The mixture was cooled and concentrated under reduced pressure to obtain 19d (6.29 g, yield shown) as a yellow oily substance. LC-MS (ESI, Method 3) t R =1.06 min, m / z(M+H) + = 370.2.

[0450] Step 5. 5-((2,4-dimethoxybenzyl)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-carbonitrile(19e) To a mixture of 19d (3.0 g, 8.12 mmol) in DCM (50 mL), a solution of O-(mesitylsulfonyl)hydroxylamine (2.10 g, 9.75 mmol) in DCM (10 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours. Another batch of O-(mesitylsulfonyl)hydroxylamine (0.58 g, 2.69 mmol) in DCM (5 mL) was added to the reaction mixture at 0°C. The mixture was stirred at room temperature for 18 hours and purified by flash chromatography on silica gel (DCM / EA = 20 / 1) to obtain 19e (730 mg, yield 26%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 8.80(s,1H),8.03(s,1H),7.21(d,J=8.4Hz,1H),6.47(d,J=2.4Hz,1H),6.41(dd,J=8.4H z,2.4Hz,1H),5.56(s,1H),4.64(d,J=5.6Hz,2H),3.90(s,3H),3.89(s,3H),3.76(s,3H).

[0451] Step 6. 5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-carbonitrile(19f) To a solution of 19e (400 mg, 1.18 mmol) in DCM (2 mL), TFA (2 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum at 30°C. The residue was dissolved in H2O (80 mL), and the solution was adjusted to pH=12 with 1 M NaOH solution. The mixture was extracted using DCM (80 mL x 3). The combined organic layer was concentrated, and the residue was purified by silica gel flash chromatography (DCM / MeOH = 10 / 1) to obtain 19f (100 mg, yield 44%) as a yellow solid. LC-MS (ESI, method 2) t R =0.60 min, m / z(M+H) + = 190.2.

[0452] Step 7. 4-((3-cyano-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)amino)-6-(cyclopropanecarboxamide)methyl nicotinate (19) A mixture of 19f (100 mg, 0.53 mmol), A2 (148 mg, 0.58 mmol), BrettPhos Pd G3 (48 mg, 0.053 mmol), BrettPhos (28 mg, 0.053 mmol), and Cs2CO3 (344 mg, 1.06 mmol) in 1,4-dioxane (1 mL) was stirred overnight at 90°C under an N2 atmosphere. After cooling to room temperature, the mixture was concentrated. The residue was purified by flash chromatography on silica gel (DCM / EA=20 / 1) to obtain 19 (58 mg, yield 27%) as a brown solid. 1¹H NMR (400MHz, DMSO-d6) δ 9.59(s,1H),9.36(s,1H),8.81(s,1H),8.71(s,1H),4.03(s,3H),3.92(s,3H),2.07-2.04(m,1H),0.85-0.81(m,4H). LC-MS (ESI, Method 2) t R =1.60 min, m / z(M+H) + = 408.2.

[0453] Example 20

[0454] [ka]

[0455] Step 1. 4-((3-cyano-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)amino)-6-(cyclopropanecarboxamide)-N-methylnicotinamide(20) To a solution of 19 (100 mg, 0.25 mmol) and CH3NH2 (2.45 mL, 2.45 mmol, 1 M in THF) in THF (4 mL), trimethylaluminum (1.23 mL, 1.23 mmol, 1 M in petroleum ether) was slowly added dropwise. The reaction mixture was stirred at 70°C for 5 hours. After cooling to room temperature, the reaction was quenched with H2O (1 mL), the pH was adjusted to 6 with 2 M HCl, and the mixture was extracted with siRNA (5 mL x 2). The organic layer was separated and concentrated, and the residue was purified by preparative HPLC (Method A) to obtain 20 (6 mg, yield 6%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 12.17(s,1H),10.86(s,1H),9.54(s,1H),9.26(s,1H),8.81(s,1H),8.68(s,1H),8.65(s,1H),4.00(s,3H),2.84(d,J=4.4Hz,3H),2.05-1.98(m,1H),0.86-0.83(m,4H). LC-MS (ESI, Method 2) t R =2.60 min, m / z(M+H) + = 407.1.

[0456] Example 21

[0457] [ka]

[0458] Step 1. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-6-((5-fluoropyridine-2-yl)amino)-N-(methyl-d3)nicotinamide(21) 8c (30 mg, 0.072 mmol), 5-fluoropyridine-2-amine (12 mg, 0.11 mmol), and K2CO3 (35 mg, 0.25 mmol) t BrettPhos Pd G3 (10 mg, 0.011 mmol) and BrettPhos (10 mg, 0.019 mmol) were added to a solution in BuOH (2 mL) under an N2 atmosphere. The mixture was stirred at 110°C for 5 hours. The reaction mixture was diluted with water (20 mL) and then extracted with  (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method E) to obtain 21 (12 mg, yield 34%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),9.87(s,1H),9.02(s,1H),8.76(s,1H),8.56(s,1H),8.53(s,1H),8.34(s,1H),8.25(d,J=2.8 Hz,1H),7.78-7.72(m,1H),7.68-7.61(m,1H),4.93(t,J=13.2Hz,2H),3.91(s,3H),1.71(t,J=19.2Hz,3H). LC-MS (ESI, method 4) R =2.32 min, m / z(M+H) + = 490.3.

[0459] Example 22

[0460] [ka]

[0461] Step 1. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazole-3-yl)amino)nicotinamide(22) 8c (30 mg, 0.072 mmol), 1-methyl-1H-pyrazole-3-amine (11 mg, 0.11 mmol), and K2CO3 (35 mg, 0.25 mmol) t BrettPhos Pd G3 (10 mg, 0.011 mmol) and BrettPhos (10 mg, 0.019 mmol) were added to a solution in BuOH (2 mL) under an N2 atmosphere. The mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with water (20 mL) and then extracted with  (20 mL × 2). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method E) to obtain 22 (21 mg, yield 60%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.74(s,1H),9.32(s,1H),8.71(s,1H),8.64(s,1H),8.47-8.44(m,2H),8.33(s,1H),7.53(d,J=2.4Hz ,1H),6.22(d,J=2.4Hz,1H),4.93(t,J=13.2Hz,2H),3.90(s,3H),3.76(s,3H),1.70(t,J=19.2Hz,3H). LC-MS (ESI, method 4) R =2.08 min, m / z(M+H) + = 475.4.

[0462] Example 23

[0463] [ka]

[0464] Step 1. 6-Chloro-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-methylnicotinamide (23a) To a solution of 8b (60 mg, 0.25 mmol) in DMF (4 mL), NaH (40 mg, 0.99 mmol, 60% in mineral oil) was added at 0°C. The mixture was stirred for 30 minutes, then 4,6-dichloro-N-methylnicotinamide (66 mg, 0.32 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was quenched with saturated NH4Cl (20 mL) and extracted with  (20 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried, and concentrated under vacuum. The residue was purified by flash chromatography ( in DCM was 65%) to obtain 23a (53 mg, yield 52%) as a yellow solid. LC-MS (ESI, method 4) t R =2.81 min, m / z(M+H) + = 411.2.

[0465] Step 2. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-methylnicotinamide (23) To a solution of 23a (20 mg, 0.049 mmol) and cyclopropanecarboxamide (17 mg, 0.19 mmol) in dioxane (2 mL), Pd(OAc)2 (2 mg, 0.009 mmol), dppf (11 mg, 0.019 mmol), and K3PO4 (31 mg, 0.015 mmol) were added under an N2 atmosphere. The mixture was stirred at 100°C for 3 hours. The reaction mixture was diluted with water (20 mL) and then extracted with siRNA (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (Method E) to obtain 23 (6 mg, yield 29%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),10.73(s,1H),9.22(s,1H),8.76-8.64(m,2H),8.56(s,1H),8.32(s,1H),4.93(t,J=13.2H z,2H),3.89(s,3H),2.82(d,J=4.4Hz,3H),2.05-1.97(m,1H),1.70(t,J=19.2Hz,3H),0.84-0.76(m,4H). LC-MS (ESI, method 4) R =1.97 min, m / z(M+H) + = 460.3.

[0466] Example 24

[0467] [ka]

[0468] Step 1. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(24) To a solution of 8b (10 mg, 0.041 mmol), Int.F (16 mg, 0.062 mmol), dppf (9 mg, 0.017 mmol), and K3PO4 (26 mg, 0.12 mmol) in dioxane (3 mL), Pd(OAc)2 (2 mg, 0.008 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 6 hours under nitrogen protection. The reaction mixture was added to H2O (10 mL) and extracted with siRNA (20 mL). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography and preparative HPLC (Method E) to obtain 24 (1.5 mg, yield 8%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 12.15(s,1H),11.32(s,1H),9.63(s,1H),9.26(s,1H),8.73(s,1H),8.36(s,1H),4.94(t, J=12.8Hz,2H),3.93(s,3H),2.18-2.08(m,1H),1.70(t,J=19.2Hz,3H),0.91-0.83(m,4H). LC-MS (ESI, method 4) R =2.13 min, m / z(M+H) + = 464.3.

[0469] Example 25

[0470] [ka]

[0471] Step 1. N-[(tert-butoxy)carbonyl]-N-(2-chloro-3-methoxypyridine-4-yl)carbamate tert-butyl(25a) A solution of 14a (3g, 18.92 mmol), DMAP (2.31g, 18.92 mmol), and DIPEA (4.89g, 37.83 mmol, 6.59 mL) in THF (50 mL) was mixed with Boc2O (8.26 g, 8.68 mL) in an ice bath, and the mixture was stirred overnight at room temperature. The mixture was diluted with H2O (100 mL), extracted with SiO2 (100 mL x 3), washed with brine (100 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain crude compound 25a (6.79 g, yield shown) as a white solid. LC-MS (ESI, method 4) t R =3.44 min, m / z(M+H) + = 359.3.

