STAT6 degraders

Abstract

The present disclosure relates to a compound according to formula (I) and pharmaceutically acceptable salts, hydrates, or solvates thereof. The disclosure further relates to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases, e.g. dermal diseases, with said compounds, and to the use of said compounds in the manufacture of medicaments.

Description

This application claims priority to European Patent Application No. EP24167017.3, filed March 27, 2024, which is incorporated herein in its entirety for all purposes. FIELD Provided herein are novel azaindole compounds and pharmaceutically acceptable salts thereof that modulate STAT6 and pharmaceutical compositions comprising said compounds for use in therapy (e.g., for treating STAT6 associated diseases in a subject in need thereof). BACKGROUND The disclosure relates generally to methods and compounds, and pharmaceutically acceptable salts thereof, for modulating a Signal transducer and activator of transcription 6 (STAT6) protein activity and treating STAT6 associated diseases. The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. The present disclosure relates novel bifunctional compounds and pharmaceutically acceptable salts thereof, which may function to recruit STAT6 proteins to E3 ubiquitin ligase for degradation, compositions containing such compounds and methods and uses thereof. In particular, the present disclosure provides bifunctional compounds and pharmaceutically acceptable salts thereof, which find utility as modulators of targeted ubiquitination of STAT6 proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds as described herein. Ubiquitin-Proteasome Pathway (UPP) is a pathway that regulates key regulator proteins and degrades proteins, such as misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it can lead to pathogenesis of a variety of diseases. The attachment of ubiquitin to specific protein substrates can be achieved through the action of E3 ubiquitin ligases. There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be generally divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally 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, 399434) titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.” UPP plays a role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), in immune surveillance / viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles. Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target. The UPP can be used to induce selective protein degradation, including via use of fusion proteins to ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand, can induce proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds can be capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551 -555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1): 40-46). The signal Transducer and Activator of Transcription 6 (STAT6) belongs to a family of transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) which may be structurally and / or functionally related, and which may be involved in mediating signalling from multiple cytokine and / or growth factor receptors. Without being bound by theory, STAT6 can selectively mediate signaling from IL-4 and IL-13 via the IL-4Ra subunit complexing with either the common gamma chain (yc) to form the type I receptor or with the IL-13Ral subunit to form a type II receptor. When IL-4 or IL-13 activates the receptor complex, the Janus Kinases (Jak) associated with the cytoplasmic tail of IL-4Ra can be activated and phosphorylate tyrosine residues on the intracellular part of the receptor. This phosphorylation can generate docking site(s) for STAT6, which can bind to the phosphorylated receptor via its Src homology-2 (SH2) domain. This may allow Jak kinases to phosphorylate tyrosine (Y)-641 on STAT6, potentially leading to activation. Activated STAT6 may form a homodimer and relocate to the nucleus and activate gene transcription. The genes transcribed by activated STAT6 can be cell specific and could in general induce Th2 immune responses (Walford and Taylor 2013: STAT6 and lung inflammation. JAK-STAT 2:4, e25301; October / November / December 2013; © 2013 Landes Bioscience). STAT6 is expressed in numerous cell types including epithelial cells, fibroblasts, and immune cells. Without being bound by theory, inhibition of STAT6 activity can inhibit the IL-4 and IL-13 mediated effects in cells, including the differentiation of T-cells into Th2 cells and B-cell class shift into IgE and IgGl producing cells (Walford). In epidermal keratinocytes, a STAT6 inhibitor could inhibit the secretion of pro-inflammatory chemokines and revert the cytokine-induced inhibition of 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. Antibodies targeting Th2 immune responses, such as the IL-4Ra (dupilumab) or IL-13 (tralokinumab, lebrikizumab), have shown efficacy in a number of Th2-driven diseases. Targeting STAT6 with a small molecule inhibitor allows for targeting the same pathway by an oral or dermal administration route and may have efficacy in diseases where dupilumab has shown effect. A compound antagonizing STAT6 could, therefore, have utility in treating conditions characterized by Th2-mediated inflammation such as atopic dermatitis, prurigo nodularis, Bullous phemphigoid, asthma, chronic rhinosinusitis with nasal polyposis, urticaria (such as chronic spontaneous urticaria), rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD. STAT6 is also involved in differentiation and activity of M2 macrophages, including the tumor-associated macrophages (TAMs) in solid tumors. TAMs protect the tumor from immune attack by inducing a pro-tumor immunosuppressive environment. TAMs may inhibit T-cell proliferation, block migration of CD8 T-cells into 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). In addition, IL-13 may 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 a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology. Pathology - Research and Practice 223 (2021) 153477). Together these data suggests that a STAT6 degraders may treat different cancers such as lymphomas, non-small cell lung cancer and solid fibrous cancers either as a stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors. Although various antibodies against IL-4R or IL-13 are approved for medical use, there are currently no approved, orally available degraders of STAT6. Therefore, there remains a continuous need to develop degraders of STAT-6, particularly small molecules suitable for oral administration. In addition, some patients may be treated by topical application of degraders of STAT-6. This can be particularly suitable, for example, for patients with skin lesions that are readily accessible and limited to areas on the body surface. Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the STAT-6 pathway, for example when undergoing treatment for infections or gastrointestinal problems. SUMMARY The inventors have surprisingly found that the novel compounds and salts thereof as described in the present disclosure exhibit modulating effects on the STAT-6 signalling pathway. For example, the compounds and pharmaceutically acceptable salts thereof as described herein may be beneficial in preventing, treating or ameliorating a variety of diseases which involve up-regulation or deregulation of STAT-6. Furthermore, the compounds and phar maceutically acceptable salts thereof as described herein have advantageous properties such as high metabolic stability, membrane permeability and / or solubility that make them particularly suitable for oral administration. Moreover, some patients may be treated by topical application of degraders of STAT-6. This can be particularly suitable, for example, for patients with skin lesions that are readily accessible and limited to areas on the body surface. Topical treatment may also be prescribed for certain patients who could benefit from avoiding systemic modulation of the STAT-6 pathway, for example when undergoing treatment for infections or gastrointestinal problems. Thus, some aspects of the present disclosure relate to methods for the topical application of the compounds and salts thereof as described herein. Accordingly, in some embodiments, provided herein are compounds and pharmaceutically acceptable salts thereof according to formula (I): A' is selected from X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14and N, and wherein whenX4 is N the N may be an N-oxide, or X1 is CR11 and taken together with R forms a 5-membered heteroaryl ring which is optionally substituted with C(O)CF3; X5 is selected from CR4R4 and CO; Xa is selected from N and oxidized N; Y1 is selected from N and CR7; Y2 is selected from N and CR8; Y3 is selected from N and CR17; Z is selected from N and CR10; R is selected from NHR° and -CONHR0; R° is selected from hydrogen, Curalkyl, C3 4 cycloalkyl, C3 rcycloalkyl-Ciralkyl, phenyl-Cmalkyl, halo-Ciualkyl, -(CH2)n-O-R\ -(CH2)n-CO-Ci-4alkyl and -(CHd.-COiR'. wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Ci ^alkyl, halo-Cr 4alkyl, C3 4cycloalkyl, hydroxy, Ci ^alkoxy, cyano, -NR'R", -CONR'R" and -CO2R', wherein R' and R" are each independently selected from hydrogen and Ci ralkyl and n is 0, 1 or 2; R1 and Rla are independently selected from hydrogen, fluoro and Cwalkyl; R2 is selected from hydrogen, Cusalkyl, -SO2-C Malkyl and deuterated Ci ralkyl, wherein said Cisalkyl may optionally be substituted one or more times with fluoro; R3 is independently selected from hydrogen, Ci ralkyl, and deuterated Cmalkyl; each R4 and R6 are independently selected from hydrogen, Cmalkyl, and Ci ^alkoxy, wherein said Ci 4alkyl and Ci ^alkoxy may optionally be substituted with one or more halogen; R5 is selected from hydrogen, halogen, Ci ralkyl and Cwalkoxy, wherein said Ci ^alkyl and Ci 4alkoxy may optionally be substituted with one or more halogen; R10 is selected from hydrogen and fluoro; or R5 and R10 together form a bond between the two carbon atoms to which they are attached; R5a is hydrogen; or R5 and R,a are both fluoro or R5 and R,a together with the atom attached thereto form a CO group; R5b and R5c are each independently selected from hydrogen and fluoro; R7, R8, and R17 are each independently selected from hydrogen, halogen, cyano, Ci-4alkyl and Cr 4alkoxy,and C3 ucycloalkyl, wherein said Ci ralkyl and Ciualkoxy may optionally be substituted with one or more halogen; R9 is -A-L-LBM; R11, R12, R13 and R14 are each independently selected from hydrogen, halogen, Ci-4alkyl, C3 4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, - NR'R", -CONR'R", -CO2R', -CO-CO2R', -CO-(CH2)mOH, tetrazolyl and -SO^-Ci ifilkyL wherein said Ci-4alkyl and Cmalkoxy are optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci ialkoxy, wherein m is 1, 2 or 3; or R11 and R° together with the atoms attached thereto form a 5-6 membered heteroaromatic or 5 heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or heterocyclic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Cj-4alkyl, halo-Ci-4alkyl, C3-4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, -COF3, -NR'R", -CONR'R" and -CChR, wherein said Cmalkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci ialkoxy; L is selected from: wherein R17 is selected from hydrogen and fluoro; 5           R18 is selected from hydrogen and fluoro; R19 is selected from hydrogen and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; 10            n2 is selected from 1 and 2; X6 is CH or N; X7 is selected from N and CH; and LBM is selected from R21    R23                       R22                R21    R22 R22 wherein X8 is selected from O, NH, and triazolyl; 5            R21 is selected from hydrogen, fluoro, chloro, cyano, Ci-4alkyl and trifluoroniethyl; R22 is selected from hydrogen and fluoro; R23 is selected from hydrogen, fluoro and Cwalkoxy; or a pharmaceutically acceptable salt or stereoisomer thereof. Accordingly, in some embodiments, provided herein are compounds and pharmaceutically 10 acceptable salts thereof according to formula (I’): A-L-LBM wherein: X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14 and N, and wherein when X4 is N the N may be oxidized to a N-oxide; 15          X5 is CO or CR4R4; Y1 is selected from N and CR7; Y2 is selected from N and CR8; Z is selected from N and CR10; R is NHR°; R° is selected from hydrogen, Ci ralkyl, C3 rcycloalkyl, Cmcycloalkyl-Ciialkyl, phenyl-Cmalkyl, halo-Ci ralkyl, -(CHi)n-O-R / , -(CH2)n-CO-Ci-4alkyl and -(CH2)n-CO2R', wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Cmalkyl, halo-Ciralkyl, C3-4 cycloalkyl, hydroxy, Cmalkoxy, cyano, - NR'R", -CON R'R". and -CO2R'. wherein R' and R" are each independently selected from hydrogen and Cmalkyl and n is 0, 1, or 2; R1 and Rla are independently selected from hydrogen, fluoro, and Ci-4alkyl; R2 is selected from hydrogen, Ci salkyl, and deuterated Ci-4alkyl, wherein said Cmalkyl may optionally be substituted one or more times with fluoro; R3 is selected from hydrogen, Ci ialkyl and deuterated Cmalkyl; each of R4 and R6 are independently selected from hydrogen, Cmalkyl, and Cmalkoxy, wherein said Cmalkyl and Cmalkoxy may optionally be substituted with one or more halogen; R5 is selected from hydrogen, fluoro, and Ci-4alkyl; wherein said Cmalkyl may optionally be substituted with one or more halogen, and R5a and R10 is hydrogen; or R5 and R,a are both selected from fluoro and R10 is hydrogen; or R5 and R10 together form a bond between the two carbon atoms to which they are attached, and R5a is hydrogen; R7 and R8 are independently selected from hydrogen, halogen, Ci ralkyl, and Cmalkoxy. wherein said Cmalkyl and Ci ^alkoxy may optionally be substituted with one or more halogen; R11, R12, R13 and R14 are independently selected from hydrogen, halogen, Ciaalkyl, C3 4 cycloalkyl, Ci ralkoxy, hydroxy, cyano, -NR'R"', -CONR'R", -CO2R', -CO-CO2R', -CO-(CH2)mOH, tetrazolyl and -SO2-C malkyl, wherein said Cmalkyl and Ciralkoxy is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and Cmalkoxy, wherein m is 1, 2 or 3; R11 and R° may together form a 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic ring containing one or two N atoms is optionally be substituted one or more times with a substituent independently selected from halogen, Cmalkyl, halo-C malkyl, C3 4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, -COF3, -NR'R", -CONR'R", and -CO2R', wherein said Cmalkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Cmalkoxy; A is CO or L is selected from: wherein R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen and fluoro; R19 is selected from hydrogen and Ciralkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; n2 is selected from 1 and 2; X6 is CH or N; X7 is selected from N and CH; and LBM is selected from R22 5           wherein X8 is selected from 0, NH, and triazolyl; R21 is selected from hydrogen, fluoro, chloro, cyano, Cj-4alkyl and trifluoromethyl; R22 is selected from hydrogen and fluoro; R23 is selected from hydrogen, fluoro and Ci-4alkoxy; 10            or a pharmaceutically acceptable salt or stereoisomer thereof. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient. In another embodiment, the present disclosure provides a method of treating an immune mediated 15 disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the present disclosure. In another embodiment, the present disclosure provides a method of modulating a signal transducer and activator of transcription 6 (STAT6) protein activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the present disclosure. In another embodiment, the present disclosure provides a method of treating a disease or condition mediated by a signal transducer and activator of transcription 6 (STAT6) protein activity in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of the present disclosure. In another embodiment, the present disclosure provides a method of treating a disease or condition mediated by interleukin 4 (IL-4) or interleukin 3 (IL-3) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof or stereoisomer, or a pharmaceutical composition of the present disclosure. In an embodiment the disclosure provides a method of preventing, treating or ameliorating a diseases characterized by Th2-mediated inflammation. In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating a disease or condition mediated by a signal transducer and activator of transcription 6 (STAT6) protein activity in a subject in need thereof, characterized in that a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is used. In another embodiment, the present disclosure provides a method for manufacturing a medicament for the treatment of a disease or condition mediated by a signal transducer and activator of transcription 6 (STAT6) protein in a subject. In some embodiments, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in treating a disease or condition mediated by a signal transducer and activator of transcription 6 (STAT6) protein in a subject in need thereof. In some embodiments, the present disclosure provides the compound of the present disclosure, or a pharmaceutically acceptable salt thereof or stereoisomer, for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the sensorgrams for Examples 2al, 2tl, 2ml, and 2a2 are shown below (where RU is plotted vs. time in seconds; dotted lines / points were excluded from the analysis due to effects from nonspecific binding) FIG. 2 shows the dose-response curves for Examples 2a2, 2tl, 2h3, and 2rl are shown below (where percent degradation is plotted vs. test compound concentration in M on a log-scale). FIG. 3 shows the data from the human whole blood eotaxin-3 assay is shown below for Examples 2qll, 2110, and 2c49 (where the effect in % is plotted against the test concentration in M on a log-scale). Definitions Whenever the compound of formula (I) is mentioned herein it should be understood that the compound of formula (I’), (II), (III), (I-b), (Il-b), and (Ill-b), and other subformulas described herein, are subgroups of the compound of formula (I) and that a statement related to the compound of formula (I) relates equally well to its subgroups. The prefix “Cu v” indicates that the following group has from u to v carbon atoms. For example, “Cm alkyl” indicates that the alkyl group has from 1 to 4 carbon atoms. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount + 5%. In certain other embodiments, the term “about” includes the indicated amount ±1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. The term “CMalkyl” is used herein to refer to hydrocarbon radical obtained when one hydrogen atom is removed from a branched or linear hydrocarbon. Said alkyl comprises (1-4) carbon atoms, 1-3 carbon atoms, 2-3 carbon atoms or 1-2 carbon atoms. The term includes the subclasses normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term “(Ci-C4)alkoxy” is used herein to refer to a radical of the formula -ORa, wherein Ra is (Ci-C4)alkyl as indicated herein, wherein the (Ci-C4)alkyl group is appended to the parent molecular' moiety through an oxygen atom, e.g. methoxy (-OCHa), and ethoxy (-OCH2CH3). The term “cyano” is used herein to refer to a -CN group attached to the parent molecular moiety through the carbon atom. The term “(C3-C4)cycloalkyl” is used herein to refer to a saturated (C3-C4)cycloalkane hydrocarbon radical, comprising 3-4 carbon atoms, e.g. cyclopropyl or cyclobutyl. The term “halogen” or “halo” is used herein to refer to chloro, bromo, fluoro, or iodo. In some embodiments, halogen is chloro, bromo, or fluoro. “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) including fused systems. An aryl may have 6 to 20 ring carbon atoms (i.e., C6 20 aryl), 6 to 12 carbon ring atoms (i.e., Ce 12 aryl), or 6 to 10 carbon ring atoms (i.e., Ce 10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of point of attachment. If one or more aryl groups are fused with a cycloalkyl, the resulting ring system is cycloalkyl regardless of point of attachment. “Heteroaromatic ring” or “heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur unless specified otherwise. A heteroaryl may include 1 to 20 ring carbon atoms (i.e., Ci-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C312 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur'. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, thiophenyl (i.e., thienyl), triazolyl, tetrazolyl, and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either 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 the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. “Heterocyclic ring” or “heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, unless specified otherwise. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro, and may comprise one or more (e.g., 1 to 3) oxo (=0) or N-oxide (-0 ) moieties. Any nonaromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, an aryl, or heteroaryl ring, regardless of the attachment to the remainder of the molecule. A heterocyclyl may have 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2 12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C210 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C312 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3 8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3 6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1 -dioxo-thiomorpholinyl. The term “halo-Cmaikyl” or “halo-Ci ralkoxy” is used herein to refer to an “Cwalkyl” or “Ci 4alkoxy” group respectively as defined above in which one or more hydrogen atoms have been replaced by halogen ( e.g. fluorine). Examples of “halo-Cmalkyl” or “halo-Ci 4alkoxy” include -CHF2, -CF3, -CH2CF3, -CF2CF3 or -OCF3. The term “deuterated Ciralkyl” is used herein to refer to an “Ci 4alkyF group in which one or more hydrogen atoms have been replaced by deuterium. Examples of “deuterated Chalky!” include -CH2D2, -CHD2 or -CD3. The term “Cmalkoxyl-Cmalkyl” is used herein the refer to “Cmalkyl” group in which one hydrogen atom have been replaced by (C1-C4)alkoxy. Examples of “Ci-4alkoxyl-Ci-4alkyl” include methoxymethyl or methoxy ethyl. The term “(Cs-CrKycloalkyl-Cmalkyl” is used herein the refer to “Ci ialkyl” group in which one hydrogen atom have been replaced by (C3-C4)cycloalkyl. Examples of “(C3-C4)cycloalkyl-Ci-4alkyl” include cyclopropylmethyl. The term “phenyl-Ci-4alkyl” is used herein the refer to “Ciralkyl” group in which one hydrogen atom have been replaced by phenyl. Examples of “phenyl-Ciralkyl” include benzyl. If substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent may therefore be identical or different from the other substituent(s). The term “optionally substituted” means “unsubstituted or substituted.” In some embodiments, formulas described herein encompasses compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s). In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three. As used herein whenever a molecular drawing of a substituent contains an arrow - the arrow indicates the bond attaching the substituent to the rest of the molecule. The term “pharmaceutically acceptable salt” is intended to indicate non-toxic salts including a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from an appropriate basic moiety, with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic, 2-hydroxyethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula (1) comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, zinc hydroxide, barium hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines (such as diethylamine, tetraalkylammonium hydroxide), hydroxy-lower alkylamines (such as diethanolamine, 2-(diethylamino)-ethanol, ethanolamine, triethanolamine, tromethamine, deanol), cycloalkylamines, ethylene diamine, or benzylamines, (such as benethamine and benzathine), betaine, choline hydroxide, N-methyl-glucamine, hydrabamine, IH-imidazole, 4-(2-hydroxyethyl)-morpholine, piperazine, l-(2-hydroxyethyl)-pyrrolidine, L-arginine or L-lysine. Further examples of pharmaceutical acceptable salts are listed in Berge, S.M.; J. Pharm. Sci.; (1977), 66(1), 1-19, and Stahl, P.H. and in Wermuth, C.G, Handbook of Pharmaceutical Salts, Properties, Selection and Use, 2nd Edition, Wiley-VCH, 2011 both of which are incorporated herein by reference. Compounds of the disclosure containing an amine function may also form N- oxides. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane. The term “solvate” is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a crystalline form. When water is the solvent, said species is referred to as a hydrate. The term “treatment” as used herein means the management and care of a patient for the purpose of combating a disease, disorder or condition. The term is intended to include the delaying of the progression of the disease, disorder or condition, the amelioration, alleviation or relief of symptoms and complications, and / or the cure or elimination of the disease, disorder or condition. The term may also include prevention of the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects. “Administering” refers to oral administration, administration as a suppository, topical contact (e.g., transdermal), parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, inhaled, intradermal, and / or subcutaneous administration, intrathecal administration, and / or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. The administration can be carried out according to a schedule specifying frequency of administration, dose for administration, and other factors. “Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient. Compounds Provided herein are compounds that modulate the activity of STAT6. In one embodiments, provided is a compound of formula (I): X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14 and N, and wherein when X4 is N the N may be an N-oxide, or X1 is CR11 and taken together with R forms a 5-membered heteroaryl ring which is optionally substituted with C(O)CFj; X5 is selected from CR4R4 and CO; Xa is selected from N and oxidized N; Y1 is selected from N and CR7; Y2 is selected from N and CR8; Y3 is selected from N and CR17; Z is selected from N and CR10; R is selected from NHR° and -CONHR0; R° is selected from hydrogen, Ci^alkyl, C3-4 cycloalkyl, C; rcycloalkyl-Ci ralkyl, phenyl-Ci ralkyl, halo-Ci ralkyl, -(CH2)n-O-R\ -(CH2)n-CO-Ci-4alkyl and-(CfFh-CChlC. wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Cwalkyl, halo-Cr 4alkyl, C3 4cycloalkyl, hydroxy, Cmalkoxy, cyano, -NR'R", -CONR'R" and -CO2R', wherein R' and R" are each independently selected from hydrogen and Ci ^alkyl and n is 0, 1 or 2; R1 and Rla arc independently selected from hydrogen, fluoro and Ci-4alkyl; R2 is selected from hydrogen, Ci salkyl, -SO2-C । 4alkyl and deuterated Ci ralkyl, wherein said Ci ,alkyl may optionally be substituted one or more times with fluoro; R3 is independently selected from hydrogen, Ci ralkyl, and deuterated Cmalkyl; each R4 and R6 are independently selected from hydrogen, Cmalkyl, and Cmalkoxy, wherein said Ci 4alkyl and Cmalkoxy may optionally be substituted with one or more halogen; R5 is selected from hydrogen, halogen. Ci ralkyl and Cwalkoxy. wherein said Ci-4alkyl and Cn 4alkoxy may optionally be substituted with one or more halogen; R10 is selected from hydrogen and fluoro; or R5 and R10 together form a bond between the two carbon atoms to which they are attached; R5a is hydrogen; or R5 and R5a are both fluoro or R5 and R5a together with the atom attached thereto form a CO group; R5b and R5c are each independently selected from hydrogen and fluoro; R7, R8, and R17 are each independently selected from hydrogen, halogen, cyano, Ci 4alkyl and Ci 4alkoxy,and C; rcycloalkyl, wherein said Ci ralkyl and Cmalkoxy may optionally be substituted with one or more halogen; R9 is -A-L-LBM; R11, R12, R13 and R14 are each independently selected from hydrogen, halogen, Ci ralkyl, C3 4 cycloalkyl, Cr4alkoxy, hydroxy, cyano, - NR'R", -CONR'R A -CO2R'. -CO-CO2R'. -C0-(CH2)m0H, tetrazolyl and -SO2-Cr4alkyl, wherein said Ci ralkyl and Ci ralkoxy are optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci ralkoxy, wherein m is 1, 2 or 3; or R11 and R° together with the atoms attached thereto form a 5-6 membered heteroaromatic or heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or heterocyclic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Cmalkyl, C3 4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, -COF3, -NR'R", -CONR'R" and -CO2R', wherein said C । 