Stat6 degradation agents

Abstract

The present disclosure provides a compound according to Formula (I) and pharmaceutically acceptable salts, hydrates, or solvates thereof. The present disclosure also relates to the compound for use in therapy, a pharmaceutical composition comprising the compound, a method of treating a disease, for example, a skin disease, with the compound, and the use of the compound in the manufacture of a medicament.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to European Patent Application No. EP24167026.4, filed on 27 March 2024, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] This article provides novel compounds that regulate STAT6 and their pharmaceutically acceptable salts, as well as pharmaceutical compositions comprising said compounds for use in therapy (e.g., for treating STAT6-related diseases in subjects of need). Background Technology

[0004] This disclosure relates in general to methods and compounds for modulating the activity of signal transducer and activator of transcription 6 (STAT6) proteins and for treating STAT6-related diseases, as well as pharmaceutically acceptable salts thereof. The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0005] This disclosure relates to novel bifunctional compounds and pharmaceutically acceptable salts thereof (which may function to recruit STAT6 protein to E3 ubiquitin ligases for degradation), compositions containing such compounds, and methods and uses thereof. In some embodiments, this disclosure provides bifunctional compounds and pharmaceutically acceptable salts thereof (which may act as regulators of targeted ubiquitination of STAT6 protein, which may then be degraded and / or otherwise inhibited by the bifunctional compounds as described herein).

[0006] The ubiquitin-proteasome pathway (UPP) is a pathway that regulates key regulatory proteins and degrades proteins such as misfolded or abnormal proteins. The UPP is central to many cellular processes, and defects or imbalances in it can lead to the development of a variety of diseases. The attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0007] There are more than 600 types of E3 ubiquitin ligases. These E3 ubiquitin ligases promote the ubiquitination of different proteins in the body. These E3 ubiquitin ligases can generally be divided into four families: HECT domain E3, U-box E3, monomeric ring E3, and multi-subunit E3. See also Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled “RINGdomain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBRE3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) Title "Roles of F-box proteins incanceR".

[0008] UPP plays a crucial role in the degradation of short-lived and regulatory proteins essential to a variety of fundamental cellular processes, including cell cycle regulation, regulation of cell surface receptors and ion channels, and antigen presentation. This pathway is involved in the pathogenesis of several forms of malignancy, several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle loss. Many diseases are associated with UPP abnormalities, and they negatively impact cell cycle and division, cellular responses to stress and extracellular regulators, morphogenesis of neuronal networks, regulation of cell surface receptors, ion channels, secretory pathways, DNA repair, and organelle biogenesis.

[0009] Recent findings suggest that abnormalities in this process are associated with the development of several diseases (both hereditary and acquired). These diseases are divided into two main categories: (a) diseases caused by loss of function and the resulting stabilization of certain proteins, and (b) diseases caused by gain of function (i.e., abnormal or accelerated degradation of protein targets).

[0010] UPPs can be used to induce selective protein degradation, including ubiquitination of target proteins using fusion proteins and proteasome-dependent degradation using synthetic small molecule probes. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand can induce proteasome-mediated degradation of selected proteins by recruiting them to an E3 ubiquitin ligase followed by ubiquitination. These drug-like molecules offer the possibility of time-controlled protein expression. Such compounds can induce the inactivation of target proteins when added to cells or administered to animals or humans and can be used as biochemical agents to bring about new paradigms of disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1): 40-46).

[0011] Signal transducer and activator of transcription 6 (STAT6) belongs to the transcription factor family (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6), which can be structurally and / or functionally related and can be involved in mediating signal transduction from a variety of cytokine and / or growth factor receptors.

[0012] Unbound by theory, STAT6 can selectively mediate signaling from IL-4 and IL-13 by complexing the IL-4Ra subunit with the common γ chain (γc) to form a type I receptor, or with the IL-13Rα1 subunit to form a type II receptor. When the receptor complex is activated by IL-4 or IL-13, Janus kinase (Jak), associated with the cytoplasmic tail region of IL-4Ra, can be activated and phosphorylate tyrosine residues on the intracellular portion of the receptor. This phosphorylation creates a docking site for STAT6, which binds to the phosphorylated receptor via its Src homology-2 (SH2) domain. This allows Jak kinase to phosphorylate tyrosine (Y)-641 on STAT6, potentially leading to activation. Activated STAT6 can form a homodimer and relocate to the nucleus, activating gene transcription. Genes transcribed from activated STAT6 can be cell-specific and can often induce Th2 immune responses (Walford and Taylor 2013:STAT6 and lung inflammation. JAK-STAT 2:4, e25301; Oct / November / December 2013; ©2013 Landes Bioscience).

[0013] STAT6 is expressed in a variety of cell types, including epithelial cells, fibroblasts, and immune cells. Unbound by theory, inhibition of STAT6 activity can suppress IL-4 and IL-13-mediated effects in cells, including T cell differentiation into Th2 cells and the conversion of B cell classes to IgE and IgG1-producing cells (Walford). In epidermal keratinocytes, STAT6 inhibitors can suppress the secretion of pro-inflammatory chemokines and restore the inhibition of cytokine-induced barrier function proteins such as filaggrin (Tollenaire et al., 2017: Skin Barrier and Inflammation Genes Associated with Atopic Dermatitis are Regulated by Interleukin-13 and Modulated by Tralokinumab In vitro. Acta Derm Venereol 2021; 101: adv00447).

[0014] Antibodies targeting the Th2 immune response, such as IL-4Ra (dupilumab) or IL-13 (tralokinumab, lebrikizumab), have shown efficacy in many Th2-driven diseases. Targeting STAT6 with small molecule inhibitors allows for targeting the same pathway via oral or transdermal administration and can be effective in diseases where dupilumab has already shown efficacy. Therefore, compounds antagonizing STAT6 could be used to treat conditions characterized by Th2-mediated inflammation, such as atopic dermatitis, nodular prurigo, bullous pemphigoid, asthma, chronic sinusitis with nasal polyps, urticaria (such as chronic spontaneous urticaria), rhinitis, eosinophilic esophagitis, food allergies, diffuse systemic sclerosis, alopecia areata, and / or COPD.

[0015] STAT6 is also involved in the differentiation and activity of M2 macrophages, including tumor-associated macrophages (TAMs) in solid tumors. TAMs protect tumors from immune attack by inducing a pro-tumor immunosuppressive environment. TAMs can inhibit T cell proliferation, block the migration of CD8 T cells to the tumor, and recruit Tregs into the tumor microenvironment (Karpathiou et al., 2021:STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathology - Research and Practice 223 (2021) 153477).

[0016] In addition, IL-13 can act as a growth factor for some tumors, and for some tumors, gain-of-function mutations in STAT6 have been described as oncogenes (Karpathiou et al., 2021: STAT6: A review of asignaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathology - Research and Practice 223 (2021)153477).

[0017] These data collectively suggest that STAT6 degraders can be used as standalone treatments or in combination with other anticancer drugs, such as checkpoint inhibitors, to treat various cancers, including lymphoma, non-small cell lung cancer, and solid fibrotic cancer.

[0018] Although various antibodies against IL-4R or IL-13 have been approved for medical use, there are currently no approved, orally available STAT6 degraders.

[0019] Therefore, there remains a need to develop STAT-6 degraders, especially small molecules suitable for oral administration.

[0020] In addition, some patients can be treated with topical application of STAT-6 degraders. This may be particularly suitable for patients with skin lesions that are easily accessible and confined to the surface of the body. Topical treatment can also be prescribed for certain patients who can benefit from avoiding systemic modulation of the STAT-6 pathway, such as when receiving treatment for infections or gastrointestinal problems. Summary of the Invention

[0021] The inventors have unexpectedly discovered that the novel compounds and their salts, as described in this disclosure, exhibit a regulatory effect on the STAT-6 signaling pathway.

[0022] For example, compounds as described herein, and their pharmaceutically acceptable salts, may be beneficial in the prevention, treatment, or improvement of a variety of diseases involving the upregulation or downregulation of STAT-6.

[0023] In addition, the compounds described herein and their pharmaceutically acceptable salts have advantageous properties such as high metabolic stability, membrane permeability and / or solubility, which makes them particularly suitable for oral administration.

[0024] Additionally, some patients can be treated with topical application of STAT-6 degraders. This may be particularly suitable for patients, for example, with skin lesions that are easily accessible and confined to areas of the body surface. Topical treatment can also be prescribed for certain patients who may benefit from avoiding systemic modulation of the STAT-6 pathway, such as when receiving treatment for infections or gastrointestinal problems. Therefore, some aspects of this disclosure relate to methods for the topical application of compounds as described herein and their salts.

[0025] Therefore, in some embodiments, this disclosure provides a compound according to formula (I):

[0026]

[0027] in:

[0028] A1 Selected from , , , , and ;

[0029] R 9 It is -AL-LBM;

[0030] X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N;

[0031] X 4 Selected from CR 4 R 4 and CO;

[0032] X 5 Selected from N and oxidized N;

[0033] Y 1 Selected from N and CR 7 ;

[0034] Y 2 Selected from N and CR 8 ;

[0035] Y 3 Selected from N and CR 17 ;

[0036] Z is selected from N and CR. 10 ;

[0037] R is NHR 0 ;

[0038] R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n-CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR'R", -CONR'R", and -CO2R', wherein R' and R" are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2;

[0039] R 1 and R 1a Independently selected from hydrogen, fluorine, and C 1-4 alkyl;

[0040] R 2 Selected from hydrogen, C 1-5 Alkyl group, -SO2-C 1-4 Alkyl and deuterated C 1-4 Alkyl, wherein the C 1-5 Alkyl groups may optionally be substituted with halogens once or multiple times;

[0041] R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0042] R 4 and R 6 Each of them is independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0043] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0044] R 10 Selected from hydrogen and fluorine;

[0045] Or R 5 and R 10 They form bonds together between the two carbons to which they are attached;

[0046] R 5a It is hydrogen;

[0047] Or R 5 and R 5aBoth are fluorine, or R 5 and R 5a Together with the atoms attached to it, they form CO groups;

[0048] R 5b and R 5c Each is independently selected from hydrogen and fluorine;

[0049] R 7 R 8 and R 17 Each is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0050] R 11 R 12 and R 13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR', -CONR', -CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and each is independently selected from hydrogen and C. 1-4 Alkyl; or

[0051] R 11 and R 0 Together with the atoms attached thereto, it forms a 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms, wherein the 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -COCF3, -NR', -CONR', and -CO2R', wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy, wherein R' and each independently select from hydrogen and C. 1-4 alkyl;

[0052] R 12 and R13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR', -CONR', -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and each is independently selected from hydrogen and C. 1-4 alkyl;

[0053] A is CO;

[0054] L is selected from

[0055]

[0056]

[0057] ;

[0058] Where n1 is selected from 0 and 1;

[0059] n2 is selected from 1 and 2;

[0060] R 17 Selected from hydrogen and fluorine;

[0061] R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0062] R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0063] R 20 Selected from hydrogen and C 1-4 alkyl;

[0064] X 6 It is C;

[0065] X 7 It is CR 24 Or N;

[0066] R 24 Selected from hydrogen and hydroxyl groups;

[0067] X 8 and X 9 It is CH or N independently; and

[0068] LBM is

[0069]

[0070] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0071] R 21 Selected from hydrogen, fluorine, and chlorine;

[0072] R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times;

[0073] Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or

[0074] Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O;

[0075] Or its pharmaceutically acceptable salts or stereoisomers.

[0076] In some embodiments, this disclosure provides a compound according to formula (I'):

[0077] (I')

[0078] in:

[0079] X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N;

[0080] X 4 It is CR 4 R 4 or CO;

[0081] Y 1 Selected from N and CR 7 ;

[0082] Y 2 Selected from N and CR 8 ;

[0083] Z is selected from N and CR. 10 ;

[0084] R is NHR 0 ;

[0085] R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR', -CONR', and -CO2R', wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2;

[0086] R 1a It is hydrogen;

[0087] R 2 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 Alkyl; wherein the C 1-4 Alkyl groups may optionally be substituted with halogens once or multiple times;

[0088] R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0089] R 4 and R 6 Independently selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted with one or more halogens;

[0090] R5 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0091] R 10 Selected from hydrogen and fluorine;

[0092] Or R 5 and R 10 They form bonds together between the two carbons to which they are attached;

[0093] R 5a It is hydrogen; or R 5 and R 5a Both are fluorine;

[0094] R 7 and R 8 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group can be independently and optionally substituted with one or more halogens;

[0095] R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl; or

[0096] R 11 and R 0 Together with the atoms attached thereto, a 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N can be formed, wherein the 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4Alkyl, cyano, -NR'R'', -CONR'R'' and -CO2R', wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy group, wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl;

[0097] R 12 and R 13 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl;

[0098] A is CO;

[0099] L is selected from

[0100]

[0101]

[0102] ;

[0103] Where n1 is selected from 0 and 1;

[0104] n2 is selected from 1 and 2;

[0105] R 17 Selected from hydrogen and fluorine;

[0106] R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0107] R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0108] R 20 Selected from hydrogen and C 1-4 alkyl;

[0109] X6 It is C;

[0110] X 7 It is CR 24 Or N;

[0111] R 24 Selected from hydrogen and hydroxyl groups;

[0112] X 8 and X 9 It is CH or N independently; and

[0113] LBM is

[0114]

[0115] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0116] R 21 Selected from hydrogen, fluorine, and chlorine;

[0117] R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times;

[0118] Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or

[0119] Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O;

[0120] Or its pharmaceutically acceptable salts or stereoisomers.

[0121] In another embodiment, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0122] In another embodiment, this disclosure provides a method for treating an immune-mediated disease or condition in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of this disclosure.

[0123] In another embodiment, this disclosure provides a method for modulating the activity of signal transducer and activator of transcription 6 (STAT6) protein in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of this disclosure.

[0124] In another embodiment, this disclosure provides a method for treating a subject in need of a disease or symptom mediated by the activity of the signal transducer and activator of transcription 6 (STAT6) protein, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of this disclosure.

[0125] In another embodiment, this disclosure provides a method for treating a subject in need of a disease or condition mediated by interleukin-4 (IL-4) or interleukin-3 (IL-3), the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of this disclosure.

[0126] In one embodiment, this disclosure provides a method for preventing, treating, or improving a disease characterized by Th2-mediated inflammation.

[0127] In another embodiment, this disclosure provides a method for manufacturing a medicament for treating a disease or symptom mediated by the activity of the signal transducer and activator of transcription 6 (STAT6) protein in a subject of need, characterized by the use of a compound of this disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0128] In another embodiment, this disclosure provides a method for manufacturing a medicament for treating a subject with a disease or symptom mediated by the signal transducer and activator of transcription 6 (STAT6) protein.

[0129] In some embodiments, this disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, for the treatment of a subject in need of a disease or condition mediated by the signal transducer and activator of transcription 6 (STAT6) protein.

[0130] In some embodiments, this disclosure provides compounds of the disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, for use in a therapeutic manner. Attached Figure Description

[0131] Figure 1The results of anHiBit assays are shown, namely the dose-response curves for Examples 3u208, 3u246, 3u118, 3u119, 3u120 and 3u74 (where the percentage of degradation is plotted on a logarithmic scale relative to the concentration of the test compound (in M).

[0132] Figure 2 Data from whole blood eosinophil chemokine-3 assays in human samples 3u208, 3u246, 3u118, 3u119, 3u120, and 3u74 are shown (where the effect (in %) is plotted on a logarithmic scale relative to the test concentration (in M)). Detailed Implementation

[0133] definition

[0134] Whenever a compound of formula (I) is mentioned herein, it should be understood that compounds of formulas (I'), (I''), (II), (II'), (III), (IV), (IV'), (VII), (VIII), (VIII'), (IX), (IXa), and (IXb), as well as compounds of other subforms described herein, are subgroups of compounds of formula (I), and statements relating to compounds of formula (I) are equally well applied to their subgroups.

[0135] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-4 "alkyl" indicates that the alkyl group has 1 to 4 carbon atoms.

[0136] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some other embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Moreover, unless the context clearly specifies otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art. The term "C" 1-4 "Alkyl" is used herein to refer to a hydrocarbon group obtained by removing a hydrogen atom from a branched or straight-chain hydrocarbon. The alkyl group comprises (1-4) carbon atoms, 1-3 carbon atoms, 2-3 carbon atoms, or 1-2 carbon atoms. This term includes n-alkyl (…). n -alkyl), secondary alkyl and tertiary alkyl subclasses, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tertiary butyl.

[0137] Term "C" 1-4 "Alkyl" is used herein to refer to a hydrocarbon group obtained by removing a hydrogen atom from a branched or straight-chain hydrocarbon. The alkyl group comprises (1-4) carbon atoms, 1-3 carbon atoms, 2-3 carbon atoms, or 1-2 carbon atoms. This term includes n-alkyl (…). n -alkyl), secondary alkyl and tertiary alkyl subclasses, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tertiary butyl.

[0138] The term “(C1-C4)alkoxy” is used herein to refer to a group of the formula -OR’, where R’ is a (C1-C4)alkyl group as shown herein, wherein the (C1-C4)alkyl group is attached to the parent molecule moiety by an oxygen atom, such as methoxy (-OCH3) and ethoxy (-OCH2CH3).

[0139] The term "cyano" is used in this document to refer to the -CN group attached to the parent molecule via an oxygen atom.

[0140] The term “(C3-C4)cycloalkyl” is used herein to refer to a saturated (C3-C4)cycloalkane group containing 3-4 carbon atoms, such as cyclopropyl or cyclobutyl.

[0141] The terms "halogen" or "halogenated" are used herein to refer to chlorine, bromine, fluorine, or iodine. In some embodiments, the halogen is chlorine, bromine, or fluorine.

[0142] "Aromatic ring" or "aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. Aryl groups can have 6 to 20 ring carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl, regardless of the connection point. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic, regardless of the connection point. If one or more aryl groups are fused with a cycloalkyl group, the resulting ring system is cycloalkyl, regardless of the connection point.

[0143] Unless otherwise stated, "heteroaryl ring" or "heteroaryl group" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. A heteroaryl group may comprise 1 to 20 ring carbon atoms (i.e., C atoms) independently selected from nitrogen, oxygen, and sulfur. 1-20(heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 (Heteroaryl group), and 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom. In some cases, heteroaryl groups include 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzooxazolyl, benzothiophene (benzobenzylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothiaphene, furanyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isothiazolyl, imidazolyl, indazole, indazole, isothiazolyl ... Indolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, phenylthio (i.e., thiophene), triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, inzolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., through any of the fused rings). A heteroaryl does not encompass aryl groups as defined above or overlap with them.

[0144] Unless otherwise stated, "heterocyclic" or "heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. Heterocyclic groups can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocyclic, and can include one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. -The term "heterocyclic group" refers to any non-aromatic ring containing at least one heteroatom, regardless of its connection (i.e., bonded by carbon atoms or heteroatoms). Furthermore, the term "heterocyclic group" is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of its attachment to the rest of the molecule. Heterocyclic groups can have 2 to 20 ring carbon atoms (i.e., C2, C3, C4, C5, C6, C6, C7 ... 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C2- 10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6 Heterocyclic groups); having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 cyclic heteroatoms independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirroyl, benzodioxazolyl, benzo[b][1,4]dioxepine, 1,4-benzodioxyl, benzopyranyl, benzodioxinyl, benzopyranone, benzofuranone, dioxacyclopentyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazoalkyl, indololinyl, indolazinyl, isoindololinyl, isothiazolyl, isoxazolyl, and isoxazolidine. The following groups are listed: morpholino, octahydroindolo, octahydroisoindolo, 2-oxopiperazino, 2-oxopiperidino, 2-oxopiperidyl, oxazolyl, ethylene oxide, oxacyclobutyl, phenothiazino, phenothiazino, piperidino, piperazino, 4-piperidinone, pyrrolyl, pyrazolyl, quininecyclo, thiazolyl, tetrahydrofurano, tetrahydropyrano, trithiaalkyl, tetrahydroquinolino, thiomorpholino, thiomorpholino, 1-oxo-thiomorpholino, and 1,1-dioxo-thiomorpholino.

[0145] The term "halogenated-C" 1-4 Alkyl or halogenated-C 1-4 In this article, "alkoxy" is used to refer to "C" as defined above. 1-4 Alkyl or C 1-4 An "alkoxy" group, in which one or more hydrogen atoms have been replaced by a halogen (such as fluorine). "Halogenated-C" 1-4 Alkyl or halogenated-C 1-4 Examples of "alkoxy groups" include -CHF2, -CF3, -CH2CF3, -CF2CF3, or -OCF3.

[0146] The term "deuterated C"1-4 In this article, "alkyl" refers to a C-shaped compound in which one or more hydrogen atoms have been replaced by deuterium. 1-4 Alkyl group. Deuterated C 1-4 Examples of "alkyl" include -CH2D2, -CHD2, or -CD3.

[0147] Term "C" 1-4 Alkoxy-C 1-4 In this text, "alkyl" refers to a alkyl group in which one of its hydrogen atoms has been replaced by a (C1-C4) alkoxy group. 1-4 Alkyl group. 1-4 Alkoxy-C 1-4 Examples of "alkyl" include methoxymethyl or methoxyethyl.

[0148] The term "(C3-C4)cycloalkyl-C" 1-4 In this article, "alkyl" is used to refer to a cycloalkyl group in which one of the hydrogen atoms has been replaced by a (C3-C4) cycloalkyl group. 1-4 Alkyl group. (C3-C4)cycloalkyl-C 1-4 Examples of "alkyl" include cyclopropylmethyl.

[0149] The term "phenyl-C" 1-4 In this article, "alkyl" is used to refer to a "C" in which one of the hydrogen atoms has been replaced by a phenyl group. 1-4 Alkyl group. Phenyl-C 1-4 Examples of "alkyl" include benzyl.

[0150] If the substituents are described as being selected independently from the group, then the selection of each substituent is independent of the other substituents. Therefore, each substituent can be the same as or different from the other substituents.

[0151] The term "optionally substituted" means "unsubstituted or substituted". In some embodiments, the formulas described herein cover compounds containing specified optional substituents as well as compounds not containing optional substituents.

[0152] In some implementations, as used herein, the phrase "one or more" refers to one to five. In some implementations, as used herein, the phrase "one or more" refers to one to three.

[0153] As used in this article, whenever the molecular diagram of a substituent contains an arrow, the arrow indicates a bond that attaches the substituent to the rest of the molecule.

[0154] The term "pharmaceutically acceptable salt" is intended to refer to a non-toxic salt of a compound in its free base form, which possesses the desired pharmacological activity of the free base. These salts can be derived from a suitable base moiety and a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactopyric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, aminosulfonic acid, or fumaric acid.

[0155] In some embodiments, pharmaceutically acceptable salts of compounds of formula (I) containing an acid moiety can also be prepared by reacting with a suitable base (such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, barium hydroxide, ammonia, etc.) or a suitable non-toxic amine (such as lower alkylamines (e.g., diethylamine, tetraalkylammonium hydroxide), hydroxy-lower alkylamines (such as diethanolamine, 2-(diethylamino)-ethanol, ethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, tannin), cycloalkylamines, ethylenediamine or benzylamine (such as benzylamine and benzathine), betaine, choline hydroxide, N-methyl-glucosamine, hebamin, 1H-imidazolium, 4-(2-hydroxyethyl)-morpholine, piperazine, 1-(2-hydroxyethyl)-pyrrolidine, L-arginine or L-lysine). Other examples of pharmaceutically acceptable salts are listed in Berge, SM; J. Pharm. Sci.; (1977), 66(1), 1-19 and Stahl, PH, in Wermuth, CG, Handbook of Pharmaceutical Salts, Properties, Selection and Use, 2nd ed., Wiley-VCH, 2011, both of which are incorporated herein by reference.

[0156] The term "solvent" is intended to refer to a substance formed by the interaction between a compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a solvent (e.g., an alcohol, glycerol, or water), wherein the substance is in crystalline form. When water is the solvent, the substance is called a hydrate.

[0157] As used herein, the term "treatment" refers to the management and care of a patient for the purpose of combating a disease, symptom, or condition. This term is intended to include delaying the progression of the disease, symptom, or condition; improving, reducing, or alleviating symptoms and complications; and / or curing or eliminating the disease, symptom, or condition. The term may also include symptom prevention, where prevention is understood as the management and care of a patient for the purpose of combating a disease, symptom, or condition, and includes the administration of active compounds to prevent the onset of symptoms or complications. However, preventive (avoidant) and therapeutic (curative) treatment are two separate aspects.

[0158] "Administration" refers to oral administration to a subject, administration as a suppository, local contact (e.g., transdermal), parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, inhalation administration, intradermal and / or subcutaneous administration, intrathecal administration, and / or implantation of a slow-release device (e.g., a microosmotic pump). Administration may be performed according to a schedule based on the specified administration frequency, dosage, and other factors.

[0159] As used herein, “co-administration” means administering a unit dose of the compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after several hours (e.g., 1 hour to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after several hours (e.g., 1 to 12 hours). Co-administration of the compound disclosed herein with one or more additional therapeutic agents generally means administering the compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the patient.

[0160] compound

[0161] This article provides compounds that regulate the activity of STAT6.

[0162] In one embodiment, this disclosure provides a compound of formula (I).

[0163]

[0164] in:

[0165] A 1 Selected from , , , , and ;

[0166] R 9 It is -AL-LBM;

[0167] X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N;

[0168] X 4 Selected from CR 4 R 4 and CO;

[0169] X 5 Selected from N and oxidized N;

[0170] Y 1 Selected from N and CR 7 ;

[0171] Y 2 Selected from N and CR 8 ;

[0172] Y 3 Selected from N and CR 17 ;

[0173] Z is selected from N and CR. 10 ;

[0174] R is NHR 0 ;

[0175] R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2)n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkoxy, cyano, -NR', -CONR', and -CO2R', wherein R' and each are independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2;

[0176] R 1 and R 1a Independently selected from hydrogen, fluorine, and C 1-4 alkyl;

[0177] R 2 Selected from hydrogen, C 1-5 Alkyl group, -SO2-C 1-4 Alkyl and deuterated C 1-4 Alkyl, wherein the C 1-5 Alkyl groups may optionally be substituted with halogens once or multiple times;

[0178] R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0179] R 4 and R 6 Each of them is independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0180] R 5 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0181] R 10 Selected from hydrogen and fluorine;

[0182] Or R 5 and R 10 They form bonds together between the two carbons to which they are attached;

[0183] R 5a It is hydrogen;

[0184] Or R 5 and R 5aBoth are fluorine, or R 5 and R 5a Together with the atoms attached to it, they form CO groups;

[0185] R 5b and R 5c Each is independently selected from hydrogen and fluorine;

[0186] R 7 R 8 and R 17 Each is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0187] R 11 R 12 and R 13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR', -CONR', -CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and each is independently selected from hydrogen and C. 1-4 Alkyl; or

[0188] R 11 and R 0 Together with the atoms attached thereto, it forms a 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms, wherein the 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -COCF3, -NR', -CONR', and -CO2R', wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy, wherein R' and each independently select from hydrogen and C. 1-4 Alkyl; and

[0189] R 12 and R13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR', -CONR', -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and each is independently selected from hydrogen and C. 1-4 alkyl;

[0190] A is CO;

[0191] L is selected from

[0192]

[0193]

[0194] ;

[0195] Where n1 is selected from 0 and 1;

[0196] n2 is selected from 1 and 2;

[0197] R 17 Selected from hydrogen and fluorine;

[0198] R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0199] R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0200] R 20 Selected from hydrogen and C 1-4 alkyl;

[0201] X 6 It is C;

[0202] X 7 It is CR 24 Or N;

[0203] R 24 Selected from hydrogen and hydroxyl groups;

[0204] X 8 and X 9 It is CH or N independently; and

[0205] LBM is

[0206]

[0207] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0208] R 21 Selected from hydrogen, fluorine, and chlorine;

[0209] R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times;

[0210] Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or

[0211] Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O;

[0212] Or its pharmaceutically acceptable salts or stereoisomers.

[0213] In one embodiment, this disclosure provides a compound of formula (I').

[0214] (I')

[0215] in:

[0216] X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N;

[0217] X 4 It is CR 4 R 4 or CO;

[0218] Y 1 Selected from N and CR 7 ;

[0219] Y 2 Selected from N and CR 8 ;

[0220] Z is selected from N and CR. 10 ;

[0221] R is NHR 0 ;

[0222] R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR', -CONR', and -CO2R', wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2;

[0223] R 1a It is hydrogen;

[0224] R 2 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 Alkyl; wherein the C 1-4 Alkyl groups may optionally be substituted with halogens once or multiple times;

[0225] R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl;

[0226] R 4 and R 6 Independently selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted with one or more halogens;

[0227] R 5Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group may optionally be replaced by one or more halogens;

[0228] R 10 Selected from hydrogen and fluorine;

[0229] Or R 5 and R 10 They form bonds together between the two carbons to which they are attached;

[0230] R 5a It is hydrogen; or R 5 and R 5a Both are fluorine;

[0231] R 7 and R 8 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group can be independently and optionally substituted with one or more halogens;

[0232] R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl; or

[0233] R 11 and R 0 Together with the atoms attached thereto, a 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N can be formed, wherein the 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4Alkyl, cyano, -NR'R'', -CONR'R'' and -CO2R', wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy group, wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl;

[0234] R 12 and R 13 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl;

[0235] A is CO;

[0236] L is selected from

[0237]

[0238]

[0239] ;

[0240] Where n1 is selected from 0 and 1;

[0241] n2 is selected from 1 and 2;

[0242] R 17 Selected from hydrogen and fluorine;

[0243] R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0244] R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0245] R 20 Selected from hydrogen and C 1-4 alkyl;

[0246] X6 It is C;

[0247] X 7 It is CR 24 Or N;

[0248] R 24 Selected from hydrogen and hydroxyl groups;

[0249] X 8 and X 9 It is CH or N independently; and

[0250] LBM is

[0251]

[0252] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0253] R 21 Selected from hydrogen, fluorine, and chlorine;

[0254] R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times;

[0255] Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or

[0256] Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O;

[0257] Or its pharmaceutically acceptable salts or stereoisomers.

[0258] In one embodiment, this disclosure provides a compound of formula (II) or formula (II'):

[0259] (II)

[0260] (II')

[0261] Where X 1 X 2 X 3X 4 Y 1 Y 2 Z, R, R 1a R 2 R 5 R 5a R 6 A, L, and LBM are as defined anywhere in this document; and R 3 It is C 1-4 alkyl;

[0262] Or its pharmaceutically acceptable salts or stereoisomers.

[0263] In some implementation schemes, X 1 It is N, X 2 It is CR 12 X 3 It is CR 13 And X 4 It is CR 14 .

[0264] In some implementation schemes, X 1 It is CR 11 X 2 It is CR 12 X 3 It is CR 13 And X 4 It is CR 14 .

[0265] In one embodiment, this disclosure provides a compound of formula (III).

[0266] (III)

[0267] Where Y 1 Y 2 X 4 Z, R, R 1a R 2 R 3 R 5 R 5a R 6 R 11 R 12 R 13 A, L and LBM as defined anywhere in this document; or their pharmaceutically acceptable salts or stereoisomers.

[0268] In one embodiment, this disclosure provides a compound of formula (IV).

[0269] (IV)

[0270] Where Y1 Y 2 X 4 Z, R, R 1a R 2 R 5 R 5a R 6 R 11 R 12 R 13 A, L, and LBM are as defined anywhere in this document; and R 3 It is C 1-4 Alkyl group; or its pharmaceutically acceptable salt or stereoisomer.

[0271] In one embodiment, this disclosure provides a compound of formula (IV').

[0272] (IV')

[0273] Where Y 1 Y 2 X 4 Z, R, R 1a R 2 R 5 R 5a R 6 R 11 R 12 R 13 A, L, and LBM are as defined anywhere in this document; and R 3 It is C 1-4 Alkyl group; or its pharmaceutically acceptable salt or stereoisomer.

[0274] In some implementations, when R 11 R 12 R 13 and R14 Each of these elements, when present, is independently selected from hydrogen, halogens, and C. 1-4 Alkyl group.

[0275] In some implementation schemes, R 12 and R 13 Both are hydrogen.

[0276] In some implementation schemes, R 11 R 12 and R 13 It's all hydrogen.

[0277] In some implementation schemes, X 1 It is CR 11 ;X 2 It is CR 12 ;X 3 It is CR13 ;X 4 It is CR 14 And R 11 and R 0 Together with the atoms attached thereto, a 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N can be formed, wherein the 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR'R'', -CONR'R'' and -CO2R', wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy group, wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl group. In some embodiments, the 5-6 membered heteroaromatic ring containing one or two N atoms is a pyrazole ring.

[0278] In some implementations, the 5-6 membered heterocycle containing one or two N atoms is a pyrrolidine ring.

[0279] In some implementations, R is NHR 0 And R 0 It is hydrogen.

[0280] In some implementations, R is NHR 0 And R 0 Selected from C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR', -CONR', and -CO2R', wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2;

[0281] In some implementations, R is NHR 0 And R 0 Selected from hydrogen and C 1-4 alkyl.

[0282] In some implementations, R is NHR 0 And R 0 It is C 1-4 Alkyl (e.g., methyl).

[0283] In one embodiment, this disclosure provides a compound of formula (VII).

[0284] (VII)

[0285] Where Y 1 Y 2 X 4 Z, R 1a R 2 R 3 R 5 R 5a R 6 R 12 R 13 A, L, and LBM are as defined anywhere in this document, R 16 Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times by substituents independently selected from halogens.

[0286] In one embodiment, this disclosure provides a compound of formula (VIII).

[0287] (VIII)

[0288] Where Y 1 Y 2 X 4 Z, R 1a R 2 R 3 R 5 R 5a R 6 R 12 R 13 A, L, and LBM are as defined anywhere in this document, and R 16 Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times by substituents independently selected from halogens.

[0289] In one embodiment, this disclosure provides a compound of formula (VIII').

[0290] (VIII')

[0291] Where Y 1 Y 2 X 4 Z, R 1a R 2 R 3 R 5 R 5a R 6 R 12 R 13 A, L, and LBM are as defined anywhere in this document, and R 16 Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be substituted once or multiple times by substituents independently selected from halogens.

[0292] In some implementation schemes, R 16 It is hydrogen.

[0293] In one embodiment, this disclosure provides a compound of formula (IX):

[0294] (IX)

[0295] Where R 16 and R 16a Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be substituted once or multiple times by a substituent independently selected from halogens; or a pharmaceutically acceptable salt or stereoisomer thereof.

[0296] In one embodiment, this disclosure provides a compound of formula (IXa) or (IXb):

[0297] (IXa) or

[0298] (IXb)

[0299] Where R 16 and R 16a Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be substituted once or multiple times by a substituent independently selected from halogens; or a pharmaceutically acceptable salt or stereoisomer thereof.

[0300] In some implementation schemes, R 16and R 16a Both are hydrogen.

[0301] In some implementations, Z is N.

[0302] In some implementations, Z is CR 10 And R 5 and R 10 They form bonds together between the two carbons to which they are attached.

[0303] In some implementations, Z is CR 10 And R 10 It is hydrogen.

[0304] In some implementation schemes, R 5a It is hydrogen.

[0305] In some implementation schemes, X 4 It is CR 4 And R 4 Selected from hydrogen and C 1-4 alkyl.

[0306] In some implementation schemes, Part of it is or .

[0307] In some implementation schemes, Y 1 It is N, and Y 2 It is CR 8 .