[0472] Step 2. (2-chloro-3-methoxypyridine-4-yl)carbamate tert-butyl(25b) To a solution of 25a (6.79 g, 18.92 mmol) in MeOH (70 mL), K2CO3 (13.08 g, 94.62 mmol) was added. The mixture was then stirred at 70°C for 4 hours. The mixture was concentrated, diluted with H2O (100 mL), extracted with siRNA (50 mL x 3), washed with brine (50 mL), dried over Na2SO4, filtered, the filtrate was concentrated, and purified by flash chromatography (PE / EA = 20 / 1~1 / 1) to obtain compound 25b (4.0 g, yield 82%) as a white solid. LC-MS (ESI, method 4) t R =2.97 min, m / z(M+H) + = 259.1.

[0473] Step 3. (2,2,2-trifluoroethyl)carbamate = tert-butyl = (2-chloro-3-methoxypyridine-4-yl) (25c) In a solution of 25b (500 mg, 1.93 mmol) in THF (5 mL) t BuOK (281 mg, 2.51 mmol) was added, and the mixture was stirred at 60°C for 30 minutes. Then, 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (583 mg, 2.51 mmol) was added to the mixture, and the mixture was stirred at 60°C for 2 hours. Then, the mixture was cooled to room temperature. t Another batch of BuOK (281 mg, 2.51 mmol) was added. The mixture was then stirred at 60°C for 30 minutes. Next, 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (583 mg, 2.51 mmol) was added to the mixture and stirred at 60°C for 2 hours. The mixture was diluted with H2O (30 mL), extracted with  (30 mL x 3), washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain crude compound 25c (500 mg, yield 76%) as a yellow solid. LC-MS (ESI, method 4) t R =3.37 min, m / z(M+H) + = 341.2.

[0474] Step 4. 2-Chloro-3-methoxy-N-(2,2,2-trifluoroethyl)pyridine-4-amine(25d) To a solution of 25c (500 mg, 1.47 mmol) in DCM (5 mL), TFA (2.24 g, 19.60 mmol, 1.5 mL) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated, diluted with H2O (10 mL), adjusted to pH > 7 with aqueous Na2CO3 solution, extracted with siRNA (10 mL x 3), washed with brine (20 mL), dried over Na2SO4, filtered, the filtrate was concentrated, and purified by flash chromatography (PE / EA = 20 / 1~2 / 1) to obtain compound 25d (233 mg, yield 66%) as a white solid. LC-MS (ESI, method 4) t R =2.07 min, m / z(M+H) + = 241.0.

[0475] Step 5. 2-Chloro-3-methoxy-5-nitro-N-(2,2,2-trifluoroethyl)pyridine-4-amine(25e) To a solution of 25d (200 mg, 0.83 mmol) in concentrated H2SO4 (2 mL), KNO3 (109 mg, 1.08 mmol) was added at 0°C, and the mixture was stirred at room temperature for 6 hours. The mixture was added dropwise to ice water, then basicized to pH > 9 with NH3·H2O, extracted with siRNA (15 mL × 4), washed with brine (20 mL), dried over Na2SO4, and concentrated to obtain compound 25e (160 mg, yield 67%) as a yellow solid. LC-MS (ESI, method 4) t R =2.93 min, m / z(M+H) + =286.0.

[0476] Step 6. 6-Chloro-5-methoxy-N 4 -(2,2,2-trifluoroethyl)pyridine-3,4-diamine(25f) A mixture of 25e (160 mg, 0.56 mmol), Fe powder (156 mg, 2.80 mmol), and NH4Cl (150 mg, 2.80 mmol) in MeOH (2 mL) and H2O (0.5 mL) was stirred at 70°C for 2 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was concentrated, diluted with H2O (10 mL), basicized to pH > 13 with NH3·H2O, extracted with ethyl acetate (10 mL x 3), washed with brine (10 mL), dried over Na2SO4, and concentrated to obtain compound 25f (130 mg, yield 91%) as a yellow solid. LC-MS (ESI, method 4) t R =2.09 min, m / z(M+H) + = 256.1.

[0477] Step 7. 6-Chloro-7-methoxy-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine (25g) To a solution of 25 f (130 mg, 0.51 mmol) of trimethoxymethane (2 mL), HCOOH (0.1 mL) was added, and the mixture was stirred at 105°C for 4 hours. The mixture was concentrated, diluted with H2O (20 mL), extracted with  (15 mL x 3), washed with brine (15 mL), dried over Na2SO4, and concentrated to obtain 25 g (130 mg, yield 96%) of the crude compound as a yellow solid. LC-MS (ESI, method 4) t R =2.24 min, m / z(M+H) + =266.0.

[0478] Step 8. 7-Methoxy-N-(4-methoxybenzyl)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-6-amine (25h) A mixture of 25 g (120 mg, 0.45 mmol), (4-methoxyphenyl)methaneamine (124 mg, 0.90 mmol), BrettPhos Pd G3 (82 mg, 0.09 mmol), and tBuONa (108 mg, 1.13 mmol) in dioxane (1.5 mL) was stirred at 90°C for 2 hours. The mixture was concentrated and purified by flash chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to obtain compound 25 h (150 mg, yield 90%) as a yellow solid. LC-MS (ESI, method 4) t R =2.24 min, m / z(M+H) + = 367.2.

[0479] Step 9. 7-Methoxy-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-6-amine(25i) To a solution of 25h (150 mg, 0.41 mmol) in DCM (2 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, diluted with H2O (20 mL), adjusted to pH > 10 with aqueous Na2CO3 solution, and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, concentrated, and purified by flash chromatography (DCM / MeOH = 100 / 1~5 / 1) to obtain compound 25i (57 mg, yield 57%) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 8.19 (s, 1H), 8.02 (s, 1H), 5.63 (s, 2H), 5.15 (q, J=9.2Hz, 2H), 3.76 (s, 3H). LC-MS (ESI, Method 4) t R =0.44 min, m / z(M+H) + = 247.1.

[0480] Step 10. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridine-6-yl)amino)-N-(methyl-d3)nicotinamide(25) A mixture of 25i (10 mg, 0.041 mmol), Int.A (10 mg, 0.041 mmol), Pd(OAc)2 (0.9 mg, 0.004 mmol), dppf (4.5 mg, 0.008 mmol), and K3PO4 (17 mg, 0.08 mmol) in dioxane (0.5 mL) was stirred at 100°C for 4 hours. The mixture was concentrated and purified by preparative HPLC (Method E) to obtain compound 25 (6.3 mg, yield 33%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d6) δ 11.55(s,1H), 10.71(s,1H), 9.15(s,1H), 8.66(s,1H), 8.56(s,1H), 8.54(s,1H), 8.33(s,1H), 5.28(q,J=9.2Hz,2H), 3.90(s,3H), 2.00-1.98(m,1H), 0.81-0.77(m,4H). LC-MS (ESI, Method 4) t R =2.01 min, m / z(M+H) + = 467.3.

[0481] Example 26

[0482] [ka]

[0483] Step 1. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)methyl nicotinate (26) To a solution of 8b (20 mg, 0.083 mmol), A2 (32 mg, 0.12 mmol), dppf (18 mg, 0.033 mmol), and K3PO4 (53 mg, 0.25 mmol) in dioxane (3 mL), Pd(OAc)2 (4 mg, 0.017 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 6 hours under nitrogen protection. The reaction mixture was added to H2O (10 mL) and extracted with siRNA (20 mL). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography and preparative HPLC (Method E) to obtain 26 (25 mg, yield 66%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.92(s,1H),10.91(s,1H),9.32(s,1H),8.78(s,1H),8.73(s,1H),8.37(s,1H),4.94(t,J=13.2 Hz,2H),3.92(s,3H),3.91(s,3H),2.07-1.98(m,1H),1.70(t,J=19.2Hz,3H),0.84-0.80(m,4H). LC-MS (ESI, method 4) R =2.57 min, m / z(M+H) + = 461.3.

[0484] Example 27

[0485] [ka]

[0486] Step 1. 3-Bromo-2-methoxy-6-nitroaniline (27b) To a solution of 27a (3.00 g, 17.84 mmol) in ACN (30 mL), NBS (3.22 g, 17.84 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with H2O (100 mL), extracted with siRNA (50 mL x 3), washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography (EA in PE was 5-20%) to obtain 27b (1.35 g, yield 31%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 4.96 (brs, 2H), 3.99 (s, 3H). LC-MS (ESI, method 4) R =2.76 min, m / z( 79 Br, M+H) + = 247.0.

[0487] Step 2. 4-Bromo-3-methoxybenzene-1,2-diamine(27c) To a solution of 27b (500 mg, 2.02 mmol) in EtOH (8 mL), an aqueous solution of Na2S2O4 (8 mL, 1 M) was added, and the mixture was stirred at 80°C for 2 hours. The mixture was diluted with H2O (30 mL), extracted with siRNA (30 mL x 3), washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to obtain crude product 27c (400 mg, yield 91%) as a yellow solid. LC-MS (ESI, method 4) t R =1.21 min, m / z( 79 Br, M+H) + = 217.0.