4a! kyI may optionally be substituted one or more times with a substituent independently selected from halogen and Cmalkoxy; A is CO or L is selected from: wherein R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen and fluoro; R19 is selected from hydrogen and Ciralkyl, wherein said Ci-4alkyl may optionally be substituted one 10 or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; n2 is selected from 1 and 2; X6 is CH or N; 15           X7 is selected from N and CH; and LBM is selected from X8 is selected from O, NH, and triazolyl; R21 is selected from hydrogen, fluoro, chloro, cyano, Cj-4alkyl and trifluoromethyl; R22 is selected from hydrogen and fluoro; R23 is selected from hydrogen, fluoro and Ci-4alkoxy; 10            or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, provided is a compound of formula (I’): A-L-LBM wherein: X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14 and N, and wherein when X4 is N the N may be oxidized to a N-oxide; X5 is CO or CR4R4; Y1 is selected from N and CR7; Y2 is selected from N and CR8; Z is selected from N and CR10; R is NHR°; R° is selected from hydrogen, Ci-4alkyl, C3 4cycloalkyl, C3 4cycloalkyl-Ci-4alkyl, phenyl-Ciralkyl, halo-Ci-4alkyl, -(CtOn-O-R', -(CH2)n-CO-Ci-4alkyl and -(CH2)n-CO2R', wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C3-4 cycloalkyl, hydroxy, Ci-4alkoxy, cyano, - NR'R", -CON R'R", and -CO2R, wherein R' and R" are each independently selected from hydrogen and Cmalkyl and n is 0, 1, or 2; R1 and Rla are independently selected from hydrogen, fluoro, and Ci-4alkyl; R2 is selected from hydrogen, Ci-salkyl, and deuterated Ci-4alkyl, wherein said Crsalkyl may optionally be substituted one or more times with fluoro; R3 is selected from hydrogen, Ci-4alkyl and deuterated Ci ralkyl; each of R4 and R6 are independently selected from hydrogen, Cj-4alkyl, and Ci-4alkoxy, wherein said Ci-4alkyl and Ci-4alkoxy may optionally be substituted with one or more halogen; R5 is selected from hydrogen, fluoro, and Ci-4alkyl; wherein said Cmalkyl may optionally be substituted with one or more halogen, and R5a and R10 is hydrogen; or R5 and R5a are both selected from fluoro and R10 is hydrogen; or R5 and R10 together form a bond between the two carbon atoms to which they are attached, and R5a is hydrogen; R7 and R8 are independently selected from hydrogen, halogen, Ci ralkyl, and Cmalkoxy, wherein said Ci-4alkyl and Ci-4alkoxy may optionally be substituted with one or more halogen; R11, R12, R13 and R14 are independently selected from hydrogen, halogen, Ci-4alkyl, C3 4 cycloalkyl, Cmalkoxy, hydroxy, cyano, -NR'R", -CONR'R", -CO2R, -CO-CO2R', -CO-(CH2)mOH, tetrazolyl and -SO2-C i^alkyl, wherein said Ciralkyl and Ci ^alkoxy is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and Cmalkoxy, wherein m is 1, 2 or 3; R11 and R° may together form a 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic ring containing one or two N atoms is optionally be substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Cmalkyl, C3-4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, -COH, -NR'R", -CONR'R", and -CO2R', wherein said Cmalkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci-4alkoxy; wherein R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen and fluoro; R19 is selected from hydrogen and Ci ralkyl, wherein said Ci ialkyl may optionally be substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; n2 is selected from 1 and 2; X6 is CH or N; 5           X7 is selected from N and CH; and X8 is selected from O, NH, and triazolyl; R21 is selected from hydrogen, fluoro, chloro, cyano, Cmalkyl and trifluoromethyl; 15           R22 is selected from hydrogen and fluoro; R23 is selected from hydrogen, fluoro and Ci ^alkoxy; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment is provided a compound of formula (II): A-L-LBM R2                            (II) wherein X1, X2, X3, X4, X5, Y1, Y2, Z, R, R1, Rla, R2, R5, R5\ R6, A, L and LBM are as defined herein and R3 is Ci-4alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment L is: Ri® and wherein R19 is as defined herein. In one embodiment R19 is hydrogen. In one embodiment L is: r20r20 wherein R20 and X7 are as defined herein. In some embodiments, X7 is CH. In some embodiments each R20 is hydrogen. In one embodiment LBM is: R21    R23 wherein R21, R22 and R23 are as defined above. In one embodiment, A-L-LBM is R21    R23 wherein R19, R21, R22 and R23 are as defined above. In one embodiment, R21 is fluoro and R22 and R23 is hydrogen. In one embodiment, X1 is N, X2is CR12, X3 is CR13 and X4 is CR14. In one embodiment, R is NHR° and R° is selected from hydrogen and CMalkyl. In one embodiment, X1 is CH, X2is CH, X3 is CH and X4 is CH and R° and R11 together form a pyrazole ring or imidazole ring; where said pyrazole or imidazole ring may optionally be substituted by a substituent independently selected from halogen, CMalkyl, halo-CMalkyl, C3-4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, -COF3, -NR'R", -CONR'R" and -CO2R\ wherein said CMalkyl may optionally be substituted one or more times with a substituent independently selected from halogen and CMalkoxy, and wherein R' and R" are each independently selected from hydrogen and CMalkyl. In one embodiment R° and R11, together with the atoms attached thereto a imidazolidinone ring optionally substituted with Cm alkyl. In a further embodiment the disclosure provides a compound as above wherein said pyrazole or imidazole is either unsubstituted or substituted by CMalkoxy-CMalkyl. In a further embodiment the disclosure provides to a compound as above wherein Z is CR10 and R10 is hydrogen. In a further embodiment the disclosure provides to a compound as above wherein Y1 is CR7 and Y2 is CR8. In a further embodiment the disclosure provides to a compound as above wherein or both of R7 and R8 is hydrogen. In a further embodiment the disclosure provides to a compound as above wherein R1 is hydrogen an R2 and R3 is methyl. In some embodiments, at least one of X1, X2, X3, and X4 is N. In some embodiments, one and only one of X1, X2, X3, and X4 is N. In some embodiments, X1 is N, X2is CR12, X3 is CR13, and X4 is CR14. In some embodiments, X1 is N, X2is CR12, X3 is CR13, and X4 is N. In some embodiments, each of R12, R13, and R14, when present, is independently selected from hydrogen, halogen, CMalkyl, CMalkoxy, and cyano. In some embodiments, R12 is hydrogen, R13 is hydrogen, and R14 is hydrogen. In some embodiments, X1 is CR11 or N; X2is CR12; X3 is CR13; X4 is CR14; and R11, R12, R13, and R14 are each independently selected from hydrogen, halogen, CMalkyl, CMalkoxy, and cyano. In some embodiments, X1 is N; X2is CR12; X3 is CR13; X4 is CR14; and R12, R13, and R14 are each independently selected from hydrogen, halogen, CMalkyl, and cyano. In some embodiments, X1 is CR11 or N; X2is CR12; X3 is CR13; X4 is CR14; and R11, R12, R13, and R14 are each independently selected from hydrogen, halogen, CMalkyl, CMalkoxy, and cyano; or R° and R11 together with the atoms attached thereto form a 5-6 membered heteroaromatic or heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic or heterocyclic ring containing one or two N atoms may optionally be substituted one or more times with a substituent independently selected from halogen, Ci-ralkyl, halo-Ciralkyl, C3 4cycloalkyl, hydroxy, Crralkoxy, cyano, -NR’R”, -CONR'R”, and -CO2R’; wherein said Crralkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Crralkoxy; and R’ and R” are each independently selected from hydrogen and Crralkyl. In some embodiments, X1 is CR11; X2is CR12; X3 is CR13; X4 is CR14; and R° and R11 together with the atoms attached thereto form a 5-6 membered heteroaromatic or heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic or heterocyclic ring containing one or two N atoms may optionally be substituted one or more times with a substituent independently selected from halogen, Cr 4alkyl, halo-Crralkyl, C34cycloalkyl, hydroxy, Crralkoxy, cyano, -NR’R”, -CONR’R”, and -CO2R’; wherein said Crralkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Crralkoxy; and R’ and R” are each independently selected from hydrogen and Cr 4 alkyl. In some embodiments, R11 and R° together with the atoms attached thereto form a 5-6 membered heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heterocyclic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Crralkyl, C3 4cycloalkyl, hydroxy, C, ralkoxy, cyano, -COF3, -NR'R”, -CONR'R” and -CO2R', wherein said Crralkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci ralkoxy. In some embodiments, R11 and R° together with the atoms attached thereto form a 5-6 membered heteroaromatic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Crralkyl, halo-Crralkyl, C3 r cycloalkyl, hydroxy, Crralkoxy, cyano, -COF3, -NR'R”, -CONR'R” and -CO2R', wherein said Crralkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Crralkoxy. In some embodiments, the 5-6 membered heteroaromatic ring containing one or two N atoms is a pyrazole ring or an imidazole ring. In some embodiments, the 5-6 membered heterocyclic ring containing one or two N atoms is a 1,3-dihydro-2H-imidazol-2-one ring. In some embodiments, X1 is CR11, X2is CH, X3 is CH, and X4 is CH, and R° and R11 together with the atoms attached thereto form a pyrazole ring, an imidazole ring, or a l,3-dihydro-2H-imidazol-2-one ring; where said pyrazole, imidazole, or l,3-dihydro-2H-imidazol-2-one ring may optionally be substituted by a substituent independently selected from halogen, Ci-4alkyl, halo-Cmalkyl, C3-4 cycloalkyl, hydroxy, Ci 4alkoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci-4alkoxy, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl. In some embodiments, X1 is CR11, X2 is CH, X3 is CH, and X4 is CH, and R° and R11 together with the atoms attached thereto form a pyrazole ring or imidazole ring; where said pyrazole or imidazole ring may optionally be substituted by a substituent independently selected from halogen, Ci-4alkyl, halo-Ciralkyl, C3-4 cycloalkyl, hydroxy, Cmalkoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, wherein said Ci ralkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci 4alkoxy, and wherein R’ and R’ ’ are each independently selected from hydrogen and Ci-4alkyl. In some embodiments, the pyrazole, imidazole, or a l,3-dihydro-2H-imidazol-2-one ring is either unsubstituted or substituted with Cmalkyl or Cmalkoxy-Cmalkyl. In some embodiments, the pyrazole or imidazole ring is either unsubstituted or substituted with Ci 4alkyl or Ci ralkoxy-Ci 4alkyl. In some embodiments, R is NHR° and R° is hydrogen or C1 4a! ky I (e.g., methyl). In some embodiments, R is NHR° and R° is Cwalkyl (e.g., methyl). In some embodiments, R is NHR° and R° is hydrogen. In some embodiments, R is NHR° and R° is selected from Ci-4alkyl, C3-4 cycloalkyl, C3 4 cycloalkyl-Ciaalkyl, phenyl-Ci-4alkyl, halo-Ci ralkyl, -(CH2)n-O-R’, -(CH2)n-CO-Ci 4alkyl, and -(CH2)n-CO2R’; wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Ci ralkyl, halo-Ciaalkyl, C3 4cycloalkyl, hydroxy, Cmalkoxy, cyano, -NR’R”, -CONR’R”, and -CO2R’; wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl, and n is 0, 1 or 2. OMe R          N-NH V-f x1^x2     Y> Y xk^x3       jj il In some embodiments, the —J— moiety is —J— ,    ~ O-    / OH —(     L         °\ NH2 y~NH ^NH NH2 / -NH    NH2 JU U u U U UL nc V               ।              F ’                                        '                        9                         '                                      9                                  > >IH     NH2 NH2        NH2 S N^yF A 5                         ?                                   9                               ' nh2       nh2   ^nh JU J MUIMtMMWI                                Of   'W*"*** In some embodiments, Rla is hydrogen. In some embodiments, R1 is hydrogen. In some embodiments, R2 is Crsalkyl. In some embodiments, R2 is methyl. In some embodiments, R3 is hydrogen or Ciralkyl. In some embodiments, R3 is hydrogen or methyl. In some embodiments, R3 is hydrogen. In some embodiments, R3 is Ci-4alkyl. In some embodiments, R3 is methyl. In some embodiments, Rla is hydrogen, R1 is hydrogen, R2 is methyl, and R3 is hydrogen or methyl. In some embodiments, Rla and R1 are both hydrogen, and R2 and R3 are both methyl. In some embodiments, Z is CR10 and R10 is hydrogen. In some embodiments, X5 is CR4R4. In some embodiments, X5 is CR4R4 and both R4 are hydrogen. In some embodiments, X5 is N. In some embodiments, X5 is N or CR4R4 and both R4 are hydrogen. In some embodiments, R5 is hydrogen and R5a is hydrogen. In some embodiments, Z is CR10, andR5 and R10 together form a bond between the two carbons to which they are attached. In some embodiments, Y1 is CR7 and Y2 is N or CR8. In some embodiments, Y1 is CR7 and Y2 is CR8. In some embodiments, R7 and R8 are independently selected from hydrogen, halogen and Ci 4alkyl. In some embodiments, R7 and R8 are independently selected from halogen (e.g., fluoro) and Ci ralkyl (e.g., methyl). In some embodiments, Y1 is CR7; Y2 is N or CR8; and R7 and R8 are independently selected from halogen (e.g., fluoro) and Ci ralkyl (e.g., methyl). In some embodiments, both of R7 and R8 are hydrogen. moiety is In some embodiments, the In some embodiments, provided is a compound of formula (I-b), (Il-b), or (Ill-b): wherein R3 is Ci-4alkyl; or a pharmaceutically acceptable salt or stereoisomer thereof. Precursor In some embodiments, compounds of formula (I) are prepared from precursors in the following table, and subsequently derivatized at the appropriate position to achieve compounds of formula (I) (i.e. wherein R9 is -A-L-LBM). lafll lafl2 lafl3 lafl4 lafl5 lafl6 lafl7 lafl8 lafl9 laf20 laf21 laf23 laf22 laf24 laf25 laf26 laf27 laf28 laf29 laf30 laf31 laf33 laf32 laf34 laf35 laf36 laf37 laf38 laf39 laf40 laf41 laf42 laf43 laf46 laf44 laf45 laf50 laf51 laf52 lk6 lk7 lk9 IklO Ikll lk26 lk27 lk31 lk32 lk33 lz27 lz28 lz29 lz30 lz31 lz32 lz33 lz34 lz35 lz36 lz37 lz38 lz39 lz40 lz41 lz42 lz43 lz44 Moiety A and Moiety L In some embodiments, A is CO. In some embodiments, A is In some embodiments, L is selected from: wherein each nl is independently selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; R18 is hydrogen; each R19 is independently selected from hydrogen, methyl, -CF3, and fluoro; 5           each R20 is independently selected from hydrogen and fluoro; and X6 is CH or N. In some embodiments, L is selected from: R19 —N           — N  \ \   / p18 ||         \   / '— '— R20 R20 R17             R19 —N Kr^ri )— R L / N. R17                  (CH2)nl— r20 R20 10           In some embodiments, L is selected from: R19 —N          —N \      / pis 1       1             \      / pl' X' R I             X / R A             R1 R20 R20 , R17 R^7 In some embodiments, L is —N \___ / R1 In some embodiments, L is In some embodiments, L is - /                      CO /                      CO /                          '                                                          / \ ( )-33 gx / y_    sx /         a     70 A = =°A^s ’A-7 : ’ P !          y O                /              J. '                                33 \   / S \          0        •                               y-7 ■                                1                    t                           , x 11 / co / / \ M x /    \ M Z--• / In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, at least one of the R17, R18, R19, and R20 of L moiety is not hydrogen. In some embodiments, R17 is hydrogen and at least one of the R18, R19, and R20 of L moiety is not 10 hydrogen. In some embodiments, A-L is selected from: In some embodiments, L is: R17 is selected from hydrogen, chloro, and fluoro; R18 is selected from hydrogen, fluoro, and hydroxy; R19 is selected from hydrogen and Cmalkyl. wherein said Ciualkyl may optionally be 10                           substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; and X7 is selected from N and CH. In some embodiments, L is: 5 R17 is selected from hydrogen, chloro, and fluoro; R18 is selected from hydrogen, fluoro, and hydroxy; R19 is selected from hydrogen and Cmalkyl. wherein said Ciualkyl may optionally be 10 substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; and X7 is selected from N and CH. 5 In some embodiments, L is selected from: In some embodiments, L is a moiety as described herein, R17 is selected from hydrogen and chloro; 5                 R18 is selected from hydrogen and hydroxy; R19 is selected from hydrogen and Ci-4alkyl; R20 is hydrogen; nl is 0; and X7 is selected from N and CH. 10         Moiety LBM In some embodiments, LBM is selected from: X8 is selected from O, C(O)NH, and NH; R21 is selected from hydrogen, fluoro, chloro, cyano, Ci-4alkyl and trifluoromethyl; R22 is selected from hydrogen and fluoro; and R23 is selected from hydrogen, halogen, Ciralkyl, and Ci-4alkoxy. 