[0308] In some implementation schemes, Y 1 It is N, and Y 2 It is N.

[0309] In some implementation schemes, Y 1 It is CR 7 And Y 2 It is CR 8 .

[0310] In some embodiments, this disclosure provides a compound as described herein, wherein

[0311] (a)R 7 and R 8 Both are C 1-4 alkyl;

[0312] (b)R 7 and R 8 Both are halogens;

[0313] (c)R 7 and R 8 One of them is C 1-4Alkyl groups, and the other is a halogen;

[0314] (d) R 7 and R 8 One of them is C 1-4 Alkyl group, and the other is hydrogen; or

[0315] (e)R 7 and R 8 One of them is halogen, and the other is hydrogen.

[0316] In some embodiments, this disclosure provides a compound as described herein, wherein

[0317] (a)R 7 and R 8 Both are C 1-4 alkyl;

[0318] (b)R 7 and R 8 Both are halogens;

[0319] (c)R 7 and R 8 One of them is C 1-4 Alkyl groups, and the other is a halogen;

[0320] (d) R 7 and R 8 One of them is C 1-4 Alkyl group, and the other is hydrogen; (e) R 7 and R 8 One of them is a halogen, and the other is hydrogen; and

[0321] (f)R 7 and R 8 Both are hydrogen;

[0322] In some implementation schemes, R 7 and R 8 Both are halogens; or R 7 and R 8 One of them is C 1-4 Alkyl group, and the other is a halogen; or R 7 and R 8 Both are hydrogen. In some implementations, R 7 and R 8 Both are halogens, or R 7 and R 8 One of them is C 1-4 Alkyl groups, and another is a halogen.

[0323] In some implementation schemes, R 7It is halogen, and R 8 It is a methyl group.

[0324] In some implementations, the halogen in b), c) and e) is fluorine.

[0325] In some embodiments, this disclosure provides a compound as described herein, wherein R 2 It is a methyl group.

[0326] In some embodiments, this disclosure provides a compound as described herein, wherein R 3 Is it hydrogen or C? 1-4 alkyl.

[0327] In some embodiments, this disclosure provides a compound as described herein, wherein R 3 It is a methyl group.

[0328] Precursor

[0329] In some embodiments, the compound of formula (I) is prepared from the precursors listed in the table below, and subsequently derivatized at the appropriate position to obtain the compound of formula (I) (i.e., where R...). 9 It is -AL-LBM).

[0330]

[0331] part A and some L

[0332] In some implementations, A is CO.

[0333] In some implementation schemes, L is selected from

[0334]

[0335]

[0336]

[0337] ;

[0338] Where n1 is selected from 0 and 1;

[0339] n2 is selected from 1 and 2;

[0340] R 17 Selected from hydrogen and fluorine;

[0341] R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0342] R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0343] R 20 Selected from hydrogen and C 1-4 alkyl;

[0344] X 6 It is C;

[0345] X 7 It is CR 24 Or N;

[0346] R 24 Selected from hydrogen and hydroxyl; and

[0347] X 8 and X 9 It can be CH or N independently.

[0348] In some implementation schemes, L is selected from:

[0349] .

[0350] In some implementation schemes, L is selected from:

[0351]

[0352] In some implementations, the R portion of L 17 R 18 R 19 and R 20 At least one of them is not hydrogen. In some implementations, R 17 It is hydrogen, and the R part of the L is... 18 R 19 and R 20At least one of them is not hydrogen.

[0353] In some implementation schemes, L is selected from:

[0354]

[0355] In some implementations, A is CO, and AL is selected from:

[0356]

[0357]

[0358]

[0359] and

[0360] In some implementations, A is CO.

[0361] In some implementation schemes, A is .

[0362] In some implementation schemes, L is selected from:

[0363]

[0364]

[0365] Each n1 is independently selected from 0 and 1;

[0366] n2 is selected from 1 and 2;

[0367] R 17 Selected from hydrogen and fluorine;

[0368] R 18 Selected from hydrogen, fluorine and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups may optionally be fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times;

[0369] Each R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine;

[0370] R 20 Selected from hydrogen and C 1-4 alkyl;

[0371] X 6 It is C; and

[0372] X 9 It is CH or N.

[0373] In some implementation schemes, L is selected from:

[0374]

[0375] In some implementations, L is .

[0376] In some implementations, L is .

[0377] In some implementations, L is .

[0378] In some implementations, L is .

[0379] In some implementations, L is .

[0380] In some implementations, L is .

[0381] In some implementations, L is .

[0382] In some implementations, the R portion of L 17 R 18 R 19 and R 20 At least one of them is not hydrogen.

[0383] In some implementation schemes, R 17 It is hydrogen, and the R part of the L is... 18 R 19 and R 20 At least one of them is not hydrogen.

[0384] In some implementation schemes, AL is selected from:

[0385]

[0386] part LBM

[0387] In some implementations, LBM is

[0388]

[0389] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0390] R 21 Selected from hydrogen, fluorine, and chlorine;

[0391] R22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times; and

[0392] Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or

[0393] Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O.

[0394] In some implementation schemes, X 7 It is NR 22 ;R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution can occur once or multiple times.

[0395] In some implementation schemes, X 7 It is NR 22 ;R 22 Selected from C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution can occur once or multiple times.

[0396] In some implementation schemes, X 7 It is NR 22 ;R 22 Selected from C 1-4 Alkyl and C 3-4 Cycloalkyl.

[0397] In some implementation schemes, X 7 It is NR 22 And R 22 It is a methyl group.

[0398] In some implementation schemes, X 7 It is NR22 And R 22 It is cyclopropyl.

[0399] In some implementation schemes, X 7 It is CR 23 R 23 ; Each R 23 Independently selected from halogens and C 1-4 Alkyl; or two R 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O.

[0400] In some implementation schemes, X 7 It is CR 23 R 23 ; Each R 23 Independently selected from hydrogen and C 1-4 alkyl.

[0401] In some implementation schemes, X 7 It is CR 23 R 23 And two R 23 Both are methyl or two R 23 They're all fluorine.

[0402] In some implementation schemes, X 7 It is CR 23 R 23 And two R 23 They are all methyl groups.

[0403] In some implementation schemes, X 7 It is CR 23 R 23 Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O.

[0404] In some implementation schemes, X 7 It is CR 23 R 23 And two R 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl.

[0405] In some implementation schemes, X 7 It is CR 23 R 23 And two R 23 Together with the carbon atoms attached to them, they form 3-6 membered heterocycles, in which the heterocycle contains a heteroatom of type O.

[0406] In some implementation schemes, R 21 It is either hydrogen or fluorine.

[0407] In some implementations, LBM is selected from:

[0408]

[0409] In some implementations, LBM is

[0410]

[0411] Where X 7 It is O, NR 22 or CR 23 R 23 ;

[0412] R 21 Selected from hydrogen, fluorine, and chlorine;

[0413] R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times;

[0414] Each R 23 Independently selected from hydrogen and C 1-4 Alkyl, or R 23 Two instances of this, together with the atoms to which they are attached, form a 3- or 4-membered carbon ring, which can optionally be... 1-4 Alkyl, fluorine, or hydroxyl substitution once or multiple times; and

[0415] R 24 Selected from hydrogen and C 1-4 alkyl.

[0416] In some implementation schemes, X 7 It is NR 22 ;R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl; and wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution can occur once or multiple times.

[0417] In some implementation schemes, X 7 It is NR 22 ;R22 Selected from C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl; and wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution can occur once or multiple times.

[0418] In some implementation schemes, X 7 It is NR 22 ;R 22 Selected from C 1-4 Alkyl and deuterated C 1-4 Alkyl; and wherein the C 1-4 Alkyl groups may optionally be converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution can occur once or multiple times.

[0419] In some implementation schemes, X 7 It is NR 22 And R 22 It is C 3-4 Cycloalkyl.

[0420] In some implementation schemes, X 7 It is CR 23 R 23 Two Rs 23 It is C 1-4 Alkyl; or two R 23 Together with the atoms to which they are attached, they form ternary or quaternary carbon rings, which can optionally be bonded by C. 1-4 Alkyl, fluorine, or hydroxyl substitution may be performed once or multiple times. In some embodiments, X 7 It is CR 23 R 23 ; Each R 23 Independently selected from hydrogen and C 1-4 alkyl.

[0421] In some implementation schemes, X 7 It is CR 23 R 23 Two Rs 23 Together with the atoms to which they are attached, they form ternary or quaternary carbon rings, which can optionally be bonded by C. 1-4 Alkyl, fluorine, or hydroxyl substitution may occur once or multiple times.

[0422] In some implementation schemes, R 24 It is hydrogen.

[0423] In some implementation schemes, R 21 It is hydrogen, chlorine, or fluorine.

[0424] In some implementation schemes, R 21 It is either hydrogen or fluorine.

[0425]

[0426] In some implementations, LBM is selected from:

[0427]

[0428] In some implementations, LBM is selected from:

[0429]

[0430] In some implementations, LBM is selected from:

[0431]

[0432] In some implementations, LBM has the following formula: , where R 21 It is either hydrogen or fluorine.

[0433] part AL-LAM

[0434] In some implementations, AL-LBM is

[0435] ,

[0436] Where R 17 As defined anywhere in this document.

[0437] In some implementations, AL-LBM is

[0438]

[0439] Where R 17 As defined anywhere in this document, and n3 is 0, 1, 2, or 3.

[0440] In some implementations, AL-LBM has the following formula:

[0441] ,

[0442] And where A is CO, n1 is 1, and R 18 and R 21 As defined anywhere in this document.

[0443] In some implementations, AL-LBM has the following formula:

[0444] ,

[0445] And where A is CO, n1 is 1, and X 7 R 18 and R 21 As defined anywhere in this document.

[0446] In some implementations, AL-LBM has the following formula:

[0447] ,

[0448] And where A is CO, n is 1, and R is... 18 Is it hydrogen or C? 1-4 Alkyl, and R 21 It consists of hydrogen and fluorine.

[0449] In some implementations, AL-LBM has the following formula:

[0450] ,

[0451] And where A is CO, n is 1, and R is... 18 Is it hydrogen or C? 1-4 Alkyl, R 21 It is hydrogen, chlorine, or fluorine, and X 7 As defined anywhere in this document.

[0452] In some embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof, is provided.

[0453] Table 1

[0454]

[0455] In one or more embodiments of this disclosure, the compound of formula (I) has an EC50 concentration of less than 100 μmol / L, or less than 10 μmol / L, or less than 100 nanomol / L, or less than 10 nanomol / L in an eosinophil chemokine-3 release assay. 50 )value.

[0456] In one or more embodiments of this disclosure, the compound of formula (I) has a concentration of less than 100 μmol / L, or less than 10 μmol / L, or less than 10 nanomol / L or less than 10 nanomol / L in the STAT6 assay described below (DC). 50 )value.

[0457] The compounds of formula (I) can be obtained directly in crystalline form by concentration from an organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and a co-solvent, which can be organic or inorganic (such as water). The crystals can be separated in a substantially solvent-free form or as a solvate (such as a hydrate). This disclosure also provides crystalline forms of the compounds of this disclosure (such as polymorphs and pseudopolymorphs) and mixtures thereof.

[0458] Compounds of formula (I) may contain asymmetrically substituted (chiral) carbon atoms, which result in the existence of isomers, such as enantiomers, diastereomers, and other stereoisomers, which can be defined in absolute stereochemistry as ( R )-or( S This disclosure provides for all such isomers, which are optically pure forms or mixtures thereof (e.g., racemic mixtures or partially purified optically active mixtures). Pure stereoisomers of the compounds and intermediates of this disclosure can be obtained by applying procedures known in the art. Various isomer forms can be separated by physical separation methods, such as selective crystallization and chromatographic techniques, e.g., high-performance liquid chromatography using a chiral stationary phase. Enantiomers can be separated from each other by selective crystallization of their diastereomer salts, which can be formed with an optically active amine or an optically active acid. The optically purified compound can then be released from the purified diastereomer salt. Enantiomers can also be resolved by forming diastereomer derivatives. Alternatively, enantiomers can be separated by chromatographic techniques using a chiral stationary phase. Pure stereoisomers can also be derived from corresponding pure stereoisomers of suitable starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is required, the compound will be synthesized by stereoselective or stereospecific preparation methods. These methods will advantageously employ chiral pure starting materials.

[0459] Furthermore, geometric isomers can be formed when double bonds or fully or partially saturated ring systems are present in the molecule. Any geometric isomer, such as isolated, pure, or partially purified geometric isomers or mixtures thereof, is included within the scope of this disclosure. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, and unless otherwise stated, the compounds are intended to include E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. When a compound is expressed in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomers or enantiomer-enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomers or enantiomer-enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0460] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0461] "STAT6 regulator" refers to compounds disclosed herein that inhibit or reduce some or all of the activity of signal transducer and activator of transcription 6 (STAT6), including STAT6 degraders.

[0462] "STAT6 degrader" refers to the compounds of this disclosure that bind to and / or inhibit both the STAT6 protein and the E3 ligase with measurable affinity, thereby causing ubiquitination and subsequent degradation of the STAT6 protein. In some embodiments, the STAT6 degrader has a DC50 of less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. As used herein, the term "monovalent" refers to a degrader compound that does not have an attached E3 ligase-binding moiety.

[0463] STAT6-mediated diseases, illnesses, and / or symptoms refer to any disease or other harmful symptom in which STAT6 or its mutants are known to play a role.

[0464] "Subject" or "patient" is intended to describe a human or vertebrate animal (including dogs, cats, horses, cattle, mice, etc.).

[0465] "Treatment" is a method used to obtain a beneficial or desired outcome (including clinical outcomes) such as suppressing a disease or symptom (e.g., reducing one or more symptoms caused by the disease or symptom, and / or alleviating the severity of the disease or symptom), slowing or preventing the development of one or more clinical symptoms associated with the disease or symptom, and / or alleviating the disease, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging survival.

[0466] In compounds of formula (I), atoms may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those found in nature. This disclosure includes all suitable isotopic variants of compounds of formula (I). For example, different isotopic forms of hydrogen include... 1 H, 2 H and 3 H, different isotopic forms of carbon include 12 C 13 C and 14 C, and different isotopic forms of nitrogen include 14 N and 15 N. Deuterium ( 2 Enrichment of (H) can, for example, increase the in vivo half-life or reduce the dosage regimen, or provide compounds that can be used as standards for characterizing biological samples. Compounds enriched by isotopes in formula (I) can be prepared using conventional techniques well known to those skilled in the art or by methods similar to those described in the procedures and examples herein, using appropriate isotope-enriching reagents and / or intermediates.

[0467] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, have one to n hydrogen atoms attached to a carbon atom, substituted with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of hydrogen. Such compounds can increase resistance to metabolism and are therefore used to increase the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” TRENDS PHARMACOL. SCI., 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been substituted with deuterium.

[0468] In some embodiments, the compounds disclosed herein are solvates or hydrates.

[0469] In one embodiment, this disclosure provides the above-described compound for use in a therapy.

[0470] In one embodiment, this disclosure provides the above-described compound for treating a disease, symptom, or condition that responds to regulation of STAT-6.

[0471] In one embodiment, this disclosure provides the above-described compound for treating autoimmune diseases.

[0472] The compounds disclosed herein can be used to prevent, treat, or improve diseases characterized by Th2-mediated inflammation, such as atopic dermatitis, asthma, chronic sinusitis with nasal polyps, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse systemic sclerosis of the cutaneous tissue, alopecia areata, and / or COPD (chronic obstructive pulmonary disease), as well as as a standalone treatment or in combination with other anticancer drugs (such as checkpoint inhibitors) for the prevention, treatment, or improvement of various cancers (such as lymphoma, triple-negative breast cancer, and solid fibrotic cancer).

[0473] In one embodiment, the present invention provides the use of compounds of formula (I) as defined above in the manufacture of a medicament for the prevention, treatment or improvement of any of the following diseases characterized by Th2-mediated inflammation: such as atopic dermatitis, asthma, chronic sinusitis with nasal polyps, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse systemic sclerosis of the cutaneous tissue, alopecia areata and / or COPD (chronic obstructive pulmonary disease), and as a standalone treatment or in combination with other anticancer drugs (such as checkpoint inhibitors) for the prevention, treatment or improvement of various cancers (such as lymphoma, triple-negative breast cancer and solid fibrotic cancer).

[0474] In one embodiment, this disclosure provides a method for preventing, treating, or improving diseases characterized by Th2-mediated inflammation, such as atopic dermatitis, asthma, chronic sinusitis with nasal polyps, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse systemic sclerosis of the cutaneous body, alopecia areata, and / or COPD (chronic obstructive pulmonary disease), as well as a method for preventing, treating, or improving various cancers (such as lymphoma, triple-negative breast cancer, and solid fibrotic cancer) as a standalone treatment or in combination with other anticancer drugs (such as checkpoint inhibitors), the method comprising administering to a person suffering from at least one of the said diseases an effective amount of one or more compounds according to formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

[0475] In one embodiment, this disclosure provides a method for preventing, treating, or improving autoimmune diseases or conditions characterized by Th2-mediated inflammation, such as atopic dermatitis, asthma, chronic sinusitis with nasal polyps, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse systemic sclerosis of the cutaneous system, alopecia areata, and / or COPD (chronic obstructive pulmonary disease), as well as a method for preventing, treating, or improving various cancers (such as lymphoma, triple-negative breast cancer, and solid fibrotic cancer) as a standalone treatment or in combination with other anticancer drugs (such as checkpoint inhibitors), the method comprising administering to a person suffering from at least one of the diseases an effective amount of one or more compounds according to formula (I), optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

[0476] In addition to their use in human treatment, the compounds disclosed herein can also be used in veterinary treatment of animals, including mammals such as horses, cattle, sheep, pigs, dogs, and cats.

[0477] Pharmaceutical Compositions and Administration Methods

[0478] For use in therapy, the compounds of this disclosure are generally in the form of pharmaceutical compositions. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of formula (I), optionally together with one or more other therapeutically active compounds, and together with a pharmaceutically acceptable excipient, medium, or carrier. In some embodiments, the excipient is "acceptable," meaning it is compatible with the other components of the composition and harmless to its recipient.

[0479] In some embodiments, the compounds disclosed herein are provided in amounts ranging from 0.0001% to 99.9% by weight of the formulation.

[0480] The compounds disclosed herein can be administered once or more daily at appropriate intervals in the form of dosage units. In some embodiments, the dosage unit of the formulation contains 0.001 mg to 1000 mg, such as 0.01 mg to 300 mg of the compound of formula (I).

[0481] The appropriate dosage of the compounds disclosed herein may depend, in particular, on the patient's age and condition, the severity of the disease to be treated, and other factors known to a practicing physician. The compounds may be administered via oral, parenteral, topical, transdermal, or intradermal routes, according to different dosing schedules, such as daily, weekly, or monthly intervals. In some embodiments, a single dose containing a compound of this disclosure may provide an amount of the compound ranging from 0.001 mg / kg body weight to 400 mg / kg body weight.

[0482] In one embodiment, the compounds of this disclosure are provided in combination with one or more therapeutically active compounds. If treatment involves the administration of another therapeutically active compound... Goodman & Gilman's The Pharmacological Basis of Therapeutics , 9th edition, JG Hardman and LE Limbird (eds.), McGraw-Hill 1995, may refer to the useful dosage of the compound.

[0483] The application of the disclosed compounds with one or more other active compounds may be simultaneous or sequential.

[0484] The formulations include those suitable for oral, rectal, parenteral, transdermal, intradermal, ophthalmic, topical, nasal, sublingual, or buccal administration.

[0485] The formulation can conveniently exist in dosage units and can be produced using any of the methods known in the pharmaceutical field, such as Remington. The Science and Practice of Pharmacy The methods disclosed in the 21st edition, 2005, are used for preparation. All methods involve the step of associating the active ingredient with a carrier that constitutes one or more auxiliary ingredients. Generally, formulations can be prepared by homogeneously and tightly associating the active ingredient with a liquid carrier, a semi-solid carrier, or a fractionated solid carrier, or a combination thereof, and then, if desired, shaping the product into the desired formulation.

[0486] The formulations of this disclosure suitable for oral and buccal application may be in the form of discrete units, such as capsules, pouches, tablets, chewable tablets, or lozenges, each of which contains a predetermined amount of active ingredient.

[0487] Tablets can be prepared by compression, molding, or freeze-drying of an active ingredient optionally containing one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form—for example, an active ingredient containing a lubricant, disintegrant, or dispersant—in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredient and a suitable carrier in a suitable machine. Freeze-dried tablets can be formed from a solution of the active pharmaceutical ingredient in a freeze dryer.

[0488] Suitable parenteral formulations conveniently comprise sterile oily or aqueous preparations of the active ingredient, preferably isotonic with the recipient's blood, such as isotonic saline, isotonic glucose solution, or buffer solution. Liposome formulations are also suitable for parenteral administration.

[0489] Transdermal formulations can be in the form of ointments, patches, microneedles, liposomes or nanoparticle delivery systems, or other skin formulations applied to the skin.

[0490] Formulations suitable for ophthalmic application may be in the form of sterile aqueous preparations of the active ingredient. Liposome formulations or biodegradable polymer systems may also be used to provide the active ingredient for ophthalmic application.

[0491] Formulations suitable for topical application (such as skin application, intradermal application, or ophthalmic application) include liquid or semi-solid preparations, solutions, or suspensions.

[0492] Formulations suitable for nasal or buccal application include powders, self-propelled propellants, and spray formulations (such as aerosols and nebulizers).

[0493] In some implementations, application may be local (including transdermal application, epidermal application, ophthalmic application, and application to mucous membranes, including intranasal delivery, vaginal delivery, and rectal delivery).

[0494] In some embodiments, pharmaceutical compositions and formulations for topical application may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional drug carriers, aqueous, powdered, or oily bases, thickeners, etc., may be necessary or desired.

[0495] In some embodiments, the composition is suitable for topical application. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or encapsulated in such a carrier in the form of, for example, capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid, or liquid material that acts as a medium, carrier, or mediator of the active ingredient.

[0496] In some embodiments, one or more compounds or pharmaceutical compositions thereof, as disclosed herein, are formulated for topical application to the skin or mucous membranes (e.g., dermal or transdermal application).

[0497] In some embodiments, the topical composition may include ointments and creams. In some embodiments, ointments are semi-solid preparations typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing selected active agents are typically viscous liquids or semi-solid emulsions, typically oil-in-water or water-in-oil. For example, the cream base is washable and contains an oil phase, an emulsifier, and an aqueous phase. For example, the oil phase, sometimes also referred to as the "internal" phase, typically consists of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol); the aqueous phase typically (but not necessarily) exceeds the volume of the oil phase and typically contains a humectant. In some embodiments, the emulsifier in the cream formulation is typically a nonionic surfactant, anionic surfactant, cationic surfactant, or amphoteric surfactant. In some embodiments, the ointment base, like other carriers or mediators, should be inert, stable, non-irritating, and non-sensitizing.

[0498] All references cited in this document, including publications, patent applications and patents, are incorporated herein by reference in their entirety as if each reference were individually and specifically indicated to be incorporated by reference, regardless of whether such inclusion is provided separately elsewhere in this document.

[0499] Combination therapy

[0500] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, may be combined with therapeutically effective amounts of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0501] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent inflammatory and / or skin diseases or conditions such as atopic dermatitis (AD). Non-limiting examples of such agents include topical corticosteroids (TCS) (e.g., desonid, hydrocortisone, fluocinolone, triamcinolone, betamethasone diproprionate), topical calcineurin inhibitors (TCIs) (e.g., tacrolimus, pimecrolimus), cyclosporine, methotrexate, and mycophenolate mofetil. mofetil, azathioprine, interferon-gamma, phosphodiesterase 4 (PDE4) inhibitors (such as crisaborole), JAK inhibitors (e.g. ruxolitinib, upadacitinib, abrocitinib, baricitinib), dupilumab, and anti-IL-13 antibodies (e.g. trolurumab).

[0502] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as acne. Non-limiting examples of such agents include topical therapies such as benzoyl peroxide, topical retinoids, topical antibiotics, clascoterone, salicylic acid, and azelaic acid; and systemic therapies such as doxycycline, minocycline, sarecycline, combination oral contraceptives, spironolactone, and isotretinoin.

[0503] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as alopecia areata. Non-limiting examples of such agents include topical therapies such as systemic corticosteroids (such as prednisolone), cyclosporine, azathioprine, methotrexate, sulfasalazine, simvastatin / exetimibe, inosine, antihistamines (such as fexofenadine), and oral JAK inhibitors (such as ritlecitinib or brepocitinib).

[0504] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as asthma. Non-limiting examples of such agents include inhaled ICS-formoterol (such as budesonide-formoterol), short-acting β2 agonists (such as albuterol sulfate), leukotriene receptor antagonists (such as montelukast), immunoglobulin E antibodies (such as omalizumab), and long-acting muscarinic antagonists (such as tiotropium).

[0505] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as chronic obstructive pulmonary disease (COPD). Non-limiting examples of such agents include short-acting β2 agonists (such as salbutamol sulfate), short-acting muscarinic antagonists (such as ipratropium), long-acting β2 agonists (such as olodaterol), and long-acting muscarinic antagonists (such as tiotropium).

[0506] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as chronic sinusitis with polyps. Non-limiting examples of such agents include intranasal corticosteroids or biologics such as benazepril zumab (targeting IL-5), dupilumab (targeting IL-13), and omalizumab (targeting IgE).

[0507] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as contact dermatitis. Non-limiting examples of such agents include topical corticosteroids, topical calcineurin inhibitors (such as pimecrolimus, tacrolimus), topical phosphodiesterase 4 inhibitors (such as criborole), systemic immunosuppressants, and modulators (such as systemic corticosteroids, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, or dupilumab).

[0508] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as dermatomyositis. Non-limiting examples of such agents include topical corticosteroids, topical calcineurin inhibitors (such as pimecrolimus, tacrolimus), systemic corticosteroids (such as prednisone), antimalarial drugs (such as hydroxychloroquine, chloroquine, quinacrine), methotrexate, mycophenolate mofetil, intravenous immunoglobulins, rituximab, and JAK inhibitors (such as tofacitinib).

[0509] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as esophageal eosinophilia. Non-limiting examples of such agents include systemic corticosteroids (such as budesonide, fluticasone, prednisone), topical corticosteroids, and proton pump inhibitors (such as omeprazole, esomeprazole, pantoprazole, and lansoprazole).

[0510] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof, are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as psoriasis.Non-limiting examples of such agents include topical treatments, such as topical corticosteroids (e.g., betamethasone dipropionate, clobetasol propionate, desoximetasone, diflorasone diacetate, fluocinonide, flurandrenolide, halobetasol propionate, amcinonide, mometasone furoate, triamcinolone acetonide, fluticasone propionate, hydrocortisone valerate, clocortolone valerate). Topical calcineurin inhibitors (such as pivalate), topical vitamin D analogs (such as calcipotriene, calcitriol, tacalcitol, or mazacalcitol), topical retinoids (such as tazarotene); systemic non-biological therapies, such as methotrexate, phosphodiesterase 4 inhibitors (such as apremilast), immunosuppressants (such as cyclosporine), oral retinoids (such as acitretin), oral Janus kinase inhibitors (such as tofacitinib), fumarates (such as dimethyl fumarate), systemic immunosuppressants and antimetabolites (such as hydroxyurea, mycophenolate mofetil, thiourea, etc.). Azopurine, leflunomide, tacrolimus, and thioguanine; and biological therapies such as TNF-α inhibitors (such as etanercept, infliximab, adalimumab, certolizumab), IL-12 / IL-23 inhibitors (such as ustekinumab), IL-17 inhibitors (such as secukinumab, ixekizumab, brodalumab), and IL-23 inhibitors (such as guselkumab, tildrakizumab, risankizumab).

[0511] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as scleroderma. Non-limiting examples of such agents include immunosuppressive therapies (such as methotrexate, mycophenolate mofetil, cyclophosphamide, tocilizumab, and rituximab) and autologous hematopoietic stem cell transplantation.

[0512] In some embodiments, the compounds of this disclosure or their pharmaceutically acceptable salts or stereoisomers are co-administered with one or more agents that can be used to treat and / or prevent skin conditions such as vitiligo. Non-limiting examples of such agents include topical treatments such as topical corticosteroids, topical calcineurin inhibitors (such as pimecrolimus, tacrolimus), topical vitamin D analogs (such as calcipotriene); and systemic therapies such as oral corticosteroids (such as betamethasone).