[0488] Step 3. 6-bromo-7-methoxy-1H-benzimidazole (27d) A solution of 27c (400 mg, 1.84 mmol) in HCOOH (5 mL) was stirred at 100°C for 1 hour. The mixture was concentrated, diluted with NaHCO3 aqueous solution (30 mL), extracted with ₹ (30 mL x 3), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM was 0-10%) to obtain 27d (370 mg, yield 88%) as a yellow solid. LC-MS (ESI, method 4) t R =0.99 min, m / z( 79 Br, M+H) + = 227.0.

[0489] Step 4. 6-Bromo-7-methoxy-1-(2,2,2-trifluoroethyl)benzimidazole (27e) To a solution of 27d (100 mg, 0.44 mmol) in DMF (1.5 mL), K3PO4 (140 mg, 0.66 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (112 mg, 0.48 mmol) were added, and the mixture was stirred at 80°C for 12 hours. The mixture was diluted with H2O (30 mL), extracted with siRNA (20 mL x 3), washed with brine (40 mL), dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography (PE in EA was 10-50%) to obtain 27e (40 mg, yield 29%) as a yellow gum-like substance. 1 ¹H NMR (400MHz, CDCl3): δ 7.87 (s, 1H), 7.48-7.40 (m, 2H), 5.02 (q, J=8.4Hz, 2H), 4.04 (s, 3H). LC-MS (ESI, Method 4) t R =2.77 min, m / z( 79 Br, M+H) + =309.0.

[0490] Step 5. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-yl)amino)methyl nicotinate (27f) A mixture of 27e (23 mg, 0.10 mmol), Int.D (35 mg, 0.10 mmol), BrettPhos Pd G3 (9 mg, 0.01 mmol), BrettPhos (11 mg, 0.02 mmol), and Cs2CO3 (159 mg, 0.50 mmol) in dioxane (2 mL) was stirred under N2 at 100°C for 16 hours. The mixture was diluted with H2O (10 mL), extracted with  (10 mL x 3), washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography (MeOH / DCM = 10 / 1) to obtain 27f (25 mg, yield 55%) as a yellow solid. LC-MS (ESI, method 4) t R =2.98 min, m / z(M+H) + = 464.2.

[0491] Step 6. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-yl)aminonicotinic acid (27g) A mixture of 27f (25 mg, 0.05 mmol) and LiOH·H2O (7 mg, 0.15 mmol) in THF (2 mL) and water (1 mL) as cosolvents was stirred at 20°C for 24 hours. A yellow solution was formed. The reaction mixture was concentrated and vacuum-dried to obtain 27 g (24 mg, crude product) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) R =1.83 min, m / z(M+H) + = 450.2.

[0492] Step 7. 6-(cyclopropanecarboxamide)-4-((7-methoxy-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-6-yl)amino)-N-(methyl-d3)nicotinamide(27) A mixture of CD3NH2·HCl (6 mg, 0.08 mmol), 27 g (24 mg, crude product), DIPEA (21 mg, 0.16 mmol), and T3P (52 mg, 0.08 mmol, 50% purity in Â) in DMF (1 mL) was stirred at 30°C for 3 days. A yellow solution was formed. The reaction mixture was diluted with water (30 mL) and extracted with  (40 mL × 3). The combined organic layer was washed with water (40 mL × 3) and brine (40 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM was 0-10%) to obtain 27 (5.3 mg, yield 21%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.68(s,1H),10.41(s,1H),8.60(s,1H),8.51(s,1H),8.26(s,1H),7.70(s,1H),7.47(d,J=7.2Hz,1 H),7.19(d,J=7.2Hz,1H),5.30(q,J=9.2Hz,2H),3.78(s,3H),1.97-1.90(m,1H),0.76-0.66(m,4H). LC-MS (ESI, method 4)R =3.33 min, m / z(M+H) + = 466.3.

[0493] Example 28

[0494] [ka]

[0495] Step 1. 2-Chloro-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide(28a) To a solution of 8b (70 mg, 0.29 mmol) and Int.E (91 mg, 0.43 mmol) in DMF (10 mL), NaH (35 mg, 1.44 mmol, 60% of mineral oil) was added at 0°C under nitrogen protection. The reaction mixture was stirred at 0°C to room temperature for 3 hours. H2O (10 mL) was added, and the solution was extracted with  (20 mL x 2). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by flash chromatography (MeOH in DCM was 1-15%) to obtain 28a (25 mg, yield 21%) as a yellow solid. LC-MS (ESI, method 4) t R =2.12 min, m / z(M+H) + = 415.2.

[0496] Step 2. 2-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide(28) To a solution of 28a (20 mg, 0.048 mmol), BrettPhos Pd G3 (9 mg, 0.01 mmol), BrettPhos (10 mg, 0.02 mmol), and Cs2CO3 (47 mg, 0.14 mmol) in dioxane (2 mL), cyclopropanecarboxamide (21 mg, 0.24 mmol) was added at room temperature. The reaction mixture was stirred at 100°C for 3 hours under nitrogen protection. H2O (10 mL) was added, and the solution was extracted with  (20 mL). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (Method E) to obtain 28 (2.5 mg, yield 11%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.12(s,1H),10.28(s,1H),8.74(s,1H),8.72(s,1H),8.67(s,1H),8.37(s,1H),4.98(t,J=13.2Hz ,2H),3.83(s,3H),2.73-2.61(m,1H),1.70(t,J=19.2Hz,3H),0.72-0.64(m,2H),0.49-0.41(m,2H). LC-MS (ESI, method 4) R =2.12 min, m / z(M+H) + = 464.3.

[0497] Example 29

[0498] [ka]

[0499] Step 1. 5-((tert-butoxycarbonyl)amino)-4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate methyl(29a) A mixture of methyl propionate (749 mg, 8.91 mmol, 7.93 mL), 6c (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 ₹ (50 mL × 2). The combined organic layer was washed with water (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (₹10-30%) to obtain 29a (350 mg, yield 24%) as a yellow solid. 1 ¹H NMR (400MHz, CDCl3) δ 8.35 (s, 1H), 8.28 (d, J=7.6Hz, 1H), 8.01 (d, J=7.6Hz, 1H), 7.32 (brs, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 1.55 (s, 9H). LC-MS (ESI, Method 4) t R =4.13 min, m / z(M+H) + =322.1.

[0500] Step 2. 4-methoxypyrazolo[1,5-a]pyridine-5-amine (29b) The mixture of 29a (350 mg, 1.09 mmol) in concentrated H2SO4 / H2O (3 mL, v / v=1 / 1) was stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was basicized to pH=9 with 10% NaOH aqueous solution and extracted with siRNA (10 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain 29b (152 mg, yield 86%) as a black solid. LC-MS (ESI, method 3) t R =0.79 min, m / z(M+H) + = 164.0.

[0501] Step 3. 6-(cyclopropanecarboxamide)-4-((4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino)-N-(methyl-d3)nicotinamide(29c) A solution of 29b (150 mg, 0.92 mmol), Int.A (236 mg, 0.92 mmol), and TsOH·H2O (4 mg, 0.02 mmol) in dioxane (0.5 mL) was stirred at 100°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH = 20 / 1) to obtain compound 29c (90 mg, yield 26%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.76(s,1H),10.51(s,1H),8.60(s,1H),8.52(s,1H),8.51(d,J=7.2Hz,1H),7.98(d,J=2.4Hz,1H),7.82 (s,1H),6.90(d,J=7.2Hz,1H),6.70(d,J=2.4Hz,1H),3.92(s,3H),1.98-1.95(m,1H),0.76-0.74(m,4H). LC-MS (ESI, method 2) R =2.21 min, m / z(M+H) + =384.1.

[0502] Step 4. 4-((3-bromo-4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino)-6-(cyclopropanecarboxamide)-N-(methyl-d3)nicotinamide(29) To a solution of 29c (90 mg, 0.23 mmol) in DMF (1 mL), NBS (50 mg, 0.28 mmol) was added at 0°C. After stirring at 30°C for 12 hours, the reaction mixture was poured into H2O (5 mL), and the resulting solid was filtered. The filtered cake was collected by filtration and purified by preparative HPLC (Method A) to obtain 29 (12 mg, yield 11%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.83(s,1H),10.74(s,1H),8.65(s,1H),8.59(d,J=7.6Hz,1H),8.56(s,1H),8.07(s,1H) ),7.91(s,1H),7.02(d,J=7.6Hz,1H),3.82(s,3H),1.99-1.96(m,1H),0.78-0.75(m,4H). LC-MS (ESI, method 2) R =1.11 min, m / z( 79Br, M+H) + = 462.0.

[0503] Example 30

[0504] [ka]

[0505] Step 1. 5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylate methyl (30a) A mixture of 5g (6.7g, 30.15 mmol) and DMF-DMA (7.19g, 60.31 mmol) in 20 mL of DMF was stirred at 50°C for 4 hours. The mixture was concentrated to obtain 30a (8g, 96% yield) as a brown oily substance, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R =0.73 min, m / z(M+H) + = 278.3.

[0506] Step 2. 5-(((dimethylamino)methylene)amino)-4-methoxypyrazolo[1,5-c]pyrimidine-3-carboxylic acid (30b) NaOH (2.16 g, 54.10 mmol) was added to a mixture of 30a (7.5 g, 27.05 mmol) in MeOH (50 mL) and H2O (25 mL). The mixture was stirred at 45°C for 4 hours and diluted with 25 mL of water. The resulting mixture was concentrated to remove the organic layer, and the aqueous layer was adjusted to pH=1 with 2 M HCl. The formed solid was filtered and dried to obtain 30b (7.12 g, yield shown) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 9.57 (s, 1H), 8.95 (s, 1H), 8.58 (s, 1H), 3.86 (s, 3H), 3.45 (s, 3H), 3.38 (s, 3H).