5 In some embodiments, LBM is               H wherein X8 is selected from C(O)NH and 10 NH. In some embodiments, LBM is a moiety as described herein, X8 is NH; R21 is selected from hydrogen and fluoro; R22 is selected from hydrogen and fluoro; and R23 is selected from hydrogen and Cmalkoxy. Moiety A-L-LBM In some embodiments, A is CO; L is: R17                                      R17 r2°r2° wherein R17 is selected from hydrogen, chloro, and fluoro; R18 is selected from hydrogen, fluoro, and hydroxy; 10                 R19 is selected from hydrogen and Chalky!, wherein said Ci ralkyl may optionally be substituted one or more times with fluoro; R20 is independently selected from hydrogen and fluoro; nl is selected from 0 and 1; X7 is selected from N and CH; and 15 LBM is selected from X8 is selected from O, C(O)NH, and NH; R21 is selected from hydrogen, fluoro, chloro, cyano, Ci 40I ky 1 and trifluoromethyl; R22 is selected from hydrogen and fluoro; R23 is selected from hydrogen, halogen, Ci 4alkyl, and Ci 4alkoxy. In a further embodiment the disclosure provides a compound as above wherein A-L-LBM is R17 wherein R17 and R18 are as defined above. In some embodiments, -A-L-LBM is In certain embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof: Table 1 Example Structure Name 2a 1 O           .0         F N-NH        / =<       '-N A"CO / -^ fll       / '                     _ / N—' 3-((4-( 1-(2-(4-(4-( 1-((4-( 1H-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl )methyl)-piperidin-4-yl)benzoyl)piperazin-1 -yl)-2-oxoethyl)piperidin-4-yl)-3-fluorophenyl) amino)piperidine-2,6-dione 2a2 0    / —\  .0       F N-nh         / =( '—(        M—NH S 1        \ /                                      0 N—' S-^n 3-((4-(4-(2-(4-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)mcthyl)-pipcridin-4-yl) benzoyl)piperazin-1 -yl)-2-oxoethyl)piperazin-1 -yl)-3 -fluoropheny 1) amino)piperidine-2,6-dione 2b 1 0   / —\ N-NH         / =(        N—\ L O    Q y»„ r jPt—f               hn—( to 3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)phcnyl)amino)pipcridinc-2,6-dione 2b2 ° / N / — HN-N       / =(    ' N—V ¢9 P Q 1 II y—'                   F HN—< feo N . 3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2-fluorophenyl) amino)piperidine-2,6-dione 2b3 \            0. f—\ <        O-A yNH        / =<       / N“\ Nyk            VN> to  bv 1 || y'                   F HN—< =0 N * 3-((2-fluoro-4-(4-(( 1 -(4-(1 -((4-(2-(methoxymethyl)- 1H-benzo [d ] imidazol-5 -yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2c 1 0    7--\ N-NH         / =(       N—i Vn M     f X o   bv N~'              >—( y-NH r IF /                    HN—( ^=0 3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino )piperidine-2,6-dione 2c2 0  j—I / N / —\ nh2        / ^x '—' / N—\ k'r                      F X- O Q K jF?— /              HN—( to N M 3-((4-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c3 o   / —x nh2        / =\    ' / N—\ L IL / “f                HN—( >O X-NH '                                  0 3-((4-(4-(( 1 .(4-(1 -((4-(6-amino-5-fluoropyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c4 owe             %. / —X. yNH        / =( Nyk       Q F_^-- [ IL                       HN—( >=O X-NH '                                0 3-((3-fluoro-4-(4-(( 1 -(4-(1 -((4- (2-(methoxymethyl)- 1H-benzo [d ] imidazol-5 -yl)-1 -methyl-1 H-pyrrolo[2,3-b] pyridin-2-yl)methyl )piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)phenyl)-amino)piperidine-2,6-dione 2c5 2c6 0   / —i / N N-NH        / =(      .N^ W w F X (j       V N~'              ^-( y-NH F ]L / —(                HNih( to N N °   / —x / N n-nfi         / ^X '—' / N—\ SA,   V v? F xL c? N— /            'x / ”NH r |F y—HN— / to N l( (S)-3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl) benzoyl)piperidin-4-y 1)-methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione (R)-3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c7 0   / —V / N / V NH2         / =<         N-V N*^]                       N F o   bv N—'              '—( y-NH r jT'W              HN—< to N N 3.((4.(4.(( 1-(4-(1 -((4-(6-amino-2-niethylpyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino )piperidine-2,6-dione 2c8 O / —< / N nh2        / =\ '—' / N—\ NX   JJ>    vN> ncxi (~S L OL /                      HN—( )=0 X-NH '                                   0 6-amino-3-(2-((4-(4-(4-((4-(4-((2,6-dioxopiperidin-3- yl) amino)-2- fluorophenyl)piperazin-1 -yl)-methyl)piperidine-1 -carbonyl)phenyl)piperidin-1 -yl)methyl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-picolinonitrile 2c9 0   / —I nh2        / =\        / N—\ r^N       Z-A         N F YjT [ I 7—HN—< >O A-nh '                                 0 3-((4-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-methylbenzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl)-amino)piperidine-2,6-dione 2cl0 0    / —>. / N / A X  Ju?   CN> Y  Q     ■"-Q yK„ [ |F y— /                HN—( to N N 3-((4-(4-((1-(4-(1-(1-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl) -piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2cll 0   / —1 nh2                     / N—\ r |N                                N F t\ 0    0 0« 0 xJL / X                HN-( to n" w (3R)-3-((4-(4-((l-(4-(l-(l-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2cl2 0   / —1 NH2        / =\  '—' N—\ ri^N                       N F Q    0 0« H 207-(                HN-< S=0 n" N (3S)-3-((4-(4-((l-(4-(l-(l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino )piperidine-2,6-dione 2cl3 0    / --K / N / — nh2                      ,N-\ (| N       2= /          N JL                                              °\\ N—'              '“a y-NH r JL / —(                 HN— / )=0 N N * 3-((4-(4-((l-(4-(l-((R)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino )piperidine-2,6-dione 2cl4 0   / —V / N / A S i o      f-C^ °a N— /            'x 7”nh r o)—hn—< N 3-((4-(4-(( 1-(4-(1-((8)-1-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2.6-dione 2cl5 0   / —i / N / A nh2                 zNA N xi       2= /          N (|J     .__ / \ i  O    f-O v r^S-^\ N~'              '—A y-NH r jr y—f                 hn—< to n n 3-((4-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6- tetr ahydropyridin-4-yl) -3,5 -diniethylbenzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2cl6 HnCL   O O )=7           N F V O   bt N—'              '—( y-NH L E y—C                 HN—( )=0 ^N^N '                 '—f 3-((3-fluoro-4-(4-(( 1 -(4-( 1 -((S)-1 -(4-(2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)piperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2cl7 0   / —< / N N—NH         / =(        N—\ P Q I O    F-O v N—'               ^--( y-NH d <L                   HN—( )=O n" 3-((4-(4-((l-(4-(l-((S)-l-(4-(lH-indazol-5-yl)-1 -methyl- 1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2cl8 OMe            0 i—i —C             / N VN.H                 / NA n' 1         \ 7        \ / rll       / J        N F Y_ O    q%„ L JL / K.              HN—( to "n N 3-((3-fluoro-4-(4-((l-(4-( 1 -((S)-1-(4-(2-((8)-1 -methoxyethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl )methyl)piperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2cl9 2c20 0   / —V nh2                     ,N-\ )= /         N F iLjP   p [ IT / “C                     HN>»< o f—i / N / A nh2       n~\        ,N-^ r^N       )=Z         N F jLjP    0V™ L HL / “C                    HN-Z )=0 (S)-3-((4-(4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) -amino) -piperidine-2,6-dione (R)-3-((4-(4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophcny 1) amino) -pipcridinc-2,6-dione 2c21 OMe           0   / —\ / NA n' 1          \ /        \ / L ll                                     N F w   Q U HZ                    HN—< to "n if 3-((3-fluoro-4-(4-(( 1 -(4-( 1 -((S)-1 -(4-(2-((R)-1 -methoxyethyl)-1 H-benzo [d] imidazol-5 -yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2c22 0   / —v / N / —\ NH2 N*^      )= /        N F NC>1 CZ /            V N—'                     y-NH QZ JL / X               HN—f )=0 N 6-amino-3-(2-(( 1S) -1 -(4-(4-(4-((4-(4-((2,6-dioxopiperidin-3-yl) amino) -2-fluorophenyl) -piperazin-1-yl)methyl)piperidine-1 -carbony l)pheny l)piperidin-1 -yl)ethyl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)picolinonitrile 2c23 0 / N zVA NH2        / =(      F I^N      V-y      \—N I*3   O        F—°v r^v*A N—            ^=( y-NH r jTy—(                hn—( ^o N If 3-((4-(4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl Jethyl) -piperidin-4- yl)benzoyl)-4-fluoropiperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino) -piperidine -2,6-dione 2c24 0 / —1 Z N / — nh2       n~k        ,n~k )=f          N F L jL / \                HN—( )=0 "n If 3-((4-(4-((l-(4-(l-((S)-l-(4-(6-amino-5-fluoropyridin-3-yl)-1 -methyl-1 H-pyrrolo[2,3- b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl)-amino)piperidine-2,6-dione 2c26 -oh       °\ / —y J          / N z”K hn^       / =\       / N—\ I L / “(                 HN—< >=0 '                      X-NH '                                0 3-((3-fluoro-4-(4-(( 1 -(4-( 1 -((S)-1-(4-(6-((2- hydroxyethyl)amino)pyridin-3-yl) -1 -methyl- lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl )methyl )piperazin-1 - yl)phenyl)-amino)piperidine-2,6-dione 2c27 \= /  Z-Z M X^z^S c? -jQC z^***^-n <r o 3-((4-(4-(( 1-(4-(1-((S)-1-(4-(6-aminopyridazin-3-yl)-l-methyl-1 H-pyrrolo [2,3 - b ] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c28 0   / —k o               y-N y-NH                   N-\ _-N X       \ /       \ f 111                    N F X_ O Q F jL?-(               HN— / to N “ 3-((3-fluoro-4-(4-(( 1 -(4-( 1 -((S)-1-(1 -methyl-4-(3-methyl-2-oxo-2,3-dihydro- 1H- benzo [d ] imidazol-5 -yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 - yl)phenyl)amino)piperidine-2,6-dione 2c30 7—k yp y—y '                                  0 3-((4-(4-((l-(4-(l-((S)-l-(4-(5-amino-3-fluoropyridin-2-yl)-1 -methyl-1 H-pyrrolo[2,3- b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl)-amino)piperidine-2,6-dione 2c32 O / —y / N / A nh2        t=\ '—' ,N—y X  W  Q F &p L IL / X                HN—( ^N^N '                 X-NH '                               O 3-((4-(4-(( 1-(4-(1-((8)-1-(4-(6-amino-2-methoxypyridin-3-yl)-1 -methyl-1 H-pyrrolo[2,3- b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino) -piperidine-2,6-dione 2c33 °   / —V / N / —\ nh2                '^-f rf^l                    \—N F Y<J      yN„ Q? JL / X               HN—( S=O XN N 3-((4-(4-((1-(4-(1-((8)-1-(4-(5-aminopyridin-2-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)piperidin-4-yljmethyljpiperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c34 o / — y-N / —\ n-nh          / =<         / N—\ U  M  W F r 10HN— / )=O X-NH '                                   0 3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -y 1)-3,5-difluorophenyl)amino (piperidine -2,6-dione 2c37 O.                           F y-N n-n 'x / k^k NH2                   AA 1          (' '>                    ^NH V 0 ^v-\ n—                  n 03-^             0 N 3-((4-(l-((5-(l’-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-r,2',3’,6’-tetrahydro-[2,4'-bipyridine]-5-carbonyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl) amino)piperidine-2,6-dione 2c38 oK                      f y-N n-n nh2       / fL            U-A 1        v y               — nh 9 d    & n—f                      n OCH          0 N 14 3-((4-(l-((5-(l'-((4-(6-aminopyridazin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-r,2',3',6'-tetrahydro-[2,4’-bipyridine]-5-carbonyl)-4,5,6,7 - tetrahy dropyr azolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl) amino Jpiperidine-2,6-dione 2c39 o / —< y- n V-\ nh2       n~\        ,N-\ [p^N       )= /      \—N T 0   f-b V N—'            =( y-NH t A ?—1              HN— / S=0 N M 3-((4-(4-((1-(4-(4-((4-(6-amrnopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)piperazin-1 -yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophenyl) amino)piperidine-2,6-dione 2c40 y- n nh2 / An      y-y      \-n ? o bv 1 II ')—(                —0 HN—( fco ^n^n '                 \-f 3-((4-(4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2-methoxyphenyl)amino)piperidin e-2,6-dione 2c41 o. ^7^7^ y-N n-n xnh       / =<            1 JL 6 Z    (V 1     ( /                   ^NH x<x^\  n—<                     n N N 3-((3-fluoro-4-(l -((5-(4-( 1 -((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropy razolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)phenyl) amino)piperidine-2,6-dione 2c42 2c43 O / — y-N n-n ■^nh         / =( '—'           Il O' r~x n—'                         if frv<            ° X y-N N-n 'xx^XZ-^ xnh        / =( —f         II J X     W        f-xz-nh O' / ~\ nr \ / ^x-a. n—'                     n lo-c             0 (S)-3-((3-fluoro-4-(l-((5-(4-( 1 -((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropyrazolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)phenyl) amino)piperidine-2,6-dione (R)-3-((3-fluoro-4-( 1-((5-(4-( 1 -((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropyrazolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)phenyl) amino)piperidine-2,6-dione 2c44 ° ^-(^71^1^ y-N N-n XZ^X<;XvzOx nh2       / =( '—f        T IT JL           \\ / } ¥ rS I \ /                <NH n—'                          n CTV-c               ° 3-((4-( 1-((5-(4-(1 -((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)inethyl)piperidin- 4-yl)-2- methoxyphenyl)amino)piperidin e-2.6-dione 2c45 °   / —I / N\ / J X F-W V2 F T O'     \ W        M' ^-NH L I Z—(                 HN—( )=0 N                   \-f 3-((5-fluoro-6-((S)-4-((l-(3-fluoro-5-methyl-4-( 1 -((S)-1 -(1 -methyl-4-(6-(methyl-amino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)benzoyl)-piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)pyridin-3-yl) amino)piperidine -2,6 -dione 2c46 ..09 0 3-((4-(4-(( 1 -(3-fluoro-5-methyl-4-(l-((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4- yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2-methoxyphenyl)amino)piperidin e-2,6-dione 2c47 0 / —\ / \ A / NH        Z=\ '—'  N—\ A F m w - 9 A N—'              'Mt y—NH C jPy—(                HN— / )=0 "n n 3-((3-fluoro-4-((S)-4-((l-(3- fluoro-5-methyl-4-( 1 -((S)-1 -(1 -methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6- tetrahydropyridin-4- yl) benzoy l)piperidin-4- yl)methyl)-3-methylpiperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2c48 0. V-N N-n NH2        / =\              JlxJL 1     ~(\ / >           F-^^NH 9 0 n—f                        if OCV          0 N N 3-((4-(l-((5-(l’-((4-(6- aminopyridazin-3-yl)-l-methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-3-methyl-r,2’,3’,6’-tetrahydro- [2,4'-bipyridine]-5-carbonyl)-4,5,6,7-tetrahydropyrazolo[ 1,5- a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl)amino)piperidine-2,6-dione 2c49 6 A    rV 1  O         M" N—                            IT £j£H            0 N N 3-((4-( l-((5-(3-fluoro-5-methyl-4-(l-((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)cthyl)-l,2,3,6- tetrahydropyridin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-2- methoxyphenyl)amino)piperidin e-2,6-dione 2c52 2c53 <     hvh Hih N' V           \ /         \ / Ik il         7^7            N F tLC / 0 L I 'W               HN-Z )=0 (R)-3-((3-fluoro-4-(4-((l -(4-( 1 -((S)-l-(4-(2-(methoxymethyl)-1 H-benzo [d] imidazol-5 -yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 - \            o / —< (     _ / NO^ « o o U L / “(               HN»'< to N N yl)phenyl)amino)piperidine-2,6-dione (S)-3-((3-fluoro-4-(4-((l-(4-( 1 - ((S)-1 -(4-(2-(methoxymethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3- b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 - yl)phenyl)amino)piperidine-2,6-dione 2c54 0   / —V nh2        / =(- An      V-y      X-N F O   0%« [ I / “(                 HN—( 3-((4-((S)-4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)-3- fluoropheny 1) amino)piperidine-2,6-dione 2c55 o / —y NHi   ^“^yc y  yj y „ r o W       'M' 4^« L JL / ““C                   HN—( S=0 N N 3-((6-((S)-4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-l-methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl) -5 -fluoropyridin-3 -yl)amino)piperidine-2,6-dione 2c56 )°         v (         7"\ A          H n Y-nh         / =(        / N—\ \X  W  Q _ AlJ V rT ZTV^ 1-(1-(4-((4-((1-(4-(1-((4-(2-(methoxymethyl) -1H-benzo [d] iniidazol-5 -y 1)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 - yl)methyl)-phenyl)-lH-l,2,3-triazol-4-yl)dihydropyrimidinc-2,4(lH,3H)-dione 2c57 -      _TNvJ^ / ~'n C 2H    vi / ^X                  NH U IL / %                   Vr-^n ^n^~n *                      n \                                   0 3-((4-( 1-(2-( l-(3-fluoro-5-methyl-4-( 1 -((R)-1-(1 -methyl-4-(6-(methylamino)pyridin-3-yl)-1 H-pyrrolo [2,3 -b] pyridin-2- yl)ethyl)-l,2,3.6- tetrahydropyridin-4- yl) benzoyl)piperidin-4-yl)ethy 1) -lH-l,2,3-triazol-4- yl)phenyl)amino)piperidine-2,6-dione 2dl 0    / --V / N N-NH          / =(     ' N—i Vy            n T C}     fa Y” iiCV^N           N—Vnh4> o' 6-(4-(( 1 -(4-( 1 -((4-( 1 H-indazol-5-yl) -1 -methyl- lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)- piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-l-yl)-N-(2,6-dioxopiperidin-3-yl)pyridazine-3-carboxamide 2el o n-nh        / =< Q  q „ (C 7)                                      NH / )           °' .z' )—\ N—'                     0=< > r IT v~f                          hn-a 0 3-((4-(4-(( 1-(4-( 1-((4-( 1H-indazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-bJpyridin-2-yl)methyl)-piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)piperazine-1 -carbonyl)-3- fluorophenyl)amino)piperidine-2,6-dione 2e2 0   / —\ NH2       f=\ X p [Cl|     / — /            X—C / -NH Y    \ /          °Z z' )—k N~'                 F 0=a / \ jr 'a__z                            hn—a "N \ ° 3-((4-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)piperazine-1 -carbonyl)-3- fluorophenyl) amino)piperidine-2,6-dione 2fl OMe            O ;—i <      _rNCX / O <n-5 L^i]         Jr                 N F Y.^ O    Q Q. jL / X                  HN—< feo N N 3-((3-fluoro-4-((R)-4-(( 1 -(4-(1-((S)-1 -(4-(2-(methoxymethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4- yl)benzoyl)piperidin-4- yl)methyl)-3-methylpiperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2f2 °   / —I / N / A nh2       n~L        ,N—( rp>N       2= /         n' T Q N—'             \=( y-NH L IL / “C                  HN— / )=0 ^n^n '            w 3-((4-((R)-4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-l-methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)mcthyl)-3-mcthylpipcrazin-1 -yl) - 3 - lluoropheny 1) amino) -piperidine-2,6-dione 2f3 0   / —i / =r^x X w Q L ij I*1                       F—°\ N—'              '=\ y-NH r jF y—'                HN—( to N N 3-((4-((S)-4-(( 1-(4-( 1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl) - 3 -fluorophenyl) amino) -piperidine-2,6-dione 2f4 0    / --V MeO—v               r-N         / Y-NH        / =<       N-( Pr                   F—°\ r^S-A. N—'             ^~\ r-NH r jEy—hn—( to N N 3-((3-fluoro-4-((S)-4-(( 1 -(4-( 1 -((4-(2-(methoxymethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)phenyl)-amino)piperidine-2,6-dione 2f5 0    ji N-NH         / =<  '—'  ,N~( Q Q f—°\ N—             ^=( v-nh [ IL z—1                   hn—( ' 3-((4-((S)-4-((l-(4-(l-((4-(lH-indazol-5 -yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)-3- fluoropheny 1) amino)piperidine-2,6-dione 2f6 0   / —i / N / A ♦ NH2       / =( W N-f Y-Z          N L j                   \_ nr          /           f—°\ N—'             ^=\ r-NH [ 11 Z-^                  HN—( to ^n^n 3-((4-((R)-4-(( 1-(4-( 1-((4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 - b ] pyridin-2-yl) -methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl) -3 -fluorophenyl) amino) -piperidine-2,6-dione 2f7 0   / —V MeO—v                y~N^ 2~~\ / Y-NH        / =( '—' N—\ nr                   f—o r^S-A N—'            'x / “NH [ IT                         HN—( '—f 3-((3-fluoro-4-((R)-4-(( 1 -(4-(1-((4-(2-(methoxymethyl)-1H-benzo[d]imidazol-5-yl)-l-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)phenyl)-amino)piperidine-2,6-dione 2f8 °   / —V / N / —# N-NH        / =\       N—\ Q Q nr         /           f—°\ r^S-A N—           ^A 7“NH [ IL Z-^                 HN—( to 3-((4-((R)-4-((l-(4-(l-((4-(lH-indazol-5 -yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)-3- fluorophenyl) amino)piperidine-2,6-dione 2f9 0. / N\ /     zCF3 X P Of Ip V '                                 o' 3-((4-(4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4- yl) benzoyl)piperidin-4- yl)methy 1) - 3 - (trifluoromethyl) - piperazin-1 -yl)-3-fluorophenyl)-amino) piperidine - 2,6 -dione 2fl0 2fll o / —i y-N         ^f3 nh2       / =\       / N—\ [ IT y—(                   HN—< )=0 \                     X—nh '                               o o / —\ y-N )—i cf3 nh2       / =\       -( X   w   VN> F Lo [ IL z“(                HN—Z >0 '                     A-NH '                               o 3-((4-((S)-4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)piperazin-1 -yl)-3-fluorophenyl)- amino)piperidine-2,6-dione 3-((4-((R)-4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)-3- (trifluoromethyl)piperazin-1 -yl)-3-fluoro- phenyl)amino)piperidine-2,6-dione 2fl2 2fl3 OMe           Q / —\ N I           \ /         \ / III        I'               N F r. 0   Q [ |T y— /                    HNi"Z feo XN * OMe pNH             / P N ' 1           \ /         \ / Lil                    N F X_ Q    Q v„ U IL                    hn-z ^=o "n rZ (S)-3-((3-fluoro-4-((R)-4-((l-(4-(l-((S)-l-(4-(2- (methoxymethyl)- lH-benzo[d] -imidazol-5 -yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl )ethyl )piperidin-4-yl)benzoyl)piperidin-4-yl)-methyl)-3-methylpiperazin-1 -yl)phenyl)amino)piperidine-2,6-dione (R)-3-((3-fluoro-4-((R)-4-((l-(4-(l-((S)-l-(4-(2- (methoxymethyl) -1H-benzo [d] imidazol-5 -y 1) -1 -methyl-1 H-pyrrolo[2,3-b] pyridin-2-yl) -ethy l)piperidin-4-yl) benzoy l)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2gl ° / —\ / N / — JX3         Cd 9 f-C N—'                       \ Il T 7“^                  HN'T0 JL '                                 ° H 3-((l-(l-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl )methyl )piperidin-4-yl)-1H-indazol-4-yl)amino)piperidine-2,6-dione 2g63 o / — V-N N—V nh2                    )"A O    0 yN„ L jL / X             HN—< "n n 3-((4-(4-((4-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl) benzoy l)piperazin-1 -yl)methyl)piperidin-1 -yl)-3 -fluorophenyl) amino )piperidine-2,6-dione 2hl 0 y—l HN—N       / =<        N—< J3 O  O Or F—°K\ '                     =( y-NH HN—( to 3-((4-(l'-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3',3’-difluoro-[ 1,4'-bipiperidin] -4-y 1) -3 -fluorophenyl)-amino)piperidine-2,6-dione 2h2 O y—k / N / A A P P / —(           F N—. N—7 f—C y O \                      ^=( y-NH HN—( to 3-((4-(l'-((l-(4-(l-((4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3',3'-difluoro-[l,4'-bipiperidin] -4-y 1) -3 -fluoro-phenyl)amino)piperidine-2,6-dione 2h3 MeO        o / “A hn- /     / > or ^-T r^V-'X 'N—'              '—\ F“\^ °A '                     =( y-NH HN—( tO 3-((4-(3',3'-difluoro-1 ’-((1 -(4-( 1 -((4-(2-(methoxymethyl)-1H-benzo[d]imidazol-5-yl)-l-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)- [ 1,4'-bipiperidin] -4-yl)-3- fluoropheny 1) amino)piperidine-2,6-dione 2il o / —I / N / A N-NH         Z=\  '—' N—V <X           <_> r il                               N f i O   b\ rAr-?< / N- /              / =( / “NH 1^,       '                MeO HN—^=O 3-((4-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-5 -fluoro-2-methoxyphenyl)amino)-piperidine-2,6-dione 2i2 OMe            0 / —i < n^T    o <^> W   r-{         )=<CN Y O    Q yNH r jr p— /                 hn—< to N N 5-((2,6-dioxopiperidin-3-yl)amino)-2-(4-(( 1 -(4-( 1 -((S)-1 -(4-(2-(methoxymethyl)-1H-benzofd] -imidazol-5-yl)-1-methyl-1 H-pyrrolo[ 2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoy l)piperidin-4- yl)methyl)-piperazin-1 -yl)benzonitrile 2i3 0   / —< / N / A NH2                  ,N^ r^N      \= /       >—N CN Y. O    Qy™ F jL / X              HN— / feo N N 2-(4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl) -piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-5 -((2,6-dioxopiperidin-3-yl) amino) -benzonitrile 2i4 OMe               / —\ >=<CI O   Qv™ r jPy— /                HN— / to 3-((3-chloro-4-(4-((l-(4-(l-((S)-1 -(4-(2-(methoxymethyl)-1H-benzo [d] iniidazol-5 -y 1)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)mcthyl)pipcrazin-1 -yl)phenyl)amino)piperidine-2,6-dione 2i5 OMe            O / —i <      _rNGY / Ta      / nA n' 1          v y        <  / Y O    Q Vnh [ I / X                 HN— / )=O 3-((4-(4-(( 1-(4-( 1-((S)-1-(4-(2-(methoxymethyl) -1H-benzo [d] imidazol-5 -y 1)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -(trifluoromethyl)phenyl)amino)p iperidine-2,6-dione 216 0   J—i NH2      ^X       ,N-V r^N                        \__zCI O     Q Vnh Q. JL / X               HN— / ^=O "N \ 3-((4-(4-(( 1 -(4-(1-((8)-1-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4- yl) benzoy l)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -chlorophenyl) amino) piperidine -2,6-dione 2i7 °   / —k nh2       ifX        / N~\ f^N       2= /       \—N CF3 XX X C- JL / X                 HN— / S=O N 3-((4-(4-((1-(4-(1-((8)-1-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)-ethyl) -piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -(trifluoromethyl)phenyl)amino)-piperidine-2,6-dione 2jl 1 / % N—'            N   F '                         Y—NH HN—< feo 4.( 1 .((4.( 1 H-indazol-5-yl)-1 -methyl-lH-pyiTolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-N-(4-( 1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl )phenyl )-N-methy Ibenzamide 2j2 % / % » '                 ^=( v-nh HN—( feo 4-( 1 .((4-( 1 H-indazol-5-yl)-1 -methyl-lH-pyrrolo[2,3- b]pyridin-2-yl)methyl)piperidin-4-yl)-N-(4-( 1-(4-((2,6-dioxopiperidin- 3 - yl) amino)phenyl)piperidin-4-yl)phenyl)-N-methylbenzamide 2kl O   / —\ / N / A HN-N       Z=\ X'   N—v V n    m oK N”^                \ t“nh [ T')—t                HN—( ko "n n 3-((2-(4-(( 1-(4-( 1-((4-( 1H-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyrimidin-5- yl)amino)piperidine-2,6-dione 2k2 0   / —I / N / "K HN-N       Z=\        N—\        .0 (_ / / -^ n           V—'           N     (   NH r~\        ^x—'A T     \   /             n   / )-NH N—' fTp 3-((2-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl )methyl )-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyrimidin-4- yl)amino)piperidine-2,6-dione 2k3 0 / — HN-N        / =Z '—' N—1        0 A? V Q O,„ M r-C    M H. T    <  /            \\ ')”NH 0 oo^ N M 3-((4-(4-(( 1-(4-( 1-((4-( 1H-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyrimidin-2- yl)amino)piperidine-2,6-dione 211 °   !—1 HN—N        / =^ '—' .N—X        / ° &     << dr X /                V< 77 NH '° N—f N 3-((3-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)phcnyl)amino)pipcridinc-2,6-dione 2ml 0   / —V / N / A N-NH         / =(       N—\ <5 P o TO  rn N—            'x J-NH [ Il                       HN—( to '—Z 3-((4-(l-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-fluoropheny 1) amino )piperidine-2,6-dione 2m2 0   / —i / N / A nh2        / =( '—' / N—\ 6 P O d /      dy T N—'                K V-NH r r y— /               hn—( to N W 3-((4-(l-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3,3-difluoropiperidin-4-yl)-3 -fluorophenyl) amino) -piperidine-2,6-dione 2m3 O / —i y—OMe    V-N / -^ HN-Z       / =(  '—'   / N—\ W    \_ / c Qf        FO=( d /         v v °w N—•                    V-NH [ HL / -(                 HN—( to m^N '                  f 3-((4-(3,3-difluoro-l-((l-(4-(l-((S)-l-(4-(2-(methoxymethyl)- 1 H-benzo [d] imidazol-5 -yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)-3-fluoropheny 1) amino)piperidine-2,6-dione 2nl 0 y—y / N / \ N-NH         / =(        N—i %) t d to  d N“'                    r-NH K jP y—hn—< to N Z 3-((6-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl (methyl )piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyridin-3- yl)amino)piperidine-2,6-dione 2nl0 0   / —V / N / A nh2        / =( '—' / N—\ f^N                   N F 9 o w       M' ^nh 0 T / ”(               HN—( to N N 3-((6-(4-((l-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-5 -fluoropyridin-3-yl)amino)-piperidine-2,6-dione 2nll o f—i MeO—v               y- N V-NH        / =(  '—'   / N—\ V / /     ( / O   r-(      VNV^ N^^ 0 r^V^. N—             )=( r-NH r fP y— /               F HN—( to N Z 3-((2-fluoro-6-(4-(( 1 -(4-( 1 -((S)-1 -(4-(2-(methoxymethyl)-1H-benzo[d] -imidazol-5-yl)-1-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-piperidin-4-yl)methyl)piperazin-1 -yl)pyridin-3- yl)amino)piperidine-2,6-dione 2nl2 o / —< MeO—k               / \ n' 1        v y       \ / il                                    N F jL O 0 L I / (                  HN—< / =0 *                      X-nh '                                    0 3-((5-fluoro-6-(4-(( 1 -(4-(l-((S)-1 -(4-(2-(methoxymethyl)-1H-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl )methyl )piperazin-1 -yl)pyridin-3- yl)amino)piperidine-2,6-dione 2nl3 0 J--- X _p  o / —{            y-N \ ?            