[0513] In some implementations, the adjunctive therapeutic agents include one or more of the following: 608, 610, 611, clindamycin phosphate + benzoyl peroxide, 101BHG-D01, 1-H-11, 4P-022, 5-OXO-ETE receptor antagonist, 9MW-1911, AB-1000, AB-101a, abatacept, ABBV-712, ABCL-575, Ab-IPL-IL-17, ABM-125, abuxitinib, ABY-035 / AFO2, ABY-062, AC-201, ACE-1334, acyclovir, aclidinium bromide, aclidinium bromide + formoterol fumarate. fumarate), acumamotome, AD-17002, adakitug, adalimumab, adapalene, adapalene + benzoyl peroxide, adapalene + clindamycin hydrochloride, adapalene + clindamycin phosphate, aderamasstat, Adi, ADi-100, Adipocell, adipose tissue-derived mesenchymal stem cell-derived exosomes, adipose-derived stem cell therapy, AD-MSC-CM, ADSTEM, A DX-246, aerosolized hydroxychloroquine, afamelanotide, AJ-101, AJ-303, AK-101, AK-119, AKP-08, salbutamol sulfate, ALD-R491, alefacept, Allergovac reservoir, allogeneic adipose-derived mesenchymal stem cell therapy, allogeneic adult pluripotent stem cells, allogeneic mesenchymal stem cell therapy, allogeneic UC-MSC therapy, allogeneic umbilical cord mesenchymal stem cell therapy, AlloRx, alprazolam, AM-1476, ambroxol hydrochloride Hydrochloride, AMG-0101, Amilo-5MER, Aminolevulin, Aminolevulin Hydrochloride, Aminopterin, Amlitelimab, AMTX-100, AMTX-100 CF, Anapsos, ANB-032, ANB-101, Anifrolumab, Anti-CD19 CAR T-cell Therapy, Anti-CD7 CAR T-cell Therapy, Anti-EMAPII. Fully humanized antibodies, anti-IL-4 / IL-13 vaccines, humanized anti-P2X7 monoclonal antibodies, anti-PAR2 therapy, antroquinonol, APD-588, APG-222, APG-777, APG-808, APG-990, APGT-001, APIRx-1603, aprepitant, aprepitant, APT-101, AQ-001S, AQ-280, AR-100DP1, AR-110 Arformoterol, ARG-201, ARGX-118, ARN-4079, ARO-MUC5AC, ARO-RAGE, ARO-TSLP, ARQ-234, Arsenic Trioxide, ARTS-011, AS-012, asengeprast, asivatrep, ASN-008, astegolimab, AT-004, AT-005, AT-0287, AT-1 93, ATB-1606, ATI-2138, ATL-105, ATR-006, ATR-01, ATTO-002, ATTO-1310, atuliflapon, AUR-101, auremolimab, autologous leukocyte therapy, avenciguat, AVI-3307, AVID-200, AVX-001, AWEPO-003, AX-158, AX-202, AZD-0284, AZD-0449, AZD-86 30. Azelaic acid, azelastine, azithromycin, B-244, Bacmune, bambuterol, baricitinib, barzolvolimab, BAT-6026, bazlitoran, BB-1511, BBACN, BBI-03, BBI-6000, BCG polysaccharide + nucleic acid, BCI-332, beclometasone dipropionate dipropionate + formoterol fumarate, beclomethasone dipropionate, beclomethasone dipropionate + formoterol fumarate + glycopyrronium bromide, bedoradrine, begelomab, belimumab, belumosudil, beempikibart, benzylquidium bromide, benalizumab, benzoyl peroxide, benzoyl peroxide + tretinoin, berdazimer sodiumsodium), bermekimab, bersiporocindihydrochloride, bertilimumab, betamethasone, betamethasone dipropionate, betamethasone valerate, bexotegrast, BFP-002, BFP-102, BGB-23339, BI-1291583, BI-1323495, BI-765250, bilastine, bimek Izumab, bimiralisib, BIO-11006 inhalation solution, BioLexa, BITT-CD4D11, BITT-CD4F10, BLR-200, BLU-808, BMS-986313, BMS-986322, BMS-986326, BMX-010, boningmycin, BOS-475, Bosakitug, bosentan, azosimb bovine hyaluronidase azoximer), Box-5, BR-201, branebrutinib, BRE-AD01, brenscotib, brentuximab vedotin, brexitinib, brilacidin, brilaroxazine hydrochloride, briquilimab, brodatumab, BSI-056T, BSI-502, BTX-1204, BTX-1308, BTX-1503, budesonide, budesonide + aforterol, budesonide + formoterol, budesonide + formoterol fumarate, budesonide + procaterol hydrochloride(hydrochloride), budesonide + salbutamol, budesonide + salmeterol, buloxibutid, BV-200 series, BVX-20, BZ-371, BZ-371B, C4X-6746, C-867, CABA-201, CAL-4, calcipotriol, calcipotriol + betamethasone, calcipotriol + betamethasone dipropionate, calcipotriol + cortisone, calcitriol, CALY-002. Camoteskimab, CAN-10, Cannabidiol, Cannabidiol + Droscannabinol, Cannabinoid CB2 receptor agonist antibody, Carbon dioxide + Perfluorooctane, Cavosonstat, CB-06-01, CB2 receptor agonist, CB5138-3, CC-90006, CC-92252, CCI-15106, CCX-624, CD19-CAR-DNT, CEE-321, Cendakimab, Certolizumab pegol, CG-459, Chanllergen, CHF-6333, CHF-6366, CHF-6550, Ciclesonide, Cyclosporin, Ciprofloxacin hydrochloride hydrochloride), CIT-013, CJRB-402, CKBA, Clarithromycin, CLBS-03, Clindamycin, Clindamycin Phosphate + Benzoyl Peroxide, Clindamycin Phosphate + Retinoic Acid, Clobetasol Propionate, Clobetasol Propionate + Retinoic Acid, CM-101, CM-326, CMK-389, CMR-316, CMS-D001, ColiFin, COPD Vaccine, Umbilical Cord Blood Stem Cells, Adrenocorticotropic Hormone, COYA-204, CPL-409116, Criborone, CS-12192, CS-32582, CS-43001, CSJ-117, CSPCHA-115, CT-05, CT-303, CT-P55, CTX-101, CTXT-102, Cudetaxestat Sodiumsodium), CUR-N399, Cutaquig, CVXL-0074, CXF-11, CXG-86, CXG-87, cyproterone acetate + ethinyl estradiol, D-2570, D4-103-01, D4-103-02, D4-103-03, D4-103-04, daniluromer, dapansutrile, dapsone, daridorexant hydrochloride Hydrochloride, daxdilimab, dazukibart, DB-007-4, DBI-001, DBM-1152A, DC-806, DC-853, deflazacort, delgocitinib, denifanstat, depemokimab, dersimelagon, desloratadine, desogestrel + ethinyl estradiol, desonide, deucravacitinib, deuruxolitinib phosphate, dexamethasone sodium Phosphate), dexramipexole, difamilast, dimethyl fumarate, dimethyl fumarate + calcium ethyl fumarate + magnesium ethyl fumarate + zinc ethyl fumarate, dioleuton, dithranol cream, divozilimab, DLQ-02, DLX-105, DLX-2323, DMT-210, DMT-310, DMX-700, DMXD-011, DNX-114, doxofylline (doxofylline (bronchodilator), Alitair Pharmaceuticals), doxycycline hyclate (doxycycline hydrochloride (delayed release), Mayne; doxycycline hydrochloride (easy to swallow, acne, bacterial infection), Aqua Pharmaceuticals), DPT-0218, drospirenone + ethinyl estradiol, dual α-V / β-1 and α-5 / β-1 integrin inhibitors, dual AMCase / CHIT1 inhibitors, dual anti-CD19 / anti-BAFF CARsT-cell therapy, dual JAK3 / TEC inhibitors, dupilumab, house dust mite vaccine, DW-2008S, DYV-024, DZ-2002, EB-005, EB-06, EBI-H, eblasakimab, efzofitimod, EI-001, elapegademase, elarekibep, emedastine, empasiprubart, ENA-002, ENB-109, endonuclease modulators, ENERGY-F708, enpatoran, ensifentrine, ensifentrine + glycopyrrolate, EP-104-GI, EP-262, epeleuton, Epi-13, epinastine hydrochloride Hydrochloride, epinephrine, EpiTight, EPM-301, EQ-101, erdosteine, erlotinib, ESK-001, etanercept, EtanerRel, ETD-001, ETH-47, etrasimod, etrinabdione, EVX-B4, EYD-001, F-200, F-528, Factor D inhibitors, farudodstat, FB-102, FB-401, FB-704A, FB-825, FB-918, FCR-001, FCX-013, fevipiprant, filgotinib maleate maleate, fipaxalparant, flunisolide, fluocinolone acetonide, fluticasone, fluticasone + formoterol, fluticasone furoate, fluticasone furoate + umeclidinium + vilanterol, fluticasone furoate + vilanterol trifenatate, fluticasone propionate, fluticasone propionate + formoterol fumarate, fluticasone propionate + salbutamol sulfate, fluticasone propionate + salmeterol, fluticasone propionate + salmeterol sinemet.xinafoate), formoterol, formoterol fumarate, formoterol fumarate + fluticasone propionate, formoterol fumarate + glycopyrronium bromide, FPP-003, FPP-005, froniglutide, FRTX-02, FTC-001, FWB-1313, FZ-007, FZJ-003, GABAA receptor agonist, Gamunex, GB-001, GB-0895, GD-1 34. GD-iExo-001, gefurulimab, GEN-501, GL-7190, GLPG-3667, glutathione + ascorbic acid + bicarbonate, glycopyrrolate + formoterol fumarate + budesonide, glycopyrronium + formoterol fumarate + fluticasone propionate, glycopyrronium + vilanterol, glycopyrronium bromide, glycopyrronium bromide + indacaterol maleatemaleate), GMDP, GM-XANTHO, GN-037, GNKS-356, GNR-068, GPCR antagonist, GR-010, GR-1501, GR-1802, GR-2002, GR -2301, Grastek, GRC-39815, GRT-6015, GSK-1070806, GSK-2831781, GSK-3862995B, GSK-3923868, GT-20029 Gumokimab, gusacitinib, gusecurumab, GZ-21T, H-018, halobetasol propionate, halobetasol propionate + tazarotene, halometasone, HB00-17, HB-0034, HB-0043, HB-1734, HBM-9001, HBM-9378, HCW-9302, HDM-3010, HECB-1800301, HE MP-001, HI-1640V, Histamine Human Immunoglobulin, Hizentra, HJ-787, HL-231, HLA Open Conformation Isomer-Specific Monoclonal Antibody, HLK-6002, House Dust Mite Allergen, House Dust Mite Immunotherapy, HP-1901, Hpb Glutamate Dehydrogenase Modifier, HPP-737, HpVac-R13, HRG-2005, HRS-9821, HS-10374, HS-401, HT-004, HuL-001 Human adipose-derived mesenchymal stem cells, human umbilical cord-derived mesenchymal stem cell therapy, HY-07170702, HY-072808, HY-1770, HY-209, hypericin, hypochlorous acid, HZ-J001, IBI-3002, IBI-356, IBIO-100, IBL-101, icanbelimod, ICP-332, ICP-488, iCP-NI, ifetroban, IFNα kinoide, IgE inhibitors, IHL-675A, IL-17 NanoAb, IL-25 targeted therapy agents, IL-4Rα antagonists, IL-4Ra targeted therapy agents, ILB-2107, iloprost, IMB-101, IMG-007, IMG-008, IMG-036, intravenous immunoglobulin, imsidolimab, IMX-120, IN-A002, inaticabtagene autoleucel, INCB-054707, indacaterol, indacaterol acetateAcetate) + Glycolone + Mometasone Furoate, Indamet, Inellizumab, Infliximab, Integrin α-2 / β-1 inhibitor, Integrin α-5 / β-1 inhibitor, Interleukin IL-17A inhibitor, INV-007, INV-103, INV-17, IPG-1094, IPG-7236, Ipratropium + Fenoterol, Ipratropium bromide, Ipratropium bromide + Salbutamol sulfate, IR-444, IRL-201104, IRX-4204, Isotretinoin, Itepekimab, Itolizumab, Ivacaftor, Ivarmacitinib sulfate sulfate), ivermectin, ixekizumab, izokibep, JadiCell therapy, JAK inhibitors, JAK-989, jaktinib dihydrochloride monohydrate, jaktinib hydrochloride hydrochloride), JK-0001, JK-0002, JNJ-1459, JNJ-2113, JNJ-3534, JNJ-67484703, JRF-106, JRF-401, JRP-878, JS-005, JTE-051, JTE-451, JW-1601, JW-202232, JW-2202, JYB-1904, JYP-0061, JYP-0066, K-1032, KB-5XX, KBL-693, KBL-697, KI- 696, KINE-201, KITCL-27, KN-002, KP-470, KT-294, KT-474, KT-621, KX-826, KYV-101, L-608, LABA+LAMA therapy, Langopept, larsucosterol, LAS-200019, LBG-1600M, LCK inhibitors, Lepzacitinib, Levalbuterol, Levalbuterol hydrochlorideHydrochloride, Levonorgestrel + Ethinylestradiol, LG-283, LGM-1506, LGM-2605, LH-8, LIT-00505, Lithium Succinate, LMY-920, LNK-01001, LNK-01004, LNP-1955, LNR-653.1, Londamocitinib, Long-acting β-agonists / Long-acting muscarinic agonists, Long-acting aerosol-based peptide therapy, Lonodelestat acetate Acetate), LP-003, LP-0200, LQ-036, LQ-041, LQ-043, LR-19019, LR-20016, LT-002-158, Lucinactant, Lunsekimig, LUT-014, LW-104, LY-3509754, LY-3872386, LY-3972406, LYS-006, Lysophospholipase inhibitor, LZM-012, M-119102, M3 muscarinic receptor antagonist, M-605110, M- 610101, Manfidokimab, Masitinib, MAX-40070, Masacalciferol, Masacalciferol + Betamethasone, MCM-001, MDI-1228, MDNA-413, MDPK-67b, ME-3183, Melgain, Mepolizumab, Mesalazine, Mesenchymal Stem / Stromal Cell Therapy, Mesenchymal Angiogenic Cell-Derived Mesenchymal Stem Cell Therapy, Metenkefalin Acetate Acetate) + Tridecactide acetate, Methotrexate, Methyl aminopentanoate hydrochloride, Methylprednisolone suleptanate, MG-01, MG-K10, MG-S-2525, MGY-1838, MG-ZG122, MH-004, MH-080, Minocycline, Minocycline + Adapalene, Minocycline Hydrochloride, MIT-001, Mitiperstat, Mitizax, MM-09, Mometasone, Mometasone + Formoterol, Mometasone Furoate, Mometasone Furoate + Indacaterol Acetate, Monlunabant, Montelukast, Montelukast Sodium, Montelukast Sodium + Levocetirizine Hydrochloridedihydrochloride, mosedipimod, mouse monoclonal antibody against human interleukin-8, MP-1032, MSB-01, MSB-03, MSB-3163, MSM-605, MT-5562, MTC-896, mucosa-associated lymphoid tissue lymphoma translocation protein 1 inhibitor, mufemilast, MufroSyn, Artemisia argyi pollen allergen vaccine, muscarine M3 receptor antagonist, MYJ-1633, nacystelyn, nadifloxacin, nadolol, nalfurafine, NBL-012, NCP-111, NCP-112, ND-003, NDX-3 315, NDX-3324, Nedocromil, Nemolizumab, Netakimab, Nibrozetone, Niclosamide, NIK inhibitors, Nitric oxide, Nitroglycerin, NLP-91, NM26-2198, Nomacopan, Norethindrone Acetate + Ethinylestradiol, Noscapine / Noscapine analogs, NP-339, NRF2 activator, NS-402, NTR-441, NVS-451, NX-73, OATD-01, OB-756, Obefazimod, OC-701, OCR-4715, Octagam 10%, Olodaterol, Olodaterol hydrochloride + Tiotropium bromide monohydrate, Olopatadine, OLX-103, OM-001, Omalizumab, Omegananpenta hydrochloride, Omilancor, OMN-71, ONO-4685, OP-2101, Opinercept, OpSCF, Ordesekimab, ORI-001, Orismilast, ORKA-001, ORKA-002, Orticumab, Ozagrel hydrochlorideHydrochloride, Ozefloxacin, PA-9159, Paridiprubart, PBF-680, PBI-100, PC-114, PDC-APB, PDE4 inhibitor, Pegtarazimod, Pemirolast, Peresolimab, PF-07264660, PF-07275315, PG-011, PG-102, Viromed, Phimellarotid e. PHP-1212, PI3K-δ inhibitor, piconzalone, piclidenoson, pimecrolimus, PIPE-791, pirfenidone, pitavastatin, PKCθ inhibitor, PLM-301, PNV-5032, POLB-002, ponemod, potassium dobesilate, PR-023, pranlukast, pranlukast hydrate, PRCL-02, Pr EP-001, prostaglandin D2 synthase inhibitor, Prozumab, PRP-PBMC autologous cell therapy, PS-35, psoriasis therapy, PT-101, P-TET, PUL-042, PUR-0110, PUR-1800, PX-128, PX-130, PZ-07 / 2024, Q-1804, Q-301, QBKPN, QLM-3003, QN-02, QP-CO1, QRX-008, quisovalimab, QX-002-N, QX-0 04-N, QX-005-N, QX-007-N, QX-008-N, QX-009-N, QX-010-N, QY-101, QY-201, QY-211, R-187, R-552, rademikibart, rare plant cannabinoids, ravulizumab, RAY-121, RB-1000, RBM-009, RBN-012759, RBO-0987, RC-1416, RCD-405, recombinant mitemmazine Midismase, reconstituted calcipotriol + betamethasone, REGEND-001, REGN-1908-1909, Remesta, Remibrutinib, Renzapride, Repirinast, repurposed aldesleukin, and repurposed aziregane.azeliragon), modified lenabasum, reslizumab, RESP-1000 series, RESP-2000 series, RESP-X, retinic acid, revenacin, REX-7117, rezpegaldesleukin, RG-6151, RG-6244, RG-6314, RG-6315, RG-6341, RG-6421, RGRN-305, rilzabrutinib, riociguat, lizulzamab, litexicitib, rituximab, RLS-1496, RLV-102, rocatinlimab, roflumilast, ropsacitinib, ROR γ-T inverse agonist, ROR-γ inverse agonist, rose bengalsodium), RP-3128, RSBT-001, RSS-0393, R-TPR-022, rupatadine + montelukast, RUTI, ruxolitinib, RYSW-01, S1P1 agonist, salbutamol, salmeterol, salmeterol sinemet + fluticasone propionate, SAMiRNA program, SAR-441566, SAR-443726, saracycline, SB-010, SB-011, SCD-044, SCD- 153, SCT-640A, SCT-650-C, SDC-1801, Secukinumab, SEGRA, Celecoxib, SEL-K2, selnoflast, seratrodast, SFA-002, SFA-004, SG-100, SGT-510, SH2 domain inhibitor program targeting STAT6, SHR-1703, SHR-1819, SHR-1905, SHR-45 97, si-544, SIG-1322, SIG-1451, SIG-1456, SIM-0278, SIM-335, sitaxentan, SKI-O-703, SKL-XYZ, SLS-008, SM-17, Small Shift Stem Cell Therapy, SMET-D1, SNC-103, SNG-001, SNG-100, SNK-01, sodium cromoglycate, sodium pyruvate, solozil (sonelokimab), s oquelitinib, sovleplenib, spesolimab, SPL84-23, SSGJ-621, SSS-07, ST-1830, stapokibart, STAR-0310, STAT3 inhibitors, STMC-103H, STS-01, STSA-1201, SUDO-286, SUL-238, SuperMApo, suplatasttosilate), SYHX-1901, SYX-5219, T-517, tacalcitol, tacrolimus, TAF-001, tagraxofusp, TAGX-0003, TAKC-02, tanimilast, TAP-1502, TAP-1503, tapinarof, Tavo-101, tazarotene, tazarotene + betamethasone dipropionate, tazarotene + clindamycin, TD-8236, TDM-180935, TDM-Atop01, TDM-Psor01, TDM-Scar01, telazorlimab, tempol, temtokibart, teprotumumab, TER-101, terbutalin, tergur ide), tesnatilimab, TEV-48574, TEV-53275, tezepelumab, TFF-HMW-HA, Thalassophrynenattereri peptide, THB-001, theophylline, THOR-809, TI-520, TI-620, tibulizumab, tiridgezumab, timolumab, tiotropium, tiotropium bromide, tipelukast, tirbanibulin, TLL-018, TLY-012, TO-210, tofacitinib, tofacitinib + fingolimod, tofacitinib citratecitrate), tonabacase, TOP-N44, TOP-N53, toruzimab, tosufloxacin, tozorakimab, TP-317, TQC-2731, TQC-2938, TQC-3564, TQC-3721, TQC-3927, TQH-2722, TQH-2929, TQH-3906, TQH-3910, trabikibart, tranilast, transcription factor pathway inhibitors, tregalizumab, treprostinil, treprostinil diethanolamine. Iolamine, retinoic acid, retinoic acid + benzoyl peroxide, trifarotene, TRIV-509, TRN-157, TRPA1 antagonist, TS-0001, TT-01, TT-01688, tulinercept, tulobuterol, TVB-3567, UA-021, UB-221, UCB-1381, UCB-9741, ucenprubart, UHE-101, UHE-105, UI-009, UI-010, UI-031, UI-033, UI-034, ulobetasol, umbilical cord blood stem cell therapy, UMC119-06, umeclidinium bromide), umemarone + vilanterol triphenylacetic acid, utpatinib, USP-4 inhibitor, uterotumab, UTAA-09, VALERGEN-DS, vamorolone, vapendavir, vardenafil, VB-1953, VC-005, VDAA, VDAD, VDJ-006, VEGFR targeting DK4 / 10, venanprubart, VENT-03, verekitug, vilanterol + fluticasone furoate + glycopyrronium bromide, vipoglanstatHydrogensulfate, VISTA agonist, vixarelimab, VLRX-001, VM-AD, VNLG-152, vonifimod, voriconazole, votucalis, VRN-04, VS-105, VSG-158, VSTM-1 agonist, VT-014, VTH-212, vunakizumab, VYN-201, VYN-202, W16P-0576, WD-890, WM-1R3, WNT inhibitor, WNT pathway agonist antibody, WNT pathway stimulator, WXFL-1 0203614, WXSH-0150, XCUR-17, XKH-001, XmAb-564, XT-0528, XZ.700, YH-25487, YH-35324, YKRH-00020, YR-001, Yso3, zabedosertib, zafirlukast, zasocitinib, ZB-168, Zemaira, ZeP-3, zetomipzomib, zevaquenabant, ZHB-107-108, zibotentan, zileuton, zirconium Zr 89 crefmirlimab berdoxam, ZL-1102, ZPL-521, and / or bispecific antibodies targeting one or more of the targets mentioned herein.

[0514] In some embodiments, the compounds provided herein or their pharmaceutically acceptable salts or stereoisomers are administered together with one or more therapeutic agents selected from PPARd inhibitors, IRAK4 inhibitors, TPL2 inhibitors, α4β7 inhibitors, BTLA agonists, PD1 agonists, or FXR agonists.

[0515] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts or stereoisomers are administered together with one or more therapeutic agents selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS-0272, GS-0151, or cilofexor.

[0516] The beneficial effects of the combination may be to increase the efficacy of the components and / or reduce their side effects, as the dosage of the component can be reduced to decrease its side effects while benefiting from the enhanced efficacy of the compounds disclosed herein.

[0517] In some implementations, the additional therapeutic agent includes agents that can be used to modulate, treat, or prevent inflammation, such as 4-1BB ligands, 5-α-reductase inhibitors, 5-HT 1a receptor antagonists, 5-HT 1a receptor partial agonists, 5-HT 2a receptor antagonists, 5-HT 2a receptor partial agonists, 5-HT 2b receptor antagonists, 5-HT 3 receptor antagonists, 5-HT 4 receptor agonists, 5-HT 6 receptor antagonists, and 5-HT 7-Receptor Antagonists, 5-Lipooxygenase Activator Inhibitors, 5-Lipooxygenase Inhibitors, Co-gene Regulator A Inhibitors, Aldehyde Dehydrogenase Regulators, Acetylcholine Receptor Agonists, Acetylcholine Receptor Antagonists, Acetylcholinesterase Inhibitors, Acidic Mammalian Chitinase Inhibitors, ACTH Receptor Agonists, Activity-Dependent Neuroprotective Agent Regulators, ADAM-33 Inhibitors, ADAM-9 Inhibitors, Adenosine A1 Receptor Antagonists, Adenosine A1 Receptor Regulators, Adenosine A2b Receptor Antagonists, Adenosine A3 Receptor Agonists, Adenosine A3 Receptor Antagonists, Adenosine Deaminase Stimulants, Adenosine Homocysteine ​​Inhibitors, Adenosine Cyclate Cyclate Enzyme stimulants, adrenergic receptor agonists, adrenocorticotropic hormone ligands, higher glycosylation product receptor antagonists, AGER gene inhibitors, AIMP multisynthetic enzyme complex protein 1 inhibitors, albumin antagonists, alcohol dehydrogenase 5 inhibitors, aldose reductase inhibitors, Alk-5 protein kinase inhibitors, α1 antitrypsin modulators, α1 antitrypsin stimulators, α1 protease inhibitors, α2 adrenergic receptor agonists, amiloride-sensitive sodium channel inhibitors, AMP-activated protein kinase α2 stimulators, AMP-activated protein kinase stimulators, amyloid deposition inhibitors, androgen receptor antagonists, angiotensin II AT-1 receptor antagonists, angiotensin II AT-2 receptor agonists, anoctamin 1 stimulators, aortic smooth muscle actin inhibitors, AP1 transcription factor modulators, apelin receptor agonists, apolipoprotein A antagonists, apolipoprotein A5 stimulators, apolipoprotein B modulators, apolipoprotein E modulators, Bcl-X inhibitors, and Bcl-X inhibitors. B-cell inhibitors, APRIL receptor modulators, aryl hydrocarbon receptor agonists, aryl hydrocarbon receptor modulators, B and T lymphocyte attenuation factor stimulators, B lymphocyte antigen CD19 inhibitors, B lymphocyte antigen CD19 modulators, B lymphocyte antigen CD20 inhibitors, B lymphocyte stimulating factor ligand inhibitors, B lymphocyte stimulating factor ligand modulators, Bcl-2 protein inhibitors, β1-adrenergic receptor antagonists, β2-adrenergic receptor agonists, β2-adrenergic receptor antagonists, β2-adrenergic receptor modulators, β-adrenergic receptor agonists, β-amyloid antagonists, β-catenin inhibitors, β-catenin modulators, bifunctional aminoacyl-tRNA synthetase inhibitors, BMP10 gene inhibitors.BMP15 gene inhibitor, myelogenous proteoglycan modulator, botulinum toxin A stimulant, bromo-containing domain protein 1 inhibitor, bromo-containing domain protein inhibitor, Btk tyrosine kinase inhibitor, C-myc binding protein inhibitor, C-type lectin domain protein 4C inhibitor, Ca2+ release-activated Ca2+ channel 1 inhibitor, calcineurin inhibitor, calcium channel inhibitor, cannabinoid CB1 receptor antagonist, cannabinoid CB1 receptor inverse agonist, cannabinoid CB2 receptor agonist, cannabinoid CB2 receptor modulator, cannabinoid receptor agonist, cannabinoid receptor antagonist, cannabinoid receptor modulator, catalase stimulant, CCL26 gene inhibitor, CCR3 chemokine modulator, CCR5 chemokine antagonist, CCR6 chemokine antagonist, CCR8 chemokine antagonist, CD11b antagonist, CD122 agonist, CD122 modulator CD19 modulators, CD2 antagonists, CD223 modulators, CD3 modulators, CD30 modulators, CD4 antagonists, CD40 ligand receptor antagonists, CD47 antagonists, CDw123 modulators, cell adhesion molecule inhibitors, cell surface glycoprotein CD200R agonists, cell surface glycoprotein MUC18 inhibitors, CFTR modulators, CFTR stimulators, chaperone stimulators, chemokine receptor antagonists, chitinase inhibitors, collagen I agonists, collagen I antagonists, collagen modulators, collagen VII antagonists, complement C1q subfraction inhibitors, complement C1s subfraction inhibitors, complement C5 inhibitors, complement C2 inhibitors, complement D inhibitors, COVID19 spike glycoprotein modulators, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, cyclic GMP AMP synthase inhibitors, cyclooxygenase inhibitors, cytokine receptor agonists, cytokine receptor antagonists, cytokine receptor common β-chain inhibitors, cytoplasmic protein NCK inhibitors, cytophospholipase A2 inhibitors, cytotoxic T lymphocyte protein-4 stimulators, deoxyribonuclease gamma stimulators, DHFR inhibitors, diacylglycerol O-acyltransferase 1 inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase I inhibitors, dipeptidyl peptidase IV inhibitors, DNA gyrase inhibitors, DNA methyltransferase inhibitors, dopamine D2 receptor partial agonists, dopamine D3 receptor agonists, dopamine D3 receptor partial agonists, dopamine D4 receptor partial agonists, DYRK-1α protein kinase inhibitors, exonucleotide pyrophosphatase-PDE-2 inhibitors, EGF-like module receptor 1 antagonists, EGFR family tyrosine kinase receptor inhibitors, elastase inhibitors, endonuclease modulators, endostatin modulators, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, enolase 1 inhibitors, eosinophil peroxidase inhibitors.Eosinophil chemokine 2 ligand inhibitors, eosinophil chemokine ligand inhibitors, EP4 prostaglandin receptor antagonists, epidermal growth factor receptor antagonists, epidermal growth factor receptor modulators, estradiol agonists, estrogen receptor agonists, extracellular signal-associated kinase-2 inhibitors, cooperating glucose transporter-1 modulators, fatty acid synthase inhibitors, FGF receptor antagonists, FGF-2 ligands, FGF-4 ligands, FGF3 receptor antagonists, filaggrin stimulators, Flt3 tyrosine kinase inhibitors, FMLP-associated receptor I agonists, FMLP-associated receptor II agonists, free fatty acid receptor 2 agonists, free fatty acid receptor 3 agonists, Fyn tyrosine kinase inhibitors, FXR agonists, G protein-coupled bile acid receptor 1 agonists, G protein-coupled receptor-44 antagonists, G protein-coupled receptor-44 modulators, GABA A receptor agonists, GABA A receptor α-2 subunit modulators, GABA A receptor α-3 subunit modulators, GABA A receptor α-5 subunit regulators, galactoglobulin-10 regulators, GATA3 transcription factor inhibitors, glucagon-like peptide-1 receptor agonists, glucocorticoid receptor agonists, glutamate dehydrogenase regulators, glutamate receptor regulators, glutathione-dependent PGD synthase inhibitors, non-glutathione-dependent PGD synthase inhibitors, glutathione reductase inhibitors, GroEL protein 2 inhibitors, guanylate cyclase stimulators, H+K+ ATPase inhibitors, heat shock protein inhibitors, heme oxygenase 1 regulators, heparin agonists, high-mobility group box B1 inhibitors, histamine H1 receptor antagonists, histamine H4 receptor antagonists, histamine receptor antagonists, histone deacetylase-1 inhibitors, histone deacetylase-2 inhibitors, histone deacetylase-2 stimulators, histone deacetylase-3 inhibitors, histone deacetylase-6 inhibitors, histone H2A regulators, histone H4 regulators, HMG CoA reductase inhibitors, Hsp90 inhibitors, Hsp70-binding protein 1 inhibitors, hyaluronidase stimulators, hypoxia-inducible factor stimulators, I-κB kinase beta inhibitors, I-κB kinase ε inhibitors, IgG receptor FcRn large subunit p51 modulators, IL-1 receptor cofactor inhibitors, IL-1 receptor antagonists, IL-10 receptor agonists, IL-10 receptor antagonists, IL-12 receptor antagonists, IL-13 receptor antagonists, IL-13 receptor modulators, IL-15 receptor antagonists, IL-17 antagonists, IL-18 antagonists, IL-2 receptor α subunit stimulators, IL-2 receptor antagonists, IL-2 receptor modulators, IL-22 antagonists, IL-23 antagonists, IL-3 receptor modulators, IL-4 receptor antagonists, IL-4 receptor modulators, IL-5 receptor antagonists, IL-6 receptor antagonists, IL-7 receptor antagonists, IL-8 receptor antagonists.IL17RA gene inhibitors, IL2 gene stimulators, immunoglobulin E antagonists, immunoglobulin E modulators, immunoglobulin G agonists, immunoglobulin G1 modulators, immunoglobulin agonists, immunoglobulin κ modulators, immunoglobulin modulators, inducible nitric oxide synthase inhibitors, insulin receptor substrate-1 inhibitors, insulin-like growth factor 1 receptor antagonists, integrin α-2 / β-1 antagonists, integrin α-4 / β-1 antagonists, integrin α-4 / β-7 antagonists, integrin α-5 / β-1 antagonists, integrin α-5 / β-3 modulators, integrin α-V / β -1 antagonists, integrin β1 binding protein modulators, interferon α14 ligands, interferon α ligand inhibitors, interferon β ligands, interferon β ligand inhibitors, interferon γ ligand inhibitors, interferon γ receptor antagonists, interferon type I receptor antagonists, interleukin 1δ ligand inhibitors, interleukin 1-like receptor (IL33R) antagonists, interleukin 1-like receptor 1 modulators, interleukin 1-like receptor 2 inhibitors, interleukin 13 ligand inhibitors, interleukin 13 receptor α1 antagonists, interleukin 15 ligand inhibitors, interleukin 17 ligand inhibitors, interleukin 17A Ligand inhibitors, interleukin 17A ligand modulators, interleukin 17E ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 18 ligand inhibitors, interleukin 23A inhibitors, interleukin 31 ligand inhibitors, interleukin 31 ligand modulators, interleukin 33 ligand inhibitors, interleukin 33 ligand modulators, interleukin receptor 17A antagonists, interleukin receptor 17B antagonists, interleukin-1α ligand inhibitors, interleukin-1β ligand modulators. Interleukin-1 ligand inhibitors, interleukin-2 ligand inhibitors, interleukin-31 receptor modulators, interleukin-4 ligand inhibitors, interleukin-5 ligand inhibitors, interleukin-6 ligand inhibitors, interleukin-8 ligand inhibitors, interleukin-9 ligand inhibitors, IRAK-4 protein kinase inhibitors, IRAK-4 protein kinase degraders, IRAK tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, kallikrein 2 inhibitors, kallikrein 5 modulators, kallikrein 7 inhibitors, kallikrein 7 modulators, kallikrein inhibitors, KCNA voltage-gated potassium channel-3 inhibitors, Kelch-like ECH-associated protein 1 inhibitors, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, LanC-like protein 2 stimulators, lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitorsLectin-mannose-binding protein inhibitors, leukocyte Ig-like receptor A4 modulators, leukocyte elastase inhibitors, leukotriene A4 hydrolase inhibitors, leukotriene BLT receptor antagonists, leukotriene C4 antagonists, leukotriene C4 synthase inhibitors, leukotriene D4 agonists, leukotriene D4 antagonists, leukotriene E4 antagonists, leukotriene receptor antagonists, liver X receptor agonists, LOXL2 gene inhibitors, pulmonary surfactant-associated protein D stimulators, Lyn tyrosine kinase inhibitors, lysophosphatidic acid-1 receptor antagonists, lysophospholipase inhibitors, macrophage migration inhibitory factor inhibitors, and major allergen I polypeptide chain 2 inhibitors. Major allergen inhibitors, MALT protein 1 inhibitors, mannan-binding lectin serine protease inhibitors, MAP kinase modulators, MAPKAPK2 inhibitors, MARCKS protein inhibitors, Mas-associated G protein receptor X2 antagonists, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, melanin MC1 receptor agonists, melanin MC5 receptor antagonists, melanocyte-stimulating hormone ligands, membrane copper amine oxidase inhibitors, metalloproteinase-12 inhibitors, MEX3B gene inhibitors, mineralocorticoid receptor antagonists, MIPs 3α-ligand inhibitors, mite allergen modulators, mitochondrial 10kDa heat shock protein stimulators, MKL cardiomyocyte-like protein inhibitors, MMP1 gene stimulators, MNK protein kinase inhibitors, monocyte chemotactic protein 1 ligand inhibitors, MS4A2 gene modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, MUC5AC gene inhibitors, muscarinic M1 receptor antagonists, muscarinic M2 receptor antagonists, muscarinic M3 receptor antagonists, muscarinic M4 receptor antagonists, muscarinic M5 receptor antagonists, muscarinic receptor agonists, muscarinic receptor antagonists, muscarinic receptor modulators, myeloperoxidase inhibitors, myosin heavy chain inhibitors, NACHTLRR PYD domain protein 3 inhibitors, NEDD4 family interacting protein 1 stimulators, neurocilia protein 2 regulators, neutral endopeptidase inhibitors, NFE2L2 gene stimulators, nicotinic ACh receptor α7 subunit stimulators, nicotinic acetylcholine receptor agonists, NK1 receptor antagonists, NKG2 D-activated NK receptor antagonists, NLR family member X1 stimulators, non-receptor tyrosine kinase TYK2 antagonists, nucleoerythrocyte 2-related factor 1 stimulators, nucleoerythrocyte 2-related factor 2 stimulators, nucleoerythrocyte 2-related factor inhibitors, nuclear factor κB gene inhibitors, nuclear factor κB-induced kinase inhibitors, nuclear factor κB inhibitors, nuclear factor κB regulators, tumor suppressor M receptor subunit β inhibitors, opioid growth factor receptor agonists, opioid receptor δ antagonists, opioid receptor κ agonists, orexin 1 receptor antagonists, orexin 2 receptor antagonists, orphan receptor antagonists, outer membrane protein regulators, OX-40 receptor agonists.OX-40 receptor antagonists, OX40 ligand inhibitors, OX40 ligand modulators, oxo-bridged eicosane receptor 1 antagonists, P-glycoprotein inhibitors, P-selectin glycoprotein ligand-1 inhibitors, P2X2 purine receptor antagonists, P2X3 purine receptor antagonists, P2X7 purine receptor modulators, P2Y6 purine receptor modulators, p38 MAP kinase inhibitors, p53 tumor suppressor protein stimulators, PcrV protein type III inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, PDE 4b inhibitors, PDE 4d inhibitors, PDE 5 inhibitors, PDGF receptor antagonists, peptidase 1 inhibitors, PGD2 antagonists, PGI2 agonists, phosphatidylinositol 4-kinase β inhibitors, phosphatidylinositol 3-kinase inhibitors, phosphatidylinositol-3-kinase δ inhibitors, phospholipase A2 inhibitors, phospholipase C inhibitors, PIM-1 protein kinase inhibitors, PIM-2 protein kinase inhibitors, PIM-3 protein kinase inhibitors, placental growth factor ligand inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet-activating factor receptor antagonists, poly-ADP-ribose polymerase 14 inhibitors, PPARγ agonists Agents, PPAR gene regulators, progesterone receptor agonists, programmed cell death ligand 1 regulators, programmed cell death protein 1 regulators, programmed cell death protein 1 stimulators, prostaglandin E synthase inhibitors, prostaglandin E synthase-1 inhibitors, protease inhibitors, protease-activated receptor-2 antagonists, proteasome β-8 subunit regulators, proteasome inhibitors, protein kinase Cθ inhibitors, protein kinase inhibitors, protein NOV homolog regulators, protein tyrosine kinase inhibitors, protoporphyrinogen oxidase regulators, pyruvate kinase muscle isoenzyme stimulators, Raf B protein kinase inhibitors, Ras gene inhibitors, reactive oxygen species regulators (ROS) inhibitors, Ret tyrosine kinase receptor inhibitors, retinoic acid receptor agonists, retinoic acid receptor antagonists, retinoic acid receptor gamma agonists, retinoic acid receptor gamma antagonists, retinoic acid receptor gamma inverse agonists, retinoic acid receptor modulators, retinoid receptor agonists, retinoid X receptor agonists, retinoid X receptor modulators, retinoid Z receptor gamma antagonists, retinoid Z receptor gamma inverse agonists, Rev protein modulators, Rho-associated protein kinase 1 inhibitors, Rho-associated protein kinase 2 inhibitors, ribose Nuclease P inhibitors, ribonuclease stimulants, RIP-1 kinase inhibitors, S100 calcium-binding protein A4 inhibitors, S100A8 gene inhibitors, S100A9 gene inhibitors, SARS coronavirus 3C protease-like inhibitors, secreted phospholipase A2 receptor antagonists, serine protease inhibitors, serine threonine protein kinase TBK1 inhibitors, serum amyloid A protein modulators, SH2 domain-containing protein inhibitors, sialic acid-binding Ig-like lectin 8 inhibitors, SIRT3 gene stimulants, SMAD inhibitors, SNAI1 transcription factor inhibitors.SOD3 gene stimulators, sodium channel inhibitors, sphingosine 1-phosphophosphatase 1 stimulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-3 modulators, sphingosine-1-phosphate receptor-4 antagonists, sphingosine-1-phosphate receptor-4 modulators, sphingosine-1-phosphate receptor-5 modulators, sphingosine phosphocholine receptor antagonists, Src tyrosine kinase inhibitors, STAT inhibitors, STAT-1 modulators, STAT-3 inhibitors, STAT-5 inhibitors, STAT-6 inhibitors, STAT-6 degraders, stearoyl-CoA desaturase-1 inhibitors, stress-induced secretory proteins. 1. Stimulants, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, synuclein α inhibitors, T cell receptor antagonists, T cell receptor modulators, T cell surface glycoprotein CD28 inhibitors, T cell antigen CD7 modulators, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 inhibitors, T cell transcription factor NFAT modulators, Tau aggregation inhibitors, Tau deposition inhibitors, Tec tyrosine kinase inhibitors, TGFβ1 ligand inhibitors, TGFβ3 ligand inhibitors, TGFβ3 ligand modulators, TGFβ ligand inhibitors, TGFβ receptor agonists, TGFβ receptor antagonists, TGFβ activated kinase-1 inhibitors, TGFβ type II receptor antagonists, TGFβ type II receptor modulators, TGFβ Type III receptor antagonists, thromboxane A2 antagonists, thromboxane synthase inhibitors, thymic stromal lymphopoietin ligands, thymic stromal lymphopoietin ligand inhibitors, thymic stromal lymphopoietin ligand modulators, thymic stromal lymphopoietin receptor antagonists, thymic stromal lymphopoietin receptor modulators, TLR agonists, TLR modulators, TLR-2 agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-6 agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 agonists, TLR-9 antagonists, TNF agonists, TNFα ligand inhibitors, TNFα ligand modulators, TNF antagonists, TNF junction inhibitors Combination therapy, TNF-related apoptosis-inducing ligands, TNF-like receptor-2 modulators, tumor necrosis factor 15 ligand inhibitors, topoisomerase IV inhibitors, TRAIL receptor agonists, transcription factor inhibitors, transcription factor modulators, thyroxine transporter modulators, Trk tyrosine kinase receptor inhibitors, TRP cation channel A1 inhibitors, TRP cation channel A1 modulators, TRP cation channel C1 inhibitors, TRP cation channel V1 antagonists, TRP cation channel V1 modulators, TRP cation channel V2 modulators, Ts1 protein kinase inhibitors, tubulin binders, tubulin receptor antagonists, tumor necrosis factor 13B receptor modulators.Tumor necrosis factor 13C receptor modulators, tumor necrosis factor 14 ligand inhibitors, tumor necrosis factor 15 ligand modulators, tumor necrosis factor ligand inhibitors, Txk tyrosine kinase inhibitors, Tyk2 tyrosine kinase inhibitors, Tyk2 tyrosine kinase modulators, type I IL-1 receptor antagonists, type I TNF receptor antagonists, type II TNF receptor modulators, tyrosine phosphatase substrate 1 inhibitors, ubiquitin inhibitors, ubiquitin ligase modulators, ubiquitin ligase stimulators, ubiquitin thioesterase-4 inhibitors, unspecified GPCR antagonists, unspecified GPCR modulators, unspecified ion channel inhibitors, uterine globin stimulators, V-set transmembrane domain protein 1 stimulators, vascular cell adhesion protein 1 antagonists, VEGF ligand inhibitors, VEGF receptor modulators, VEGF-2 receptor modulators, vimentin inhibitors, vitamin D3 receptor agonists, Wnt 5A ligand inhibitors, Wnt ligand modulators, or YSK-4 protein kinase inhibitors.