[0507] Step 3. N'-(3-iodo-4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)-N,N-dimethylformimidoamide(30c) To a solution of 30b (4g, 11.40 mmol) in DMF (30 mL), NaHCO3 (1.91 g, 22.79 mmol) was added at 0°C. NIS (5.13 g, 22.79 mmol) was added to the reaction mixture in small amounts over 10 minutes. The reaction mixture was stirred at 15°C for 1 hour, then diluted with siRNA (80 mL). The mixture was washed with saturated Na2S2O3 (30 mL x 2), saturated NaHCO3 (30 mL x 2), and brine (50 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was stirred in acetonitrile (5 mL) for 30 minutes and filtered. The filtered cake was dried to obtain 30c (1.63 g, yield 41%) as a white solid. LC-MS (ESI, method 3) t R =0.88 min, m / z(M+H) + =346.1.

[0508] Step 4. N'-(4-methoxypyrazolo[1,5-c]pyrimidine-5-yl)-N,N-dimethylformimidoamide (30d) To a solution of 30c (600 mg, 1.74 mmol) and TEA (352 mg, 3.48 mmol, 0.48 mL) in MeOH / THF (4 mL / 4 mL), Pd / C (60 mg, 10% carbon-supported material moistened with 50% water) and Pd(OH)2 / C (60 mg, 10% carbon-supported material moistened with 55% water) were added at 10°C. The mixture was stirred at 30°C for 24 hours under H2 (1 atm). The mixture was filtered, and the filtrate was concentrated to obtain 30d (350 mg, 92% yield) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI, Method 3) t R =0.66 min, m / z(M+H) + = 220.1.

[0509] Step 5. N'-(4-methoxy-3-(2,2,2-trifluoroacetyl)pyrazolo[1,5-c]pyrimidine-5-yl)-N,N-dimethylformimamide(30e) To a solution of 30d (350 mg, 1.60 mmol) of pyridine (3 mL), trifluoroacetic anhydride (503 mg, 2.39 mmol, 0.33 mL) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes and then at 30°C for 12 hours. The reaction mixture was concentrated to dryness and purified by flash chromatography on silica gel (PE / EA = 1 / 1) to obtain 30e (150 mg, yield 30%) as a brown solid. LC-MS (ESI, method 3) t R =0.97 min, m / z(M+H) + = 316.3.

[0510] Step 6. 1-(5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-yl)-2,2,2-trifluoroethane-1-one(30f) A solution of 30e (150 mg, 0.48 mmol) in HCl / MeOH (0.5 M, 0.5 mL) was stirred at 80°C for 1.5 hours. The solution was basicized to pH > 9 with saturated Na2CO3 (3 mL) and extracted with  (3 mL x 3). The organic layer was concentrated and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain compound 30f (35 mg, yield 28%) as a yellow solid. LC-MS (ESI, method 3) t R =1.04 min, m / z(M+H) + = 261.0.

[0511] Step 7. 1-(5-amino-4-methoxypyrazolo[1,5-c]pyrimidine-3-yl)-2,2,2-trifluoroethane-1-ol (30g) NaBH4 (11 mg, 0.27 mmol) was added to a solution of 30 f (35 mg, 0.13 mmol) in MeOH (1 mL) at -5°C. After stirring at -5°C for 0.5 hours, the mixture was diluted with water (1 mL) and extracted with ₹ (3 mL). The organic layer was washed with brine (1 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to obtain 30 g (30 mg, yield 85%) as a yellow solid. 1¹H NMR (400MHz, CDCl3) δ 8.80 (s,1H), 7.98 (s,1H), 5.39-5.37 (m,1H), 4.49 (s,2H), 3.91 (s,3H), 3.43-3.41 (m,1H). LC-MS (ESI, Method 3) t R =0.92 min, m / z(M+H) + =263.0.

[0512] Step 8. 6-(cyclopropanecarboxamide)-4-((4-methoxy-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrazolo[1,5-c]pyrimidine-5-yl)amino)-N-(methyl-d3)nicotinamide(30) A mixture of 30 g (10 mg, 0.038 mmol), Int.A (10 mg, 0.038 mmol), dppf (8 mg, 0.015 mmol), Pd(OAc)2 (2 mg, 0.0076 mmol), and K3PO4 (24 mg, 0.114 mmol) in dioxane (0.5 mL) was stirred at 100°C for 16 hours. The mixture was concentrated and purified by preparative HPLC (Method E) to obtain compound 30 (10 mg, yield 54%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.66(s,1H),10.80(s,1H),9.37(s,1H),8.96(s,1H),8.72(s,1H),8.59(s,1H),8.20(s,1H) ,6.89(d,J=6.0Hz,1H),5.50-5.43(m,1H),3.89(s,3H),2.02-1.97(m,1H),0.81-0.79(m,4H). LC-MS (ESI, method 4) R =1.98 min, m / z(M+H) + = 483.3.

[0513] Example 31

[0514] [ka]

[0515] Step 1. 2-amino-6-bromo-3-nitrophenol (31b) To a solution of 31a (4.50 g, 20.64 mmol) in DMSO (60 mL), 1,1,1-trimethylhydrazinium iodide (4.59 g, 22.71 mmol) was added. The mixture was stirred at room temperature for 90 minutes, and then sodium tert-pentaoxide (11.37 g, 103.21 mmol) was added. The resulting mixture was stirred at room temperature for a further 2 hours. HCl aqueous solution (62 mL, 2 M) was added at 0°C, and the mixture was stirred for 1 hour. The mixture was diluted with H2O (100 mL), extracted with siRNA (50 mL x 3), washed with brine (100 mL), dried over Na2SO4, and concentrated to obtain compound 31b (4.76 g, 98% yield) as a yellow solid. 1 ¹H NMR (400MHz, DMSO-d6): δ 10.00 (brs, 1H), 7.49 (d, J=9.6Hz, 1H), 7.18 (brs, 2H), 6.76 (d, J=9.6Hz, 1H). LC-MS (ESI, Method 4) t R =2.29 min, m / z( 79 Br, M+H) + = 233.0.

[0516] Step 2. 3-Bromo-2-methoxy-6-nitroaniline (31c) A mixture of 31b (4.76 g, 20.43 mmol), K2CO3 (6.21 g, 44.94 mmol), and iodomethane (3.19 g, 22.47 mmol, 1.40 mL) in DMF (50 mL) was stirred at 20°C for 2 hours. A brown suspension was formed. The reaction mixture was diluted with water (200 mL) and extracted with siRNA (100 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 (siRNA in PE was 10-60%) to obtain 31c (3.10 g, yield 61%) as a yellow solid. LC-MS (ESI, method 4) t R =2.86 min, m / z( 79 Br, M+H) + = 247.0.

[0517] Step 3. 3-Bromo-N-(2,2-difluoropropyl)-2-methoxy-6-nitroaniline(31d) To a solution of 31c (300 mg, 1.21 mmol) in DMF (5 mL), K3PO4 (516 mg, 2.43 mmol) and Int.C (489 mg, 1.82 mmol) were added. The resulting mixture was stirred at 30°C for 48 hours. The mixture was diluted with H2O (50 mL), extracted with  (50 mL x 3), 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 ( in PE was 5-20%) to obtain 31d (200 mg, yield 51%) as a yellow oil. LC-MS (ESI, method 4) t R =3.40 min, m / z( 79 Br, M+H) + =325.0.

[0518] Step 4. 5-Bromo-N 1 -(2,2-difluoropropyl)-6-methoxybenzene-1,2-diamine(31e) A solution of 31d (200 mg, 0.61 mmol) in EtOH (5 mL) was mixed with an aqueous solution of Na2S2O4 (5.0 mL, 1 M). The resulting mixture was stirred at 80°C for 2 hours. 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 to obtain 31e (180 mg, crude product) as a yellow oily substance, which was used directly in the next step without further purification. LC-MS (ESI, Method 4) t R =2.96 min, m / z( 79 Br, M+H) + =295.1.

[0519] Step 5. 6-bromo-1-(2,2-difluoropropyl)-7-methoxybenzimidazole (31f) The mixture of 31e (180 mg, 0.61 mmol) in HCOOH (1 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated under vacuum, diluted with NaHCO3 aqueous solution (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 (MeOH in DCM was 0-10%) to obtain 31f (100 mg, 54% yield in 2 steps) as a pale yellow solid. LC-MS (ESI, method 4) t R =2.64 min, m / z( 79 Br, M+H) + = 305.1.

[0520] Step 6. (1-(2,2-difluoropropyl)-7-methoxy-1H-benzo[d]imidazole-6-yl)carbamate tert-butyl (31g) A mixture of 31f (90 mg, 0.29 mmol), tert-butyl carbamate (52 mg, 0.44 mmol), BrettPhos Pd G3 (27 mg, 0.03 mmol), BrettPhos (32 mg, 0.59 mmol), and K3PO4 (313 mg, 1.47 mmol) in dioxane (3 mL) was stirred under N2 at 100°C for 16 hours. The reaction mixture was diluted with  (50 mL) and filtered. The filtrate was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM was 0-8%) to obtain 31 g (100 mg, yield 99%) as a yellow solid. LC-MS (ESI, method 4) t R =2.45 min, m / z(M+H) + = 342.2.