F—\ ') °\ \ N—'                    V-NH r nr y— /                hn—< to "N \ 3-((5-fluoro-6-(4-(( 1 -(4-( 1 -((S) -l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-piperazin-1 -yl)pyridin-3-yl)amino)piperidine-2,6-dione 2nl4 °   / —i ^NH        / =\    '   / N—\ f|N                  N /             N^~0 >=< JH" 1  || y—<                  F HN—<  feO N “ 3-((2-fluoro-6-(4-(( 1 -(4-( 1 -((S)-l-(l-methyl-4-(6- (methylamino)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyridin-3-yl)amino)piperidine-2,6-dione 2n2 0   / —\ / N / — Cxs ^Z2 jL O    0 Vnh QC^        / 7n-q=o 3-((6-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2-fluoropyridin-3- yl) amino)piperidine -2,6 -dione 2n3 <     JrCH Nyk W CN> X- O 0 y™ r jr y—f              f hn— / ^=o N 3-((2-fluoro-6-(4-(( 1 -(4-(1 -((4-(2-(methoxymethyl)- 1H-benzo [d ] imidazol-5 -yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyridin-3- yl)amino)piperidine-2,6-dione 2n4 °   / —i / N nh2        / =\ '—' Y. Q    0 VnH '               F HN— / ^=0 N N 3-((6-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2- fluoropyridin-3- yl)amino)piperidine-2,6-dione 2n5 0   / —V NH2        / =(  '—' N—\ f^N                   N F 9 o W       M' ^NH r                        hn—( to N N 3-((6-(4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-5 -fluoropyridin-3- yl)amino)piperidine-2,6-dione 2n6 MeO            / —\ HN-Z     / =\ n f T <2        X N—'                   ^-NH [ jF                     HN—( to "n n 3-((5-fluoro-6-(4-(( 1 -(4-(1 -((4-(2-(methoxymethyl)-1H-benzo [d] iniidazol-5 -y 1)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl) benzoyl)piperidin-4-yl)mcthyl)pipcrazin-1 -yl)pyridin-3- yl)amino)piperidine-2,6-dione 2n7 0 y—k / N / —\ a 6 o_ l| 1 z\              F HN—( to St^n '                  '—' 3-((6-(4-((l-(4-(l-((S)-l-(4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-2-fluoropyr idin-3 -yl)amino)piperidine-2,6-dione 2n8 o i—< N-nh          / =<        N—l a  W  V2 F T O      \ W       M' ^NH U xL / “C                  HN—( S=O N 3-((6-(4-((l-(4-(l-((S)-l-(4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)-5 -fluoropyridin-3-yl)amino)piperidine-2,6-dione 2n9 ° / — / N zNA N^|      )= /        N I O   O v N—'             / X y-NH r r y—(              F HN—< to \ N 3-((6-(4-(( 1-(4-( 1-((S)-1-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl) -pipcridin-4- yl) benzoyl)piperidin-4- yl)methyl)piperazin-1 -yl)-2- fluoropyridin-3- yl)amino)piperidine-2,6-dione 2ol V / / N nh2       / =\ / =\ ksJJ     / —(       '—( N—C V—NH O Y0 0 4-(1 -((4-(6-aminopyridin-3-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)- methyl)piperidin-4-yl)-N-(4-((1 -(4-((2,6-dioxopiperidin-3-yl) amino)phenyl)piperidin-4-yl)methyl)phenyl) -N -methylbenzamide 2o2 V / y-N N—NH        / ^X / =\ Ck   Vy Vy IkJJ         (             (  'M—NH ,0 Y0 4.( 1 .((4.( 1 H-indazol-5-yl)-1 -methyl-lH-pyiTolo[2,3-b]pyridin-2-yl)methyl)- piperidin-4-yl)-N-(4-((l-(4-((2,6-dioxopiperidin-3- yl) amino)phenyl)piperidin-4-yl )methyl )-phenyl)-N-methylbenzamide 2pl o / —< HN-N       / =<        N—< W O O r-T 'N—                  n F-^ °A '                     =( Y-NH HN—( to 3-((4-(4-(l-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3,3-difluoropiperidin-4-yl)piperazin-1 -y 1) -3 -fluorophenyl)-amino)piperidine-2,6-dione 2p2 0 y—l X-P F-^ 0 HN—( 3-((4-(4-(1-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3,3-difluoropiperidin-4-yl)piperazin-1 -yl) -3 -fluorophenyl) amino)piperidine-2,6-dione 2p3 Meo       kv / —X hn- /     / =\ XN w w o f^> f-^ o HN—( tO 3-((4-(4-(3,3-difluoro-1 -((1 -(4(1 -((4-(2-(methoxymethyl)-1H-benzo[d]imidazol-5-yl)-l-methyl-1 H-pyrrolo[2,3- b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)piperazin-l-yl)-3- fluoropheny 1) amino)piperidine-2,6-dione 2ql z / ^\=° j—X. / / 1 Q ° a £ z=\ )=( z-w~w: 3-((4-(1-((7-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)methyl)piperidin-4-yl)-3-fluoropheny 1) amino)piperidine-2,6-dione 2q2 o, / —\ n-nh          / =(                    \\ A i         A A      N                NH "0                    F 0;=v\ { /                         hn-^ / N N 3-((4-(l-((7-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)-5,6,7,8 -tetr ahydro-[ 1,2,4] tr iazolo [4,3 - a] pyrazin-3 -yl )methyl )piperidin-4-yl)-3-fluoropheny 1) amino)piperidine-2,6-dione 2q3 ° / — V-N N-n n-nh        / =( '—f        X xJL Ck   W      F^^NH XJ rC      V) N N 3-((4-(l-((5-(4-(l-((4-(lH-indazol-5 -yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolof 1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl) amino)piperidine-2,6-dione 2q4 o y-N n-n xyk / ^. nh2         / =( '—1           II 1         <\ / >                  ^NH ¥ rC     & T  ( / r Tw           ° N N 3-((4-(1-((5-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3-fluoro- phenyl) amino)piperidine-2,6-dione 2q5 w-CkOu. NH2      / =(           JUL I      <\ A          F^^NH 6 rT T ( /           UNH N—'                          n N W 3-((4-(l-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)-4,5,6,7 -tetrahydropyrazolof 1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3-fluorophcnyl)-amino)piperidine-2,6-dione 2q6 ov ^-N n-n <zk-N nh2        / =( '—Il JL 6 Jr 1    ( /              UNH n—'                          n N 3-((6-(l-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)-4,5,6,7 -tetrahydropyrazolof 1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-5 -fluoropyridin-3 -yl)amino)piperidine-2,6-dione 2q7 N Z*>'S OMe              Q / --X "   1   1 /                v-N n-n V A      &° I     ( )                      kz-NH ArV         ° 3-((3-fluoro-4-( 1 -((5-(4-(1 -((4-(2-(methoxymethyl)- 1H-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin- 4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)- methyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione 2q8 ° / -^71^7^^1 MeO—v                 V-N N-n ISmz4s>^N. v-nh                      jljl N 1        V V T \ /              ^NH N-                       n S^N 3-((5-fluoro-6-( 1 -((5-(4-(1 -((4-(2-(methoxymethyl)- 1H-benzo[d]imidazol-5-yl)-l-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)methyl)piperidin- 4-yl)pyridin-3-yl)amino)piperidine-2,6-dione 2q9 °. ^Y”^^ 7 / N N"N nh2        / =<           A Lk Jl I     < >                   ^NH n-<                         Tf □CH N * 3-((4-(l-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl- 1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropyr azolo [1,5-a]pyrazin-2-yl)methyl)-3,3-difluoro-piperidin-4-yl) -3 -fluorophenyl) amino)piperidine-2,6-dione 2ql0 2qll V—N N-n NH2         / =\                Jl zJL 1                 ft 1     \ )                  ^NH n~'                       n □CH          0 N O —Z^Y^N^ V-N N-n ls>z*l,s1z^1 nh2         / =( f          Jl JL 1          <\ i)               F'^»Z^NH G r< nr \ /                   >^h n—f                       n OCH          0 N * (R)-3-((4-(l-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropyr azolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl) amino )piperidine-2,6-dione (S)-3-((4-(l-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)-4,5,6,7 - tetrahy dropyr azolo [1,5-a]pyrazin-2-yl)methyl)piperidin-4-yl)-3- fluorophenyl) amino)piperidine-2,6-dione 2ql2 OMe      Q  \ "ill /          y-n n-n yvx. VnH       / =(         F F kjl W           iH UH T    \ /                 <zNH N—'                              IT N * 3-((4-(3,3-difluoro-1 -((5-(4-( 1 -((4-(2-(methoxymethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin- 4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazin-2-yl)methyl)piperidin- 4-yl)-3- fluorophenyl) amino)piperidine-2,6-dione 2ql4 o y-N N-n    ___.N N- nh2        / =( '—'          B JL 6 M 1     \ )                   VNH 6ch         ’ N * 3-((6-(4-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)ethyl)-piperidin-4-yl)benzoyl)-4,5,6,7-tetrahydropyrazolof 1,5-a]pyrazin-2-yl)methyl)piperazin-1 -yl) -5 -fluoropyridin-3 -yl)amino)piperidine-2,6-dione 2ql5 ov ^-N n-n nh2        / =( '—f          B JL 1         n           F^-^NH V rf    & T ( > n N M 3-((4-(4-((5-(4-(l-((S)-l-(4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl) -ethyl)piperidin-4-yl)benzoyl) -4,5,6,7-tetrahydropyrazolo [1,5-a]pyrazin-2-yl)methyl)piperazin-l-yl)-3-fluoro- phenyl) amino)piperidine-2,6-dione 2rl ^= / \=z' ? ZI V Or i 3-((4-(4-((1-(3-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)-piperidin-4-yl)phenyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)methyl)piperazin-1 -yl)-3 -fluorophcnyl)-amino)pipcridinc-2,6-dione 2s 1 °   / —V / N / ~\ N-NH         / =(       N—\ Vs  W  W 1><JJ       (                Vv—NH ,0 Yp   Q 3-((4-((4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)methyl)pheny 1) amino)piperidi ne-2,6-dione 2s2 o / —y / N / X nh2        / ^X '—' / N—\ N0            N^O-Nr^° N—'                  F      ( NH 'o 3-((4-((4-((1-(4-(1-((4-(6-aminopyridin-3-yl)-1 -methyl-1 H-pyrrolo [2,3 -b] pyridin-2-yl)methyl)piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)methyl)-3- fluoropheny 1) amino)piperidine-2,6-dione 2tl 0   / —y 0 / \ / N \ / ~X / =\ n-nh         / =<       '-n y—G ^-o <tzk    W          / n- / \ Ixii    r~\                        hn-4 T       \ /                                  ° N W 3_(4_(l_(2-(4-(4-(l-((4-(lH-indazol-5 -yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoy l)piperazin-1 -y 1) -2-oxoethyl)piperidin-4-yl)-3-fluorophenoxy)piperidine-2,6-dione 2t2 / N \ NH N-NH         / =\ '—' .N—X A I          XX / /        < >hn o LU N—• ^n^n 3-((2-(4-(( 1-(4-( 1-((4-( 1H-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazine-1 -carbonyl)phenyl)amino)piperidin e-2,6-dione 2t3 0   / —< / N / —X N-nh         / =<        N—X % TO  O v N—'               N—< y-NH L IL /                      HN—( )=O ^n-^n                w 3-((5-(4-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl (methyl )piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1 -yl)pyridin-2- yl)amino)piperidine-2,6-dione 2t4 ° / —< / N / X HN—N        / =<        N—\ ¢ / w N-<             Xz^' H N N 3-((l-(l-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl) benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)-1H-indazol-5-yl)amino)piperidine-2,6-dione 2t5 — / 4^^-o v Vs P N—' N N 3-((3-(3-((l-(4-(l-((4-(lH-indazol-5-yl)-1 -methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperidin-4-yl)benzoyl)piperidin-4-yl)oxy)prop-1 -yn-1 -yl)phenyl)amino) -piperidine-2,6-dione 3t5 0   / —i MeO—\              / \ )“A / Y-NH         / =(  '—' N—f \\ / /        \ / }           F—( / A 0 N~'              ^=( y-NH r jT / —(                HN—( 3-((5-fluoro-6-((R)-4-(( 1 -(4-(1-((S)-1 -(4-(2-(methoxymethyl)-lH-benzo[d]imidazol-5-yl)-1 -methyl-lH-3-((5-fluoro-6-((S)-4-((l-(4-(l-((S)-l-(4-(2-(methoxymethyl) -1H-benzo[d]imidazol-5-yI)-l-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoyl)piperidin-4-yl)methyl)-3-methylpiperazin-1 -yl)pyridin-3- yl) amino)piperidine -2,6 -dione In one or more embodiments of the present disclosure, the compounds of formula (I) have an (EC50) value in a Eotaxin- 3 release assay of less than 100 micromolar, or of less than 10 micromolar, or less than 100 nanomolar, or less than 10 nanomolar. In one or more embodiments of the present disclosure, the compounds of formula (I) have an (Kd) value in a Surface plasmon resonance (SPR) assay of less than 10 micromolar, or of less than 1 micromolar, or less than 100 nanomolar. The compounds of formula (I) may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or recrystallisation from an organic solvent or mixture of said solvent and a co-solvent that may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The disclosure also provides crystalline forms of compounds of the disclosure, such as polymorphs and pseudopolymorphs, and also mixtures thereof. Compounds of formula (I) may comprise asymmetrically substituted (chiral) carbon atoms which give rise to the existence of isomeric forms, e.g. enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present disclosure provides all such isomers, either in optically pure form or as mixtures thereof (e.g. racemic mixtures or partially purified optical mixtures). Pure stereoisomeric forms of the compounds and the intermediates of this disclosure may be obtained by the application of procedures known in the art. The various isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. high pressure liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts which may be formed with optically active amines, or with optically active acids. Optically purified compounds may subsequently be liberated from said purified diastereomeric salts. Enantiomers may also be resolved by the formation of diastereomeric derivatives. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occur stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chiral pure starting materials. Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. Any geometric isomer, as separated, pure or partially purified geometric isomers or mixtures thereof are included within the scope of the disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1:1. “Racemates” refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer. “STAT6 modulator” refers to compounds of the present disclosure that inhibit or reduce some or all of the activity of the Signal transducer and activator of transcription 6 (STAT6), including STAT6 degraders. “STAT6 degrader” refers to compounds of the present disclosure that bind to and / or inhibit both STAT6 protein and an E3 ligase with measurable affinity, resulting in the ubiquitination and subsequent degradation of the STAT6 protein. In certain embodiments, a STAT6 degrader has an 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 without an appended E3 ligase binding moiety. STAT6-mediated disorders, diseases, and / or conditions refers to any disease or other deleterious condition in which STAT6 or a mutant thereof, are known to play a role. A “subject” or “patient” is meant to describe a human or vertebrate animal, including a dog, cat, horse, cow, mouse, or the like. “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results, such as inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition), slowing or arresting the development of one or more clinical symptoms associated with the disease or condition, and / or relieving the disease, enhancing the effect of another medication, delaying the progression of the disease, increasing quality of life, and / or prolonging survival. In the compounds of formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number found in nature. The present disclosure includes all suitable isotopic variations of the compounds of formula (I). For example, different isotopic forms of hydrogen include 1H, 2H and 3H, different isotopic forms of carbon include 12C, 13C and 14C and different isotopic forms of nitrogen include 14N and 15N. Enriching for deuterium (2H) may for example increase in-vivo half-life or reduce dosage regimens, or may provide a compound useful as a standard for characterization of biological samples. Isotopically enriched compounds within formula (I) can be prepared by conventional techniques well known to a person skilled in the art or by processes analogous to those described in the general procedures and examples herein using appropriate isotopically enriched reagents and / or intermediates. In some embodiments, compounds described herein, or pharmaceutically acceptable salts, isomers, or a mixture thereof, have from 1 to n hydrogen atoms attached to a carbon atom replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” TRENDS PHARMACOL. SCI., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the ait, for example by employing stalling materials in which one or more hydrogen atoms have been replaced by deuterium. In some embodiments, a compound of the disclosure is a solvate or a hydrate. In one embodiment the disclosure provides a compound as above for use in therapy. In a further embodiment the disclosure provides a compound as above for use in the treatment of a disease, disorder or condition, which disease, disorder or condition is responsive of modulation of STAT-6. In a further embodiment the disclosure provides a compound as above for use in the treatment of autoimmune diseases. The compounds of the present disclosure may be useful for preventing, treating or ameliorating diseases characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast cancer and solid fibrous cancers either as a standalone treatment or in combination with other anticancer drugs such as check point inhibitors. In an embodiment the disclosure provides the use of a compound of formula (I) as defined above, in the manufacture of a medicament for the prophylaxis, treatment or amelioration of any of the following diseases characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast cancer and solid fibrous cancers either as a standalone treatment or in combination with other anticancer drugs such as check point inhibitors. In an embodiment the disclosure provides a method of preventing, treating or ameliorating diseases characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast cancer and solid fibrous cancers either as a stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors, the method comprising administering to a person suffering from at least one of 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. In an embodiment the disclosure provides a method of preventing, treating or ameliorating autoimmune diseases, conditions characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast cancer and solid fibrous cancers either as a stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors the method comprising administering to a person suffering from at least one of 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. Besides being useful for human treatment, the compounds of the present disclosure may also be useful for veterinary treatment of animals including mammals such as horses, cattle, sheep, pigs, dogs, and cats. Pharmaceutical Compositions and Modes of Administration For use in therapy, compounds of the present disclosure are typically in the form of a pharmaceutical composition. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient, vehicle or carrier(s). In some embodiments, the excipient is “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In some embodiments, the compound of the disclosure is provided in an amount of 0.0001-99.9% by weight of a formulation. In the form of a dosage unit, a compound of the disclosure may be administered one or more times a day at appropriate intervals. In one embodiments, a dosage unit of a formulation contains between 0.001 mg and 1000 mg, such as between 0.01 mg and 300 mg of a compound of Formula (I). A suitable dosage of the compound of the disclosure may depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound may be administered either orally, parenterally, topically, transdermally or intradermally and other routes according to different dosing schedules, e.g. daily, weekly or with monthly intervals. In some embodiments, a single dose comprising a compound of the disclosure may provide an amount of the compound in the range from 0.001 to 400 mg / kg body weight. In some embodiments, a compound of the disclosure is provided in combination with one or more therapeutically active compounds, the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th Ed., J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of said compounds. The administration of a compound of the present disclosure with one or more other active compounds may be either concomitantly or sequentially. The formulations include e.g. those in a form suitable for oral, rectal, parenteral transdermal, intradermal, ophthalmic, topical, nasal, sublingual or buccal administration. The formulations may conveniently be presented in dosage unit form and may be prepared by but not restricted to any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 21ed ed„ 2005. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, semisolid carrier or a finely divided solid carrier or combinations of these, and then, if necessary, shaping the product into the desired formulation. Formulations of the present disclosure suitable for oral and buccal administration may be in the form of discrete units as capsules, sachets, tablets, chewing gum or lozenges, each containing a predetermined amount of the active ingredient. A tablet may be made by compressing, moulding or freeze drying the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient(s) in a free-flowing form; for example with a lubricant; a disintegrating agent or a dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier. Freeze dried tablets may be formed in a freeze-dryer from a solution of the drug substance. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of the recipient, e.g. isotonic saline, isotonic glucose solution or buffer solution. Liposomal formulations are also suitable for parenteral administration. Transdermal formulations may be in the form of a plaster, patch, microneedles, liposomal or nanoparticulate delivery systems or other cutaneous formulations applied to the skin. Formulations suitable for ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredients. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for ophthalmic administration. Formulations suitable for topical, such as dermal, intradermal or ophthalmic administration include liquid or semi-solid preparations, solutions or suspensions. Formulations suitable for nasal or buccal administration include powder, self-propelling and spray formulations, such as aerosols and atomisers. In some embodiments, administration can be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery). In some embodiments, pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. In some embodiments, one or more compounds as disclosed herein or a pharmaceutical composition thereof is formulated for topical administration to the skin or mucosa (e.g., dermally or transdermally). In some embodiments, topical compositions can include ointments and creams. In some embodiments, ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. In some embodiments, creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. For example, cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. For example, the oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. In some embodiments, the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. In some embodiments, as with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing. All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incoiporated by reference, regardless of any separately provided incorporation of particular documents made elsewhere herein. Combination Therapies In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, can be combined with the therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of an inflammatory, and / or dermatologic disease or disorder, 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 (TCI) (e.g., tacrolimus, pimecrolimus), cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, interferon gamma, phosphodiesterase 4 (PDE4) inhibitor such as crisaborole, JAK inhibitor (e.g., ruxolitinib, upadacitinib, abrocitinib, baricitinib), dupilumab, and anti-IL-13 antibody (e.g., tralokinumab). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as acne. Non-limiting examples of such agents include topical therapies such as benzoyl peroxide, topical retinoids, topical antibiotic, clascoterone, salicylic acid and azelaic acid; and systemic therapies such as doxycycline, minocycline, sarecycline, combined oral contraceptives, spironolactone, and isotretinoin. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, 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, inosiplex, antihistamines (such as fexofenadine), and oral JAK inhibitors (such as ritlecitinib or brepocitinib). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as asthma. Non-limiting examples of such agents include inhaled ICS-formoterol (such as budesonide-formoterol), short-acting beta2 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). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as chronic obstructive pulmonary disease (COPD). Non-limiting examples of such agents include short-acting beta2 agonists (such as albuterol sulfate), short-acting muscarinic antagonists (such as aiprtropium), long-acting beta2 agonists (such as olodaterol), and long-acting muscarinic antagonists (such as tiotropium). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as chronic rhinosinusitis with polyps. Non-limiting examples of such agents include intranasal corticosteroid, or biologies such as benralizumab (targets IL-5), dupilumab (targets IL-13), omalizumab (targets IgE). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, 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 crisaborole, systemic immunosuppressants and modulators, such as systemic corticosteroids, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine or dupilumab. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as dermatomyositis. Non-limiting examples of such agents include topical corticosteroids, topical calcineurin inhibitors (such as pimecrolimus, tacrolimus), systemic corticosteroids (such as prednisone), antimalarials (such as hydroxychloroquine, cholorquine, quinacrine), methotrexate, mycophenolate mofetil, intravenous immunoglobulin, rituximab, and JAK inhibitors (such as tofacitinib) In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, 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). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as psoriasis. Non-limiting examples of such agents include topical treatments such as topical corticosteroids (such as betamethasone dipropionate, clobetasol propionate, desoximetasone, diflorasone diacetate, fluocinonide, flurandrenolide, halobetasol propionate, amcinonide, mometasone furoate, triamcinolone acetonide, fluticasone propionate, hydrocortisone valerate, clocortolone pivalate), topical calcineurin inhibitors (such as pimecrolimus, tacrolimus), topical vitamin D analogues (such as calcipotriene, calcitriol, tacalcitol or mazacalcitol), topical retinoids (such as tazarotene); systemic nonbiologic 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), fumaric acid esters (such as dimethyl fumarate), systemic immunosuppressants and antimetabolites (such as hydroxyurea, mycophenolate mofetil, azathioprine, leflunomide, tacrolimus and thioguanine); and biologic therapies such as TNF-a 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). In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, such as scleroderma. Non-limiting examples of such agents include immunosuppressive treatments (such as methotrexate, mycophenolate mofetil, cyclophosphamide, tocilizumab, and rituximab), and autologous haematopoietic stem cell transplantation. In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, is co-administered with one or more agents useful for the treatment and / or prophylaxis of a dermatologic condition, 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 analogues (such as calcipotriene); and systemic therapies such as oral corticosteroids (such as betamethasone). In some embodiments, an additional therapeutic agent includes one or more of 608, 610, 611, clindamycin phosphate + benzoyl peroxide, 101BHG-D01. 1-H-l 1, 4P-022, 5-OXO-ETE receptor antagonists, 9MW-1911, AB-1000, AB-lOla, abatacept, ABBV-712, ABCL-575, Ab-IPL-IL-17, ABM-125, abrocitinib, ABY-035 / AFO2, ABY-062, AC-201, ACE-1334, acitretin, aclidinium bromide, aclidinium bromide + formoterol fumarate, acumapimod, AD-17002, adakitug, adalimumab, adapalene, adapalene + benzoyl peroxide, adapalene + clindamycin hydrochloride, adapalene + clindamycin phosphate, aderamastat, Adi, ADi-100, Adipocell, adipose tissue-derived mesenchymal stem cell-derived exosomes, adipose-derived stem cell therapy, AD-MSC-CM, ADSTEM, ADX-246, aerosolized hydroxychloroquine, afamelanotide, AJ-101, AJ-303, AK-101, AK-119, AKP-08, albuterol sulfate, ALD-R491, alefacept, Allergovac depot, 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, AMG-0101, Amilo-5MER, aminolevulinic acid, aminolevulinic acid 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-EMAP II fully humanized antibodies, anti-IL-4 / IL-13 vaccine, anti-P2X7 monoclonal antibody humanized , anti-PAR2 therapeutics, antroquinonol, APD-588, APG-222, APG-777, APG-808, APG-990, APGT-001, APIRx-1603, apremilast, 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-193, ATB-1606, ATI-2138, ATL-105, ATR-006, ATR-01, ATTO-002, ATTO-1310, atuliflapon, AUR-101, auremolimab, autologous leukocyte cell therapy, avenciguat, AVI-3307, AVID-200, AVX-001, AWEPO-003, AX-158, AX-202, AZD-0284, AZD-0449, AZD-8630, 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 + formoterol fumarate, beclomethasone dipropionate, beclomethasone dipropionate + formoterol fumarate + glycopyrronium bromide , bedoradrine, begelomab, belimumab, belumosudil, bempikibart, bencycloquidium bromide, benralizumab, benzoyl peroxide, benzoyl peroxide + tretinoin , berdazimer sodium, bermekimab, bersiporocin dihydrochloride, bertilimumab, betamethasone, betamethasone dipropionate, betamethasone valerate, bexotegrast, BFP-002, BFP-102, BGB-23339, Bl-1291583, BI-1323495, BI-765250, bilastine, bimekizumab, 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, bovhyaluronidase azoximer, Box-5, BR-201, branebrutinib, BRE-AD01, brensocatib, brentuximab vedotin, brepocitinib, brilacidin, brilaroxazine hydrochloride, briquilimab, brodalumab, BSI-056T, BSI-502, BTX-1204, BTX-1308, BTX-1503, budesonide, budesonide + arformoterol, budesonide + formoterol, budesonide + formoterol fumarate, budesonide + procaterol 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 + dronabinol, cannabinoid CB2 receptor