[0518] Reagent test kit

[0519] This document also provides kits comprising the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one aspect, the kit comprises a compound of formula I (or any other formula described herein), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and / or instructions for use of the compound in a therapeutic indication, including the diseases or symptoms described herein.

[0520] This document also provides articles comprising the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0521] Example

[0522] Experimental Procedure

[0523] Unless otherwise stated, the reactions are carried out at room temperature. When the compounds described herein are used on a larger scale than their reported synthesis, it should be understood that many more substances have been prepared similarly.

[0524] The microwave reaction was carried out in a sealed vial in a dedicated microwave instrument.

[0525] Unless otherwise stated, dRecording in 6-DMSO at 250MHz-600MHz 1 H NMR spectroscopy.

[0526] Reactions occurring above the boiling point of the solvent are carried out in sealed tubes or screw-cap vials.

[0527] "Drying" refers to drying organic solutions with Na2SO4, MgSO4, or CaCl2 and then filtering out the desiccant.

[0528] "Degassing" refers to flushing an air-sensitive reaction with an inert atmosphere by evacuating and backfilling or by bubbling an inert atmosphere through the mixture for several minutes.

[0529] NaH was used as a 60% oil dispersion.

[0530] "Filtration" of a mixture refers to the removal / separation of solid matter from the mixture by filtration through filter paper, PFTE membranes, or diatomaceous earth pads. The solids are then washed using an additional solvent.

[0531] "Purification via SCX" refers to loading the substance onto an SCX column, washing with MeOH, eluting with a MeOH solution of NH3, and concentrating the fraction containing the product.

[0532] "Partition (A / B)" refers to the partitioning of a mixture between solvent A and solvent B. OL (A / B) refers to the organic layer after partitioning the mixture between solvent A and solvent B. AL (A / B) refers to the aqueous layer after partitioning the mixture between solvent A and solvent B.

[0533] After reduction with iron / zinc powder and AcOH / NH4Cl, the crude reaction mixture is usually filtered through diatomaceous earth, and then the filtrate is post-treated.

[0534] Unless otherwise specified, catalytic hydrogenation is carried out using a catalyst such as 10% Pd / C and H2 balloons. The mixture after the reaction is typically filtered through diatomaceous earth to remove the catalyst.

[0535] Obtain sufficiently pure intermediates from the procedures outlined in the instruction manual for the next step.

[0536] Some final compounds (examples) were obtained in pure form, and yields were provided accordingly, while other compounds were obtained in DMSO solution with specified concentrations and volumes.

[0537] HPLC method

[0538] Several intermediates and final compounds (examples) were purified using the HPLC methods listed below.

[0539]

[0540] LC / MS method

[0541] The compounds disclosed herein (examples) were characterized by the LC / MS methods listed below.

[0542]

[0543] abbreviation

[0544] ABPR = Automatic Back Pressure Regulator

[0545] ACN = Acetonitrile

[0546] AcOH = Acetic acid

[0547] AdBrettPhos Pd G3 = [2-(di-1-adamantyl-phosphino)-2',4',6'-triisopropyl-3,6-dimethoxybiphenyl][2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0548] aq = aqueous solution

[0549] Boc = tert-butoxycarbonyl

[0550] Boc2O = ditert-butyl dicarbonate

[0551] BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0552] B2Pin2 = 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane)

[0553] Brettphos Pd G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0554] BrettPhos Pd G4 = [2'-(methylamino)-[1,1'-biphenyl]-2-yl]palladium methanesulfonate dicyclohexyl[3,6-dimethoxy-2',4',6'-tris(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine

[0555] Salt water = saturated sodium chloride aqueous solution

[0556] cataCXium Pd G4 = [bis(adamantane-1-yl)(butyl)phosphine](methanesulfonate- O)[2'-(methylamino)-2-biphenyl]palladium

[0557] CBz = benzyloxycarbonyl

[0558] CBz-Cl = Benzyl chloroformate

[0559] CDI = 1,1'-carbonyldiimidazole

[0560] DAST = diethylaminosulfur trifluoride

[0561] dba = diphenylmethylene acetone

[0562] DCC = Dicyclohexylcarbodiimide

[0563] DCE = 1,2-dichloroethane

[0564] DCM = dichloromethane

[0565] DEA = diethylamine

[0566] DEAD = Diethyl azodicarbonate

[0567] Deoxo-Fluor = Bis(2-methoxyethyl)aminosulfur trifluoride

[0568] DIAD = diisopropyl azodicarbonate

[0569] DIPEA = diisopropylethylamine

[0570] DMAP = 4-(dimethylamino)pyridine

[0571] DME = 1,2-dimethoxyethane

[0572] DMF = dimethylformamide

[0573] DMDCH = trans- N , N' -Dimethylcyclohexane-1,2-diamine

[0574] DMEDA = N1 ,N2 -Dimethylethane-1,2-diamine

[0575] DMP = Dess-Martin periodine

[0576] DMS = dimethyl sulfide

[0577] DMSO = dimethyl sulfoxide

[0578] DPPF = 1,1'-bis(diphenylphosphino)ferrocene

[0579] EDC = N-(3-Dimethylaminopropyl)-N'-Ethylcarbodiimide

[0580] EtOAc = Ethyl acetate

[0581] EtOH = ethanol

[0582] FC = Unless otherwise specified, the eluent is used for rapid silica gel chromatography.

[0583] h = hours

[0584] HATU = (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate)

[0585] HBTU = N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)ureonium hexafluorophosphate

[0586] HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol

[0587] HOBt = Hydroxybenzotriazole

[0588] HPLC = High Performance Liquid Chromatography

[0589] Int. = intermediate

[0590] IPA = Isopropyl alcohol

[0591] KOAc = Potassium acetate

[0592] KOtBu = Potassium tert-Butoxide

[0593] LCMS = Liquid Chromatography-Mass Spectrometry

[0594] LDA = Lithium diisopropylamino

[0595] LiHMDS = Lithium bis(trimethylsilyl)amino

[0596] mCPBA = m-chloroperbenzoic acid

[0597] MeOH = methanol

[0598] 2MeTHF = 2-Methyl-tetrahydrofuran

[0599] MHz = Megahertz

[0600] MS = molecular sieve

[0601] MsCl = Methylsulfonyl chloride (methylsulfonyl chloride)

[0602] MTBE = Methyl tert-butyl ether

[0603] MW = Microwave

[0604] NaOtBu = Sodium tert-butoxide

[0605] NBS = N -bromosuccinimide

[0606] NMP = N 2-Methyl-2-pyrrolidone

[0607] NMR = Nuclear Magnetic Resonance

[0608] ON = Overnight

[0609] Pd2dba3 = tris(diphenylmethyleneacetone)dipalladium(0)

[0610] PdDPPFCl2-DCM = [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride DCM complex

[0611] Pd G3 SPhos = (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate

[0612] Pd G3 tert-butyl-Xphos = methanesulfonate (di-tert-butyl)phenylphosphino(2'-amino-1,1'-biphenyl-2-yl)palladium(II)

[0613] ppm = parts per million

[0614] PyBOP = (benzotriazol-1-yloxy)tripyrrolidinyl-phosphonium hexafluorophosphate

[0615] RT = room temperature

[0616] RU = Response Unit

[0617] RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0618] Ruphos Pd-G2 = Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0619] sat. = saturated

[0620] SCX = Strong Cation Exchange

[0621] SEM = 2-(trimethylsilyl)ethoxymethyl

[0622] SFC = Supercritical Fluid Chromatography

[0623] SPR = Surface Plasmon Resonance

[0624] STAB = Sodium triacetoxyborohydride

[0625] TBAF = Tetra-n-Butylammonium Fluoride

[0626] TBAI = Tetra-n-Butylammonium Iodide

[0627] TFA = Trifluoroacetic acid

[0628] Tf₂O = Trifluoromethanesulfonic anhydride

[0629] THF = Tetrahydrofuran

[0630] TLC = Thin-layer chromatography

[0631] TMEDA = Tetramethylethylenediamine

[0632] Ts = Toluenesulfonyl group

[0633] TsOH = p-Toluenesulfonic acid

[0634] T3P = Propanephosphonic anhydride

[0635] VCD = Vibration Circular Dichroism

[0636] XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene

[0637] XPhos = 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0638] Synthesis method

[0639] The compounds disclosed herein can be prepared in a variety of ways well known to those skilled in the art of synthesis. The compounds disclosed herein can be prepared, for example, using the reactions and techniques outlined below, as well as methods known in the field of synthetic organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents suitable for the reagents and materials used and suitable for the transformation. Furthermore, in the synthetic methods described below, it should be understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment, and post-treatment procedures) are selected as standard conditions for the reaction, which should be readily recognized by those skilled in the art. Not all compounds falling into a given category are compatible with some of the reaction conditions required in some of the described methods. This limitation on substituents compatible with the reaction conditions is readily understood by those skilled in the art, and alternative methods can be used.

[0640] If necessary, the compounds or any intermediates disclosed herein may be purified using standard methods well known to synthetic organic chemists, such as those described in “Purification of Laboratory Chemicals”, 6th edition, 2009, W. Amarego and C. Chai, Butterworth-Heinemann.

[0641] The starting materials are known or commercially available compounds, or can be prepared by conventional synthetic methods well known to those skilled in the art.

[0642] Unless otherwise specified, reagents and solvents should be used as is, from the commercial supplier. Organic solvents used are generally anhydrous. Unless otherwise specified, indicated solvent ratios are volume:volume. Thin-layer chromatography should be performed using Merck 6OF254 silica gel TLC plates. Visualization of the TLC plates should be performed using UV light (254 nm) or by appropriate staining techniques.

[0643] The compounds disclosed herein can be prepared according to the major bond formation outlined below.

[0644]

[0645] A=CO is linked to L-LBM (i.e., R) via an amide bond. 9 The L-LBM can be prepared by the corresponding acid, a suitable amine and a suitable coupling agent, for example under the conditions used to prepare Int. 1AF84.

[0646] A 1 Ring-B linkage can occur in palladium-mediated coupling reactions (where the amine (Z=N) reacts with ring-A based rings). 1In the aryl (pseudo)halide reaction), or by combining ring B, where Z is a carbon atom connected to boric acid or borate, with ring A based on ring A. 1 The coupling of aryl (pseudo)halides is achieved. Such reactions can be carried out as described for the synthesis of Int. 1M51 and 1S3.

[0647] The bond connecting the B-ring to the azaindole core (CC) can be formed by alkylation of a B-ring amine or lactam with an alkyl (pseudo)halide attached to the azaindole core (CC), or by reductive amination of a B-ring amine with a ketone / aldehyde attached to the azaindole core (CC). Such reactions can be carried out as described in the synthesis of Example 1d40 / 1d41 from Int. 1T1 or Example 1m6 from Int. 1M1.

[0648] R 2 The alkylation of the parent azaindole core (CC) can be achieved by alkylation with a suitable alkylating agent. Such reactions can be carried out as described for the synthesis of Int. 1K3.

[0649] Attaching ring D to the azaindole core (CC) can be accomplished via copper-mediated coupling of boric acid or borate attached to the azaindole (CC) core with the heteroaromatic ring D, or via a copper-mediated Ullmann reaction between an aryl (pseudo)halide derivative of the azaindole core (CC) and the heteroaromatic ring D. Such reactions can be carried out as described in the synthesis of Example 1af63 from Int. 1AF1 or Example 1ab4 from Int. 1AB4.

[0650] Alternatively or alternatively, the compounds disclosed herein can be prepared based on the major bond formations outlined below.

[0651]

[0652] The connection of A=CO to L-LBM via an amide bond can be carried out by a suitable acid, an appropriate amine, and a suitable coupling agent, for example, under the conditions used to prepare Int. 1AF84.

[0653] The bond connecting the B-ring to the azaindole core (CC) can be formed by alkylation of a B-ring amine or lactam with an alkyl (pseudo)halide attached to the azaindole core (CC), or by reductive amination of a B-ring amine with a ketone / aldehyde attached to the azaindole core (CC). Such reactions can be carried out as described in the synthesis of Example 1d40 / 1d41 from Int. 1T1 or Example 1m6 from Int. 1M1.

[0654] The bond connecting the B-ring to the azaindole core (CC) can be formed by alkylation of a B-ring amine or lactam with an alkyl (pseudo)halide attached to the azaindole core (CC), or by reductive amination of a B-ring amine with a ketone / aldehyde attached to the azaindole core (CC). Such reactions can be carried out as described in the synthesis of Example 1d40 / 1d41 from Int. 1T1 or Example 1m6 from Int. 1M1.

[0655] R 2 The alkylation of the parent azaindole core (CC) can be achieved by alkylation with a suitable alkylating agent. Such reactions can be carried out as described for the synthesis of Int. 1K3.

[0656] Attaching ring D to the azaindole core (CC) can be accomplished via copper-mediated coupling of boric acid or borate attached to the azaindole (CC) core with the heteroaromatic ring D, or via a copper-mediated Ullmann reaction between an aryl (pseudo)halide derivative of the azaindole core (CC) and the heteroaromatic ring D. Such reactions can be carried out as described in the synthesis of Example 1af63 from Int. 1AF1 or Example 1ab4 from Int. 1AB4.

[0657]

[0658] In compounds where A=CO, the -L- segment can be introduced via amide bond formation. The prerequisite acid can be prepared, for example, as described herein with respect to the preparation of Int. 1M60 from Example 1m56.

[0659] The synthesis of Int. 3E274 exemplifies a precursor in which the amide bond of CO to L-LBM is formed from the precursor substrate Int. 3E275 / 1AC4. This specification exemplifies L-LBM fragments (such as Int. 3E68) and their coupling to obtain the compounds disclosed herein, such as those described for the reaction yielding Example 3e39 from Int. 3E171 / 3E68.

[0660] Compounds in which the LBM motif is linked to the rest of the molecule via a triple bond or C-C bond to obtain a five-membered aromatic ring can be prepared from precursors such as Int. 3E240 / 3B1 via cross-coupling reactions.

[0661] Compounds in which the LBM motif is attached to the remainder of the molecule via a methylene linker can be prepared by reductive amination as described herein with respect to Int. 3E2. Compounds in which LBM is attached to the remainder of the molecule via the 4-position of the piperidine ring can be prepared as in Int. 3D1.

[0662] LBM motifs can be functionalized with Cl or F atoms, such as in Int. 3E50, 3E61 and 3E131.

[0663] LBM motifs can be functionalized with alkyl groups targeting the nitrogen atom of a benzimidazolone that does not contain a piperidine-2,6-diketone unit, such as (CH2)2OH, (CH2)2OMe, or CH2CF3, as in Int. 3E13, 3E159, and 3E106. LBM motifs can also be functionalized with alkyl groups targeting the nitrogen atom of a benzimidazolone that does not contain a piperidine-2,6-diketone unit, such as methyl or cyclopropyl, as in Int. 3E3 and 3E20.

[0664] Compounds with the LBM motif of hydroxyindole or benzoxazole can be prepared by Int. 3E288 and 3E257.

[0665] Example 1 - Preparation of Intermediates

[0666]

[0667] 0.27 g of 4-bromo-1-(phenyl-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-carboxaldehyde and 33 mg of NaBH4 were stirred for 0.5 h at 0 °C in THF / MeOH (9:1, 5 mL). OL (water / EtOAc) was washed with brine, dried, and concentrated to give Int. 1A5 (4-bromo-1-(phenyl-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol (281 mg). 0.24 g of Int. 1A5 and 0.052 mL of MsCl were stirred for 0.5 h in DCM / Et3N (29:1, 5.2 mL). 0.014 mL of MsCl was added, and stirring continued for another 0.5 h. OL (water / DCM) was washed with brine, dried, concentrated and purified by FC (heptane / EtOAc 1:0 to 1:1) to give Int. 1A4 4-bromo-2-(chloromethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.15 g).

[0668]

[0669] 4-Bromopyridin-2(1H)-one (1.0 g), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzoate (3.17 g), PdDPPFCl2-DCM (0.42 g), and K3PO4 (3.66 g) were degassed in dioxane / water (10:1, 11 mL) and stirred at 110 °C for 2 hours at MW. The mixture was filtered, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1A17 ethyl 4-(2-oxo-1H-pyridin-4-yl)benzoate (0.50 g). Int. 1A17 (3.5 g) was hydrogenated for 48 hours in EtOH / AcOH (4:1, 50 mL) with 10% Pd / C (1.5 g), filtered, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1A16 ethyl 4-(2-oxopiperidin-4-yl)benzoate (2.5 g). Int. 1A16 (0.50 g), Boc2O (0.61 g), and DMAP (23 mg) were stirred overnight in DCM / Et3N (25:1, 21 mL) at 0°C to room temperature. OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1A15 tert-butyl 4-(4-ethoxy-carbonylphenyl)-2-oxo-piperidine-1-carboxylic acid (0.40 g). Int. 1A15 (0.30 g) was stirred for 0.5 h in 11 mL of 0.1 M LiHMDS THF solution at -78 °C. CH3I (0.16 mL) was added, and stirring was continued for 2 h at -25 to -30 °C. OL (saturated NH4Cl aqueous solution / EtOAc) was washed with water and brine, dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1A14 trans-4-(4-ethoxycarbonylphenyl)-3-methyl-2-oxo-piperidine-1-carboxylic acid (0.18 g). Int. 1A14 (0.60 g) was stirred overnight in DCM / TFA (32:1, 20.6 mL) at 0°C to room temperature and concentrated. OL (10% MeOH in DCM solution / saturated NaHCO3 aqueous solution) was dried and concentrated to give Int. 1A13 ethyl 4-[trans-3-methyl-2-oxo-4-piperidinyl]benzoate (0.38 g). Int. 1A13 (0.20 g) and NaH (28 mg) were stirred in THF (10 mL) at 0°C to room temperature for 0.5 h. Int. 1J1 (0.22 g) and TBAI (25 mg) were added and stirring continued overnight.OL (citric acid aqueous solution / EtOAc) was dried and concentrated to give Int.1A12 / 1A11 ethyl 4-[trans-1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidinyl]benzoate and ethyl 4-[trans-1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidinyl]benzoate (0.30 g). 20 mg of this mixture, HNMe2 (0.11 g, hydrochloride), and HATU (0.25 g) were stirred overnight in DMF / DIPEA (28.6:1, 10.4 mL). The mixture was combined with another batch prepared in a similar manner at a scale of 30 mg, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1A10. N , N -Dimethyl-4-[trans-1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidinyl]benzamide (0.20 g).

[0670]

[0671] Int. 1A18 4-[1-[(4-chloro-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-2-oxo-4-piperidinyl]- N , N The preparation of dimethylbenzamide is similar to the preparation of Int. 1A10 from Int. 1A16 and 4-chloro-2-(chloromethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (whose preparation is similar to that of Int. 1J1).

[0672]

[0673] Int. 1J1 (8g) and N , N Dimethyl-4-(4-piperidinyl)benzamide (9.9 g, hydrochloride) was stirred overnight in DMF / DIPEA (0.7:1, 47 mL) at 0 °C to room temperature. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:3) to give Int. 1AB1 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N- Dimethylbenzamide (9g). Int. 1AB1' 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N -bis(methyl- d 3) The preparation of benzamide is similar to that from HN(CD3)2.

[0674]

[0675] Add Na2CO3 (9.2g), 1,1,1-trifluoro- N -phenyl- N -((trifluoromethyl)sulfonyl)methane-sulfonamide (10 g) and (4-(dimethylcarbamoyl)phenyl)boronic acid (5.5 g) were degassed in toluene / water (4:1, 250 mL) and stirred at 100 °C for 3 hours. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 2:3) to give Int. 1AB14 4-[4-(dimethylcarbamoyl)phenyl]-6-oxo-2,3-dihydropyridine-1-carboxylic acid tert-butyl ester (5.1 g). Int. 1AB14 (4.4 g) was hydrogenated overnight in 10% Pd / C (0.45 g) in MeOH (100 mL), filtered, and concentrated to give Int. 1AB13 4-(4-(dimethylcarbamoyl)-phenyl)-2-oxopiridine-1-carboxylic acid tert-butyl ester (3.9 g). Int. 1AB13 (8.1 g) was stirred overnight in a dioxane solution of DCM / 4M HCl (4.2:1, 124 mL) and concentrated. The solution was then dried over dryness and concentrated to obtain Int. 1AB12. N , N-Dimethyl-4-(2-oxo-piperidin-4-yl)-benzamide (2.9 g). This substance was resolved by SFC (using a Chiralpak IG 250×25 5 µm column (operated at 30 °C) with 50% CO2 and 50% MeOH as eluent (100 g / min) and a back pressure of 100 bar) to give Int. 1AB11 (0.93 g, first peak) and Int. 1AB12 (0.91 g, second peak). The absolute configurations of these compounds were not determined. Int. 1AB12 (95 mg) and NaH (20 mg) were stirred in DMF (1 mL) for 0.25 h. Int. 1J1 (0.10 g) was added and stirring was continued for 0.5 h. OL (DCM / water) was washed with water and brine, dried, concentrated, and ground in ACN to obtain Int. 1AB3 (S)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)- N , N -Dimethylbenzamide or (R)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)- N , N -Dimethylbenzamide (31 mg). Int. 1AB2 (S)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxoperidin-4-yl)- N , N -Dimethylbenzamide or (R)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)- N , N The preparation of dimethylbenzamide (35 mg) was similar to that from Int. 1AB11 / 1J1 (95 mg / 0.10 g). The absolute configurations of these compounds were not determined.

[0676]

[0677] Int. 1AB1 (0.15 g), B2Pin2 (0.13 g), KOAc (81 mg), and PdDPPFCl2-DCM (27 mg) were degassed in dioxane (3 mL), stirred at 90 °C, filtered, and concentrated to obtain Int. 1AB4 / 1AB4'. N , N-Dimethyl-4-[1-[[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidinyl]benzamide and [2-[[4-[4-(dimethylcarbamoyl)phenyl]-1-piperidinyl]methyl]-1-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid and N , N -bis(methyl- d 3)-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzamide and (2-((4-(4-(bis-(methyl- d 3) Carbamoyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid.

[0678]

[0679] 4-bromo- N , N 3-Trimethylbenzamide (9.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (15.2 g), PdDPPFCl2-DCM (0.67 g), and Na2CO3 (9.62 g) were degassed in dioxane (180 mL) and stirred overnight at 90 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 2:3) to give Int. 1AB7 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (11.0 g). Int. 1AB7 (0.6 g) was stirred overnight in DCM / TFA (30:1, 15.5 mL), concentrated, and then ground in Et2O to obtain Int. 1AB6. N , N3-Trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (TFA salt). Int. 1AB6 / 1AB8 (0.23 g, TFA salt / 0.1 g) was stirred overnight in DCE / DIPEA (11.4:1, 5.4 mL) at 0 °C to room temperature. STAB (26 mg) was added and stirring was continued at 0 °C to room temperature for 2 hours. The solution was dried over OL (water / DCM), concentrated, and purified by FC (MeOH / DCM 1:9) to give Int. 1AB5 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)- N , N 3-Trimethylbenzamide (0.10g).

[0680]

[0681] 5.0 g of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine was stirred for 2 hours at -78 °C in 33 mL of 1.1 M LDA in THF. 3.46 g of DMF (in 20 mL of THF) was added and the mixture was stirred overnight at -78 °C to room temperature. OL (saturated NH4Cl aqueous solution / EtOAc) was washed with water and brine, dried, concentrated, and ground in EtOAc / pentane to give Int. 1AB8 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde (3.1 g).

[0682]

[0683] PdDPPFCl2-DCM (1.1 g), 6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10.2 g), (4-(dimethylcarbamoyl)phenyl)boronic acid (5.7 g), and Na2CO3 (9.4 g) were stirred in toluene / water (150 / 40 mL) at 100 °C for 3 hours. The mixture was filtered. The filtrate was concentrated and purified by FC (EtOAc / hexane 3:2) to give Int. 1AB14 4-(4-(dimethylcarbamoyl)-phenyl)-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (5.2 g). Int. 1AB14 (5 g) and 10% Pd / C (2.5 g) were hydrogenated in EtOAc (100 mL) at 60 psi for 48 hours. The mixture was filtered and concentrated to give Int. 1AB13 4-(4-(dimethylcarbamoyl)phenyl)-2-oxopiridine-1-carboxylic acid tert-butyl ester (4.0 g). Int. 1AB13 (0.1 g) was stirred in a dioxane solution (5 / 0.4 mL) of DCM / 4M HCl for 12 hours. The concentrated residue was ground in Et2O to give Int. 1AB10 / 1AB12N,N-dimethyl-4-(2-oxopiridine-4-yl)benzamide (78 mg).

[0684]

[0685] Int. 1AB8 (6.0 g) and methyl 4-(1-piperidin-4-yl)benzoate (7.1 g, hydrochloride) were stirred in DCE / DIPEA (7.7:1, 113 mL) for 4 hours. STAB (11.0 g) was added and stirring was continued overnight at 0°C to room temperature. OL (water / EtOAc) was washed with brine, dried, concentrated, and ground in EtOAc / MeOH to give Int. 1AC5 methyl 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoate. Int. 1AC5 (0.4 g) and NaOH (0.18 g) were stirred overnight in THF / MeOH (2:1, 9 mL), concentrated, and ground in dilute HCl aqueous solution to obtain Int. 1AC4 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidinyl]-benzoic acid (0.38 g). Int. 1AC4 (0.5 g) and CDI (0.7 g) were stirred for 2 hours in DMF / Et3N (30:1, 7.2 mL). 25% NH3 aqueous solution (1.51 mL) was added, followed by water, to precipitate a solid, which was precipitated in 1,1-dimethoxy- N ,N Stirring in dimethyl methylamine (10 mL) overnight yields Int. 1AC3 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzamide (0.35 g).

[0686]

[0687] 4-bromo-1-toluenesulfonyl-1 H -pyrrolo[2,3- b Pyridine (1.0 g) was stirred for 1 hour at -78 °C in 14.2 mL of 0.6 M LDA in THF solution. DMF (1.3 mL) was added and stirring continued for 2 hours at -78 °C. The solution was dried over OL (saturated NH4Cl aqueous solution / EtOAc), concentrated, and purified by FC (hexane / EtOAc 1:0 to 9:1) to give Int. 1AD8 4-bromo-1-(p-toluenesulfonyl)-pyrrolo[2,3-b]-pyridine-2-carboxaldehyde (0.6 g). N,N- Dimethyl-4-(4-piperidinyl)-benzamide (1.4 g, hydrochloride) and Int. 1AD8 (1.3 g) were stirred overnight in DCE / DIPEA (20:1, 21 mL) at 0 °C to room temperature. Stirring was continued for 2 hours with STAB (1.1 g) at 0 °C to room temperature. The mixture was dried over OL (water / DCM), concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AD7 4-[1-[[4-bromo-1-(p-toluenesulfonyl)-pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidinyl]-N,N-dimethyl-benzamide (2.3 g).

[0688]

[0689] KOtBu (37 mg), tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate (0.16 g), K2CO3 (83 mg) and N , N Dimethyl-2-oxo-1H-pyridin-4-carboxamide (50 mg) was degassed in DME (5 mL) and stirred overnight at 120 °C. The solution was dried over OL (water / MeOH / DCM) and concentrated to give Int. 1AE2 4-[4-(dimethyl-carbamoyl)-2-oxo-1-pyridyl]-piperidine-1-carboxylic acid tert-butyl ester. Int. 1AE2 (0.25 g) was stirred in DCM / TFA (8.6:1, 5.6 mL). The mixture was concentrated to give Int. 1AE1. N , N-Dimethyl-2-oxo-1-(piperidin-4-yl)-1,2-dihydropyridine-4-carboxamide (0.15 mg, TFA salt).

[0690]

[0691] 4-bromo- N , N Dimethylbenzamide (25 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (40.7 g), Na2CO3 (34.5 g), and PdDPPFCl2-DCM (2.24 g) were degassed in dioxane / water (7.7:1, 260 mL) and stirred overnight at 90 °C, then filtered. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 55:45) to give 4-(4-(dimethyl-carbamoyl)-phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (36.0 g). 5.0 g of this substance was stirred overnight in DCM / TFA (6.9:1, 46 mL) and concentrated. OL (saturated NaHCO3 aqueous solution / 10% MeOH in DCM solution) was washed with brine, dried, concentrated, and ground in Et2O to obtain Int. 1AE7 4-(3,6-dihydro-2H-pyridin-4-yl)- N , N -Dimethyl-benzamide (2.80g).

[0692]

[0693] Methyl 4-bromobenzoate (10 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (14.4 g), NaHCO3 (11.7 g), and PdDPPFCl2-DCM (1.2 g) were degassed in dioxane (300 mL) and stirred overnight at 100 °C. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1AE14 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (11 g). 4.5 g of the substance and 3.0 g of LiOH-H2O were stirred for 4 hours at 0 °C to room temperature in MeOH / THF / water (4:2:1, 35 mL). The mixture was partially concentrated and diluted with aqueous citric acid to precipitate Int. 1AE37 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (3.9 g). Int. 1AE37 (4.0 g), HATU (7.52 g), and HN(CD3)2 (1.73 g, hydrochloride) were stirred overnight in DMF / DIPEA (2.5:1, 42 mL). OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give tert-butyl 4-[4-[bis-(trideutermethyl)-carbamoyl]phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.5 g). 2.5 g of this substance was stirred overnight in DCM / TFA (1:1, 30 mL) at 0°C to room temperature and concentrated. OL (NaHCO3 aqueous solution / 10% MeOH in DCM solution) was dried, concentrated, and ground in Et2O / pentane to give Int. 1AE7' N , N -bis(methyl- d 3)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (1.7g).

[0694]

[0695] 33.7 g of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 4-bromo- N , N3-Trimethylbenzamide (20.0 g), Na2CO3 (21.4 g), and PdDPPFCl2-DCM (1.48 g) were degassed in dioxane / water (9:1, 200 mL) and stirred overnight at 110 °C. The mixture was filtered, concentrated, and purified by FC (heptane / EtOAc 1:1) to give tert-butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (25 g). 15 g of this substance was hydrogenated overnight in 10% Pd / C (5.0 g) in MeOH (200 mL), filtered, and concentrated to give tert-butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-piperidine-1-carboxylate (14.0 g). 10g of this substance was stirred overnight in DCM / TFA (1:1, 200mL) at 0℃ to room temperature, concentrated, and then ground in Et2O to obtain Int. 1AE8 N , N 3-Trimethyl-(4-piperidin-4-yl)benzamide (9.2 g, TFA salt).

[0696]

[0697] 4.0 g of 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was stirred in a 4 M HCl solution in dioxane (40 mL) for 0.5 hours, concentrated, and ground in Et2O to obtain Int.1AE8' N , N 3-Trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (1.06 g, hydrochloride).

[0698]

[0699] Int. 1J1 / 1 (0.70 g / 0.49 g, hydrochloride) and KI (0.11 g) were stirred overnight in DMF / DIPEA (8.3:1, 11.2 mL) at 0 °C to room temperature. OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (EtOAc / hexane 7:3) to give Int. 1AE9 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methyl- N , N -bis(methyl- d 3) Benzamide (0.45g).

[0700]

[0701] Methyl 4-bromo-3-fluoro-5-methylbenzoate (20 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (27.5 g), K2CO3 (44.8 g), and PdDPPFCl2-DCM (3.31 g) were degassed in dioxane / water (4:1, 0.5 L) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane to EtOAc) to give 4-(2-fluoro-4-methoxy-carbonyl-6-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (15.5 g). The substance and LiOH-H2O (3.72 g) were stirred overnight in MeOH / water (1:1, 0.3 L) and acidified to precipitate 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-fluoro-5-methylbenzoic acid (11.8 g). 5.0 g of this substance, HN(CD3)2 (1.44 g, hydrochloride), and HATU (6.8 g) were stirred overnight in DMF / DIPEA (6.4:1, 58 mL), concentrated, and purified by FC (hexane to EtOAc) to give 4-[4-[bis(trideuteryl)carbamoyl]-2-fluoro-6-methyl-phenyl]-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (5.1 g). The substance was stirred in an HFIP / 10M HCl aqueous solution (31:1, 52 mL) for 1 hour and diluted with MTBE to precipitate Int. 1AE12 3-fluoro-5-methyl- N , N -bis(methyl- d 3)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (3.45 g, hydrochloride). Int.1AE12' 3-fluoro-5-methyl- N , N The preparation of bis(methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide is similar to that from HN(CH3)2.

[0702]

[0703] Int. 1J3 (0.50 g) was stirred for 1 hour at 0 °C in DCM (20 mL) and MsCl (0.8 mL). OL (water / DCM) was washed with a saturated NaHCO3 aqueous solution and concentrated to give methyl (4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methanesulfonate (0.52 g). 0.5 g of this substance, KI (0.13 g), and Int. 1AE12' (0.51 g) were stirred overnight at 0 °C to room temperature in DMF / DIPEA (14:1, 21.5 mL). OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AE13 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro- N , N 5-Trimethyl-benzamide (0.52g).

[0704]

[0705] Int. 1AB1 (0.15 g), Mo(CO)6 (87 mg), Pd2dba3 (8 mg), and XantPhos (10 mg) were degassed in EtOH (5 mL) and stirred at 120 °C for 0.5 h at MW. The mixture was filtered and purified by HPLC to give ethyl 2-((4-(4-(dimethylcarbamoyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (0.25 g). The substance and LiOH (69 mg) were stirred and concentrated in water / EtOH (2:1, 1.5 mL) and purified by HPLC to obtain Int. 1AE15 2-((4-(4-(dimethylcarbamoyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (0.15 g).