[0521] Step 7. 3-(2,2-difluoropropyl)-4-methoxybenzimidazole-5-amine (31h) To a solution of 31 g (100 mg, 0.29 mmol) in DCM (2 mL), TFA (1 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, quenched with saturated NaHCO3 (40 mL), and then extracted with Âr (20 mL x 3). The organic layer was washed with aqueous NaHCO3 solution (30 mL) and brine (30 mL). The separated solution was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM was 0-10%) to obtain 31 h (60 mg, yield 85%) as a yellow solid. LC-MS (ESI, method 4) t R = 0.51 minutes, m / z (ESI, M+H) + = 242.0.

[0522] Step 8. 6-(cyclopropanecarboxamide)-4-((1-(2,2-difluoropropyl)-7-methoxy-1H-benzo[d]imidazole-6-yl)amino)-N-(methyl-d3)nicotinamide(31) A mixture of 31h (60 mg, 0.25 mmol), Int.A (58 mg, 0.22 mmol), and pTSA (58 mg, 0.34 mmol) in dioxane (3 mL) was stirred at 100°C for 24 hours. The reaction mixture was concentrated under vacuum, diluted with NaHCO3 aqueous solution (30 mL), and then extracted with  (30 mL × 2). The combined organic layer was washed with water (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (MeOH in DCM was 0-10%) to obtain a yellow solid, which was further purified by preparative HPLC (Method D) to obtain 31 (30.0 mg, yield 26%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.66(s,1H),10.37(s,1H),8.58(s,1H),8.50(s,1H),8.14(s,1H),7.67(s,1H),7.44(d,J=8.4Hz,1H),7.15(d, J=8.4Hz,1H),4.87(t,J=14.4Hz,2H),3.75(s,3H),1.96-1.89(m,1H),1.68(t,J=19.2Hz,3H),0.74-0.66(m,4H). LC-MS (ESI, method 4) R =1.71 min, m / z(M+H) + = 462.4.

[0523] Example 32

[0524] [ka]

[0525] Step 1. 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-6-(3-ethylureido)-N-(methyl-d3)nicotinamide(32) A solution of 8c (10 mg, 0.024 mmol), Pd(OAc)2 (1 mg, 0.005 mmol), XantPhos (6 mg, 0.01 mmol), and t-BuOK (8 mg, 0.072 mmol) in dioxane (3 mL) was mixed with 1-ethylurea (11 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The resulting solution was added to H2O (10 mL) and extracted with EA (20 mL). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC (Method E) to obtain 32 (4 mg, yield 35%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),9.26(s,1H),8.69(s,1H),8.61(s,1H),8.50(s,1H),8.47(s,1H),8.34(s,1H),8.31-8.25(m, 1H), 4.93(t,J=13.2Hz,2H),3.90(s,3H),3.24-3.13(m,2H),1.70(t,J=19.2Hz,3H),1.09(t,J=7.2Hz,3H). LC-MS (ESI, method 4) R =2.04 min, m / z(M+H) + = 466.4.

[0526] Example 33

[0527] [ka] 4-((1-(2,2-difluoropropyl)-7-methoxy-1H-pyrazolo[4,3-c]pyridine-6-yl)amino)-N-(methyl-d3)-6-(3-methylureido)nicotinamide(33)

[0528] A solution of 8c (20 mg, 0.048 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), and XantPhos (11 mg, 0.02 mmol) in dioxane (3 mL) was mixed with 1-methylurea (18 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The resulting solution was added to H2O (10 mL) and extracted with EA (20 mL). The combined organic layer was washed with brine (10 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The crude product was purified by preparative HPLC (Method E) to obtain 33 (1.2 mg, yield 6%) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),9.33(s,1H),8.69(s,1H),8.61(s,1H),8.49(s,1H),8.46(s,1H),8.35(s,1H),8.25 -8.16(m,1H),4.93(t,J=12.8Hz,2H),3.90(s,3H),2.73(d,J=4.4Hz,3H),1.70(t,J=19.2Hz,3H). LC-MS (ESI, method 4) R =1.88 min, m / z(M+H) + = 452.3.

[0529] Example 34

[0530] [ka]

[0531] Step 1. 4-bromo-7-methoxy-6-nitro-1H-indazole (34b) To a solution of 34a (400 mg, 1.76 mmol) in TFA (10 mL), KNO3 (178 mg, 1.76 mmol) was added at room temperature. The mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the TFA was removed by pumping through N2. The residue was dissolved in DCM (30 mL) and basicized to pH=9 with saturated Na2CO3. The mixture was extracted with ELISA (200 mL x 3). The combined organic phase was concentrated, and the residue was purified by flash chromatography on silica gel (PE / EA=4 / 1) to obtain 34b (450 mg, yield 94%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 14.46 (s, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 3.95 (s, 3H).

[0532] Step 2. 7-Methoxy-1H-indazole-6-amine(34c) A mixture of 34b (450 mg, 1.65 mmol), Pd / C (100 mg, 10% palladium on carbon moistened with 50% water), Pd(OH)2 (100 mg, 10% palladium hydroxide on carbon moistened with approximately 55% water), and TEA (167 mg, 1.65 mmol, 0.23 mL) in  (8 mL) and MeOH (2 mL) was stirred at 30°C for 3 hours under an H2 (1 atm) atmosphere. The mixture was filtered, and the filtrate was concentrated to obtain 33c (270 mg, yield shown) as a brown solid. LC-MS (ESI, Method 3) t R =0.72 min, m / z(M+H) + = 164.3.

[0533] Step 3. N-(4-((7-methoxy-1H-indazole-6-yl)amino)-5-propionylpyridine-2-yl)cyclopropanecarboxamide (34) A mixture of Int.G (30 mg, 0.12 mmol), 34c (58 mg, 0.14 mmol), Pd2(dba)3 (9 mg, 0.009 mmol), BINAP (8 mg, 0.011 mmol), and Cs2CO3 (77 mg, 0.24 mmol) in dioxane (1 mL) was stirred at 115°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated, and the residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain 34 (10 mg, yield 22%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 13.39(s,1H),10.90(s,1H),10.85(s,1H),8.85(s,1H),8.11(s,1H),7.70(s,1H),7.52(d,J=8.4Hz,1H),7.08(d ,J=8.4Hz,1H),3.89(s,3H),3.12(q,J=7.2Hz,2H),1.99-1.95(m,1H),1.13(t,J=7.2Hz,3H),0.76-0.72(m,4H). LC-MS (ESI, method 2) R =1.10 min, m / z(M+H) + =380.0.

[0534] Example 35

[0535] [ka] N-[4-[(4-methoxypyrazolo[1,5-a]pyridine-5-yl)amino]-5-propanoyl-2-pyridyl]cyclopropanecarboxamide(35)

[0536] For the synthesis of compound 35, please refer to the patent (Chinese Patent Application Publication No. 115466257(A), pages 24-26). LC-MS (ESI, Method 4) R =0.72 min, m / z(M+H) + = 380.2. 1 H NMR(400MHz,CDCl3):δ 11.02(brs,1H),8.71(s,1H),8.42(brs,1H),8.29(d,J=7.2Hz,1H),7.93(s,1H),7.90(d,J=2.0Hz,1H),6.87(d,J=7.2Hz,1H),6.61( d,J=2.0Hz,1H),4.00(s,3H),3.03(q,J=7.2Hz,2H),1.58-1.49(m,1H),1.26(t,J=7.2Hz,3H),1.09-1.03(m,2H),0.92-0.85(m,2H).

[0537] Example 36

[0538] [ka] N-[4-[(4-methoxy-1H-benzimidazole-5-yl)amino]-5-propanoyl-2-pyridyl]cyclopropanecarboxamide(36)

[0539] For the synthesis of compound 36, please refer to the patent (Chinese Patent Application Publication No. 115466257(A), pages 33-34). LC-MS (ESI, Method 4) R =0.52 min, m / z(M+H) + = 380.2. 1H NMR(400MHz,CDCl3):δ 10.98(s,1H),9.82(brs,1H),8.61(s,1H),8.61(s,1H),7.94(s,1H),7.70(s,1H),7.23-7.13(m,2H),4.28(s ,3H),3.03(q,J=7.2Hz,2H),1.72-1.62(m,1H),1.27(t,J=7.2Hz,3H),1.03-0.95(m,2H),0.91-0.82(m,2H).

[0540] Example 37

[0541] [ka] 6-(cyclopropanecarboxamide)-4-((4-methoxypyrrolo[1,2-c]pyrimidine-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(37)

[0542] For the synthesis of compound 37, please refer to the patent (Chinese Patent Application Publication No. 116262739(A), pages 35-36). LC-MS (ESI, Method 4) R =0.76 min, m / z(M+H) + = 385.2. 1 H NMR(400MHz,DMSO-d6):δ 11.50(s,1H),11.24(s,1H),9.14(s,1H),9.01(s,1H),8.99(d,J=0.8Hz,1H),7.67(dd,J=2.8,1.2Hz,1H ),6.90(dd,J=3.6,2.8Hz,1H),6.56-6.53(m,1H),3.99(s,3H),2.13-2.07(m,1H),0.84(d,J=6.4Hz,4H).

[0543] Table 1A shows an overview of representative compounds.

[0544] [Table 3-1]

[0545] [Table 3-2]

[0546] [Table 3-3]

[0547] [Table 3-4]

[0548] [Table 3-5]

[0549] [Table 3-6]

[0550] [Table 3-7]

[0551] The compound is prepared in DMSO for a maximum dose of 200-fold, and then further serially diluted 27-fold for 3 points. When 8 μL / well is added to the echo source plate, the echo will be 75 nL / well for 11 points on the assay plate using 3-fold serial dilutions. 75 nL of DMSO for high and low control.

[0552] Prepare a 3-fold dilution (1.5 nM) of the JAK1-JH2 domain or TYK2-JH2 domain enzyme in assay buffer, and add 5 μL of the enzyme dilution per well to an assay plate containing high control. For low control, add 5 μL of assay buffer per well. Then, spin down to 1000 rpm and centrifuge for 30 seconds. After preparing the enzyme system, add 5 μL of Tb antibody solution to each well of the assay plate. Spin down to 1000 rpm and centrifuge for 30 seconds. After adding the Tb antibody, also add 5 μL of tracer to the assay plate. Spin down to 1000 rpm and centrifuge for 30 seconds. Incubate first at 25°C for 60 minutes, then incubate the plate overnight at 4°C. Read by Envision in FRET mode. Luminescence values ​​were recorded by a multi-label reader Envision (PerkinElmer). Inhibition rates were calculated using the following formula, compared to vehicle (DMSO) treated control wells.

[0553]

number

[0554] Dose-response (inhibition rate) curves were plotted, and the IC50 value (concentration that causes 50% growth inhibition) was determined using GraphPad software. The IC50 values ​​of the tested compounds are shown in Table 2.

[0555] [Table 4-1]

[0556] [Table 4-2]

[0557] The exemplary compounds showed excellent selectivity for JAK1. These compounds can be used to eliminate side effects caused by JAK1 inhibition in autoimmune diseases. biochemical analysis Testing of JAK1, JAK2, and TYK2 kinase activity

[0558] JAK activity was determined by microfluidic assay in reaction buffers of 50 mM HEPES, 0.01% Brij35, 10 mM MgCl2, and 2 mM DTT. Phosphorylation of the FAM-labeled peptide substrate was monitored using a Caliper EZ Reader II (Perkin Elmer). Assay conditions for each batch of enzyme (Carna Biosciences) were optimized to achieve a 10% conversion rate of the peptide substrate.

[0559] The test compound was dissolved in DMSO to a stock concentration of 10 mM. Three-fold serial dilutions of the compound, up to a maximum concentration of 5 μM, were pre-incubated with JAK1, JAK2, or TYK2 at room temperature for 10 minutes. The final DMSO concentration of the assay mixture was 1%. FAM-labeled peptide substrate (final concentration 3 μM) and ATP (Km concentration or 1 mM) were added sequentially to initiate the kinase reaction at 28°C for 90 minutes (JAK), 15 minutes (JAK2), and 30 minutes (TYK2), respectively. The reaction was stopped by adding 50 mM EDTA.

[0560] Wells in the test plate that lacked the enzyme were defined as 100% inhibition. Wells containing no compound but an equal amount of DMSO were defined as no inhibition. The inhibition rate was calculated using the following formula.

[0561]

number

[0562] Dose-response (inhibition rate) curves were plotted, and IC50 values ​​were determined using GraphPad software. The IC50 values ​​of the tested compounds are listed in Table 3.

[0563] [Table 5]

[0564] The exemplary compounds showed excellent selectivity for inhibiting JAK1, JAK2, and TYK2 kinase domains. Antiproliferative assay

[0565] A dimerized domain of the Tel protein fused with the JAK kinase domain was persistently introduced into Ba / F3 cells that proliferated in a JAK activity-dependent manner in the absence of IL-3 induction. These modified Ba / F3-FL-TYK2-P760L cells were used to monitor the JAK inhibitory activity of the compound within the cell. Ba / F3 cells were cultured in RPMI-1640 (Corning) containing 10% fetal bovine serum. Cells were seeded at 2000 cells / well in a white, flat-bottomed, 96-well plate. Wells containing only the culture medium were used as background controls. After 24 hours of culture, cells were treated with the compound. The test compound was dissolved in DMSO to a stock concentration of 20 mM. Nine 3-fold serial dilutions of the compound, with a maximum concentration of 20 μM, were added to each well. The final DMSO concentration was 0.1%. After compound treatment, cells continued to grow for 72 hours at 37°C, 5% CO2. Viability was measured by cellular ATP measurement using the Cell-Titer Glo-luciferase reagent (Promega). Luminescence values ​​were recorded using a multi-label reader, Envision (PerkinElmer). Inhibition rates were calculated using the following formula, compared to control wells treated with vehicle (DMSO).

[0566]

number

[0567] Dose-response (inhibition rate) curves were plotted, and the IC50 value (concentration that causes 50% growth inhibition) was determined using GraphPad software. The IC50 values ​​of the tested compounds are shown in Table 4.

[0568] [Table 6]

[0569] IFN-γ release in IL-12-stimulated NK92 cells Objective: To evaluate the inhibitory activity of TYK2 inhibitors on the TYK2 pathway in NK92 cells using ELISA.

[0570] material:

[0571] [Table 7]

[0572] Procedure: 1) Seed NK92 cells in a 96-well plate. Cell density is 1.5E5 cells / well, 100uL / well. 2) Add the prepared test substance to the designated wells at 50uL / well and incubate at 37°C for 1 hour. 3) After compound treatment, add IL-12 to the designated wells at 50uL / well. The final concentration of IL-12 is 2.5ng / mL. 4) Incubate the cytokine-stimulated cells in a CO2 incubator at 37°C for a further 15 hours. 5) After cytokine stimulation, transfer the culture supernatant to a new plate, centrifuge at 350×g for 5 minutes, and detect the IFN-γ concentration in the supernatant using an ELISA kit. 6) Analyze the data using GraphPad Prism 6.0 software.

[0573] [Table 8]

[0574] The exemplary compounds showed good TYK2 pathway inhibitory activity in cells.

[0575] Phosphorylation inhibition of STAT in human whole blood studies: The inhibitory activity of the test substance in a human whole blood assay was evaluated using flow cytometry.

[0576] IFN-α binds to the IFN receptor and activates JAK1 and TYK2 kinases in T cells, subsequently causing phosphorylation of STAT1 and STAT2. Phosphorylated STAT1 enters the nucleus and promotes the transcription and expression of IFN-γ. To evaluate the efficacy of TYK2i in T cells, freshly collected human whole blood is stimulated in an incubator for 20 minutes with a specific unit of human IFN-α (Universal Type I IFN (1MU), R&D, 11200-2). After stimulation, cells are fixed with Phosflow® Fix Buffer I (BD, 557870) and then collected by centrifugation (500g, 8 min). Cells are washed once with pre-cooled PBS and then permeabilized on ice for 45 minutes with cold Perm Buffer III (BD, 558050). Cells are collected by centrifugation (600g, 8 min) and washed twice with cold PBS. Cells were stained with anti-human CD3 (FITC mouse anti-human CD3, BD, 555332) antibody and anti-pSTAT1_Y701 (Alexa Fluor 647 mouse anti-Stat1(pY701), BD, 612597) antibody. pSTAT1 was detected by flow cytometry (CytoFlex S), and the data were analyzed using FlowJo and GraphPad Prism 8 software. The IC50 values ​​of the test substances were determined using a four-parameter logistic equation.

[0577] Table 6 summarizes the exemplary results.

[0578] [Table 9]

[0579] ADME Microsomal metabolic stability assay Microsomes were pre-incubated at 37°C for 5 minutes in 100 mM potassium phosphate buffer, pH 7.4, 1.0 mM EDTA, together with the test compound or control compound. The reaction was initiated at each time point by adding 15 μL of NADPH regeneration system to 30 μL of each incubation mixture. The final incubation conditions consisted of 0.5 mg / mL microsomal protein, 1 μM test substance / positive control, and 2 mM NADPH. Samples at 0 minutes were prepared by adding a 30 μL aliquot of each incubation mixture to 135 μL of quench reagent to precipitate the protein. Then, a 15 μL aliquot of NADPH regeneration system was added. At 5, 15, 30, and 45 minutes, the reaction was stopped by adding a cold acetonitrile solution containing an internal standard. Samples taken at all time points were centrifuged at 5000 × g for 15 minutes. 50 μL of supernatant is collected in a 96-well assay plate pre-filled with 50 μL of ultrapure water, and then analyzed by LC / MS / MS.

[0580] The concentrations of the test substance and control compound in the sample were determined using LC / MS / MS. Chromatogram plotting and peak area integration were performed using Analyst (AB Sciex).

[0581] In determining the in vitro elimination constant (ke) of a control compound, the analyte / internal standard peak area ratio is converted to a residual percentage (residual %) using the following formula.

[0582]

number

[0583] Microsomal CL intThis was calculated using the following formula:CL int(mic) =0.693 / T 1 / 2 / mg microsomal protein / mL. The slope was measured by the natural logarithm of the percentage of residual compounds and time, and T1 / 2 was calculated according to the following formula.

[0584]

number

[0585] The exemplary results are summarized in Table 7.

[0586] [Table 10]

[0587] kinetic solubility Add 8 μL aliquots of stock solutions (10 mM / 5 mM) of the reference compound and the test compound to 792 μL of 100 mM pH 7.4 phosphate buffer. The final DMSO concentration is 1%. Shake the sample tube at 1000 rpm for 2 hours at room temperature. Centrifuge the sample at 12000 rpm for 10 minutes to precipitate undissolved particles. Transfer the supernatant to a new tube or plate. For LC-MS / MS analysis, add 5 μL of the sample (undiluted, 10-fold dilution, and 100-fold dilution) and the standard curve sample to 95 μL of ACN containing IS. The exemplary results are summarized in Table 8.

[0588] [Table 11]

[0589] The exemplary compounds exhibited ideal solubility for further development.