[0706]

[0707] Piperazin-2-one (1.0 g), 4-bromo- N , N Dimethylbenzamide (1.14 g), K3PO4 (6.4 g), Pd(OAc)2 (0.22 g), and RuPhos (0.93 g) were degassed in tert-butanol (15 mL) and stirred overnight at 80-90 °C. The mixture was filtered, concentrated, and purified by FC (DCM / MeOH 9:1) to obtain... N , N-Dimethyl-4-(3-oxopiperazin-1-yl)benzamide (0.70 g). 0.25 g of this substance and NaH (81 mg) were stirred for 1 hour in THF / DMF (10:1, 5.5 mL) at 0°C to room temperature. Int. 1J1 (0.25 g) was added and stirring continued overnight at 0°C to room temperature. The mixture was dried over OL (10% MeOH in DCM / water solution), concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AE16 4-(4-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-oxopiperazin-1-yl)- N , N - Dimethylbenzamide (0.20g).

[0708]

[0709] 6-Bromo-5-methylpyridin-3-carboxylic acid (4.5 g), HATU (9.5 g), and HN(CH3)2 (8.4 g, hydrochloride) were stirred overnight in DMF / DIPEA (2.5:1, 45 mL) at 0 °C to room temperature. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane / EtOAc 3:7) to give Int. 1AE21 6-Bromo- N , N 5-Trimethylnicotinamide (4.2 g). 3.2 g of this substance, NaHCO3 (3.9 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-pyridine-1(2H)-carboxylic acid tert-butyl ester (6.1 g), and PdDPPFCl2-DCM (0.27 g) were degassed in dioxane / water (3.7:1, 14 mL) and stirred overnight at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1AE205-(dimethylcarbamoyl)-3-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (4.0 g). 0.25 g of this substance was stirred overnight in DCM / TFA (8.4:1, 5.6 mL) at 0°C to room temperature, concentrated, and ground in Et2O / pentane to obtain Int. 1AE19 N , N 5-Trimethyl-6-(1,2,3,6-tetrahydro-pyridin-4-yl)pyridine-3-carboxamide (0.28 g, TFA salt).

[0710]

[0711] Int. 1AE19 / 1J1 (0.5 g / 0.5 g) was stirred overnight in ACN / Et3N (18:1, 26 mL), concentrated, and purified by HPLC to obtain Int. 1AE22 6-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N 5-Trimethyl-pyridine-3-carboxamide (0.3 g). Int. 1AE22 (3 g), B2Pin2 (5.0 g), KOAc (5.0 g), and PdDPPFCl2-DCM (0.05 g) were degassed in dioxane (25 mL) and stirred overnight at 80 °C. The solution was dried over OL (water / EtOAc) and concentrated to give Int. 1AE23 (2-((5-(dimethylcarbamoyl)-3-methyl-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid / N , N 3-Trimethyl-1'-((1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (1.0 g).

[0712]

[0713] 4-bromo-3-fluoro N , NDimethylbenzamide (1.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.51 g), Na2CO3 (1.72 g), and PdDPPFCl2-DCM (0.17 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AE27 4-[4-(dimethyl-carbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g). In a sealed tube under H2 atmosphere, the substance was hydrogenated overnight in 10% Pd / C (40 mg) in MeOH (10 mL), filtered, and concentrated to obtain Int. 1AE26 4-[4-(dimethylcarbamoyl)-2-fluoro-phenyl]piperidine-1-carboxylic acid tert-butyl ester (0.60 g). This substance was then stirred overnight in a 4M HCl solution in dioxane (10 mL), concentrated, and purified by HPLC to obtain Int. 1AE25 3-fluoro- N , N -Dimethyl-4-(piperidin-4-yl)benzamide (63 mg).

[0714]

[0715] 4-bromo-1-toluenesulfonyl-1 H -pyrrolo[2,3- b Pyridine (1.0 g) was stirred for 1 hour at -78 °C in 14 mL of 0.6 M LDA in THF solution. DMF (1.3 mL) was added and stirring was continued at -78 °C for 2 hours. The solution was dried over OL (saturated NH4Cl aqueous solution / EtOAc), concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1AE35 4-bromo-1-(p-toluenesulfonyl)pyrrolo[2,3-b]pyridine-2-carboxaldehyde (0.6 g). Int. 1A35 (1.5 g) and N , N Dimethyl-4-(piperidin-4-yl)benzamide (1.6 g, hydrochloride) was stirred overnight in DCM / DIPEA (5:1, 24 mL). STAB (2.5 g) was added and stirring continued for 2 hours at 0°C to room temperature. The solution was dried over OL (DCM / water), concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AE34 4-[1-[[4-bromo-1-(p-toluenesulfonyl)-pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidinyl]- N ,N -Dimethyl-benzamide (1.0g).

[0716]

[0717] Int. 1AC4 (0.10 g), HATU (164 mg), and (3,4-dimethoxybenzyl)(methyl)-amine (58 mg) were stirred in DMF / DIPEA (25:1, 3.1 mL) for 3 hours. The solution was dried over OL (saturated NaHCO3 aqueous solution / DCM), concentrated, and purified by FC (DCM to DCM / MeOH 93:7) to give Int. 1AE36 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N -(3,4-Dimethoxybenzyl)- N -Methylbenzamide (0.12g).

[0718]

[0719] 4.0 g of 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was stirred in a 4M HCl solution in dioxane (40 mL) for 0.5 hours, concentrated, and ground in Et2O to obtain Int.1AE38. N , N 3-Trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (1.06 g, hydrochloride).

[0720]

[0721] 0.50 g of tert-butyl 3-oxoperazine-1-carboxylate and 4-bromo- N , N Dimethylbenzamide (0.68 g), K3PO4 (1.06 g), CuI (71 mg), and DMDCH (36 mg) were degassed in dioxane (10 mL) and stirred overnight at 100 °C. The mixture was dried over OL (water / EtOAc), concentrated, and purified by FC (EtOAc / MeOH 1:0 to 9:1) to give 0.80 g of tert-butyl 4-(4-(dimethylcarbamoyl)-phenyl)-3-oxopiperazine-1-carboxylate. 0.23 g of this substance was stirred in DCM / TFA (1:1, 6 mL) for 1 hour and concentrated to give Int. 1AE39. N , N -Dimethyl-4-(2-oxo-piperazin-1-yl)benzamide (0.24 g, TFA salt).

[0722]

[0723] Int. 1J1 / 1AE7' (0.33 g / 0.30 g) and KI (21 mg) were stirred overnight in DMF / DIPEA (7.3:1, 9 mL) at 0 °C to room temperature. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane to EtOAc) to give Int.1AF1 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)- N , N -bis(methyl- d 3) Benzamide (0.20g).

[0724]

[0725] Methyl 2-bromopyrimidine-5-carboxylate (10.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (15.6 g), K2CO3 (25.5 g), and PdDPPFCl2-DCM (1.88 g) were degassed in dioxane / water (4:1, 0.25 L) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give methyl 2-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrimidine-5-carboxylate (14.7 g). The substance and LiOH-H2O (2.15 g) were stirred overnight in MeOH / water (1:1, 200 mL) and acidified to precipitate 2-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrimidine-5-carboxylic acid (8.0 g). 4.0 g of this substance, HN(CD3)2 (1.21 g, hydrochloride), and HATU (5.27 g) were stirred in DMF / DIPEA (3:1, 27 mL), concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-[5-[bis(trideuterylmethyl)carbamoyl]pyridin-2-yl]-3,6-dihydro-2H-pyridin-1-carboxylic acid (2.20 g). The substance was stirred in an HFIP / 10M HCl aqueous solution (30:1, 23 mL) for 1 h, concentrated, and ground in MTBE to obtain Int. 1AF2. N , N -bis(methyl- d 3)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide (1.40 g, hydrochloride).

[0726]

[0727] Int. 1AF2 / 1J1 (0.5 g / 0.5 g) was stirred, concentrated, and purified by HPLC in an ACN / Et3N (19:1, 26 mL) to obtain Int. 1AF3 2-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N -Bis(trideuterylmethyl)pyrimidine-5-carboxamide (0.3g).

[0728]

[0729] 4-bromo-3-fluoro N , N Dimethylbenzamide (1 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.5 g), Na2CO3 (1.7 g), and PdPDDFCl2-DCM (0.17 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AF11 4-[4-(dimethylcarbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.2 g). Int. 1AF11 (0.6 g) was stirred overnight in a 4M HCl solution in dioxane (10 mL). The concentrated residue was purified by HPLC to obtain Int. 1AF10 3-fluoro- N , N -Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g). Int. 1AF10 / 1J1 (0.5 g / 0.5 g) was stirred overnight in ACN / Et3N (19:1, 26 mL), concentrated, and purified by HPLC to give Int. 1AF9 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)-methyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N 3,5-Tetramethyl-benzamide (0.3 g). Int. 1AF9 (3 g), B2pin2 (5 g), KOAc (5 g), and PdDPPFCl2-DCM (50 mg) were degassed in dioxane and stirred overnight at 80 °C. OL (EtOAc / water) was dried and concentrated to give Int. 1AF8 3-chloro- N , N-Dimethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide / (2-((4-(2-chloro-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (1g).

[0730]

[0731] Int. 1S5 / 1J1 (0.5 g / 0.5 g, hydrochloride) was stirred overnight in ACN / Et3N (19:1, 26 mL), concentrated, and purified by HPLC to obtain Int. 1AF13 6-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N -Dimethyl-pyridine-3-carboxamide (0.3 g). Int. 1AF13 (3.0 g), KOAc (5.0 g), B2Pin2 (5.0 g), and PdDPPFCl2-DCM (50 mg) were degassed in dioxane (25 mL) and stirred overnight at 80 °C. The solution was concentrated in OL (water / EtOAc) to obtain Example 1AF12. N , N -Dimethyl-1'-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide / (2-((5-(dimethylcarbamoyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (1.0 g).

[0732]

[0733] Methyl 5-bromopyrazine-2-carboxylate (11.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester (17.2 g), K₂CO₃ (28.0 g), and PdPDDFCl₂-DCM (2.07 g) were degassed in dioxane / water (5:1, 250 mL) and stirred overnight at 100 °C. The aqueous layer (water / EtOAc) was acidified to precipitate 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (12.0 g). 4.5 g of this substance, 1.40 g of HN(CD3)2 (hydrochloride), and 6.20 g of HATU were stirred overnight in DMF / DIPEA (2.6:1, 28 mL), concentrated, and purified by FC (hexane to EtOAc) to give 2.0 g of 4-[5-[bis(trideuterylmethyl)carbamoyl]pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. This substance was stirred and concentrated in 1 h of HFIP / 10M HCl aqueous solution (29:1, 21 mL) and ground in MTBE to give Int. 1AF14 5-(1,2,3,6-tetrahydropyridine-4-yl)- N , N -Bis(trideuterylmethyl)pyrazine-2-carboxamide (0.88 g, hydrochloride).

[0734]

[0735] Int. 1AF14 / 1J1 (0.5 g / 0.5 g) and Et3N (1.2 mL) were stirred overnight in ACN (25 mL), concentrated, and purified by HPLC to obtain Int. 1AF15 5-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)- N , N -bis(methyl- d 3) Pyrazine-2-carboxamide (0.3g).

[0736]

[0737] A 1.0 M MeMgBr THF solution (185 mL) was added at 0 °C to a solution of Int. 1AB8 (29.5 g) in THF (1.2 L) and stirring was continued for 3 hours. OL (saturated NH4Cl aqueous solution / EtOAc) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 3:1) to give Int. 1AF21 1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanol-1-ol (25.5 g). 0.30 g of this substance was stirred at 0 °C in toluene / SOCl2 (12.5:1, 10.8 mL), and then stirred at 110 °C for 0.5 hours. The mixture was concentrated. The residue, Cs2CO3 (1.15 g), KI (0.98 g), and... N , N 0.41 g of dimethyl-4-(4-piperidinyl)-benzamide was stirred overnight in 10 mL of ACN at 0 °C to room temperature. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1AF17 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)- N , N - Dimethylbenzamide (0.28g).

[0738]

[0739] Int. 1AF17 (0.70 g), B2Pin2 (0.51 g), KOAc (0.4 g) and Pd(PPh3)2Cl2 (0.1 g) were degassed in THF (50 mL), stirred overnight at 100 °C, filtered, concentrated and ground in pentane to obtain Int. 1AF24 (2-(1-(4-(4-(dimethyl-carbamoyl)phenyl)piperidin-1-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g).

[0740]

[0741] Int. 1AF17 (0.70 g), B2Pin2 (0.51 g), KOAc (0.4 g) and Pd(PPh3)2Cl2 (0.1 g) were degassed in THF (50 mL), stirred overnight at 100 °C, filtered, concentrated and ground in pentane to obtain Int. 1AF24 (2-(1-(4-(4-(dimethyl-carbamoyl)phenyl)piperidin-1-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g).

[0742]

[0743] Int. 1AF17 (0.70 g), B2Pin2 (38 mg), KOAc (45 mg), and PdDPPFCl2-DCM (25 mg) were degassed in dioxane (10 mL) and stirred overnight at 110 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to obtain Int. 1AF27. N , N -Dimethyl-4-(1-(1-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzamide (0.85 g).

[0744]

[0745] 0.20 g of 1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl-1-ol was concentrated in toluene / SOCl2 (29:1, 5.2 mL) at 0 °C to 110 °C for 1.5 h with stirring. The residue, 10 mg of KI, and 0.23 g of Int. 1AF5 were stirred overnight in DMF / DIPEA (2.5:1, 2.8 mL) at 0 °C to room temperature with stirring. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 9:1 to 85:15) to give Int. 1AF34 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N-Dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), B2Pin2 (24 mg), KOAc (25 mg) and PdCl2(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred overnight at 90 °C. The mixture was filtered, concentrated and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(1-(4-(4-(dimethylcarbamoyl)-phenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.50 g).

[0746]

[0747] 0.20 g of 1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl-1-ol was concentrated in toluene / SOCl2 (29:1, 5.2 mL) at 0 °C to 110 °C for 1.5 h with stirring. The residue, 10 mg of KI, and 0.23 g of Int. 1AF5 were stirred overnight in DMF / DIPEA (2.5:1, 2.8 mL) at 0 °C to room temperature with stirring. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 9:1 to 85:15) to give Int. 1AF34 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N -Dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), B2Pin2 (24 mg), KOAc (25 mg) and PdCl2(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred overnight at 90 °C. The mixture was filtered, concentrated and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(1-(4-(4-(dimethylcarbamoyl)-phenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.50 g).

[0748]

[0749] Int. 1AF40 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]- N , NThe preparation of 3-trimethylbenzamide (0.15 g) was similar to the preparation of Int. 1AF17 from Int. 1AF21 (0.20 g) and Int. 1AE38 (0.37 g, TFA salt). The preparation of Int. 1AF39 (2-(1-(4-(4-(dimethylcarbamoyl)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)-ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (40 mg) was similar to the preparation of Int. 1AF33 from Int. 1AF40 (50 mg).

[0750]

[0751] Int. 1AF44 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-4-piperidinyl]- N , N The preparation of 3-trimethylbenzamide (0.15 g) was similar to the preparation of Int. 1AF17 from Int. 1AF24 / 1AE38 (0.20 g / 0.42 g, TFA salt). The preparation of Int. 1AF43 (2-(1-(4-(4-(dimethylcarbamoyl)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)-ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.60 g) was similar to the preparation of Int. 1AF39 from Int. 1AF44 (0.50 g).

[0752]

[0753] Int. 1AF50 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-4-piperidinyl]- N , N The preparation of bis(trideuterylmethyl)benzamide (0.65 g) was similar to the preparation of Int. 1AF17 from Int. 1AF21 / 1D7 (0.35 g / 0.53 g, TFA salt). The preparation of Int. 1AF49 [2-[1-[4-[4-[bis(trideuterylmethyl)carbamoyl]phenyl]-1-piperidinyl]ethyl]-1-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (0.41 g) was similar to the preparation of Int. 1AF25 from Int. 1AF50 (0.32 g) and B2Pin2 (0.34 g).

[0754]

[0755] Int. 1AF56 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)- N , N -bis(methyl- d 3) The preparation of benzamide (0.60 g) was similar to the preparation of Int. 1AF34 from Int. 1AF21 (0.50 g) and Int. 1AE7' (0.69 g). The preparation of Int. 1AF55 [2-[1-[4-[4-[bis(trideuterylmethyl)carbamoyl]phenyl]-3,6-dihydro-2H-pyridin-1-yl]ethyl]-1-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (0.55 g) was similar to the preparation of Int. 1AF39 from Int. 1AF56 (0.50 g).

[0756]

[0757] Int. 1AF62 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl- N , N -bis(methyl- d 3) The preparation of benzamide (0.46 g) was similar to the preparation of Int. 1AF17 from Int. 1AF24 / 1S20 (0.50 g / 0.70 g). Int. 1AF61 (2-(1-(4-(4-(bis(methyl- d 3) The preparation of carbamoyl)-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.75 g) was similar to the preparation of Int. 1AF55 from B2Pin2 (0.52 g) and Int. 1AF62 (0.5 g).

[0758]

[0759] Int. 1AF72 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-methyl- N , N -bis-(methyl- d 3) The preparation of benzamide (90 mg) was similar to the preparation of Int. 1AF17 from Int. 1AF24 / 1S22 (0.10 g / 0.19 g, TFA salt). Int. 1AF71 (2-(1-(4-(4-(bis(methyl-d 3) The preparation of carbamoyl)-2-methylphenyl)piperidin-1-yl)ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g) was similar to the preparation of 1AF55 from Int. 1AF72 (90 mg) and B2Pin2 (0.12 g).

[0760]

[0761] Int. 1AF21 (1.20 g) was stirred in toluene / SOCl2 (5.9:1, 23.5 mL) at 0 °C to 110 °C for 1 hour and concentrated. The residue, Cs2CO3 (4.60 g), KI (0.39 g), and Int. 1AE7 (1.30 g) were stirred overnight in ACN (30 mL) at 0 °C to room temperature. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 9:1 to 85:15) to give Int. 1AF73 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N -Dimethyl-benzamide (1.0 g). Int. 1AF74 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)- N , N -bis(methyl- d 3) The preparation of benzamide (0.60 g) is similar to that of Int. 1AE7' / 1AF21 (0.69 g / 0.50 g).

[0762]

[0763] Int. 1AF76 (1.50 g), B2Pin2 (1.60 g), KOAc (0.93 g), and PdPDDFCl2-DCM (0.26 g) were degassed in dioxane (30 mL), stirred at 90 °C for 6 hours, filtered, concentrated, and ground in Et2O to obtain Int. 1AF75(S)- N , N -bis(methyl- d 3)-4-(1-(1-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzamide (1.30 g).

[0764]

[0765] Int. 2C36 (0.35 g), HATU (0.3 g), and HN(CD3)2 (77 mg, hydrochloride) were stirred overnight in DMF / DIPEA (14.7:1, 10.7 mL) at 0 °C to room temperature and diluted with water to precipitate Int. 1AF76 (0.30 g). The preparation of Int. 1AF76' (3.5 g) was similar to that from Int. 2C36 (4.5 g). Int. 1AF76' (0.10 g), CuI (20 mg), NaI (63 mg), and DMDCH (30 mg) were degassed in dioxane (5 mL) at 110 °C, stirred overnight, and filtered. OL (DCM / NH3 aqueous solution) was dried, concentrated, and purified by FC (DCM / MeOH 97:3) to obtain Int. 1AF77 (S)-4-(1-(1-(4-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)- N , N -bis(methyl- d 3)-Benzamide (50 mg). The determination of 1AF76 (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl)piperidin-4-yl)- by VCD. N , N -Dimethylbenzamide and 1AF76'(S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)- N , N -bis(methyl) d 3) The absolute configuration of benzamide is S.

[0766]

[0767] CDI (7.04 g) was added at 0 °C to a solution of 4-bromo-3-fluoro-5-methylbenzoyl chloride (11.0 g) in DCM (50 mL) and stirring was continued for 0.5 h. HN(CH3)2 (7.1 g, hydrochloride) was added, and the mixture was then refluxed for 5 h. The mixture was washed with water, dried, and concentrated to give Int. 1AF7 4-bromo-3-fluoro- N , N5-Trimethylbenzamide (12.4 g). This substance, along with 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (15.0 g), K2CO3 (18.3 g), and PdDPPFCl2-DCM (0.73 g), were degassed in dioxane (100 mL) and stirred at 90 °C for 48 hours. The solution was dried over OL (water / MTBE) and concentrated to give Int. 1AF6 4-(2-chloro-4-(dimethylcarbamoyl)-6-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (11.0 g). Int. 1AF6 (0.6 g) was stirred in a dioxane solution of THF / 4M HCl (1:1, 2 mL) for 0.5 hours. OL (water / EtOAc) was dried and concentrated to give Int. 1AF5 3-chloro-5-fluoro- N , N -Dimethyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)benzamide (0.25 g, hydrochloride). This substance, K₂CO₃ (0.37 g), and Int. 1J₁ (0.23 g) were stirred overnight in DMF (5 mL). The OL (water / MTBE) layer was dried and concentrated to give Int. 1AF₄ 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)-methyl]-3,6-dihydro-2H-pyridin-4-yl]-3-chloro-5-fluoro- N , N -Dimethyl-benzamide (0.17 g). This substance, B2Pin2 (0.17 g), KOAc (0.10 g), and PdDPPFCl2-DCM (6 mg) were degassed in dioxane (5 mL) and stirred at 100 °C for 48 hours. The OL (water / MTBE) layer was dried and concentrated to give Int. 1AF82 3-chloro-5-fluoro- N , N -Dimethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide / (2-((4-(2-chloro-4-(dimethyl-carbamoyl)-6-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.19 g).

[0768]

[0769] Int. 1AF21 (8 g) was stirred in toluene / SOCl2 (4:1, 123 mL) at 0 °C to 80 °C for 0.5 h and concentrated to give Int. 1AF88 (7.5 g). Int. 1AF88 / 1AF90 (7.5 g, 7.8 g, hydrochloride), Cs2CO3 (31 g), and KI (23 g) were stirred overnight in ACN (100 mL) at 0 °C to room temperature. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc41:9) to give Int. 1AF87 methyl 4-[1-[1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5-methylbenzoate (3.9 g). Int. 1AF87 (0.2 g) was resolved by SFC (using a Chiralpak AD-H 250×21 mm 5 µm column (operated at 30 °C) with 70% CO2 and 30% MeOH as eluent (70 g / min) and a back pressure of 100 bar) to give Int. 1AF86 (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methylbenzoate (70 mg, second peak). The absolute configuration of Int. 1AF86 was determined by VCD. Int. 1AF86 (2.5 g) and LiOH (1.1 g) were stirred for 1 hour at 0 °C to room temperature in THF / MeOH / water (2:1:1, 20 mL). The mixture was concentrated and ground in an aqueous citric acid solution to precipitate Int. 1AF85 4-[1-[(1S)-1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5-methylbenzoic acid (2.3 g). 4-[1-[(1S)-1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5-methylbenzoic acid (1.8 g), HATU (2.2 g), and HNMe2 (0.93 g, hydrochloride) were stirred overnight in DMF / DIPEA (6.1:1, 23.3 mL) at 0°C to room temperature. Dilute the mixture with water to precipitate Int. 1AF84 4-[1-[(1S)-1-(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro- N , N5-Trimethylbenzamide (1.5g). Int.1AF84' (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methyl- N , N -bis(methyl- d 3) Benzamide was prepared similarly using the hydrochloride salt of HN(CD3)2. Int. 1AF84 (1.1 g), KOAc (0.86 g), B2Pin2 (1.1 g), and PdDPPFCl2-DCM (0.18 g) were stirred in dioxane (10 mL) at 110 °C for 1 hour under MW conditions. The mixture was filtered, concentrated, and ground in pentane to give Int. 1AF83 [2-[(1S)-1-[4-[4-(dimethylcarbamoyl)-2-fluoro-6-methyl-phenyl]-3,6-dihydro-2H-pyridin-1-yl]ethyl]-1-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (1.3 g).

[0770]

[0771] 2-Fluoro-4-iodo-6-methylaniline (20 g) and PdDPPFCl2-DCM were stirred overnight at 80 °C in MeOH / Et3N (23:1, 522 mL) under a CO atmosphere (200 psi). The mixture was filtered. OL (EtOAc / 10% EDTA aqueous solution) was dried and concentrated to give Int. 1AF93 methyl 4-amino-3-fluoro-5-methylbenzoate (14 g). Int. 1AF93 (25 g), tert-butyl nitrite (21.1 g), and CuBr2 (152 g) were stirred overnight at 0 °C to 80 °C in ACN (500 mL). The mixture was cooled to 0 °C, diluted with saturated NaHCO3 aqueous solution, and filtered. OL (EtOAc / 10% NH3 aqueous solution) was concentrated and purified by FC (hexane / EtOAc 9:1) to give Int. 1AF92 methyl 4-bromo-3-fluoro-5-methylbenzoate (21 g). Int. 1AF92 (1.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.9 g), NaHCO3 (1.29 g), and PdDPPFCl2-DCM (0.33 g) were degassed in dioxane / water (5:1, 18 mL) and stirred overnight at 110 °C. The mixture was filtered. OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1AF91 tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)-6-methyl-phenyl)-3,6-dihydro-pyridine-1(2H)-carboxylate (0.65 g). Int. 1AF91 (10 g) was stirred in a 1.5 M HCl solution in dioxane (160 mL) at 0 °C to room temperature. The concentrated residue was ground in Et2O to give Int. 1AF90 methyl 3-fluoro-5-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)benzoate (13 g, hydrochloride).

[0772]

[0773] Int. 1AF88 / 1AE12 (4.5 g, 5.5 g, hydrochloride), Cs2CO3 (27 g), and KI (1.4 g) were stirred overnight in ACN (50 mL) at 0 °C to room temperature. The mixture was diluted with water, filtered, and concentrated. OL (EtOAc / water) was dried and concentrated. The residue was mixed with another batch prepared similarly at a scale of 1.5 g and purified by FC (pentane / EtOAc 3:7) to give Int. 1AF96 (4.8 g). Int. 1AF96 (5.0 g) was resolved by SFC (using a Lux Cellulose.2 250 × 30 mm 5 µm column (operated at 30 °C) with 70% CO2 and 30% IPA eluent (90 g / min) and a back pressure of 120 bar) to give Int. 1AF95 (1.5 g, peak 2). Int. 1AF95 (0.5 g), B2Pin2 (0.38 g), KOAc (0.29 g), and PdDPPFCl2-DCM (81 mg) were degassed in dioxane (5 mL) and stirred at 120 °C for 1 hour under MW conditions. The mixture was concentrated and ground in pentane / Et2O to give Int. 1AF94 3-fluoro-5-methyl-4-[1-[(1S)-1-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrrolo[2,3-b]pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]- N , N Bis(trideuteryl)benzamide (0.6g).

[0774]

[0775] Int. 1AB1 (0.29 g), CuI (0.12 g), and NaN3 (83 mg) were degassed in DMSO / DMEDA (14.4:1, 1.4 mL) and stirred at 100 °C. OL (saturated NH4Cl aqueous solution / EtOAc) was washed with water and brine, dried, concentrated, purified by HPLC, and ground in MTBE to obtain Int. 1C1 4-[1-[(4-amino-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidinyl]- N , N -Dimethyl-benzamide (0.22g).

[0776]

[0777] A 2.0 M LDA solution in THF (28.1 mL) was added at -78 °C to a solution of 10.0 g of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate in THF (200 mL). The mixture was stirred at -78 °C for 0.3 hours. 1,1,1-Trifluoro- N -phenyl- N -((trifluoro-methyl)sulfonyl)methanesulfonamide (20 g, in THF (10 mL)) and stirred for 3 hours at -78 °C to room temperature. OL (NH4Cl aqueous solution / EtOAc) was washed with water and brine, dried, and concentrated to give Int. 1D13 6-methyl-4-(trifluoromethyl-sulfonyloxy)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (18.0 g). Int. 1D13 (10 g), Na2CO3 (7.67 g), (4-(dimethyl-carbamoyl)phenyl)boronic acid (8.38 g), and PdDPPFCl2-DCM (1.20 g) were degassed in toluene / water (5:1, 120 mL) and refluxed overnight. OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1D12 4-[4-(dimethylcarbamoyl)phenyl]-6-methyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5.2 g). 5.0 g of this substance was hydrogenated overnight in EtOH (75 mL) with 10% Pd / C (2.50 g) and H2 (50 psi-60 psi), filtered, concentrated, and purified by FC (hexane / EtOAc 35:65) to give Int. 1D11 4-[4-(dimethylcarbamoyl)phenyl]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (4.0 g). 5.0 g of this substance was stirred overnight in DCM / TFA (3.6:1, 26 mL) at 0°C to room temperature, concentrated, and then ground in Et2O / pentane to obtain Int.1D10. N , N-Dimethyl-4-(2-methyl-4-piperidinyl)benzamide (4.0 g, TFA salt). Int. 1D10 (10.8 g) was resolved by SFC (using a Chiral Art Cellulose SC 250×30 5 µm column (operated at 30 °C) with 60% CO2 and 40% MeOH eluent (containing 0.5% HNEt2) (90 g / min) and a back pressure of 120 bar) to racemic cis and trans diastereomers, yielding the cis racemic compound (first two peaks; 3.0 g) and the trans racemic compound (last two peaks; 7.0 g). The trans racemic compound (7.0 g) was resolved by SFC (operated at 30 °C on a Sepiatac instrument equipped with a Chiralpak IK 250 X 305 μm column, with eluent of 70% CO2 and 30% MeOH (containing 0.5% NH3) (90 g / min) and a back pressure of 100 bar) to obtain Int. 1D1 N , N -Dimethyl-4-((2S,4R)-2-methylpiperidin-4-yl)benzamide (0.95 g, first peak) and Int. 1D2 N , N -Dimethyl-4-((2R,4S)-2-methylpiperidin-4-yl)benzamide (1.2 g, second peak). Absolute configuration was determined by VCD of Int. 1D1 and 1D2. The cis racemic compound (3.0 g) was resolved by SFC (using a Chiralpak IGK250×30 5 µm column (operated at 30 °C) with MeOH eluent containing 0.5% NH3 (30 mL / min) and a back pressure of 100 bar) to give Int. 1D3. N , N -Dimethyl-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide (0.70 g, first peak) and Int. 1D4 N , N -Dimethyl-4-((2S,4S)-2-methyl-piperidin-4-yl)benzamide (0.90 g, second peak). Absolute configuration was determined by VCD of Int. 1D3 and 1D4.

[0778]

[0779] Int. 1CA4 (20 mg), HNEt2 (24 μL), and HATU (27 mg) were stirred in DMF (1 mL) for 0.25 hours. OL (saturated NaHCO3 aqueous solution / EtOAc) was washed with brine, dried, and concentrated to obtain Int. 1D5 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N -Diethylbenzamide (30 mg). Int.1D6 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N The preparation of dipropylbenzamide (37 mg) is similar to that from HNPr2.

[0780]

[0781] 5.1 g of 1-(1,1-dimethylethyl) 4-(4-carboxyphenyl)-1-piperidinic acid, 13 g of HATU, and 2.5 g of HN(CD3)2 (hydrochloride) were stirred overnight in DMF / DIPEA (1.8:1, 47 mL). Water was added to precipitate the solid, which was then dissolved in DCM / MeOH (9:1), dried, concentrated, and purified by FC (hexane / EtOAc 2:3) to give 4-[4-[bis-(trideuterylmethyl)carbamoyl]phenyl]piperidin-1-carboxylic acid tert-butyl ester (4.8 g). 1.1 g of this substance was stirred overnight in DCM / TFA (3.6:1, 26 mL) at 0 °C to room temperature, concentrated, and ground in Et2O to give Int. 1D7 N , N -bis(methyl- d 3)-4-(1l2-piperidin-4-yl)-benzamide (0.81 g, TFA salt). Int. 1D7' N , N The preparation of dimethyl-4-(4-piperidinyl)benzamide (9 g, hydrochloride) is similar to that of 1-(1,1-dimethylethyl) ester of 4-(4-carboxyphenyl)-1-piperidin-carboxylic acid (17 g) and HN(CH3)2 (13.6 g, hydrochloride).

[0782]

[0783] Int. 1AC4 (4.0 g), EDC (4.7 g, hydrochloride), HOBt (2.5 g), and HN(CD3)2 (1.4 g, hydrochloride) were stirred overnight in DMF / DIPEA (8.2:1, 89 mL). The concentrated residue was purified by FC (EtOAc / hexane) to give Int. 1D8 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N -bis(methyl- d 3) Benzamide (2.7g).

[0784]

[0785] Int. 1AB1 (1 g) and mCPBA (0.59 g) were stirred in DCM (10 mL) at 0 °C for 2 hours. The solution was dried over OL (saturated NaHCO3 aqueous solution / DCM) and concentrated. The residue was stirred in TFA for 1 hour, concentrated, and purified by FC (DCM / MeOH 1:0 to 4:1) to give Int. 1D9 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-1-oxo-piperidin-1-onthium-4-yl]- N , N -Dimethyl-benzamide (0.77g).

[0786]

[0787] The preparation of Int. 1D21, tert-butyl 4-(4-(methoxycarbonyl)phenyl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate (5.20 g), was similar to the preparation of Int. 1D12 from Int. 1D13 (10.0 g) and (4-(methoxycarbonyl)phenyl)boronic acid (7.82 g). The preparation of Int. 1D20, tert-butyl 4-(4-(methoxycarbonyl)phenyl)-2-methylpiperidine-1-carboxylate (3.0 g), was similar to the preparation of Int. 1D11 from Int. 1D21 (3.5 g). Int. 1D20 (3.0 g) and LiOH-H2O (1.50 g) were stirred for 4 hours at 0°C to room temperature in THF / MeOH / water (1.3:1:1, 50 mL) and concentrated. OL (citric acid aqueous solution / EtOAc) was dried and concentrated to give 1.50 g of 4-(1-tert-butoxycarbonyl-2-methyl-4-piperidinyl)benzoic acid. 6.0 g of this substance, 2.47 g of HN(CD3)2 (hydrochloride), 1.90 g of HOBt, and 2.70 g of EDC-HCl were stirred overnight in DMF / DIPEA (1.9:1, 46 mL) at 0 °C to room temperature. OL (water / EtOAc) was dried and concentrated to give Int. 1D19 4-(4-(bis(methyl- d 3) Carbamoyl)-phenyl)-2-methylpiperidin-1-carboxylic acid tert-butyl ester (4.50 g). 3.5 g of this substance was stirred for 4 hours at 0°C to room temperature in DCM / TFA (2.5:1, 70 mL), concentrated, and ground in Et2O / pentane to obtain Int. 1D18 4-(2-methyl-4-piperidinyl)- N , N - Bis(trideuterylmethyl)benzamide (3.50 g, TFA salt). Int. 1D18 was resolved into Int. 1D14. N , N -bis(methyl- d 3)-4-((2S,4R)-2-methylpiperidin-4-yl)benzamide, Int. 1D15 N , N -bis-(methyl- d 3)-4-((2R,4S)-2-methylpiperidin-4-yl)benzamide, Int. 1D16 N , N -bis(methyl- d 3)-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide and Int. 1D17 N , N -bis(methyl- d3)-4-((2S,4S)-2-methyl-piperidin-4-yl)benzamide, as described with respect to Int. 1D1-1D4. The absolute configuration of these compounds is undetermined. The absolute configuration of these compounds was determined by comparison with Int. 1D1-1D4 using chiral chromatography at room temperature.