[0590] The applicant's disclosures are described herein in preferred embodiments with reference to the drawings, where similar numbers represent identical or similar elements. Throughout this specification, any reference to “one embodiment,” “embodiment,” or similar terms means that certain features, structures, or characteristics described in relation to that embodiment are included in at least one embodiment of the present invention. Thus, whereever “in one embodiment,” “in an embodiment,” or similar phrases appear throughout this specification, they may all refer to the same embodiment, although not all of them necessarily refer to the same embodiment.

[0591] The features, structures, or properties described in the applicant's disclosure may be combined in any preferred manner in one or more embodiments. This specification provides numerous specific details to enable a full understanding of embodiments of the invention. However, experts in the relevant art will recognize that the applicant's configurations and / or methods can be implemented without one or more of the specific details, or using other methods, components, materials, etc. In other cases, well-known structures, materials, or operations are not described or explained in detail so as not to obscure the aspects of the disclosure.

[0592] All technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art, unless otherwise defined. Methods and materials similar to or equivalent to those described herein may also be used in the implementation or testing of this disclosure, but preferred methods and materials are described here. The methods described herein may be performed in any logically possible order, in addition to the specific order disclosed.

[0593] Embedding by reference This disclosure includes references and citations to other documents, such as patents, patent applications, patent publications, academic journals, books, articles, and web content. All such documents are incorporated herein by reference for any purpose. Any document or part thereof that is incorporated herein by reference but conflicts with existing definitions, descriptions, or other disclosures expressly stated herein is incorporated only to the extent that it does not create a conflict between the incorporated document and the disclosed document. In the event of a conflict, this disclosure shall prevail. Equivalents Representative examples are provided to illustrate the present invention and are not intended to limit the scope of the invention, nor should they be construed as such. In fact, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the entirety of this document, including the examples contained herein and references to scientific and patent literature. The examples include important additional information, illustrations, and guidance that can be adapted to the implementation of the invention in various embodiments and equivalents thereof.

Claims

1. Structural formula (I): 【Chemistry 1】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ is H, F, C １ to C ３ alkyl and CD ３ but provided that when Y ３ is NR, O or O-NH, R ４１ is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. Compounds having [a certain characteristic], or their pharmaceutically acceptable forms or isotopic derivatives.

2. Y ４ It is CH, and its structure: 【Chemistry 2】 A compound according to claim 1, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

3. Y １ CH is Y ２ It is CH, and its structure: 【Transformation 3】 A compound according to claim 2, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

4. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 4】 A compound according to claim 2, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

5. Y １ CH is Y ２ It is N, and the structure: 【Transformation 5】 A compound according to claim 2, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

6. Y １ N is Y ２ It is N, and the structure: 【Transformation 6】 A compound according to claim 2, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

7. Y ４ It is N, and the structure: 【Transformation 7】 A compound according to claim 1, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

8. Y １ CH is Y ２ It is CH, and its structure: 【Transformation 8】 The compound according to claim 7, having the following characteristics.

9. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 9】 A compound according to claim 7, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

10. Y １ CH is Y ２ It is N, and the structure: 【Chemistry 10】 A compound according to claim 7, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

11. Y １ N is Y ２ It is N, and the structure: 【Chemistry 11】 A compound according to claim 7, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

12. R Ａ H is R Ｂ The compound according to any one of claims 1 to 11, wherein is H, or a pharmaceutically acceptable form or isotopic derivative thereof.

13. R Ｃ CH ３ The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable form or isotopic derivative thereof.

14. R Ｃ CH ３ The compound described in any one of claims 1 to 12, or a pharmaceutically acceptable form or isotopic derivative thereof.

15. Structural formula (II): 【Chemistry 12】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ is H, F, C １ to C ３ alkyl and CD ３ but provided that when Y ３ is NR, O or O-NH, R ４１ is not F, R ４２ teeth, R ４２’ (R ４２’ is C １ - C ６ alkyl, C ３ - C ６ cycloalkyl or heterocycloalkyl, each substituted with from 0 to 2 halogen, CN, OR, NRR', alkyl, cycloalkyl, heterocycle, aryl and heteroaryl). Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. Compounds having [a certain characteristic], or their pharmaceutically acceptable forms or isotopic derivatives.

16. Y ４ It is CH, and its structure: 【Chemistry 13】 A compound according to claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

17. Y １ CH is Y ２ It is CH, and its structure: 【Chemistry 14】 A compound according to claim 16, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

18. Y １ CH is Y ２ It is N, and the structure: 【Chemistry 15】 A compound according to claim 16, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

19. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 16】 A compound according to claim 16, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

20. Y １ N is Y ２ It is N, and the structure: 【Chemistry 17】 A compound according to claim 16, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

21. Y ４ It is N, and the structure: [Chemistry 18] A compound according to claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

22. Y １ CH is Y ２ It is CH, and its structure: 【Chemistry 19】 A compound according to claim 21, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

23. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 20】 A compound according to claim 21, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

24. Y １ CH is Y ２ It is N, and the structure: 【Chemistry 21】 A compound according to claim 21, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

25. Y １ N is Y ２ It is N, and the structure: 【Chemistry 22】 A compound according to claim 21, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

26. R Ａ H is R Ｂ The compound according to any one of claims 15 to 25, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is H.

27. R Ｃ CH ３ The compound according to any one of claims 15 to 26, or a pharmaceutically acceptable form or isotopic derivative thereof.

28. R Ｃ CH ３ Not the compound described in any one of claims 15 to 26, or a pharmaceutically acceptable form or isotopic derivative thereof.

29. Structural formula (III): 【Chemistry 23】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, however R Ａ and R Ｂ If both are H, then R Ｃ CH ３ Or not F, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. Compounds having [a certain characteristic], or their pharmaceutically acceptable forms or isotopic derivatives.

30. Y １ CH is Y ２ It is CH, and its structure: 【Chemistry 24】 A compound according to claim 29, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

31. Y １ CH is Y ２ It is N, and the structure: 【Chemistry 25】 A compound according to claim 29, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

32. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 26】 A compound according to claim 29, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

33. Y １ N is Y ２ It is N, and the structure: 【Chemistry 27】 A compound according to claim 29, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

34. R Ａ H is R Ｂ The compound according to any one of claims 29 to 33, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is H.

35. R Ａ and R Ｂ One of these is a compound according to any one of claims 29 to 33, or a pharmaceutically acceptable form or isotopic derivative thereof, which is not H.

36. R Ｃ CH ３ Not the compound described in any one of claims 29 to 35, or a pharmaceutically acceptable form or isotopic derivative thereof.

37. Structural formula (IV): 【Chemistry 28】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, however R Ａ and R Ｂ If both are H, then R Ｃ It is not H or F, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. Compounds having [a certain characteristic], or their pharmaceutically acceptable forms or isotopic derivatives.

38. Y １ CH is Y ２ It is CH, and its structure: 【Chemistry 29】 A compound according to claim 37, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

39. Y １ N is Y ２ It is CH, and its structure: 【Transformation 30】 A compound according to claim 37, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

40. Y １ CH is Y ２ It is N, and the structure: 【Chemistry 31】 A compound according to claim 37, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

41. Y １ N is Y ２ It is N, and the structure: 【Chemistry 32】 A compound according to claim 37, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

42. R Ａ H is R Ｂ The compound according to any one of claims 37 to 41, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is H.

43. R Ｃ CH ３ The compound according to any one of claims 37 to 41, or a pharmaceutically acceptable form or isotopic derivative thereof.

44. R Ｃ CH ３ Not the compound described in any one of claims 37 to 41, or a pharmaceutically acceptable form or isotopic derivative thereof.

45. Structural formula (V): 【Transformation 33】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４６ H, CD ３ , C having 0 to 4 halogens, CN and OR １ ~C ６ Alkyl or C ３ ~C ６ It is a cycloalkyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group, R ４８ is H, halo, or C １ ~C ３ It is alkyl. Compounds having [a certain characteristic], or their pharmaceutically acceptable forms or isotopic derivatives.

46. Y １ CH is Y ２ It is CH, and its structure: 【Transformation 34】 A compound according to claim 45, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

47. Y １ N is Y ２ It is CH, and its structure: 【Chemistry 35】 A compound according to claim 45, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

48. Y １ CH is Y ２ It is N, and the structure: 【Transformation 36】 A compound according to claim 45, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

49. Y １ N is Y ２ It is N, and the structure: 【Chemistry 37】 A compound according to claim 45, or a pharmaceutically acceptable form or isotopic derivative thereof, having the above.

50. structure: 【Transformation 38】 [In the formula, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ The compound according to claim 45, having a cycloalkyl or heterocyclic group, or a pharmaceutically acceptable form or isotopic derivative thereof.

51. Y ４ The compound according to any one of claims 45 to 50, wherein CH is a pharmaceutically acceptable form or isotopic derivative thereof.

52. Y ４ The compound according to any one of claims 45 to 50, wherein is N, or a pharmaceutically acceptable form or isotopic derivative thereof.

53. R ４８ The compound according to any one of claims 45 to 52, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is H.

54. R ４８ The compound according to any one of claims 45 to 52, or a pharmaceutically acceptable form or isotopic derivative thereof, is a halo.

55. R ４７ C １ ~C ３ A compound according to any one of claims 1 to 54, which is an alkoxy, or a pharmaceutically acceptable form or isotopic derivative thereof.

56. R ４７ OCH ３ The compound according to any one of claims 1 to 54, or a pharmaceutically acceptable form or isotopic derivative thereof.

57. R ４７ OCD ３ The compound according to any one of claims 1 to 54, or a pharmaceutically acceptable form or isotopic derivative thereof.

58. Y ３ The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable form or isotopic derivative thereof, is NR.

59. Y ３ The compound according to claim 58, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is NH.

60. Y ３ The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein is O.

61. Y ３ The compound according to any one of claims 1 to 57, wherein is O-NH, or a pharmaceutically acceptable form or isotopic derivative thereof.

62. R ４１ CH ３ The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable form or isotopic derivative thereof.

63. R ４１ CD ３ The compound according to any one of claims 1 to 61, or a pharmaceutically acceptable form or isotopic derivative thereof.

64. R ４２ R ４２’ The compound according to any one of claims 1 to 63, or a pharmaceutically acceptable form or isotopic derivative thereof.

65. R ４２ is (C=O)R ４２ｂ And R ４２ｂ This is 0 to 2 R ４２ｃ C replaced by １ ~C ６ A compound according to any one of claims 1 to 63, selected from alkyl, cyclopropyl, or cyclobutyl, or a pharmaceutically acceptable form or isotopic derivative thereof.

66. R ４２ is (C=O)R ４２ｂ And R ４２ｂ F, Cl, CH ３ CF ３ The compound according to claim 65, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein the compound is a cyclopropyl optionally substituted with one or more of the CNs.

67. R ４２ is (C=O)R ４２ｂ And R ４２ｂ F, Cl, CH ３ CF ３ The compound according to claim 65, or a pharmaceutically acceptable form or isotopic derivative thereof, which is a bisspirocyclopropyl optionally substituted with one or more of the CNs.

68. R ４２ is (C=O)R ４２ｂ And R ４２ｂ F, Cl, CH ３ CF ３ The compound according to claim 65, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein the compound is cyclobutyl optionally substituted with one or more of the CNs.

69. R ４２ is (C=O)R ４２ｂ And R ４２ｂ F, Cl, CH ３ CF ３ C is optionally replaced with one or more of CN, NRR', and OR. １ ~C ６ The compound according to claim 65, which is alkyl, or a pharmaceutically acceptable form or isotopic derivative thereof.

70. R ４２ (C=O)NHR ４２ｂ And R ４２ｂ This is 0 to 2 R ４２ｃ C replaced by １ ~C ６ A compound according to any one of claims 1 to 63, selected from alkyl, cyclopropyl, or cyclobutyl, or a pharmaceutically acceptable form or isotopic derivative thereof.

71. R ４２ This is 0 to 2 R ４２ｃ A compound according to any one of claims 1 to 63, which is a pyridinyl substituted with, or a pharmaceutically acceptable form or isotopic derivative thereof.

72. R ４２ This is 0 to 2 R ４２ｃ A compound according to any one of claims 1 to 63, which is a phenyl substituted with, or a pharmaceutically acceptable form or isotopic derivative thereof.

73. R ４２ This is 0 to 2 R ４２ｃ A compound according to any one of claims 1 to 63, which is pyrazolyl substituted with, or a pharmaceutically acceptable form or isotopic derivative thereof.

74. R ４２ This is 0 to 2 R ４２ｃ A compound according to any one of claims 1 to 63, which is a pyrimidyl substituted with, or a pharmaceutically acceptable form or isotopic derivative thereof.

75. R ４２ｃ CH ３ or CD ３ The compound according to any one of claims 71 to 74, or a pharmaceutically acceptable form or isotopic derivative thereof.

76. R ４２ｃ The compound according to any one of claims 71 to 74, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein F is present.

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

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

79. A pharmaceutical composition comprising a compound according to any one of claims 1 to 78 that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent.

80. The pharmaceutical composition according to claim 79, which is suitable for oral administration.

81. A pharmaceutical composition according to claim 79 or 80, which is suitable for local administration.

82. A pharmaceutical composition according to any one of claims 79 to 81, which is suitable for restricted administration of the gastrointestinal tract.

83. A pharmaceutical composition according to any one of claims 79 to 81, useful for treating or alleviating one or more of inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders.

84. The pharmaceutical composition according to claim 83, wherein the disease or disorder is an inflammatory disease.

85. The pharmaceutical composition according to claim 84, wherein the disease or disorder is an immune-mediated disease.

86. The pharmaceutical composition according to claim 84, wherein the disease or disorder is cancer.

87. The pharmaceutical composition according to claim 86, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

88. A unit dosage form comprising the pharmaceutical composition according to any one of claims 79 to 87.

89. The unit dosage form according to claim 88, which is a tablet.

90. The unit dosage form according to claim 88, which is a capsule.

91. The unit dosage form according to claim 88, which is a topical preparation.

92. A method for treating, alleviating, or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (I) is provided to the person in need: 【Chemistry 39】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans, and the method thereof.

93. A method for treating, alleviating, or preventing a disease or disorder, wherein the therapeutically effective amount of the structural formula (II) is given to the target person in need: 【Chemistry 40】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans, and the method thereof.

94. A method for treating, alleviating, or preventing a disease or disorder, wherein the therapeutically effective amount of the structural formula (III) is given to the person in need: 【Chemistry 41】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, however R Ａ and R Ｂ If both are H, then R Ｃ CH ３ Or not F, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans, and the method thereof.

95. A method for treating, alleviating, or preventing a disease or disorder, wherein the method is administered to a person in need, in a therapeutically effective amount of the structural formula (IV): 【Chemistry 42】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, or (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R Ａ and R Ｂ Each of these is independently H, D, Halo, OR, and C １－３ Selected from alkyl groups, however R Ａ and R Ｂ If both are H, then R Ｃ It is not H or F, R Ｃ These are H, D, F, Cl, OR, and 0 to 2 Rs. ４２ａ C replaced by １－５ Alkyl, C ３－５ It is a cycloalkyl or heterocyclic group, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans, and the method thereof.

96. A method for treating, alleviating, or preventing a disease or disorder, wherein a therapeutically effective amount of structural formula (V) is provided to the person in need: 【Chemistry 43】 [In the formula, Y １ is CH, CF, or N, Y ２ is CH or N, Y ３ NR, O, CH ２ CF ２ Or O-NH, Y ４ is CH or N, R ４１ H, F, C １ ~C ３ Alkyl and CD ３ However, Y ３ If R is NR, O, or O-NH, ４１ It is not F, R ４２ teeth, R ４２’ (R ４２’ These are each substituted with 0 to 2 halogens, CN, OR, NRR', alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, C １ ~C ６ Alkyl, C ３ ~C ６ It is cycloalkyl or heterocycloalkyl. Each has 0 to 2 R ４２ａ A substituted aryl group or heteroaryl group, (C=O)R ４２ｂ , or (C=O)NHR ４２ｂ And, R and R' are independently H or C １ ~C ６ Alkyl, C １ ~C ６ If they are acyls, or if R and R' are integrated with the nitrogen atom to which they are bonded, then they form O, NR, S, and SO ２ It forms a 4-7 membered ring containing 0-2 heteroatoms selected from the above, R ４２ａ In each occurrence, D, Halo, OH, OR, CH appear independently. ３ CF ３ ,CH ２ CF ３ , CN, C(O)NR, NRR', (CH ２ ) ｎ NRR', or a 4-6 membered heteroring having 1-4 heteroatoms selected from N, O, and S, R ４２ｂ Each of these has 0 to 2 R ４２ｃ C replaced by １－６ Alkyl or C ３－６ Cycloalkyl, C ５－７ It is a spirocycloalkyl, aryl, or heteroaryl, R ４２ｃ In each occurrence, independently, Halo, CN, OR, NRR', and OCF ３ CF ３ , 0 to 3 R ４２ａ C replaced by １－６ Alkyl, C １－６ Haloalkyl, 0-3 R groups ４２ａ C replaced by ２－６ Alkenyl, 0-3 R ４２ａ C replaced by ２－６ It is alkinyl, R ４６ H, CD ３ , C having 0 to 4 halogens, CN and OR １ ~C ６ Alkyl or C ３ ~C ６ It is a cycloalkyl, R ４７ C is optionally replaced by 1 to 3 D or halos. １－３ It is an alkoxy group, R ４８ is H, halo, or C １ ~C ３ It is alkyl. This includes administering a compound having, or a pharmaceutically acceptable form thereof or an isotopic derivative thereof. The disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancers, or related diseases or disorders in mammals, including humans, and the method thereof.

97. The method according to any one of claims 92 to 96, wherein the disease or disorder is an inflammatory disease.

98. The method according to any one of claims 92 to 96, wherein the disease or disorder is an immune-mediated disease.

99. The method according to any one of claims 92 to 96, wherein the disease or disorder is cancer.

100. The method according to any one of claims 92 to 99, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

101. The method according to any one of claims 92 to 100, wherein the administration is by oral administration.

102. The method according to any one of claims 92 to 100, wherein the administration is via local administration.

103. The method according to any one of claims 92 to 100, wherein the administration is via restricted gastrointestinal administration.

104. The use of a compound according to any one of claims 1 to 78 and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a pharmaceutical product for treating a disease or disorder.

105. The use according to claim 104, wherein the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases, and cancer.

106. The use according to claim 105, wherein the disease or disorder is an inflammatory disease.

107. The use according to claim 105, wherein the disease or disorder is an immune-mediated disease.

108. The use according to claim 105, wherein the disease or disorder is cancer.

109. The use of the pharmaceutical product according to any one of claims 104 to 108, wherein the pharmaceutical product is for oral administration.

110. The use of the pharmaceutical product according to any one of claims 104 to 108, wherein the pharmaceutical product is for local administration.

111. The use of the pharmaceutical product according to any one of claims 104 to 108, wherein the pharmaceutical product is for gastrointestinal restriction administration.

112. A method for preparing the compound according to any one of claims 1 to 78.

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