[0788]

[0789] Methyl 4-bromobenzoate (25 g), PdDPPFCl2-DCM (4.7 g), NaHCO3 (49 g), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (39 g) were degassed in 1,4-dioxane / water (5:1, 0.6 L) and stirred overnight at 110 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 99:1) to give Int. 1F9 4-(4-(methoxycarbonyl)-phenyl)-3,6-dihydro-pyridine-1(2H)-carboxylate (18 g). Int. 1F9 (38 g) and SelectFluor (7.2 g) were stirred in ACN / water (3:1, 0.64 L) for 1 hour. SelectFluor (2.1 g) was added and stirring was continued for 1 hour. The solution was dried over OL (EtOAc / saturated NaHCO3 aqueous solution), concentrated, and purified by FC (hexane / EtOAc 85:15) to give Int. 1F8 tert-butyl 3-fluoro-4-(4-methoxy-carbonylphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (6.0 g). Int. 1F8 (4.8 g) was hydrogenated overnight in 10% Pd / C (0.48 g) in EtOAc (200 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1F7 tert-butyl 3-fluoro-4-(4-methoxycarbonylphenyl)piperidine-1-carboxylate (3.2 g). Int. 1F7 (3.5 g) and LiOH-H2O (1.4 g) were stirred overnight at 0°C to room temperature in MeOH / THF / H2O (3:2:1; 25 mL) and concentrated. The solution was dried over OL (10% MeOH in DCM solution / citric acid aqueous solution) and concentrated to give cis-4-(1-(tert-butoxycarbonyl)-3-fluoro-piperidine-4-yl)benzoic acid (2.1 g). 2.5 g of the compound, 4.4 g of HATU, and 1.9 g of HN(CH3)2 (hydrochloride) were stirred overnight in DMF / DIPEA (2.4:1, 35 mL) at 0 °C to room temperature. The solution was dried over OL (water / 5% MeOH in DCM solution), concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1F6 cis-4-[4-(dimethylcarbamoyl)-phenyl]-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (2.4 g). Int. 1F6 (1.5 g) was stirred overnight in DCM / TFA (3.8:1, 13 mL) at 0 °C to room temperature and concentrated. The solution was dried over OL (NaHCO3 aqueous solution / Et2O and 10% MeOH in DCM solution) and concentrated to give Int. 1F5. N ,N -Dimethyl-4-[cis-3-fluoro-4-piperidinyl]-benzamide (1.19 g). This substance was resolved by SFC (using a LuxCellulose-4 250×30 5 µm column (operated at 30 °C) with 70% CO2 and 30% 0.5% isopropylamine (in IPA) as eluent (100 g / min) and a back pressure of 100 bar) to give Int. 1F1 (0.47 g) and Int. 1F2 (0.50 g) 4-((3S,4R)-3-fluoropiperidin-4-yl)- N , N -Dimethylbenzamide and 4-((3R,4S)-3-fluoropiperidin-4-yl)- N , N -Dimethyl-benzamide. The absolute configuration of these compounds is undetermined.

[0790]

[0791] Int. 1F9 (10 g) was stirred overnight in a THF solution of THF / 2M BH3-DMS (11.6:1, 217 mL) at 0°C to room temperature. 2M NaOH aqueous solution (38 mL) and 30% H2O2 aqueous solution (5.9 mL) were added, and stirring was continued for 1 hour at 0°C to room temperature. OL (saturated NaS2O3 aqueous solution / EtOAc) was washed with water and brine, dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1F14 tert-butyl 3-hydroxy-4-(4-(methoxy-carbonyl)phenyl)piperidine-1-carboxylic acid (7.4 g). Int. 1F14 (8.0 g) and DMP (5.1 g) were stirred overnight in DCM (200 mL) at 0°C to room temperature. OL (water / DCM) was dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1F13 tert-butyl 4-(4-methoxy-carbonyl-phenyl)-3-oxo-piperidine-1-carboxylate (5.2 g). Int. 1F13 (5.0 g) was stirred overnight in a DCM / 50% Deoxo-Fluor THF solution (12.2:1, 108 mL) at -78°C to room temperature. OL (NaHCO3 aqueous solution / DCM) was washed with saturated citric acid aqueous solution, dried, concentrated, and purified by FC (hexane) to give Int. 1F12 tert-butyl 3,3-difluoro-4-(4-methoxycarbonyl-phenyl)piperidine-1-carboxylate (2.5 g). The substance and LiOH-H2O (1.5 g) were stirred in MeOH / THF / H2O (3:3:1; 60 mL) at 0 °C to room temperature for 4 hours, concentrated, and ground in dilute citric acid aqueous solution to obtain Int.1F12a 4-(1-tert-butoxycarbonyl-3,3-difluoro-4-piperidinyl)benzoic acid (2.3 g). Int. 1F12a (4.8 g), HATU (6.4 g), and HN(CH3)2 (2.3 g, hydrochloride) were stirred overnight in DMF / DIPEA (13.2:1, 108 mL) at 0 °C to room temperature. OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1F11 4-(4-(dimethylcarbamoyl)-phenyl)-3,3-difluoro-piperidin-1-carboxylic acid tert-butyl ester (4.5 g). Int. 1F11 (4.2 g) was concentrated overnight in DCM / TFA (27:1, 83 mL) at 0°C to room temperature. OL (5% MeOH in DCM solution / saturated NaHCO3 aqueous solution) was dried and concentrated to give Int. 1F10 4-(3,3-difluoro-4-piperidinyl)- N , N-Dimethyl-benzamide (3 g). This substance was resolved by SFC (using a Chiralpak IG 250×30 5 µm column (operated at 30 °C) with 60% CO2 and 40% MeOH as eluent (80 g / min) and a back pressure of 60 bar) to give Int. 1F3 (1.1 g) and Int. 1F4 (1.0 g). N , N -Dimethylbenzamide and (S)-4-(3,3-difluoropiperidin-4-yl)- N , N -Dimethylbenzamide. The absolute configuration of these compounds is undetermined.

[0792]

[0793] Int. 1J1 / 1F3 (45 mg / 60 mg), Cs2CO3 (169 mg), and NaI (26 mg) were stirred in DMF (1 mL) for 0.5 hours and purified by HPLC to obtain Int. 1F15 (48 mg). The preparation of Int. 1F16 was similar to that from Int. 1F4. Int. 1F15 and 1F16 (R)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3,3-difluoropiperidin-4-yl)- N , N -Dimethylbenzamide and (S)-4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3,3-difluoropiperidin-4-yl)- N , N -Dimethylbenzamide. The absolute configuration of these compounds is undetermined.

[0794]

[0795] 0.51 g of 4-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine and 0.12 g of NaH were stirred in 5 mL of DMF at 0 °C for 1 hour. Then, 0.3 mL of MeI was added and stirring was continued for 0.3 hours. OL (water / EtOAc / Et2O) was washed with brine, dried, and concentrated to obtain Int. 1H3 4-bromo-1,3-dimethyl-pyrrolo[2,3-b]pyridine (0.53 g). This substance was stirred in a THF solution of THF / 1.0 M LDA (2.9:1, 13.5 mL) at -78 °C for 2 hours. Then, 1 mL of DMF was added, and stirring was continued for 2 hours from -78 °C to room temperature. OL (saturated NH4Cl aqueous solution / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 1:0 to 1:1) to give Int. 1H2 4-bromo-1,3-dimethyl-pyrrolo[2,3-b]pyridine-2-carboxaldehyde (0.17 g). Int. 1H2 (30 mg) and N , N Dimethyl-4-(piperidin-4-yl)benzamide (42 mg) was stirred in DCE (2 mL) for 0.5 h. STAB (57 mg) was added and stirring continued overnight. OL (saturated NaHCO3 aqueous solution / DCM) was washed with brine, dried, concentrated, and purified by FC (DCM / MeOH 1:0 to 9:1) to give Int. 1H1 4-[1-[(4-bromo-1,3-dimethyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidinyl]- N , N -Dimethyl-benzamide (30mg).

[0796]

[0797] Int. 1I1 4-(1-((4-bromo-1,5-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- N , N Preparation of dimethylbenzamide (0.16 g) from 4-bromo-5-methyl-1H-pyrrolo[2,3-b]pyridine (0.51 g) and N , N The preparation of 0.18 g of dimethyl-4-(piperidin-4-yl)benzamide is similar to that of Int. 1H1.

[0798]

[0799] Int. 1AB8 (30 g) and NaBH4 (19 g) were stirred in MeOH (300 mL) for 2 hours at 0 °C to room temperature. The OL layer (Na2S2O3 aqueous solution / EtOAc) was dried, concentrated, and purified by FC (pentane / EtOAc 1:1 to 2:3) to give Int. 1J3 (4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methanol. Int. 1J3 (2.5 g) was stirred overnight in DCM / Et3N / MsCl (21.4:5.2:1, 39 mL) at 0 °C to room temperature and filtered. The OL layer (EtOAc / water) was washed with brine, dried, and concentrated to give Int. 1J1 4-bromo-2-(chloromethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (2.0 g).

[0800]

[0801] 0.40 g of 4-bromo-1-(trideuterylmethyl)pyrrolo[2,3-b]pyridine was stirred for 2 hours at -78 °C in a THF solution of THF / 2M LDA (7.1:1, 11.4 mL). 0.7 mL of DMF was added and the mixture was stirred for another 2 hours at -78 °C to room temperature and then diluted with water to precipitate Int. 1K3 4-bromo-1-(trideuterylmethyl)pyrrolo[2,3-b]pyridine-2-carboxaldehyde (0.35 g). 0.17 g of Int. 1K3 and methyl 4-(piperidin-4-yl)benzoate (0.16 g) were stirred for 3 hours in a DCE / DIPEA solution (28.3:1, 15.5 mL). 0.26 g of STAB was added and the mixture was stirred overnight. OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 4:1) to give methyl 4-[1-[[4-bromo-1-(trideutermethyl)pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidinyl]benzoate (0.14 g). Int. 1K2 (50 mg) was stirred in a THF / MeOH / 2M NaOH aqueous solution (7.1:3.6:1, 3.3 mL) for 0.25 h. The pH was adjusted to 5 with 1M HCl aqueous solution. The mixture was concentrated. The residue and HATU (85 mg) were dissolved in DMF / DIPEA (25.6:1, 2.1 mL), and then HN(CH3)2 (14 mg; hydrochloride) was added and stirring continued for 72 h. OL (water / DCM) was dried, concentrated, and purified by FC (DCM / MeOH 1: to 9:1) to give Int. 1K1 4-[1-[[4-bromo-1-(trideutermethyl)pyrrolo[2,3-b]pyridin-2-yl]-methyl]-4-piperidinyl]- N , N-Dimethyl-benzamide (39mg).

[0802]

[0803] 4-Bromo-3-methoxybenzoic acid (3.0 g), HN(CH3)2 (1.6 g, hydrochloride), and HATU (5.92 g) were stirred overnight in DCM / DIPEA (7.4:1, 57 mL), concentrated, and purified by HPLC to obtain 4-bromo-3-methoxybenzoic acid. N , N 1.0 g of this substance, 1.44 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, 2.14 g of K2CO3, and 0.16 g of PdDPPFCl2-DCM were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give 1.10 g of 4-(4-(dimethylcarbamoyl)-2-methoxy-phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. 0.6 g of the substance was hydrogenated overnight in 10% Pd / C (0.2 g) in MeOH (10 mL), filtered, concentrated, stirred overnight in a 4 M HCl solution of dioxane (10 mL), concentrated, and purified by HPLC to obtain Int.1M24 3-methoxy- N , N 0.23 g of dimethyl-4-(piperidin-4-yl)benzamide was prepared by stirring 0.50 g of 4-(4-(dimethylcarbamoyl)-2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.50 g) overnight in 10 mL of 4 M HCl dioxane solution, concentrating, and purifying by HPLC to obtain Int. 1M23 3-methoxy- N , N -Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.17 g).

[0804]

[0805] NaNO2 (6.1 g) and 4-amino-3-fluoro-5-methylbenzoic acid (15.0 g) were stirred in 48% HBr aqueous solution (150 mL) at 0 °C for 0.3 h. CuBr (13.0 g) was added and stirring continued for 4 h. OL (NaHCO3 aqueous solution / MTBE) was washed with water and concentrated to give 4-bromo-3-fluoro-5-methylbenzoic acid (8.50 g). 4-bromo-3-fluoro-5-methylbenzoic acid (15.0 g) was stirred in DCM / SOCl2 (83:1, 150 mL) for 5 h and concentrated. The residue and HNMe2 (3.1 g, hydrochloride) were stirred in DCM / Et3N (13.6:1, 160 mL) for 5 h, and OL (water / DCM) was concentrated. The residue, K₂CO₃ (7.3 g), PdPDPPFCl₂-DCM (0.15 g), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-pyridine-1(2H)-carboxylate (6.0 g) were degassed with dioxane (150 mL) and stirred at 90 °C for 48 hours. The solution was concentrated in OL (water / dioxane), stirred for 0.5 hours in a dioxane solution of THF / 4M HCl (1:1, 100 mL), concentrated, and purified by HPLC to obtain Int. 1M₂₅ 3-fluoro- N , N 5-Trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g).

[0806]

[0807] Int. 1M26 3-Chloro- N , N The preparation of 5-trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.11 g) is similar to the preparation of Int. 1M25 from 4-bromo-3-chloro-5-methylbenzoic acid (15 g).

[0808]

[0809] 4-bromo-3-fluoro N , NDimethylbenzamide (1.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.41 g), Na2CO3 (1.61 g), and PdDPPFCl2-DCM (0.16 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give 4-[4-(dimethylcarbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.20 g). 0.6 g of this substance was stirred overnight in a 4M HCl solution in dioxane (10 mL). The mixture was concentrated and purified by HPLC to obtain Int. 1M29 3-fluoro- N , N -Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g).

[0810]

[0811] 4-bromo-3-chloro- N , N Dimethylbenzamide (5.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.71 g), Na2CO3 (8.1 g), and PdDPPFCl2-DCM (0.78 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane to EtOAc) to give 4-[2-chloro-4-(dimethylcarbamoyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.10 g). The substance was hydrogenated overnight in 10% Pt / C (1.1 g) of MeOH (10 mL), filtered, and concentrated to give 0.60 g of tert-butyl 4-[2-chloro-4-(dimethylcarbamoyl)phenyl]-piperidin-1-carboxylate. This substance was then stirred overnight in a dioxane solution (10 mL) of 4 M HCl, concentrated, and purified by HPLC to give Int. 1M443-chloro- N , N 3-Dimethyl-4-(piperidin-4-yl)benzamide (0.15 g). 4-[2-chloro-4-(dimethyl-carbamoyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.60 g) was stirred overnight in 10 mL of 4 M HCl dioxane solution, concentrated, and purified by HPLC to give Int. 1M43 3-chloro-N , N -Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g).

[0812]

[0813] 4-Bromo-3-(trifluoromethyl)benzoic acid (3.0 g), HN(CH3)2 (1.36 g, hydrochloride), and HATU (5.1 g) were stirred overnight in DCM / DIPEA (8.6:1, 56 mL), concentrated, and purified by HPLC to obtain 4-bromo- N , N -Dimethyl-3-(trifluoro-methyl)benzamide (2.40 g). 1.0 g of this substance, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydro-pyridine-1(2H)-carboxylic acid tert-butyl ester (1.25 g), K2CO3 (1.87 g), and PdDPPFCl2-DCM (0.14 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give 4-[4-(dimethyl-carbamoyl)-2-(trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.04 g). 0.50 g of the substance was stirred overnight in 10 mL of 4 M HCl dioxane solution, filtered, and purified by HPLC to obtain Int. 1M45. N , N -Dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoro-methyl)benzamide (0.14 g). 4-[4-(dimethyl-carbamoyl)-2-(trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.50 g) was hydrogenated overnight in 10% Pd / C (0.5 g) in MeOH (10 mL). The mixture was filtered. The concentrated residue was stirred overnight in a dioxane solution (10 mL) of 4 M HCl, concentrated, and purified by HPLC to give Int. 1M46. N , N -Dimethyl-4-(piperidin-4-yl)-3-(trifluoromethyl)benzamide (0.23g).

[0814]

[0815] 6-Chloro-5-fluoro-pyridin-3-carboxylic acid (3.0 g), HN(CH3)2 (1.53 g, hydrochloride), and HATU (7.15 g) were stirred overnight in DCM / DIPEA (5.6:1, 59 mL), concentrated, and purified by FC (hexane to EtOAc) to obtain 6-chloro-5-fluoro- N , N -Dimethyl-pyridine-3-carboxamide (3.1 g). This substance, along with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.20 g), K 3 CO3 (8.50 g) and PdDPPFCl2-DCM (0.62 g) were degassed in dioxane / water (4:1, 50 mL) and stirred overnight at 100 °C. OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-[5-(dimethylcarbamoyl)-3-fluoro-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (3.10 g). 0.13 g of this substance was stirred for 1.5 h and concentrated in a dioxane solution of DCM / 4M HCl (3.6:1, 6.4 mL). OL (DCM / NaHCO3 aqueous solution) was dried, concentrated, and purified by HPLC to give Int. 1M47 5-fluoro- N , N -Dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridine-3-carboxamide (20 mg).

[0816]

[0817] (S)-2-methylpiperazin-1-carboxylic acid tert-butyl ester (1.0 g), ethyl 4-bromo-3-methylbenzoate (1.46 g), Cs₂CO₃ (4.88 g), Pd₂dba₃ (0.23 g), and XPos (0.24 g) were degassed in dioxane (20 mL) and stirred overnight at 110 °C. The solution was concentrated in OL (EtOAc / water) and purified by FC (hexane to EtOAc) to give (2R)-4-(4-ethoxy-carbonyl-2-methyl-phenyl)-2-methyl-piperazin-1-carboxylic acid tert-butyl ester (0.85 g). 0.70 g of this substance and 0.22 g of LiOH-H2O were stirred in THF / water / MeOH (10 mL) for 6 hours, concentrated, and ground in dilute citric acid aqueous solution to obtain 0.45 g of 4-[(3R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-3-methyl-benzoic acid. 0.70 g of 4-[(3R)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-3-methyl-benzoic acid, 0.26 g of HNMe2 (hydrochloride), 0.42 g of HOBt, and 0.60 g of EDC (hydrochloride) were stirred overnight in DCM / DIPEA (10:1, 11 mL) at 0 °C to room temperature. OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 3:2) to give (2R)-4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.45 g). This substance was stirred in DCM / TFA (6:1, 7 mL) at 0°C to room temperature for 6 hours, concentrated, and ground in Et2O to give Int. 1M49 (R)- N , N 3-Trimethyl-4-(3-methylpiperazin-1-yl)-benzamide (0.20 g). Int. 1M59 (S)- N , N The preparation of 3-trimethyl-4-(3-methylpiperazin-1-yl)-benzamide is similar to that of (R)-2-methylpiperazin-1-carboxylic acid tert-butyl ester.

[0818]

[0819] (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.5 g), NaOtBu (2.4 g), Pd2dba3 (0.57 g), Xphos (0.59 g) and 4-bromo- N , NDimethylbenzamide (3.1 g) was degassed in dioxane (30 mL) and stirred overnight at 100 °C. OL (Et₂O / water) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1M50 (S)-4-(4-(dimethylcarbamoyl)phenyl)-2-methyl-piperazin-1-carboxylate tert-butyl ester and tert-butyl (2.4 g). The preparation of Int. 1M52 (R)-4-(4-(dimethylcarbamoyl)phenyl)-2-methyl-piperazin-1-carboxylate (0.46 g) was similar to that from (R)-2-methylpiperazin-1-carboxylate tert-butyl ester (0.50 g).

[0820]

[0821] Int. 1M50 (46 mg) was concentrated in DCM / TFA (1:1, 1 mL) by stirring for 1 hour. The residue and 4 Å MS were stirred overnight in DCM / DIPEA (19.5:1, 1.6 mL). Int. 1J1 (23 mg) was added and stirring was continued overnight. The solution was dried over OL (DCM / saturated NaHCO3 aqueous solution), concentrated, and purified by FC (DCM / MeOH 1:0 to 95:5) to give Int. 1M51(S)-4-(4-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-methylpiperazin-1-yl)- N , N - Dimethylbenzamide (40 mg).

[0822]

[0823] Int. 1M52 (46 mg) was concentrated in DCM / TFA (1:1, 1 mL) by stirring for 1 hour. The residue, Int. 1AB8 (21 mg), and 4 Å MS were stirred in DCM / DIPEA (19.5:1, 1.6 mL) for 2 hours. STAB (56 mg) was added and stirring continued overnight. The solution was dried over OL (water / DCM), concentrated, and purified by FC (DCM / MeOH 1:0 to 95:5) to give Int. 1M53(R)-4-(4-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-methylpiperazin-1-yl)- N , N - Dimethylbenzamide (30 mg).

[0824]

[0825] Boc-piperazine (0.40 g) and 6-bromo- N ,N - Dimethylnicotinamide (0.59 g), NaOtBu (0.41 g), Xphos (0.10 g), and Pd2dba3 (0.1 g) were degassed in dioxane (4 mL) and stirred overnight at 110 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 1:1) to give 0.30 g of tert-butyl 4-(5-(dimethylcarbamoyl)pyridin-2-yl)-piperazin-1-carboxylate. 0.26 g of this substance was stirred for 1 hour in a 3M HCl solution (3 mL) at 0 °C to room temperature and concentrated to give Int. 1M55. N , N 1,2-Dimethyl-6-(piperazin-1-yl)nicotinamide (0.14 g, hydrochloride).

[0826]

[0827] 4-(4-tert-butoxycarbonylpiperazin-1-yl)benzoic acid (1.0 g), HN(CD3)2 (0.43 g, hydrochloride), HOBt (0.66 g), and EDC (0.94 g, hydrochloride) were stirred overnight in DCM / DIPEA (15.4:1, 21 mL). OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 1:1) to give 4-(5-(bis(methyl- d 3) Carbamoyl)-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.95 g). This substance was stirred, concentrated, and ground in Et2O to obtain Int. 1M56. N , N -bis(methyl- d 3) 6-(piperazin-1-yl)nicotinamide (0.85 g). Int. 1AE20 (14 g) was hydrogenated overnight in 10% Pd / C (3.5 g) in MeOH (200 mL), filtered, and concentrated to give tert-butyl 4-[5-(dimethylcarbamoyl)-2-pyridyl]piperidine-1-carboxylate (11 g). 0.9 g of this substance was stirred in DCM / TFA (10:1, 11 mL) at 0 °C to room temperature, concentrated, and ground in Et2O to give Int. 1M57. N , N 1,2-Dimethyl-6-(piperidin-4-yl)nicotinamide (0.50 g, TFA salt).

[0828] and

[0829] Int. 1M1 / 1S7 (15 mg / 22 mg, hydrochloride) was stirred in DCE (0.5 mL) for 0.5 h. STAB (25 mg) was added and stirring was continued overnight. The mixture was filtered. The filtrate was stirred in TFA (0.5 mL) for 0.5 h, concentrated, and purified by HPLC to obtain Example 1m6. N , N 3-Trimethyl-4-(4-((1-methyl-4-(4-(methylamino)-2-oxopyridin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperazin-1-yl)benzamide (6.6 mM DMSO solution (0.70 mL)). Example 1 m56 3-Fluoro- N , N The preparation of 5-trimethyl-4-(1-((1-methyl-4-(4-(methylamino)-2-oxopyridin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (10 mM DMSO solution (1.2 mL)) was similar to that of Example 1m6 prepared from Int. 1M25 (17 mg). Example 1m56 (2.4 g) and LiOH-H2O (1.1 g) were stirred in THF / water (2.5:1, 28 mL) at 0 °C to 60 °C for 3 hours. The concentrated residue was ground in an aqueous HCl solution to obtain Int. 1M60 3-fluoro-5-methyl-4-(1-((1-methyl-4-(4-(methylamino)-2-oxopyridin-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (2.4 g).

[0830]

[0831] Int. 1AB8 (0.25 g) and piperazine-1-carboxylic acid 9H-fluorene-9-yl methyl ester (0.48 g) were stirred in DCE / AcOH (100:1, 10 mL) for 2 hours. STAB (0.44 g) was added and stirring was continued for 2 hours at 0 °C to room temperature. OL (saturated NaHCO3 aqueous solution / DCM) was washed with brine, dried, and concentrated to give Int. 1N2 4-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]piperazine-1-carboxylic acid 9H-fluorene-9-yl methyl ester (0.20 g).

[0832]

[0833] Mix Int. 1AB8 (0.35g) and N , NDimethyl-4-(piperazin-1-yl)benzamide (0.40 g, hydrochloride) was stirred in DCE / DIPEA (6.5:1, 11.6 mL) for 4 hours. STAB (0.94 g) was added and stirring continued overnight. OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1N4 4-(4-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperazin-1-yl)- N , N -Dimethyl-benzamide (0.44g).

[0834]

[0835] Int. 1N4 (25 mg), KOAc (11 mg), PdDPPFCl2-DCM (4 mg), and B2Pin2 (15 mg) were degassed in dioxane (3 mL) and stirred at 70 °C for 4 hours. KOAc (11 mg), B2Pin2 (15 mg), and PdDPPFCl2-DCM (4 mg) were added, and stirring continued at 70 °C for another 4 hours, followed by stirring overnight at room temperature. KOAc (11 mg), B2Pin2 (15 mg), and PdDPPFCl2-DCM (4 mg) were added, and stirring continued at 90 °C for another 6 hours. The mixture was filtered and purified by HPLC to obtain Int. 1N5. N , N -Dimethyl-4-[4-[[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrrolo[2,3-b]pyridin-2-yl]methyl]piperazin-1-yl]benzamide and (2-((4-(4-(dimethyl-carbamoyl)-phenyl)piperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid.

[0836]

[0837] Int. 1J3 (1.0 g), B2Pin2 (1.58 g), Pd(PPh3)2Cl2 (0.29 g), and KOAc (1.02 g) were degassed with dioxane (10 mL) and stirred at 100 °C for 3 hours and concentrated. The residue was decanted with pentane and concentrated to give Int. 1O3[2-(hydroxymethyl)-1-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (0.8 g).

[0838]

[0839] 2-(4-bromophenyl)-4,4-dimethyl-4,5-dihydrooxazole (10 g), Mg scrap (1.1 g), and I2 (50 mg) were refluxed in THF (50 mL) for 1 hour. 1-Benzylpiperidin-4-one (8.0 mL) was added, and the mixture was refluxed for 3 hours. OL (saturated NH4Cl aqueous solution / MTBE) was washed with water and brine, dried, and concentrated to give Int. 1R6 1-benzyl-4-(4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl)piperidin-4-ol. Int. 1R6 (7.0 g) was stirred overnight at 90 °C in EtOH / 96% H2SO4 (10:1, 400 mL) and concentrated. OL (saturated NaHCO3 aqueous solution / DCM) was dried, concentrated, and purified by FC (DCM / 2M NH3 in MeOH solution 1:0 to 4:1) to obtain Int. 1R5 ethyl 4-(1-benzyl-4-hydroxypiperidin-4-yl)benzoate. Int. 1R5 (0.06 g) was dissolved in DCM (10 mL) at -78 °C. DAST (0.28 mL) was added, and the mixture was stirred for 2 hours at -78 °C to room temperature. OL (DCM / water) was washed with brine, dried, concentrated, and purified by HPLC to obtain Int. 1R4 ethyl 4-(1-benzyl-4-fluoro-piperidin-4-yl)benzoate. Int. 1R4 (2.0 g) was stirred for 3 hours at 0 °C to room temperature in DCM (40 mL) and 1-chloroethyl chloroformate (0.76 mL) and concentrated. The residue was refluxed in MeOH (20 mL) for 0.5 h and concentrated. The residue and Boc2O (1.56 g) were stirred overnight in DCM / Et3N (14.7:1, 27 mL). OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 1:0 to 1:1) to give 4-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)benzoic acid. 0.77 g of this substance, HATU (1.18 g), and HN(CH3)2 (0.29 g, hydrochloride) were stirred in DMF / DIPEA (5:1, 10 mL) for 1 h. OL (EtOAc / water) was dried, concentrated, and purified by FC (heptane to EtOAc / MeOH 95:5) to give Int. 1R2 4-(4-(dimethylcarbamoyl)-phenyl)-4-fluoropiperidin-1-carboxylic acid tert-butyl ester. Int. 1R2 (0.55 g) was stirred for 1 hour in a dioxane solution (MeOH / 4M HCl, 1:1, 20 mL), concentrated, and purified by SCX and HPLC to give Int. 1R1 4-(4-fluoropiperidin-4-yl)- N , N - Dimethylbenzamide (62 mg).

[0840]

[0841] Int. 1AE14 (10.0 g) was stirred overnight in a THF solution of THF / 2.0 M BH3-Me2S (11:6:1, 218 mL) at 0 °C to room temperature. 2.0 M NaOH aqueous solution (38 mL) and 30% H2O2 aqueous solution (5.9 mL) were added, and stirring continued for 1 hour. OL (saturated Na2S2O3 aqueous solution / EtOAc) was washed with water and brine, dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give tert-butyl 3-hydroxy-4-(4-(methoxycarbonyl)-phenyl)piperidine-1-carboxylate (7.4 g). 7.0 g of this substance was dissolved in DCM (140 mL) at -78 °C. A 50% Deoxo-Fluor THF solution (4.5 mL) was added, and stirring continued for 6 hours at -78 °C to room temperature. OL (saturated NaHCO3 aqueous solution / DCM) was washed with saturated citric acid aqueous solution, dried, concentrated, and purified by FC (hexane / EtOAc 85:15) to give Int. 1R11 tert-butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)-piperidin-1-carboxylic acid (4.8 g). Int. 1R11 (10.0 g) and LiOH-H2O (6.1 g) were stirred overnight in MeOH / THF / water (2:4:1, 230 mL) at 0 °C to room temperature and concentrated. OL (citric acid aqueous solution / 10% MeOH in DCM solution) was dried and concentrated to give 4-(1-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)benzoic acid (8.0 g). 22 g of the substance, 39 g of HATU, and 16.5 g of HN(CH3)2 (hydrochloride) were stirred overnight in DMF / DIPEA (6:7:1, 0.46 L) at 0 °C to room temperature. The OL (water / MeOH / DCM (5:95)) was dried, concentrated, and purified by FC (hexane / EtOAc 2:3) to give 20 g of tert-butyl 4-(4-(dimethylcarbamoyl)phenyl)-3-fluoropiperidin-1-carboxylate. This substance was stirred overnight in DCM / TFA (37:1, 513 mL) at 0 °C to room temperature and concentrated. The aqueous layer (water / Et2O) was alkalized with a saturated NaHCO3 aqueous solution and extracted with MeOH / DCM (5:95). The OL was dried and concentrated to give 4-(3-fluoropiperidin-4-yl)- N , N-Dimethylbenzamide (14.5 g). This substance was resolved by SFC (using a Chiralpak IG 250×25 5 µm column (operated at 30 °C), eluent of 70% CO2 and 30% MeOH (containing 0.5% HNEt2) (100 g / min) and a back pressure of 100 bar) to give Int. 1R8 (5.3 g, first peak) and Int. 1R9 (5.1 g, second peak) 4-((3R,4R)-3-fluoropiperidin-4-yl)- N , N -Dimethylbenzamide and 4-((3S,4S)-3-fluoropiperidin-4-yl)-N,N-dimethylbenzamide. The absolute configurations of these compounds are undetermined.

[0842]

[0843] Int. 1F1 (0.10 g), DIPEA (0.21 mL), KI (20 mg), and Int. 1J1 were stirred overnight in DMF (5 mL). OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane / EtOAc 3:7) to obtain Int. 1R12. N , N -Dimethyl-4-[(3R,4S)-1-[(4-bromo-1-methyl-pyrrolo[2,3-b]-pyridin-2-yl)methyl]-3-fluoro-4-piperidinyl]benzamide (0.12 g). Int. 1R13 N , N The preparation of 3-dimethyl-4-[(3S,4R)-1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-fluoro-4-piperidinyl]benzamide (0.12 g) is similar to that from Int. 1F2 / 1J1 (0.10 g / 0.16 g).

[0844]

[0845] KOtBu (74mg), K2CO3 (0.17g), N , N-Dimethyl-2-oxo-1H-pyridin-4-carboxamide (0.10 g) and 4-(p-tolylsulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (0.24 g) were stirred overnight in DME (5 mL) at 110 °C. The mixture was dried over OL (EtOAc / water), concentrated, and purified by FC (hexane to EtOAc) to give 4-[4-(dimethylcarbamoyl)-2-oxo-1-pyridyl]piperidine-1-carboxylic acid tert-butyl ester (70 mg). -4-[4-(dimethylcarbamoyl)-2-oxo-1-pyridyl]piperidine-1-carboxylic acid tert-butyl ester (0.20 g) was stirred and concentrated in DCM / TFA (10:1, 5.5 mL) to give Int. 1S2 N , N - Dimethyl-2-oxo-1-(4-piperidinyl)pyridine-4-carboxamide and Int. 1S2' N,N-Dimethyl-2-(4-piperidinyloxy)pyridine-4-carboxamide (0.15 g, TFA salt).

[0846]

[0847] 4-bromo- N , N 3,5-Tetramethylbenzamide (5.5 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)carboxylic acid tert-butyl ester (7.3 g), PdDPPFCl2-DCM (0.88 g), and NaHCO3 (5.4 g) were degassed in dioxane / water (3:1, 47 mL) and stirred overnight at 100 °C. The solution was dried over OL (EtOAc / water), concentrated, and purified by FC (pentane / EtOAc 1:1) to give 4-[4-(dimethylcarbamoyl)-2,6-dimethyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.5 g). 0.3 g of the substance was stirred overnight in a 2.9 M HCl solution (7 mL) in dioxane at 0 °C to room temperature, concentrated, and ground in Et₂O. The solid was treated with a saturated aqueous solution of NaHCO₃ and concentrated. The residue was dissolved in DCM, dried, and concentrated to give Int. 1S₃. N , N 3,5-Tetramethyl-4-(1,2,3,6-tetrahydro-pyridin-4-yl)benzamide (0.15 g). 4-[4-(dimethylcarbamoyl)-2,6-dimethyl-phenyl]-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (50 mg) was hydrogenated for 48 hours using PtO2 (15 mg) in AcOH (3 mL), filtered, and concentrated to give Int. 1S6. N , N3,5-Tetramethyl-4-(piperidin-4-yl)benzamide (35 mg).

[0848]

[0849] 6-bromo- N , N Dimethylnicotinamide (20.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (27.0 g), NaHCO3 (25.7 g), and PdDPPFCl2-DCM (0.71 g) were degassed in dioxane / water (4:1, 0.5 L), refluxed overnight, and filtered. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (pentane / EtOAc 45:55) to give 4-[5-(dimethyl-carbamoyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (17 g). 1.0 g of the substance was stirred overnight in a dioxane solution (2.6:1, 14 mL) of DCM / 4M HCl at 0°C to room temperature. The mixture was combined with two other batches prepared at a scale of 0.1 g and concentrated. The residue was stirred in water at pH 8 (adjusted with NaHCO3). The mixture was purified by FC (reversed-phase C18 column; 8% ACN in 0.001% formic acid aqueous solution) to give Int. 1S4. N , N -Dimethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.60 g).

[0850]

[0851] 6-bromo- N , N 5-Trimethyl-pyridine-3-carboxamide (3.2 g), NaHCO3 (3.9 g), PdDPPFCl2-DCM (0.27 g), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (6.1 g) were degassed in dioxane / water (4:1, 13 mL) and stirred overnight at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give 4-[5-(dimethyl-carbamoyl)-3-methyl-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.0 g). 0.35 g of this substance was stirred overnight in DCM / TFA (10:1, 9 mL) at 0°C to room temperature, concentrated, and then ground in Et2O / pentane to obtain Int. 1S5 N ,N 3-Trimethyl-1',2',3',6'-Tetrahydro-[2,4'-Bipyridine]-5-carboxamide (0.35 g, TFA salt).

[0852]

[0853] Piperazine-1-carboxylic acid tert-butyl ester (5.0 g), 4-bromo- N , N 3-Trimethylbenzamide (7.1 g), Pd2dba3 (1.19 g), XPhos (1.29 g), and NaOtBu (5.19 g) were degassed in dioxane (50 mL), stirred overnight at 100 °C, and filtered. The mixture was dried over OL (water / EtOAc), concentrated, and purified by FC (pentane / EtOAc 3:7) to give tert-butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]piperazine-1-carboxylate (6.1 g). 7.2 g of this substance was stirred overnight in a 4 M HCl solution in dioxane / DCM (1.8:1, 55 mL) at 0 °C to room temperature, concentrated, and ground in Et2O / pentane to give Int.1S7. N , N 3-Trimethyl-4-(piperazin-1-yl)benzamide (5.0 g, hydrochloride). Int. 1S7' 3-Methyl-N,N-bis(methyl- d 3) Preparation of 4-(piperazin-1-yl)benzamide and its preparation from 4-bromo-3-methyl-N,N-bis(methyl- d 3) Benzamide is prepared in a similar manner.

[0854]

[0855] 6-bromo- N , N5-Trimethylpyridine-3-carboxamide (3.2 g), NaHCO3 (3.9 g), PdDPPFCl2-DCM (0.27 g), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (6.1 g) were degassed in dioxane / water (4:1, 14 mL) and stirred overnight at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give 4-[5-(dimethylcarbamoyl)-3-methyl-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (4.0 g). 4.2 g of this substance was hydrogenated overnight in 10% Pd / C (2.0 g) in MeOH (100 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 1:9) to give 3.5 g of tert-butyl 4-[5-(dimethylcarbamoyl)-3-methyl-2-pyridyl]piperidine-1-carboxylate. 4.3 g of this substance was stirred overnight in DCM / TFA (1.5:1, 25 mL) at 0 °C to room temperature, concentrated, and ground in pentane / Et2O to give Int. 1S8 N , N 5-Trimethyl-6-(piperidin-4-yl)nicotinamide (5.0 g, TFA salt).

[0856]

[0857] 4-bromo-3-fluoro N , N Dimethylbenzamide (1.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.51 g), Na2CO3 (1.72 g), and PdDPPFCl2-DCM (0.17 g) were degassed in dioxane / water (4:1, 10 mL) and stirred overnight at 100 °C. OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give 4-[4-(dimethyl-carbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.20 g). The substance was hydrogenated overnight in 10% Pd / C (45 mg) in MeOH (2 mL), filtered, concentrated, stirred overnight in a 4 M HCl solution of dioxane (10 mL), concentrated, and purified by HPLC to obtain Int. 1S18 3-fluoro- N , N -Dimethyl-4-(piperidin-4-yl)benzamide (63 mg).

[0858]

[0859] A 96% aqueous solution of H₂SO₄ (2.5 mL) was added to a solution of 4-bromo-3-methylbenzoic acid (20 g) in MeOH (300 mL). The mixture was stirred overnight at 90 °C and concentrated. The organic layer (saturated NaHCO₃ aqueous solution / EtOAc) was dried and concentrated to give methyl 4-bromo-3-methylbenzoate (20 g). 10 g of the substance, 14.8 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, 13.8 g of Na2CO3, and 0.84 g of PdDPPFCl2-DCM were degassed in dioxane / water (2.3:1, 100 mL), stirred overnight at 90 °C, filtered, concentrated, and purified by FC (hexane / EtOAc 95:5) to obtain 7.0 g of 4-(4-methoxycarbonyl-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. 2.5 g of this substance and 2.0 g of LiOH-H2O were stirred overnight in EtOH / THF / water (2:1:1, 24 mL) at 0 °C to room temperature, concentrated, and ground in dilute citric acid aqueous solution to obtain Int. 1S21 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-methylbenzoic acid (2.0 g). The preparation of Int. 1S20 (0.70 g) was similar to the preparation of Int. 1D8 from Int. 1S21 (2.0 g). Int. 1S19 3-methyl- N,N -bis(methyl- d The preparation of 3)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.31 g) was similar to the preparation of Int. 1S7 from Int. 1S20 (0.80 g).

[0860]

[0861] Int. 1S20 (0.35 g) was hydrogenated overnight in 10% Pd / C (50 mg) in MeOH (10 mL), filtered, and concentrated to give Int. 1S23 (0.21 g). Int. 1S22 3-methyl- N , N -bis-(methyl- d The preparation of 3)-4-(piperidin-4-yl)benzamide (0.45 g) was similar to the preparation of Int. 1S7 from Int. 1S23 (0.90 g).

[0862]

[0863] Add Int. 1A6 (0.30g), N , N -Dimethyl-4-(4-piperidinyl)benzamide (0.34 g) and 4 Å MS were stirred in DCM (5 mL) for 0.3 h. STAB (0.52 g) was added and stirring continued overnight. The mixture was filtered, concentrated, and purified by FC (heptane to EtOAc / MeOH 1:4) to give Int. 1X2 4-[1-[[1-(benzenesulfonyl)-4-bromo-pyrrolo[2,3-b]-pyridin-2-yl]-methyl]-4-piperidinyl]- N , N -Dimethylbenzamide (0.22 g). Int. 1X2 (0.12 g) was stirred in an EtOH / 4M NaOH aqueous solution (2.5:1, 2.8 mL) at 80 °C for 2.5 h and concentrated. The solution was then concentrated with OL (water / DCM) to give Int. 1X1 4-[1-[(4-bromo-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidinyl]- N , N -Dimethyl-benzamide (94 mg).

[0864]

[0865] 1.9 g of 4-bromo-3-fluoro-1-methyl-pyrrolo[2,3-b]pyridine was stirred for 2 hours at -78 °C in a THF solution of THF / 2.0 M LDA (5:1, 24 mL). 1.6 mL of DMF was added and stirring continued for 2 hours at -78 °C to room temperature. OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 1:4) to give Int. 1Y3 4-bromo-3-fluoro-1-methyl-pyrrolo[2,3-b]pyridine-2-carboxaldehyde (0.4 g). Int. 1Y3 (0.39 g) and... N , N 0.38 g of dimethyl-4-(4-piperidinyl)benzamide trifluoroacetate was stirred overnight in DCE / DIPEA (3.8:1, 6.3 mL) at 0 °C to room temperature. STAB (0.64 g) was added and stirring continued overnight at 0 °C to room temperature. OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (pentane to EtOAc) to give Int. 1Y2 4-[1-[(4-bromo-3-fluoro-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidinyl]- N , N-Dimethyl-benzamide (0.38 g). Int. 1Y2 (0.25 g), B2Pin2 (0.17 g), KOAc (0.16 g) and PdDPPFCl2-DCM (37 mg) were degassed in THF (20 mL) and incubated overnight at 100 °C. The mixture was concentrated and ground in pentane to give Int. 1Y1 (2-((4-(4-(dimethylcarbamoyl)phenyl)-piperidin-1-yl)methyl)-3-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.2 g).

[0866]

[0867] Int. 1R5 (0.5 g) and LiOH (181 mg) were stirred overnight in MeOH / THF / water (3:5:1, 9 mL) and concentrated to give Int. 1Z4 4-(1-benzyl-4-hydroxypiperidin-4-yl)benzoic acid (0.40 g). Int. 1Z4 (0.40 g), HN(CH3)2 (0.31 g, hydrochloride) and HATU (636 mg) were stirred overnight in DMF / DIPEA (7:3:1, 9.1 mL). OL (EtOAc / water) was concentrated and purified by FC (heptane / EtOAc 5:3 to 3:7) to give Int. 1Z3 4-(1-benzyl-4-hydroxypiperidin-4-yl)- N , N -Dimethyl-benzamide. Int. 1Z3 (1.0 g) was hydrogenated in MeOH (20 mL) with 10% Pd / C (0.5 g) for 32 hours, filtered, and concentrated to give Int. 1Z2 4-(4-hydroxypiperidin-4-yl)- N , N -Dimethylbenzamide. Int. 1Z2 (0.20 g) and 4-bromo-1H-pyrrolo[2,3-b]pyridin-2-carboxaldehyde (0.19 g) were stirred in DCE / DIPEA (10:1, 3.3 mL) for 4 hours. STAB (0.51 g) was added and stirring was continued for 32 hours. OL (water / DCM) was concentrated and purified by FC (hexane / EtOAc 1:0 to 4:1) to give Int. 1Z1 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-hydroxy-4-piperidinyl]- N , N -Dimethyl-benzamide (0.15g).

[0868]

[0869] Int. 1J1 (0.97 g), KI (12 mg), Int. 1AE7 (1 g), and K2CO3 (1.6 g) were stirred in DMF (10 mL) for 11 hours. The solution was concentrated with OL (water / MTBE) to give Int. 1Z9 4-(1-(((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylbenzamide (0.67 g). Int. 1Z9 (0.67 g), KOAc (0.44 g), PdDPPFCl2-DCM (24 mg), and bis(pinacol)diboron (0.75 g) were stirred in dioxane (10 mL) at 90 °C under an inert atmosphere for 48 hours. OL (water / MTBE) was concentrated to give Int. 1Z10 N,N-dimethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.72 g). 6-bromopyridazin-3-amine (0.25 g) and di-tert-butyl dicarbonate (0.38 g) were stirred overnight in a 1 M LiHMDs solution of THF (1.9 mL) and THF (5 mL) at 0°C to room temperature under an inert atmosphere. OL (saturated NH4Cl aqueous solution / EtOAc) was dried and concentrated to give Int. 1Z11 (6- Brompyridazine -3- 0.15g of tert-butyl carbamate.

[0870]

[0871] 6-Chloro-N,N-dimethylpyridazine-3-carboxamide (0.85 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g), K 2CO3 (2.5 g) and PdDPPFCl2-DCM (0.19 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 25 mL) under an inert atmosphere. The mixture was dried over OL (water / EtOAc), concentrated, and purified by FC (CHCl3 / MTBE 1:0 to 0:1) to give Int. 1Z15 4-(6-(dimethylcarbamoyl)pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1 g). Int. 1Z15 (1 g) was stirred for 1 hour in 1,1,1,3,3,3-hexafluoro-2-propanol / 10M HCl (19:1, 10.5 mL). The mixture was diluted with MTBE to precipitate Int.1Z16 N,N-dimethyl-6-(1,2,3,6-tetrahydro-pyridin-4-yl)pyridazin-3-carboxamide (0.8 g, hydrochloride). Int.1J1 / 1Z16 (0.2 g / 0.3 g) was stirred in ACN / Et3N (48:1, 20.4 mL) for 12 hours. The mixture was concentrated and purified by HPLC to give Int. 1Z14 6-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylpyridazin-3-carboxamide (70 mg).

[0872]

[0873] 1 g of 6-chloropyridazine-3-carboxylic acid was stirred and concentrated in DCM / SOCl2 (40:1, 20.5 mL) at 40 °C for 2 hours. Bis(methyl-) d 3) A solution of amine hydrochloride (0.61 g) in DCM (20 mL) and Et3N (2.6 mL) was prepared and stirred overnight. The mixture was concentrated and purified by FC (CHCl3 / ACN 1:0 to 1:1) to give Int. 1Z18 6-chloro-N,N-bis(methyl- d 3) Pyridazine-3-carboxamide (1.2 g). Int. 1Z18 (1.2 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.1 g), K2CO3 (3.5 g), and PdDPPFCl2-DCM (0.26 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 25 mL) under an inert atmosphere. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (CHCl3 / MTBE 1:0 to 0:1) to give Int. 1Z19 4-(6-(bis-(methyl- d3) Carbamoyl)-pyridazin-3-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (0.55 g). Int. 1Z19 (0.55 g) was stirred in 1,1,1,3,3,3-hexafluoro-2-propanol / 10M HCl (26:1, 5.2 mL) for 1 hour. The mixture was diluted with MTBE to precipitate Int. 1Z20 N,N-bis(methyl- d 3)-6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridazine-3-carboxamide (0.2 g, hydrochloride). Int. 1J1 / 1Z20 (0.2 g / 0.2 g) was stirred in ACN / Et3N (48:1, 20.4 mL) for 12 hours. The mixture was concentrated and purified by HPLC to give Int. 1Z17 6-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-bis(methyl- d 3) Pyridazine-3-carboxamide (50mg).

[0874]

[0875] 4-Chloro-3-cyanobenzoic acid (3.4 g) and di(1H-imidazol-1-yl) ketone (3.0 g) were refluxed in dioxane (50 mL) for 0.3 h. Dimethylamine hydrochloride (1.5 g) was added and stirring was continued for 10 h. The mixture was concentrated. OL (NaHSO4 aqueous solution / CHCl3) was concentrated to give Int. 1Z24 4-chloro-3-cyano-N,N-dimethylbenzamide (0.87 g). Int. 1Z24 (1 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g), K 2CO3 (2.0 g) and PdDPPFCl2-DCM (0.20 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 20 mL) under an inert atmosphere. The mixture was filtered, concentrated, and purified by FC (CHCl3 / ACN 1:0 to 4:1) to give Int. 1Z25 tert-butyl 4-(2-cyano-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid (0.44 g). Int. 1Z25 (0.44 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The mixture was concentrated to give Int. 1Z26 3-cyano-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridine-4-yl)benzamide (0.3 g, hydrochloride). Int. 1J1 / 1Z26 (0.3 g / 0.3 g) and K2CO3 (0.5 g) were stirred in DMF (10 mL) for 11 hours. The mixture was diluted with water to precipitate Int. 1Z27 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-cyano-N,N-dimethylbenzamide (0.12 g).

[0876]

[0877] Int. 1J1 / RR44 (0.3 g / 0.3 g) was stirred in ACN / Et3N (29:2, 10.7 mL) for 12 hours. The mixture was concentrated and purified by HPLC to give Int. 1Z29 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,3,5-tetramethylbenzamide (0.3 g). Int. 1Z29 (0.3 g), bis(pinacol)diboron (0.4 g), KOAc (0.5 g), and PdDPPFCl2-DCM (50 mg) were stirred in dioxane (10 mL) at 80 °C for 12 hours under an inert atmosphere. OL (water / EtOAc) was concentrated to give Int. 1Z30 N,N,3,5-tetramethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.3 g).

[0878]

[0879] Int. 1Z50 (0.75 g), bis(pinacol)diboron (0.78 g), PdDPPFCl2-DCM (0.13 g), and KOAc (0.45 g) were stirred in dioxane (10 mL) at 110 °C under an inert atmosphere for 1.3 h at MW. The mixture was filtered through diatomaceous earth and concentrated to give Int. 1Z31 3-fluoro-N,N,5-trimethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.85 g).

[0880]

[0881] Int. 1Z65 (0.50 g), bis(pinacol)diboron (0.52 g), PdDPPFCl2-DCM (83 mg), and KOAc (0.30 g) were stirred in dioxane (10 mL) at 110 °C under an inert atmosphere for 1 hour at MW. The mixture was filtered through diatomaceous earth, concentrated, and washed with pentane to give Int. 1Z33 3,5-difluoro-N,N-dimethyl-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.50 g).

[0882]

[0883] 5-Bromo-N,N-dimethylpyrimidin-2-carboxamide (1.3 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.9 g), K 2 CO3 (2.3 g) and PdDPPFCl2-DCM (0.22 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 20 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (MTBE / MeOH) to give Int. 1Z35 4-(2-(dimethylcarbamoyl)pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.9 g). Int. 1Z35 (0.9 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The mixture was concentrated to give Int. 1Z36 N,N-dimethyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-2-carboxamide (0.65 g, hydrochloride). Int. 1J1 / 1Z36 (0.3 g / 0.3 g) and K2CO3 (0.5 g) were stirred in DMF (10 mL) for 11 hours. The mixture was diluted with water to precipitate Int. 1Z37 5-(1-(((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylpyrimidin-2-carboxamide (0.35 g). Int. 1Z37 (0.35 g), bis(pinacol)diboron (0.70 g), PdDPPFCl2-DCM (10 mg), and KOAc (0.40 g) were stirred in dioxane (10 mL) at 90 °C for 14 hours under an inert atmosphere. OL (water / chloroform) was concentrated and purified by HPLC to obtain Int. 1Z38 N,N-dimethyl-5-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-carboxamide (90 mg).

[0884]

[0885] Int. 1Z65 (0.50 g), bis(pinacol)diboron (0.52 g), PdDPPFCl2-DCM (82 mg), and KOAc (0.30 g) were stirred in dioxane (6 mL) at 120 °C for 1 hour under MW conditions. The mixture was filtered through diatomaceous earth and concentrated to give Int. 1Z40 3,5-difluoro-N,N-bis(methyl- d 3)-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.60 g).

[0886]

[0887] 5-Bromo-N,N-dimethylpyridineamide (1.5 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.2 g), K2CO3 (2.7 g), and PdDPPFCl2-DCM (0.27 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 20 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (hexane / MTBE 1:0 to 0:1) to give Int. 1Z52 6-(dimethyl-carbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (1 g). Int. 1Z51 (1 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The mixture was concentrated to give Int. 1Z52 N,N-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.5 g, hydrochloride). Int. 1J1 / 1Z52 (0.6 g / 0.5 g) and K2CO3 (0.9 g) were stirred in DMF (10 mL) for 11 hours. The mixture was diluted with water to precipitate Int. 1Z50 1'-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N,N-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.4 g).

[0888]

[0889] Int. 1AE9 (0.45 g), bis(pinacol)diboron (0.35 g), PdDPPFCl2-DCM (75 mg), and KOAc (0.27 g) were stirred in dioxane (5 mL) at 110 °C for 1 hour under MW conditions. The mixture was filtered through diatomaceous earth and concentrated to obtain Int. 1Z53 3-fluoro-5-methyl-N,N-bis(methyl- d 3 )-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.40 g).

[0890]

[0891] PdDPPFCl2-DCM (0.25 g), 4-bromo-2-fluoro-N,N-dimethylbenzamide (1.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.1 g), and K2CO3 (2.5 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 20 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (hexane / MTBE 3:2 to 0:1) to give Int. 1Z55 tert-butyl 4-(4-(dimethyl-carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g). Int. 1Z55 (1 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The mixture was concentrated to give Int. 1Z56 2-fluoro-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.5 g, hydrochloride). Int. 1J1 / PP60 (0.5 g / 0.5 g) and K2CO3 (0.8 g) were stirred in DMF (10 mL) for 11 hours. The mixture was diluted with water to precipitate Int. 1Z54 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluoro-N,N-dimethylbenzamide (0.4 g).

[0892]

[0893] A solution of CDI (2.6 g) in THF (175 mL) was added dropwise to a mixture of 6-chloro-5-methylpyridazin-3-carboxylic acid (2 g) in THF (175 mL). The mixture was refluxed for 3.5 hours. Dimethylamine hydrochloride (2.8 g) and Et3N (5.2 mL) were added, and stirring was continued at room temperature for 16 hours. The solution was concentrated in OL (saline / EtOAc) to give Int. 1Z58 6-chloro-N,N,5-trimethylpyridazin-3-carboxamide (0.8 g). Int. 1Z58 was refluxed overnight in trimethylbromosilane (10 mL). The mixture was concentrated and purified by preparative TLC (hexane / EtOAc, 3:1) to give Int. 1Z59 6-bromo-N,N,5-trimethylpyridazin-3-carboxamide (0.9 g). PdDPPFCl2-DCM (0.3 g), Int. 1Z59 (0.9 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.0 g), and K2CO3 (2.0 g) were refluxed overnight in dioxane / H2O (15:4, 190 mL) under an inert atmosphere. The solution was dried over OL (NaHCO3 aqueous solution / EtOAc) and concentrated to give Int. 1Z60 4-(6-(dimethylcarbamoyl)-4-methylpyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.3 g). Int. 1Z60 (1.3 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The concentrated residue was ground in EtOAc to give Int. 1Z61 N,N,5-trimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-carboxamide (0.9 g, hydrochloride). STAB (0.30 g) and Int. 1AB8 / 1Z61 (0.1 g / 0.1 g) were stirred overnight in DCE / Et3N (73:1, 10.1 mL) at 0 °C to room temperature. The concentrated residue was dissolved in THF, filtered through silica, and concentrated to give Int. 1Z57 6-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,5-trimethylpyridazin-3-carboxamide (0.19 g).

[0894]

[0895] PdDPPFCl2-DCM (1.1 g), 4-bromo-N,N,2-trimethylbenzamide (3.3 g), K2CO3 (5.7 g), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.9 g) were refluxed overnight in dioxane / H2O (15:4, 190 mL) under an inert atmosphere. The solution was dried over OL (NaHCO3 aqueous solution / EtOAc) and concentrated to give Int. 1Z63 4-(4-(dimethylcarbamoyl)-3-methyl-phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1 g). Int. 1Z63 (4.1 g) was stirred overnight in a 2.8 M HCl solution in dioxane (30 mL). The concentrated residue was ground in EtOAc to give Int. 1Z64 N,N,2-trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (2.3 g, hydrochloride). STAB (0.30 g) and Int. 1AB8 / 1Z64 (0.1 g / 0.1 g) were stirred overnight in DCE / Et3N (73:1, 10.1 mL) at 0 °C to room temperature. The concentrated residue was dissolved in THF, filtered through silica and concentrated to obtain Int. 1Z62 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,2-trimethylbenzamide (0.19 g).

[0896]

[0897] LiOH .H2O (9.5 g) and Int. 3C18 (16 g) were stirred for 16 hours at 0°C to room temperature in THF / MeOH / H2O (2:1:1, 300 mL). The concentrated residue was stirred in an aqueous citric acid solution to precipitate Int. 1Z66 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoic acid (10 g). Int. 1Z66 (5 g), HATU (8.4 g), and dimethylamine hydrochloride (1.8 g) were stirred for 16 hours at 0°C to room temperature in DMF (40 mL) and DIPEA (13 mL). OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to give Int. 1Z67 tert-butyl 4-(4-(dimethylcarbamoyl)-2,6-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.7 g). Int. 1Z67 (3.7 g) was stirred for 16 hours in a 2M HCl solution of dioxane (60 mL) at 0°C to room temperature. The mixture was concentrated to give Int. 1Z68 3,5-difluoro-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridine-4-yl)benzamide (2.9 g, hydrochloride). Int. 1J1 / 1Z68 (0.35 g / 0.49 g), KI (22 mg), and K2CO3 (0.56 g) were stirred in ACN (20 mL) at 0 °C to room temperature for 16 hours. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (PE / EtOAc 3:7) to give Int. 1Z65 4-(1-(((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluoro-N,N-dimethylbenzamide (0.35 g).

[0898]

[0899] LiOH .H2O (33 g) and Int. 1AF87 (76 g) were stirred for 16 hours at 0°C to room temperature in THF / MeOH / H2O (2:1:1, 1.5 L). The concentrated residue was stirred in an aqueous citric acid solution at 0°C to precipitate Int. 1Z704-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methylbenzoic acid (68 g). Int. 1Z70 (70 g), dimethylamine hydrochloride (36 g), and HATU (84 g) were stirred for 12 hours at 0°C to room temperature in DMF (300 mL) and DIPEA (180 mL). The mixture was diluted with water to precipitate a solid, which was then dried to give Int. 1Z69 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (63 g).

[0900]

[0901] Int. 1AF88 / 1S4 (1.5 g / 1.5 g), KI (91 mg), and Cs2CO3 (8.9 g) were stirred in ACN (15 mL) for 16 hours at 0 °C to room temperature. The mixture was dried over OL (water / EtOAc), concentrated, and purified by FC (DCM / MeOH 19:1) to give Int. 1Z71 1'-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-N,N-dimethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.50 g).

[0902]

[0903] 3-Fluoro-5-methyl-N,N-bis(methyl- d 3)-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0904] Int. 1AE9 (0.45 g), bis(pinacol)diboron (0.35 g), PdDPPFCl2-DCM (75 mg), and KOAc (0.27 g) were stirred in dioxane (5 mL) at 110 °C for 1 hour under MW conditions. The mixture was filtered through diatomaceous earth and concentrated to obtain Int. 1Z73 3-fluoro-5-methyl-N,N-bis(methyl-d 3)-4-(1-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.40 g).

[0905]

[0906] Int. 1AE38 (3.2 g) and Cs2CO3 (18 g) were stirred in ACN (20 mL) for 0.3 h. Int. 1AF88 (3 g) and KI (0.91 g) were added and stirring was continued for 12 h at 0 °C to room temperature. OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:9) to give Int. 1Z75 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide (0.90 g). Int. 1Z75 (0.90 g) was separated by SFC (operated at 30 °C on an SFC-150-022 instrument equipped with a Chiral ART Amylose-C NEO 250×30 mm 5 µm column) with 80% CO2 and 20% MeOH eluent (100 g / min) and a back pressure of 100 bar, yielding Int. 1Z76 (0.15 g, first peak) and Int. 1Z77 (0.15 g, second peak) (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide and (R)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide. The absolute configurations of these compounds are undetermined.

[0907]

[0908] A 3M CH3MgCl THF solution (32 mL) was slowly added at -78 °C to a solution of Int. 1A6 (11.5 g) in THF (310 mL). The mixture was stirred at -78 °C to room temperature for 0.5 hours. OL (NH4Cl aqueous solution / EtOAc) was dried and concentrated to give Int. 1Z79 1-(4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanol-1-ol (12 g).

[0909]

[0910] SOCl2 (0.18 mL) was added to a solution of Int. 1Z79 (0.1 g) in toluene (3 mL). The mixture was stirred for 0.5 h and concentrated. Int. 1AE12' (90 mg), KI (20 mg), and Cs2CO3 (0.40 g) were added to the residue in a solution of ACN (5 mL) and stirred overnight. The mixture was purified by HPLC to give Int. 1Z80 4-(1-(1-(4-bromo-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (13 mg).

[0911]

[0912] LiOH . H2O (9.8 g) and Int. 3C17 (16.5 g) were stirred for 16 hours at 0°C to room temperature in THF / MeOH / H2O (2:1:1, 600 mL). The concentrated residue was stirred, filtered, and dried in an aqueous citric acid solution to obtain Int. 1Z87 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3,5-difluorobenzoic acid (11.5 g). HATU (8.3 g), Int. 1Z87 (5 g), and dimethylamine hydrochloride (1.8 g) were stirred for 16 hours at 0°C to room temperature in DMF (30 mL) and DIPEA (13 mL). OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to give Int. 1Z86 tert-butyl 4-(4-(dimethylcarbamoyl)-2,6-difluorophenyl)piperidine-1-carboxylate (3.2 g). Int. 1Z86 (3.2 g) was stirred for 16 hours in a 2M HCl solution in dioxane (60 mL) at 0°C to room temperature. The mixture was concentrated to give Int. 1Z85 3,5-difluoro-N,N-dimethyl-4-(piperidine-4-yl)benzamide (2.3 g, hydrochloride). Int. 1J1 / 1Z85 (0.35 g / 0.36 g) and K2CO3 (0.93 g) were stirred for 16 hours in ACN (10 mL) at 0°C to room temperature. The mixture was filtered, concentrated, and purified by FC (PE / EtOAc 1:4) to obtain Int. 1Z84 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3,5-difluoro-N,N-dimethylbenzamide (0.40 g).

[0913]

[0914] Add Int. 1Z66 (5g), bis(methyl- d 3) Aminohydrochloride (1.5 g) and HATU (8.4 g) were stirred in DMF (40 mL) and DIPEA (13 mL) for 16 hours at 0 °C to room temperature. OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to obtain Int. 1Z94 4-(4-(bis(methyl- d 3) Carbamoyl)-2,6-difluoro-phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.5 g). Int. 1Z94 (3.6 g) was stirred for 16 hours in a 2M HCl solution of dioxane (60 mL) at 0 °C to room temperature. The mixture was concentrated to give Int. 1Z93 3,5-difluoro-N,N-bis-(methyl- d 3)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (2.7 g, hydrochloride). Int. 1J1 / 1Z93 (0.40 g / 0.57 g), KI (77 mg) and K2CO3 (0.64 g) were stirred in ACN (20 mL) at 0 °C to room temperature for 16 hours. The solution was dried over OL (water / EtOAc), concentrated and purified by FC (PE / EtOAc 3:7) to give Int. 1Z92 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluoro-N,N-bis(methyl- d 3) Benzamide (0.41g).

[0915]

[0916] PdDPPFCl2-DCM (0.2 g), methyl 5-bromo-4,6-dimethylpyridinecarboxylate (1.1 g), K2CO3 (2 g), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g) were stirred in dioxane (8:1, 45 mL) at 80 °C for 12 hours under an inert atmosphere. The mixture was filtered and concentrated to give Int. 1Z99 1'-(tert-butoxycarbonyl)-2,4-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid (1.4 g). LiOH was then added... .H2O (0.3 g) and Int. 1Z99 (1.4 g) were stirred in MeOH / H2O (1:1, 60 mL) for 12 hours. The mixture was concentrated to give Int. 1Z98 1'-(tert-butoxycarbonyl)-2,4-dimethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid (1.3 g, lithium salt). Int. 1Z98 (1.4 g), dimethylamine hydrochloride (0.4 g), and HATU (1.7 g) were stirred in DMF (50 mL) and Et3N (2.8 mL) for 12 hours. The mixture was concentrated. Concentrate OL (water / EtOAc) to give Int. 1Z97 0.95 g of tert-butyl 6-(dimethylcarbamoyl)-2,4-dimethyl-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate. Int. 1Z97 (0.95 g) was stirred overnight in a dioxane solution (1:1, 40 mL) of MeOH / 2.8 M HCl. The mixture was concentrated to give Int. 1Z96 0.7 g of N,N,2,4-tetramethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (hydrochloride). Int. 1AF89 (0.3 g) was stirred at 80 °C in toluene (20 mL) and SOCl2 (0.61 mL) for 0.5 h. The mixture was concentrated. The residue Int. 1Z96 (0.5 g) and Cs2CO3 (0.3 g) were stirred in DMF (10 mL) for 12 hours. The solution was concentrated in OL (water / EtOAc) and purified by HPLC to give Int. 1Z95 1'-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-N,N,2,4-tetramethyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.5 g).

[0917]

[0918] Int. 1Z87 (2g), bis(methyl- d 3) Aminohydrochloride (0.62 g) and HATU (3.3 g) were stirred in DMF (30 mL) and DIPEA (5.1 mL) for 16 hours at 0 °C to room temperature. OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to give Int. 1Z103 4-(4-(bis(methyl- d3) Carbamoyl)-2,6-difluorophenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.4 g). Int. 1Z103 (1.4 g) was stirred for 16 hours in a 2.2 M HCl solution in dioxane (18 mL) at 0 °C to room temperature. The mixture was concentrated to give Int. 1Z102 3,5-difluoro-N,N-bis(methyl- d 3)-4-(piperidin-4-yl)benzamide (1.1 g, hydrochloride). Int. 1J1 / 1Z102 (0.50 g / 0.60 g), KI (0.16 g) and K2CO3 (1.3 g) were stirred in ACN (20 mL) for 16 hours at 0 °C to room temperature. OL (water / EtOAc) was concentrated and purified by FC (hexane / EtOAc 1:4) to give Int. 1Z101 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3,5-difluoro-N,N-bis(methyl- d 3) Benzamide (0.45g).

[0919]

[0920] NaIO4 (2.6 g) was added in portions to a mixture of I2 (8.9 g) and sulfuric acid (100 mL). The mixture was stirred for 0.5 h, then 4-bromo-N,N-dimethylbenzamide (17 g) was added and stirring continued for 18 h. The mixture was diluted with water to precipitate a solid, which was dried and crystallized from CCl4 to give Int. 1Z105 4-bromo-3-iodo-N,N-dimethylbenzamide (17 g). PdDPPFCl2-DCM (2.0 g), Int. 1Z105 (17 g), cyclopropylboronic acid (5.0 g), and K2CO3 (20 g) were refluxed overnight in dioxane / H2O (3:1, 200 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCl3 to CHCl3 / ACN 1:1) to give Int. 1Z106 4-bromo-3-cyclopropyl-N,N-dimethylbenzamide (12 g). PdDPPFCl2-DCM (1.9 g), Int. 1Z106 (12 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (21 g) and K2CO3 (19 g) were refluxed overnight in dioxane / H2O (6:1, 140 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCl3 to CHCl3 / ACN 1:1) to give Int. 1Z107 4-(2-cyclopropyl-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.1 g). Int. 1Z107 (4.1 g) was stirred overnight in a 4M HCl solution in dioxane (50 mL). The mixture was concentrated and ground in EtOAc to give Int. 1Z108 3-cyclopropyl-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridine-4-yl)benzamide (0.10 g, hydrochloride). STAB (0.30 g) and Int. 1AB8 / 1Z108 (0.1 g / 0.1 g) were stirred overnight in DCE / Et3N (73:1, 10.1 mL) at 0 °C to room temperature. The mixture was concentrated, dissolved in THF, filtered through silica, and concentrated to give Int. 1Z109 4-(1-(((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-cyclopropyl-N,N-dimethylbenzamide (0.19 g).

[0921]

[0922] NaIO4 (2.3 g) was added in portions to a mixture of I2 (8.0 g) and sulfuric acid (100 mL), and the mixture was stirred for 0.5 h. 4-Bromo-3-fluoro-N,N-dimethylbenzamide (17 g) was added, and stirring continued for 18 h. The reaction mixture was diluted with water to precipitate a solid, which was dried and precipitated from CCl4 to give a mixture (13 g) of Int. 1Z122 4-bromo-5-fluoro-2-iodide-N,N-dimethylbenzamide and a mixture of 4-bromo-3-fluoro-5-iodide-N,N-dimethylbenzamide. PdDPPFCl2-DCM (1.4 g), Int. 1Z122 (13 g), cyclopropylboronic acid (3.6 g), and K2CO3 (14 g) were refluxed overnight in dioxane / H2O (3:1, 200 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCl3 to CHCl3 / ACN 1:1) to give a mixture (7 g) of Int. 1Z121 4-bromo-2-cyclopropyl-5-fluoro-N,N-dimethylbenzamide and 4-bromo-3-cyclopropyl-5-fluoro-N,N-dimethylbenzamide. PdDPPFCl2-DCM (1.0 g), Int. 1Z121 (7 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (11 g) and K2CO3 (10 g) were refluxed overnight in dioxane / H2O (6:1, 140 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCl3 to CHCl3 / ACN 1:1) to give a mixture (2.6 g) of Int. 1Z120 4-(5-cyclopropyl-4-(dimethylcarbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and 4-(2-cyclopropyl-4-(dimethylcarbamoyl)-6-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. Int. 1Z120 (2.6 g) was stirred overnight in a 4M HCl solution in dioxane (50 mL). The mixture was concentrated and ground in EtOAc to obtain a mixture of Int. 1Z119 2-cyclopropyl-5-fluoro-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide and 3-cyclopropyl-5-fluoro-N,N-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (2.0 g, hydrochloride).

[0923]

[0924] STAB (0.30 g) and Int. 1AB8 / 1Z119 (0.1 g / 0.1 g) were stirred overnight in DCE / Et3N (73:1, 10.1 mL) at 0 °C to room temperature. The concentrated residue was dissolved in THF, filtered through silica, and concentrated to obtain a mixture (0.17 g) of Int. 1Z123 / 1Z124 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-cyclopropyl-5-fluoro-N,N-dimethylbenzamide and 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-cyclopropyl-5-fluoro-N,N-dimethylbenzamide.

[0925]

[0926] N-iodosuccinimide (196 g) and 2-fluoro-6-methylaniline (100 g) were stirred in ACN (2.0 L) for 2 hours at 0 °C to room temperature. OL (Na₂S₂O₃ aqueous solution / EtOAc) was dried and concentrated to give Int. 1Z131 2-fluoro-4-iodo-6-methylaniline (180 g). Int. 1Z131 (30 g), dimethylamine hydrochloride (24 g), and PdDPPFCl₂-DCM (4.9 g) were stirred in dioxane / Et₃N (14:3, 364 mL) at 85 °C under CO₂ at 200 psi for 16 hours. The mixture was filtered and concentrated. OL (1 M HCl / EtOAc) was neutralized with Na₂CO₃ to approximately pH 8. OL (water / EtOAc) was dried and concentrated to give Int. 1Z1304-amino-3-fluoro-N,N,5-trimethylbenzamide (17 g). CuBr2 (85 g) and 1Z130 (15 g) were heated at 0-85°C in ACN (300 mL) and tThe mixture was stirred in BuONO (14 mL) for 16 hours. OL (NH3 aqueous solution / PE) was dried, filtered, and concentrated to obtain Int. 1Z129 4-bromo-3-fluoro-N,N,5-trimethylbenzamide (14 g). Int. 1Z129 (1 g), PdDPPFCl2-DCM (0.31 g), bis(pinacol)diboron (2.0 g), and KOAc (1.1 g) were stirred in dioxane (10 mL) at 110 °C for 1 hour under MW conditions. The mixture was filtered through diatomaceous earth, concentrated, and washed with pentane to obtain Int. 1Z128 3-fluoro-N,N,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzamide (0.80 g). PdDPPFCl2-DCM (0.11 g), Int. 3E284 / 1Z128 (0.50 g / 0.77 g), and Na2CO3 (0.43 g) were stirred for 1.5 h at 110 °C in dioxane / H2O (4:1, 10 mL) under MW conditions. The mixture was filtered. OL (water / EtOAc) was concentrated and purified by FC (hexane / EtOAc 3:7) to give Int. 1Z127 tert-butyl 4-(4-(dimethylcarbamoyl)-2-fluoro-6-methylphenyl)-3,3-difluoro-3,6-dihydro-pyridine-1(2H)-carboxylic acid (65 mg). Int. 1Z127 (0.50 g) was stirred for 16 h in a dioxane solution of DCM / 4M HCl (2:1, 6 mL) at 0 °C to room temperature. The mixture was concentrated to give Int. 1Z126 4-(3,3-difluoro-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.40 g, hydrochloride). Int. 1AF88 / 1Z126 (0.40 g / 0.59 g), KI (0.17 g), and Cs2CO3 (3.3 g) were stirred in ACN (10 mL) at 0 °C to room temperature for 12 hours. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 4:1) to give Int.1Z125 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]-pyridin-2-yl)ethyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.13 g).

[0927]

[0928] Int. 1Z127 (0.40 g) and PtO2 (0.80 g) were hydrogenated at 70 psi in THF / EtOH / AcOH (8:8:1, 17 mL) for 75 hours. The mixture was filtered and concentrated to give Int. 1Z132 tert-butyl 4-(4-(dimethylcarbamoyl)-2-fluoro-6-methylphenyl)-3,3-difluoropiperidin-1-carboxylate (0.40 g). The preparation of Int. 1Z133 4-(3,3-difluoropiperidin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.20 g, hydrochloride) was similar to that of Int. 1Z126 from Int. 1Z132 (0.25 g). Int. 1AF88 / 1Z133 (0.15 g / 0.18 g), KI (64 mg), and Cs2CO3 (0.12 g) were stirred in ACN (10 mL) for 16 hours at 0 °C to room temperature. OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 1:1 to 1:2) to give Int. 1Z134 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-3,3-difluoropiperidin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.13 g).

[0929]

[0930] Di(1H-imidazol-1-yl) ketone (1.0 g) and 4-bromo-3-(trifluoromethoxy)benzoic acid (1.8 g) were refluxed in dioxane (50 mL) for 0.3 h. Dimethylamine hydrochloride (0.51 g) and Et3N (5.2 mL) were added and stirring was continued for 10 h. The mixture was concentrated. The solution was concentrated in OL (NaHSO4 aqueous solution / CHCl3) to give Int. 1Z139 4-bromo-N,N-dimethyl-3-(trifluoro(oxo)-λ6-methyl)benzamide (1.5 g). Int. 1Z139 (1.5 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g), K2CO3 (2.0 g), and PdDPPFCl2-DCM (0.20 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 20 mL) under an inert atmosphere. The mixture was concentrated and purified by FC to give Int. 1Z138 4-(4-(dimethylcarbamoyl)-2-(trifluoromethoxy)phenyl)-3,6-dihydro-pyridine-1(2H)-carboxylic acid tert-butyl ester (0.78 g). Int. 1Z138 (0.78 g) was stirred overnight in a 2.8 M HCl solution in dioxane (10 mL). The mixture was concentrated to give Int. 1Z137 N,N-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethoxy)benzamide (0.43 g, hydrochloride). Int. 1J1 / 1Z137 (0.36 g / 0.43 g) and K2CO3 (0.57 g) were stirred in DMF (10 mL) for 11 hours. The mixture was diluted with water to precipitate Int. 1Z136 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethyl-3-(trifluoromethoxy)benzamide (0.14 g).

[0931]

[0932] The preparation of Int. C3,4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (0.11 g) is similar to the preparation of Int. 2C9 from Int. 3E37 (0.12 g).

[0933]

[0934] Methyl 4-bromo-3-methylbenzoate (2.5 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.0 g), NaHCO3 (2.8 g), and PdDPPFCl2-DCM (0.45 g) were degassed in dioxane / water (10:1, 30 mL) and stirred overnight at 100 °C. The mixture was diluted with EtOAc (100 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 9:1 to 85:15) to give Int. 2C41 4-(4-methoxy-carbonyl-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.2 g). Int. 2C41 (0.25 g) was stirred overnight and concentrated in a dioxane solution of DCM / 4M HCl (4:1, 10 mL). The residue was ground in pentane to give Int. 2C42 methyl 3-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate (0.19 g, hydrochloride). Int. 1AB8 / 2C42 (1.2 g / 1.2 g, hydrochloride) was stirred for 4 hours in DCE / DIPEA (2:2:1, 7.3 mL) at 0 °C to room temperature. STAB (1.9 g) was added and stirring continued overnight. OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give methyl 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzoate (1.0 g).

[0935]

[0936] 6-Bromonicotinic acid methyl ester (5.0 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (7.8 g), K 2CO3 (3.0 g) and PdDPPFCl2-DCM (1.9 g) were stirred overnight at 100 °C in dioxane / H2O (4:1, 100 mL) under an inert atmosphere. The mixture was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane / MTBE 1:0 to 0:1) to give Int. 2C65 3',6'-dihydro-[2,4'-bipyridine]-1',5(2'H)-dicarboxylic acid 1'-(tert-butyl)5-methyl ester (5.9 g). Int. 2C65 (2.0 g) was stirred in a 2M HCl solution in dioxane (40 mL) for 16 hours, concentrated, and washed with Et2O to give Int. 2C64 1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylic acid methyl ester (1.8 g, hydrochloride). Int. 1AB8 / 2C64 (616 mg / 750 mg) and 4 Å MS were stirred overnight in DCE / Et3N (9:1, 11.1 mL). (AcO)3BHNa (1.6 g) was added and stirring was continued for 3 hours, followed by concentration and HPLC purification to give Int. 2C63 1'-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylic acid methyl ester (0.57 g). Int. 2C63 (0.29 g), bis(pinacol)diboron (0.18 g), KOAc (0.19 g), and PdDPPFCl2-DCM (53 mg) were stirred overnight in dioxane (10 mL) at 80 °C under an inert atmosphere. The concentrated residue was dissolved in THF, filtered through silica, and concentrated to obtain methyl Int. 2C62 1'-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (0.30 g).

[0937]

[0938] Int. 1AB8 / 2C78 (0.50 g / 1.0 g) and 4 Å MS were stirred overnight in a DCE / Et3N (15:1, 15.9 mL). (AcO)3BHNa (1.0 g) was added and stirring was continued for 3 hours. The mixture was concentrated and purified by HPLC to give methyl Int. 2C771'-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-methyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (0.61 g). Int. 2C77 (0.30 g), bis(pinacol)diboron (0.30 mg), KOAc (0.30 mg), and PdDPPFCl2-DCM (30 mg) were stirred overnight in dioxane (3 mL) at 80 °C under an inert atmosphere. The concentrated residue was dissolved in THF, filtered through silica, and concentrated to give Int. 2C76 methyl-1'-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylic acid methyl ester (0.30 g).

[0939]

[0940] Int. 1AB8 / 3C25 (8.0 g / 12.6 g) was stirred for 16 hours in DCE (80 mL) and DIPEA (35 mL) at 0 °C to room temperature under an inert atmosphere. STAB (28 g) was added in portions at 0 °C and stirring was continued for 12 hours. The solution was dried over OL (water / DCM), filtered, concentrated, and purified by FC (PE / EtOAc 3:2) to give methyl Int. 3C31 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.3 g).

[0941]

[0942] Int. 1AF88 / 2G97 (2.0 g / 2.3 g), KI (0.85 g), and Cs2CO3 (9.5 g) were mixed in ACN (20 mL) at 0 °C and stirred at room temperature for 16 hours. The mixture was then filtered and concentrated. The residue was purified by FC (hexane / EtOAc 4:1) to give Int. 2G85 methyl 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (2.0 g).

[0943]

[0944] Int. 1AF89 (1.5 g) was stirred at 90 °C in toluene / SOCl2 (7:3, 14.3 mL) for 0.3 h. The concentrated residue, Cs2CO3 (7.7 g), KI (0.49 g), and Int. 3C16 (2.1 g) were stirred in ACN (10 mL) at 0 °C to room temperature under an inert atmosphere for 16 h. The reaction mixture was concentrated and milled in water to precipitate a solid, which was washed with water, dried, and purified by FC (PE / EtOAc 9:1 to 17:3) to give Int. 2G96 methyl 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3,5-difluorobenzoate (1.5 g).

[0945]

[0946] Int. 1AF90 (15 g), Boc2O (17 g), and DMAP (0.64 g) were mixed and stirred in DCM / Et3N (4:1, 187 mL) at 0 °C for 16 hours and then filtered. OL (water / DCM) was dried, concentrated, and purified by FC (hexane / EtOAc 2:1) to give Int. 2G105 tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)-6-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid (14 g).

[0947]

[0948] Int. 2G105 (14 g) and Pd / C (7 g) were hydrogenated in MeOH (140 mL) for 16 hours, filtered, and concentrated to give Int. 2G104 tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)-6-methylphenyl)piperidin-1-carboxylate (13.2 g). Int. 2G104 (13.2 g) was stirred in a dioxane solution (2:5, 105 mL) of DCM / 4M HCl at 0 °C to room temperature for 16 hours. The mixture was concentrated and washed with pentane to give Int. 2G97 methyl 3-fluoro-5-methyl-4-(piperidin-4-yl)benzoate (9.0 g, hydrochloride). Int. 1AF88 / 2G97 (2.0 g / 2.3 g), KI (0.85 g), and Cs2CO3 (9.5 g) were stirred in ACN (20 mL) at 0 °C to room temperature for 16 hours. The mixture was filtered and concentrated. The residue was purified by FC (hexane / EtOAc 4:1) to give Int. 2G85 methyl 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (2.0 g).

[0949]

[0950] DIPEA (15 mL) was added at 0 °C to a solution of Int. 1AB8 / 2G97 (8.0 g / 12.5 g) in DCE / DMSO (5:1, 600 mL), and stirred at room temperature for 16 hours. STAB (28 g) was added and stirring continued for 16 hours. The solution was dried over OL (water / DCM / MeOH), filtered, concentrated, and purified by FC (hexane / MeOH 4:1 to 2:1) to give Int. 2G115 methyl 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (8.0 g).

[0951]

[0952] 4-Bromo-3,5-difluorobenzoate methyl ester (100g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (160g), PdDPPFCl 2-DCM (16 g) and NaHCO3 (100 g) were stirred in dioxane / H2O (10:3, 1.3 L) at 100 °C for 16 h under an inert atmosphere. The mixture was filtered. OL (brine / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 1:0 to 9:1) to give Int. 3C18 4-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (45 g). Int. 3C18 (100 g) and 5% wetted Pd / C (20 g) were stirred in MeOH (0.7 L) under a hydrogen atmosphere for 16 h. The mixture was filtered and concentrated to give Int. 3C17 tert-butyl 4-(2,6-difluoro-4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (90 g). Int. 3C17 (20 g) was stirred for 16 hours in a dioxane solution (2:1, 600 mL) of DCM / 4M HCl at 0 °C to room temperature. The mixture was concentrated and washed with Et2O to give Int. 3C16 methyl 3,5-difluoro-4-(piperidine-4-yl)benzoate (12 g, hydrochloride). Int. 1AB8 / 3C16 (3.5 g / 3.6 g) was stirred for 16 hours in a DCE / DMSO / DIPEA solution (7:3:1, 112 mL). STAB (12 g) was added at 0 °C, and the mixture was stirred for 16 hours at 0 °C to room temperature. OL (water / DCM) was dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give methyl 3,5-difluorobenzoate (4.0 g).

[0953]

[0954] The preparation of Int. 3C25. methyl 3,5-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate (16 g, hydrochloride) is similar to the preparation of Int. 3C16 from Int. 3C18 (20 g).

[0955]

[0956] Int. 1AF89 (9.0 g) was stirred at 90 °C in toluene / SOCl2 (6:1, 174 mL) for 0.5 h. The concentrated residue, Cs2CO3 (43 g), KI (2.7 g), and Int. 3C25 (10 g) were stirred in ACN (250 mL) at 0 °C to room temperature under an inert atmosphere for 16 h. The mixture was concentrated. OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 4:1) to give Int. 3C26 methyl 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.1 g). Int. 3C26 (0.85 g) was separated by SFC (operated at 30 °C on an SFC-150-008 instrument equipped with a Chiralpak-AD-H 150×25 mm 5 µm column, with eluent of 65% CO2 and 35% MeOH (80 g / min) and a back pressure of 100 bar) to obtain Int. 3C27 (0.30 g, first peak) and Int. 3C28 (0.30 g, second peak) methyl (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate and methyl (R)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate. The absolute configurations of these compounds are undetermined.

[0957]

[0958] Int. 1AB8 / 3C25 (8.0 g / 12.6 g) was stirred for 16 hours in DCE (80 mL) and DIPEA (35 mL) at 0 °C to room temperature under an inert atmosphere. STAB (28 g) was added in portions at 0 °C and stirring was continued for 12 hours. The solution was dried over OL (water / DCM), concentrated, and purified by FC (PE / EtOAc 3:2) to give methyl 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.3 g).

[0959]

[0960] ZnCl2 (1M Et2O solution, 31 mL) was added at 0 °C to a solution of Int. 1AB8 (2.7 g) and ethyl 4-(piperazin-1-yl)-benzoate (2.4 g) in THF (30 mL), and the mixture was stirred at room temperature for 16 hours. NaCNBH3 (3.4 g) was added and stirring was continued for 16 hours. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (PE / EtOAc 1:1) to give ethyl Int. 3C59 4-(4-(((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperazin-1-yl)benzoate (2.2 g).

[0961]

[0962] DIPEA (7.3 mL) was added to a solution of Int. 1AB8 / 1AF90 (2.0 g / 2.9 g) at 0 °C, and stirred in DCE (10 mL) at room temperature for 16 hours under an inert atmosphere. STAB (5.2 g) was added at 0 °C and stirring was continued for 2 hours. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane / EtOAc 3:2) to give methyl Int. 3C73 4-(1-((4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methylbenzoate (1.3 g).

[0963]

[0964] Int. 3E35 (1.7 g) and LiOH-H2O (1.1 g) were stirred in THF / MeOH / H2O (4:2:1, 25 mL) at 0 °C to room temperature for 3 hours and then concentrated. Al (water / Et2O) was acidified with KHSO4 to precipitate Int. 2C36 (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (1.5 g). The absolute configurations of derivatives 1AF76 and 1AF76' were determined.

[0965]

[0966] Int. 1AC5 (3.0 g), B2Pin2 (1.1 g), KOAc (2.0 g), and PdDPPFCl2-DCM (50 mg) were degassed in dioxane (30 mL) and stirred overnight at 90 °C. The filtered filtrate was concentrated and purified by FC (pentane / EtOAc 1:4) to give methyl 4-[1-[[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidinyl]benzoate (1.7 g).

[0967]

[0968] Int. 1AF21 (1.0 g) was stirred in toluene / SOCl2 (7.1:1, 22.8 mL) at 85-90 °C for 0.3 h. The concentrated residue, Cs2CO3 (3.8 g), KI (0.33 g), and methyl 4-(piperidin-4-yl)benzoate (1.3 g, hydrochloride) were stirred overnight in ACN (25 mL) at 0 °C to room temperature. The mixture was concentrated to half its volume and diluted with water to precipitate Int. 3E37 methyl 4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoate (1.4 g). Int. 3E37 (7.4 g) was resolved by SFC (using a Chiralpak IA 250×25 5 µm column (operated at 30 °C), with 60% CO2 and 40% MeOH as eluent, a flow rate of 90 g / min, and a back pressure of 100 bar) to obtain Int. 3E35 (S)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)methyl benzoate (3.0 g, first eluting isomer) and Int. 3E36 (R)-4-(1-(1-(4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)methyl benzoate (3.0 g, second eluting isomer). Determine the absolute configurations of derivatives 1AF76 and 1AF76'.

[0969]

[0970] 4-Bromo-3,5-dimethylbenzoate (0.50 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.70 g), Na 2CO3 (0.26 g) and PdDPPFCl2-DCM (84 mg) were degassed in dioxane / water (9:1; 8 mL) and stirred overnight at 90 °C. The solution was concentrated in OL (water / EtOAc) and purified by FC (hexane / EtOAc 7:3) to give Int. 3E45 tert-butyl 4-(4-methoxycarbonyl-2,6-dimethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid (0.55 g). This substance was stirred and concentrated in a dioxane solution of DCM / 4M HCl (5:4; 9 mL) at 0 °C to room temperature for 3 hours to give Int. 3E44 methyl 3,5-dimethyl-4-(1,2,3,6-tetrahydro-pyridine-4-yl)benzoate (0.44 g, hydrochloride). Int. 1AB8 / 3E44 (0.23 g / 0.30 g) was stirred in DCE / DIPEA (12.5:1, 5.4 mL) for 4 hours. STAB (0.41 g) was added and stirring continued overnight. The solution was dried over OL (water / EtOAc), concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 3E43 methyl 4-[1-[(4-bromo-1-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-dimethylbenzoate (0.33 g).

[0971]

[0972] Int. 3E35 (2.0 g), B2Pin2 (1.7 g), PdDPPFCl2-DCM (0.18 g), and KOAc (0.9 g) were degassed in dioxane (15 mL), stirred at 95℃-100℃ for 5 hours, filtered, concentrated, and ground in Et2O to obtain Int. 3E1704-[1-[(1S)-1-[1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-pyrrolo[2,3-b]pyridin-2-yl]-ethyl]-4-piperidinyl]methyl benzoate (2.3 g).

[0973]

[0974] Int. 3E35 (0.50 g), B2Pin2 (0.41 g), PdDPPFCl2-DCM (44 mg), and KOAc (0.21 g) were degassed in dioxane (10 mL), stirred at 95-100 °C for 5 hours, filtered, concentrated, and ground in Et2O to obtain Int. 3E170 and 3E177. A mixture of (S)-(2-(1-(4-(4-(methoxycarbonyl)phenyl)piperidin-1-yl)-ethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid and (S)-4-(1-(1-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)methyl benzoate (0.50 g).

[0975]

[0976] PdDPPFCl2-DCM (40 mg), Int. 1Z69 (0.24 g), bis(pinacol)diboron (0.15 g), and KOAc (0.14 g) were stirred overnight in dioxane (5 mL) at 100 °C under an inert atmosphere. The mixture was concentrated and purified by FC (THF) to give Int. 1Z47 3-fluoro-N,N,5-trimethyl-4-(1-(1-(1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.27 g). Int. 1AF84 (0.20 g), bis(pinacol)diboron (0.20 g), PdDPPFCl2-DCM (32 mg), and KOAc (0.12 g) were stirred in dioxane (10 mL) at 90 °C for 6 hours under an inert atmosphere. The mixture was filtered thro...

Claims

1. A compound having the following formula (I) in: A 1 Selected from , , , , and ; R 9 It is -AL-LBM; X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N; X 4 Selected from CR 4 R 4 and CO; X 5 Selected from N and oxidized N; Y 1 Selected from N and CR 7 ; Y 2 Selected from N and CR 8 ; Y 3 Selected from N and CR 17 ; Z is selected from N and CR. 10 ; R is NHR 0 ; R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR'R", -CONR'R", and -CO2R', wherein R' and R" are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2; R 1 and R 1a Independently selected from hydrogen, fluorine, and C 1-4 alkyl; R 2 Selected from hydrogen, C 1-5 Alkyl group, -SO2-C 1-4 Alkyl and deuterated C 1-4 Alkyl, wherein the C 1-5 Alkyl groups can be optionally substituted with halogens once or multiple times; R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl; R 4 and R 6 Each of them is independently selected from hydrogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy group can be optionally replaced by one or more halogens; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group can be optionally replaced by one or more halogens; R 10 Selected from hydrogen and fluorine; Or R 5 and R 10 They form bonds together between the two carbons to which they are attached; R 5a It is hydrogen; Or R 5 and R 5a Both are fluorine, or R 5 and R 5a Together with the atoms attached to it, they form CO groups; R 5b and R 5c Each is independently selected from hydrogen and fluorine; R 7 R 8 and R 17 Each is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl and C 1-4 Alkoxy and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group can be optionally replaced by one or more halogens; R 11 R 12 and R 13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R", -CONR'R", -CO2R' and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R" are each independently selected from hydrogen and C. 1-4 Alkyl; or R 11 and R 0 Together with the atoms attached thereto, it forms a 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms, wherein the 5-6 membered heteroaromatic ring or heterocycle containing one or two N atoms is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -COCF3, -NR'R", -CONR'R", and -CO2R', wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy group, wherein R' and R" are each independently selected from hydrogen and C. 1-4 Alkyl; and R 12 and R 13 Each is independently selected from hydrogen, halogen, and C. 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R”, -CONR'R”, -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R" are each independently selected from hydrogen and C. 1-4 alkyl; A is CO; L is selected from ； Where n1 is selected from 0 and 1; n2 is selected from 1 and 2; R 17 Selected from hydrogen and fluorine; R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can be optionally fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times; R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine; R 20 Selected from hydrogen and C 1-4 alkyl; X 6 It is C; X 7 It is CR 24 Or N; R 24 Selected from hydrogen and hydroxyl groups; X 8 and X 9 It is CH or N independently; and LBM is Where X 7 It is O, NR 22 or CR 23 R 23 ; R 21 Selected from hydrogen, fluorine, and chlorine; R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups can be optionally converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times; Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O; Or its pharmaceutically acceptable salts or stereoisomers.

2. A compound having the following formula (I') (I’) in: X 1 Selected from N and CR 11 ;X 2 Selected from N and CR 12 And X 3 Selected from N and CR 13 The condition is that only X 1 X 2 and X 3 One of them can be N; X 4 It is CR 4 R 4 or CO; Y 1 Selected from N and CR 7 ; Y 2 Selected from N and CR 8 ; Z is selected from N and CR. 10 ; R is NHR 0 ; R 0 Selected from hydrogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, Halogenated -C 1-4 Alkyl group, -(CH2) n -OC 1-4 Alkyl group, -(CH2) n -CO-R' and -(CH2) n -CO2R', wherein the phenyl group is optionally substituted once or more independently by a substituent selected from the following: halogen, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR'R'', -CONR'R'', and -CO2R', wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl group, and n is 0, 1, or 2; R 1a It is hydrogen; R 2 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 Alkyl; wherein the C 1-4 Alkyl groups can be optionally substituted with halogens once or multiple times; R 3 Selected from hydrogen, C 1-4 Alkyl and deuterated C 1-4 alkyl; R 4 and R 6 Independently selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can optionally be substituted with one or more halogens; R 5 Selected from hydrogen, halogens, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy group can be optionally replaced by one or more halogens; R 10 Selected from hydrogen and fluorine; Or R 5 and R 10 They form bonds together between the two carbons to which they are attached; R 5a It is hydrogen; or R 5 and R 5a Both are fluorine; R 7 and R 8 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 Alkyl groups can be independently and optionally substituted with one or more halogens; R 11 Selected from hydrogen, halogens, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 Alkyl; or R 11 and R 0 Together with the atoms attached thereto, it can form a 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N, wherein the 5-6 membered heterocycle or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted once or more independently by substituents selected from: halogens, C 1-4 Alkyl, Halogenated -C 1-4 Alkyl, C 3-4 Cycloalkyl, hydroxyl, C 1-4 Alkyl, cyano, -NR'R'', -CONR'R'' and -CO2R', wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times independently by substituents selected from the following: halogens and C. 1-4 Alkoxy group, wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl; R 12 and R 13 Independently selected from hydrogen, halogen, C 1-4 Alkyl, C 3-4 cycloalkyl, C 1-4 Alkyl, hydroxyl, cyano, -NR'R'', -CONR'R'', -CO2R', -CO-CO2R', and -CO-(CH2) m OH, wherein the C 1-4 The alkyl group is optionally substituted once or more independently by substituents selected from the following: halogen, hydroxyl, and C. 1-4 Alkoxy group, wherein m is 1, 2 or 3, and wherein R' and R'' are each independently selected from hydrogen and C. 1-4 alkyl; A is CO; L is selected from ； Where n1 is selected from 0 and 1; n2 is selected from 1 and 2; R 17 Selected from hydrogen and fluorine; R 18 Selected from hydrogen, fluorine, and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can be optionally fluorinated or C 1-4 Alkyl groups may be substituted once or multiple times; R 19 Independently selected from hydrogen and C 1-4 Alkyl and fluorine; R 20 Selected from hydrogen and C 1-4 alkyl; X 6 It is C; X 7 It is CR 24 Or N; R 24 Selected from hydrogen and hydroxyl groups; X 8 and X 9 It is CH or N independently; and LBM is Where X 7 It is O, NR 22 or CR 23 R 23 ; R 21 Selected from hydrogen, fluorine, and chlorine; R 22 Selected from hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl and C 3-4 cycloalkyl, wherein the C 1-4 Alkyl groups can be optionally converted to fluorine, hydroxyl, or C. 1-4 Alkoxy or C 3-4 Cycloalkyl substitution once or multiple times; Each R 23 Independently selected from hydrogen, halogens and C 1-4 Alkyl; or Two Rs 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl or 3-6 membered heterocycles, wherein the heterocycle contains one or two heteroatoms selected from O; Or its pharmaceutically acceptable salts or stereoisomers.

3. The compound according to claim 2, wherein the compound has formula (II) or formula (II'). (II) (II’) Where R 3 It is C 1-4 alkyl; Or its pharmaceutically acceptable salts or stereoisomers.

4. The compound according to claim 2, wherein the compound has the following formula (III) (III) Or its pharmaceutically acceptable salts or stereoisomers.

5. The compound according to claim 4, wherein the compound has the following formula (IV). (IV) Where R 3 It is C 1-4 alkyl; Or its pharmaceutically acceptable salts or stereoisomers.

6. The compound according to any one of claims 1 to 5, wherein R is NHR 0 And R 0 Selected from hydrogen and C 1-4 alkyl.

7. The compound according to claim 2, wherein the compound has the following formula (VII). (VII) Where R 16 Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times by substituents independently selected from halogens; Or its pharmaceutically acceptable salts or stereoisomers.

8. The compound according to claim 7, wherein the compound has the following formula (VIII) (VIII) Where R 16 Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times by substituents independently selected from halogens; Or its pharmaceutically acceptable salts or stereoisomers.

9. The compound according to claim 2, wherein the compound has the following formula (IX): (IX) Where R 16 and R 16a Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times by substituents independently selected from halogens; Or its pharmaceutically acceptable salts or stereoisomers.

10. The compound according to claim 2, wherein the compound has the following formula (IXa) or formula (IXb): (IXa) or (IXb) Where R 16 and R 16a Selected from hydrogen and C 1-4 Alkyl, wherein the C 1-4 Alkyl groups can optionally be substituted once or multiple times by substituents independently selected from halogens; Or its pharmaceutically acceptable salts or stereoisomers.

11. The compound according to any one of claims 1 to 10, wherein X 7 It is NR 22 And R 22 It is a methyl group.

12. The compound according to any one of claims 1 to 10, wherein X 7 It is NR 22 And R 22 It is cyclopropyl.

13. The compound according to any one of claims 1 to 10, wherein X 7 It is CR 23 R 23 And two R 23 Both are methyl or two R 23 They're all fluorine.

14. The compound according to any one of claims 1 to 10, wherein X 7 It is CR 23 R 23 And two R 23 Together with the carbon attached to them, they form C 3-6 Cycloalkyl.

15. The compound according to any one of claims 1 to 10, wherein X 7 It is CR 23 R 23 And two R 23 Together with the carbon atoms attached to them, they form 3-6 membered heterocycles, wherein the heterocycles contain a heteroatom that is O.

16. The compound according to any one of claims 1 to 10, wherein AL-LBM is 。 17. The compound according to any one of claims 1 to 10, wherein AL-LBM is Where n3 is 0, 1, 2 or 3.

18. The compound according to any one of claims 1 to 17, wherein Z is N.

19. The compound according to any one of claims 1 to 17, wherein Z is CR 10 And R 5 and R 10 They form bonds together.

20. The compound according to any one of claims 1 to 17, wherein Z is CR 10 And R 10 It is hydrogen.

21. The compound according to any one of claims 1 to 20, wherein Y 1 It is N, and Y 2 It is CR 8 .

22. The compound according to any one of claims 1 to 20, wherein Y 1 It is N, and Y 2 It is N.

23. The compound according to any one of claims 1 to 20, wherein Y 1 It is CR 7 And Y 2 It is CR 8 .

24. The compound according to claim 23, wherein... (a)R 7 and R 8 Both are C 1-4 alkyl; (b)R 7 and R 8 Both are halogens; (c)R 7 and R 8 One of them is C 1-4 Alkyl groups, and the other is a halogen; (d) R 7 and R 8 One of them is C 1-4 Alkyl group, and the other is hydrogen; or (e)R 7 and R 8 One of them is halogen, and the other is hydrogen.

25. The compound according to claim 24, wherein R 7 It is halogen, and R 8 It is a methyl group.

26. The compound according to claim 24, wherein the halogen in b), c) and e) is fluorine.

27. The compound according to any one of claims 1 to 26, wherein R 12 and R 13 It is hydrogen.

28. The compound according to any one of claims 1 to 7 and 16 to 27, wherein R 11 R 12 and R 13 It is hydrogen.

29. The compound according to any one of claims 1 to 28, wherein X 4 It is CR 4 R 4 And each R 4 Independently selected from hydrogen and C 1-4 alkyl.

30. The compound according to any one of claims 1 to 29, wherein R 2 It is a methyl group.

31. The compound according to any one of claims 1 to 30, wherein R 3 Is it hydrogen or C? 1-4 alkyl.

32. The compound according to any one of claims 1 to 31, wherein R 3 It is a methyl group.

33. The compound according to any one of claims 1 to 32, wherein R 5a It is hydrogen.

34. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from Table 1.

35. The compound according to any one of claims 1 to 34, wherein the compound is used in a therapeutic manner.

36. The compound according to any one of claims 1 to 34, wherein the compound is used to treat a disease, symptom or condition that is responsive to regulation of STAT6.

37. The compound according to any one of claims 1 to 34, wherein the compound is used to treat autoimmune diseases.

38. The compound or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 34, wherein the compound or a pharmaceutically acceptable salt or stereoisomer thereof is used to prevent, treat or improve any of the following diseases characterized by Th2-mediated inflammation: such as atopic dermatitis, asthma, chronic sinusitis with nasal polyps, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse systemic sclerosis of the cutaneous body, alopecia areata and / or COPD (chronic obstructive pulmonary disease), and as a standalone treatment or in combination with other anticancer drugs such as checkpoint inhibitors for the prevention, treatment or improvement of various cancers, such as lymphoma, triple-negative breast cancer and solid fibrotic cancer.

39. The use of any compound of claims 1 to 34, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for treating a subject for a disease or symptom mediated by the activity of the signal transducer and activator of transcription 6 (STAT6) protein.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable medium or excipient or pharmaceutically acceptable carrier.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable excipient.

42. The pharmaceutical composition according to claim 40 or 41, wherein the pharmaceutical composition further comprises one or more additional therapeutic agents.

43. A method of treating an immune-mediated disease or condition in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to any one of claims 40 to 42.

44. A method for modulating the activity of signal transducer and activator of transcription 6 (STAT6) protein in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to any one of claims 40 to 42.

45. The method of claim 44, wherein the method comprises degrading STAT6 protein in a subject in need.

46. ​​A method for treating a subject in need of a disease or symptom mediated by the activity of a signal transducer and activator of transcription 6 (STAT6) protein, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to any one of claims 40 to 42.

47. The method of claim 46, wherein the STAT6-mediated condition or disease belongs to the disease category of rheumatism, gastrointestinal disease, lung disease, liver disease, kidney disease, skin disease, or allergic disease.

48. The method of claim 46, wherein the STAT6-mediated condition or disease is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), ulcerative colitis (UC), Crohn's disease (CD), idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD), metabolic dysfunction-associated steatohepatitis (MASH), diabetic kidney disease (DKD), diabetic nephropathy (DN), or atopic dermatitis (AD).

49. The method of claim 46, wherein the STAT6-mediated condition or disease is atopic dermatitis, contact dermatitis, vitiligo, alopecia areata, acne, psoriasis, dermatomyositis, scleroderma, or morphine.

50. The method of claim 46, wherein the STAT6-mediated condition or disease is atopic dermatitis.

51. A method for treating a subject in need of a disease or condition mediated by interleukin-4 (IL-4) or interleukin-3 (IL-3), the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to any one of claims 40 to 42.

52. A method for manufacturing a medicament for treating a disease or symptom mediated by the activity of the signal transducer and activator of transcription 6 (STAT6) protein in a subject of need, the method being characterized by using a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt or stereoisomer thereof.

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