agonist antibody , carbon dioxide + perfluorooctyl bromide, cavosonstat, CB-06-01, CB2 receptor agonists, 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, ciclosporin, ciprofloxacin hydrochloride, CIT-013, CJRB-402, CKBA, clascoterone, CLBS-03, clindamycin, clindamycin phosphate + benzoyl peroxide, clindamycin phosphate + tretinoin, clobetasol propionate, clobetasol propionate + tretinoin, CM-101, CM-326, CMK-389, CMR-316, CMS-D001, ColiFin, COPD vaccine, cord blood derived stem cells, corticotropin, COYA-204, CPL-409116, crisaborole, CS-12192, CS-32582, CS-43001, CSJ-117, CSPCHA-115, CT-05, CT-303, CT-P55, CTX-101, CTXT-102, cudetaxestat sodium, 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, daxdilimab, dazukibart, DB-007-4, DBI-001, DBM-1152A, DC-806, DC-853, deflazacort, delgocitinib, denifanstat, depemokimab, dersimelagon, desloratadine, desogestrel + ethinylestradiol, desonide, deucravacitinib, deuruxolitinib phosphate, dexamethasone sodium phosphate, dexpramipexole, difamilast, dimethyl fumarate, dimethyl fumarate + ethyl hydrogen fumarate calcium + ethyl hydrogen fumarate magnesium + ethyl hydrogen fumarate zinc, diroleuton, dithranol cream, divozilimab, DLQ-02, DLX-105, DLX-2323, DMT-210, DMT-310, DMX-700, DMXD-011, DNX-114, doxofylline, doxofylline (bronchiectasis), Alitair Pharmaceuticals, doxycycline hyclate, doxycycline hyclate (delayed release), Mayne, doxycycline hyclate (easy-to-swallow, acne, bacterial infection), Aqua Pharmaceuticals, DPT-0218, drospirenone + ethinylestradiol, dual alpha-V / beta-1 and alpha-5 / beta-l integrin inhibitors, dual AMCase / CHITl inhibitors, dual anti-CD19 / anti-BAFF CAR T-cell therapy, dual JAK3 / TEC inhibitor, dupilumab, 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, ENERGI-F708, enpatoran, ensifentrine, ensifentrine + glycopyrrolate, EP-104-GI, EP-262, epeleuton, Epi-13, epinastine 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 inhibitor, farudodstat, FB-102, FB-401, FB-704A, FB-825, FB-918, FCR-001, FCX-013, fevipiprant, filgotinib maleate, fipaxalparant, flunisolide, fluocinonide, 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 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 agonists, Gamunex, GB-001, GB-0895, GD-134, GD-iExo-001, gefurulimab, GEN-501, GL-7190, GLPG-3667, glutathione + ascorbic acid + bicarbonate, glycopyrrolate + formoterol fumar ate + budesonide, glycopyrronium + formoterol fumarate + fluticasone propionate, glycopyrronium + vilanterol, glycopyrronium bromide, glycopyrronium bromide + indacaterol maleate, GMDP, GM-XANTHO, GN-037, GNKS-356, GNR-068, GPCR antagonists, 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, guselkumab, GZ-21T, H-018, halobetasol propionate, halobetasol propionate + tazarotene, halogenated xanthene, halometasone, HB00-17, HB-0034, HB-0043, HB-1734, HBM-9001, HBM-9378, HCW-9302. HDM-3010, HECB-1800301, HEMP-001, HI-1640V, histamine human immunoglobulin, Hizentra, HJ-787, HL-231, HLA-open conformer-specific monoclonal antibody, HLK-6002, house dust mite allergen, house dust mites immunotherapy, HP-1901, Hpb glutamate dehydrogenase modulator, 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, IFNalpha kinoide, IgE inhibitors, IHL-675A, IL-17 NanoAb, IL-25 targeted therapeutic, IL-4R alpha antagonist, IL-4Ra targeted therapeutic, ILB-2107, iloprost, IMB-101, IMG-007, IMG-008, IMG-036, immune globulin intravenous, imsidolimab, IMX-120, IN-A002, inaticabtagene autoleucel, INCB-054707, indacaterol, indacaterol acetate + glycopyiTonium bromide + mometasone furoate, Indamet, inebilizumab, infliximab, Integrin alpha-2 / beta-1 inhibitor, Integrin alpha-5 / beta-l 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, ivermectin, ixekizumab, izokibep, JadiCell therapy, JAK inhibitors, JAK-989, jaktinib dihydrochloride monohydrate, jaktinib 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, K1NE-201, K1TCL-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 inhibitor, lebrikizumab, lepzacitinib, levalbuterol, levalbuterol hydrochloride, 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 beta agonist / long acting muscarinic agonist, long-acting aerosolized peptide-based therapy, lonodelestat 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-l 19102, M3 muscarinic receptor antagonists, M-605110, M-610101, manfidokimab, masitinib, MAX-40070, maxacalcitol, maxacalcitol + betamethasone, MCM-001, MDI-1228, MDNA-413, MDPK-67b, ME-3183, Melgain, mepolizumab, mesalazine, Mesenchymal stem / stromal cell therapy , mesenchymoangioblast-derived mesenchymal stem cell therapy, metenkefalin acetate + tridecactide acetate, methotrexate, methyl aminolevulinate 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 dihydrochloride, 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 inhibitors, mufemilast, MufroSyn, mugwort pollen allergen vaccine, muscarinic M3 receptor antagonist, MYJ-1633, nacystelyn, nadifloxacin, nadolol, nalfurafine, NBL-012, NCP-111, NCP-112, ND-003, NDX-3315, 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 1, olopatadine, OLX-103, OM-001, omalizumab, omiganan pentahydrochloride, omilancor, OMN-71, ONO-4685, OP-2101, opinercept, OpSCF, ordesekimab, ORI-001, orismilast, ORKA-001, ORKA-002, orticumab, ozagrel hydrochloride, ozenoxacin, 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, phimelanotide, PHP-1212, PI3K-delta inhibitor, picankibart, piclidenoson, pimecrolimus, PIPE-791, pirfenidone, pitavastatin, PKC theta inhibitors, PLM-301, PNV-5032, POLB-002, ponesimod, potassium dobesilate, PR-023, pranlukast, pranlukast hydrate, PRCL-02, PrEP-001, prostaglandin D2 synthase inhibitors, Prozumab, PRP-PBMC autologous cellular therapy, PS-35, psoriasis therapeutics, PT-101, P-TET, PUL-042, PUR-0110, PUR-1800, PX-128, PX-130, PZ-07 / 2024, Q-1804, Q-301, QB KPN, QLM-3003, QN-02, QP-CO1, QRX-008, quisovalimab, QX-002-N, QX-004-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 phytocannabinoids, ravulizumab, RAY-121, RB-1000, RBM-009, RBN-012759, RBO-0987, RC-1416, RCD-405, recombinant midismase, reformulated calcipotriol + betamethasone, REGEND-001, REGN-1908-1909, remetinostat, remibrutinib, renzapride, repirinast, repurposed aldesleukin, Repurposed azeliragon, repurposed lenabasum, reslizumab, RESP-1000 series, RESP-2000 series, RESP-X, retinoic acid, revefenacin, REX-7117, rezpegaldesleukin, RG-6151, RG-6244, RG-6314, RG-6315, RG-6341, RG-6421, RGRN-305, rilzabrutinib, riociguat, risankizumab, ritlecitinib, rituximab, RLS-1496, RLV-102, rocatinlimab, roflumilast, ropsacitinib, ROR gamma T inverse agonists, ROR-gamma inverse agonists, rose bengal sodium, RP-3128, RSBT-001, RSS-0393, R-TPR-022, rupatadine + montelukast, RUTI, ruxolitinib, RYSW-01, S1P1 agonist, salbutamol, salmeterol, salmeterol xinafoate + fluticasone propionate, SAMiRNA program, SAR-441566, SAR-443726, sarecycline, SB-010, SB-011, SCD-044, SCD-153, SCT-640A, SCT-650-C, SDC-1801, secukinumab, SEGRA, seletalisib, 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-4597, si-544, SIG-1322, SIG-1451, SIG-1456, SIM-0278, SIM-335, sitaxentan, SKI-0-703, SKL-XYZ, SLS-008, SM-17, small mobile stem cell therapy, SMET-D1, SNC-103, SNG-001, SNG-100, SNK-01, sodium chromoglycate, sodium pyruvate, sonelokimab, soquelitinib, sovleplenib, spesolimab, SPL84-23, SSGJ-621, SSS-07, ST-1830, stapokibart, STAR-0310, STAT3 inhibitor, STMC-103H, STS-01. STSA-1201, SUDO-286, SUL-238, SuperMApo, suplatast tosilate, 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-AtopOl, TDM-PsorOl, TDM-ScarOl, telazorlimab, Tempol, temtokibart, teprotumumab, TER-101, terbutalin, terguride, tesnatilimab, TEV-48574, TEV-53275, tezepelumab, TFF-HMW-HA, Thalassophryne nattereri peptide, THB-001, theophylline, THOR-809, TL520, TI-620, tibulizumab, tildrakizumab, timolumab, tiotropium, tiotropium bromide, tipelukast, tirbanibulin, TLL-018, TLY-012, TO-210, tofacitinib, tofacitinib + fingolimod, tofacitinib citrate, tonabacase, TOP-N44, TOP-N53, torudokimab, tosufloxacin, tozorakimab, TP-317, TQC-2731, TQC-2938, TQC-3564, TQC-3721, TQC-3927, TQH-2722, TQH-2929, TQH-3906, TQH-3910, trabikibart, tralokinumab, tranilast, transcription factor pathway inhibitor , tregalizumab, treprostinil, treprostinil diolamine, tretinoin, tretinoin + benzoyl peroxide, trifarotene, TRIV-509, TRN-157, TRPA1 antagonists, 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-derived stem cell therapy , UMC119-06, umeclidinium bromide, umeclidinium bromide + vilanterol trifenatate, upadacitinib, USP-4 inhibitors, ustekinumab, UTAA-09, VALERGEN-DS, vamorolone, vapendavir, vardenafil, VB-1953, VC-005, VDAA, VDAD, VDJ-006, VEGFR targeted DK4 / 10 , venanprubart, VENT-03, verekitug, vilanterol + fluticasone furoate + glycopyrronium bromide, vipoglanstat hydrogensulfate, 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 antibodies, wnt pathway stimulator, WXFL-10203614, 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 bi-specific antibodies targeting one or more targets referenced herein. In some embodiments a compound of the disclosure provided herein, or pharmaceutically acceptable salt or stereoisomer thereof, is administered with one or more therapeutic agents selected from a PPARd inhibitor, IRAK4 inhibitor, TPL2 inhibitor, a4p7 inhibitor, BTLA agonist, PD1 agonist, or an FXR agonist. In some embodiments a compound of the disclosure provided herein, or pharmaceutically acceptable salt or stereoisomer thereof, is administered with one or more therapeutic agents selected from seladelpar, edecesertib, tilpisertib fosmecarbil, GS-1427, GS-0272, GS-0151, or cilofexor. The benefit of combination may be increased efficacy and / or reduced side effects for a component as the dose of that component may be adjusted down to reduce its side effects while benefiting from its efficacy augmented by the efficacy of the compound of the present disclosure. In some embodiments, the additional therapeutic agent includes an agent useful for modulating, treating, or preventing inflammation, such as a 4-1BB ligand, 5-Alpha-reductase inhibitor, 5-HT la receptor antagonist, 5-HT la receptor partial agonist, 5-HT 2a receptor antagonist, 5-HT 2a receptor partial agonist, 5-HT 2b receptor antagonist, 5-HT 3 receptor antagonist, 5-HT 4 receptor agonist, 5-HT 6 receptor antagonist, 5-HT 7 receptor antagonist, 5-Lipoxygenase activating protein inhibitor, 5-Lipoxygenase inhibitor, Accessory gene regulator A inhibitor, Acetaldehyde dehydrogenase modulator, Acetylcholine receptor agonist, Acetylcholine receptor antagonist, Acetylcholinesterase inhibitor, Acidic mammalian chitinase inhibitor, ACTH receptor agonist, Activity-dependent neuroprotector modulator, ADAM-33 inhibitor, ADAM-9 inhibitor, Adenosine Al receptor antagonist, Adenosine Al receptor modulator, Adenosine A2b receptor antagonist, Adenosine A3 receptor agonist, Adenosine A3 receptor antagonist, Adenosine deaminase stimulator, Adenosylhomocysteinase inhibitor, Adenylate cyclase stimulator, Adrenergic receptor agonist, Adrenocorticotrophic hormone ligand. Advanced glycosylation product receptor antagonist, AGER gene inhibitor, AIMP multisynthetase complex protein 1 inhibitor, Albumin antagonist, Alcohol dehydrogenase 5 inhibitor, Aldose reductase inhibitor, Alk-5 protein kinase inhibitor, Alpha 1 antitrypsin modulator, Alpha 1 antitrypsin stimulator, Alpha 1 proteinase inhibitor, Alpha 2 adrenoceptor agonist, Amiloride sensitive sodium channel inhibitor, AMP activated protein kinase alpha 2 stimulator, AMP activated protein kinase stimulator, Amyloid protein deposition inhibitor, Androgen receptor antagonist, Angiotensin II AT-1 receptor antagonist. Angiotensin II AT-2 receptor agonist, Anoctamin 1 stimulator. Aortic smooth muscle actin inhibitor, API transcription factor modulator, Apelin receptor agonist, Apolipoprotein A antagonist, Apolipoprotein A5 stimulator, Apolipoprotein B modulator, Apolipoprotein E modulator, Apoptosis regulator Bel X inhibitor, Apoptosis regulator Bel w inhibitor, APRIL receptor modulator, Aryl hydrocarbon receptor agonist, Aryl hydrocarbon receptor modulator, B and T lymphocyte attenuator stimulator, B-lymphocyte antigen CD 19 inhibitor, B-lymphocyte antigen CD 19 modulator, B-lymphocyte antigen CD20 inhibitor, B-lymphocyte stimulator ligand inhibitor, B-lymphocyte stimulator ligand modulator, Bcl-2 protein inhibitor, Beta 1 adrenoceptor antagonist, Beta 2 adrenoceptor agonist, Beta 2 adrenoceptor antagonist, Beta 2 adrenoceptor modulator, Beta adrenoceptor agonist, Beta amyloid antagonist, Beta-catenin inhibitor, Beta-catenin modulator, Bifunctional aminoacyl tRNA synthetase inhibitor, BMP10 gene inhibitor, BMP15 gene inhibitor, Bone marrow proteoglycan modulator, Botulinum toxin A stimulator, Bromodomain containing protein 1 inhibitor, Bromodomain containing 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 stimulator, CCL26 gene inhibitor, CCR3 chemokine modulator, CCR5 chemokine antagonist, CCR6 chemokine antagonist, CCR8 chemokine antagonist, CDllb antagonist, CD 122 agonist, CD 122 modulator, CD 19 modulator, CD2 antagonist, CD223 modulator, CD3 modulator, CD30 modulator, CD4 antagonist, CD40 ligand receptor antagonist, CD47 antagonist, CDwl23 modulator, Cell adhesion molecule inhibitor, Cell surface glycoprotein CD200R agonist, Cell surface glycoprotein MUC18 inhibitor, CFTR modulator, CFTR stimulator, Chaperonin stimulator, Chemokine receptor antagonist, Chitinase inhibitor, Collagen I agonist. Collagen I antagonist, Collagen modulator. Collagen VII antagonist, Complement Clq subcomponent inhibitor, Complement Cis subcomponent inhibitor, Complement C5 factor inhibitor, Complement factor C2 inhibitor, Complement factor D inhibitor, C0VID19 spike glycoprotein modulator, CSF-1 antagonist, CXC10 chemokine ligand inhibitor, CXCR2 chemokine antagonist, cyclic GMP AMP synthase inhibitor, Cyclooxygenase inhibitor, Cytokine receptor agonist, Cytokine receptor antagonist, Cytokine receptor common beta chain inhibitor, Cytoplasmic protein NCK inhibitor. Cytosolic phospholipase A2 inhibitor, Cytotoxic T-lymphocyte protein-4 stimulator. Deoxyribonuclease gamma stimulator, DHFR inhibitor, Diacylglycerol O acyltransferase 1 inhibitor, Dihydroorotate dehydrogenase inhibitor, Dipeptidyl peptidase I inhibitor, Dipeptidyl peptidase IV inhibitor, DNA gyrase inhibitor, DNA methyltransferase inhibitor, Dopamine D2 receptor partial agonist, Dopamine D3 receptor agonist, Dopamine D3 receptor partial agonist, Dopamine D4 receptor partial agonist, DYRK-1 alpha protein kinase inhibitor, Ectonucleotide pyrophosphatase-PDE-2 inhibitor, EGF like module receptor 1 antagonist, EGFR family tyrosine kinase receptor inhibitor, Elastase inhibitor, Endonuclease modulator. Endostatin modulator, Endothelin ET-A receptor antagonist, Endothelin ET-B receptor antagonist, Enolase 1 inhibitor, Eosinophil peroxidase inhibitor, Eotaxin 2 ligand inhibitor, Eotaxin ligand inhibitor, EP4 prostanoid receptor antagonist, Epidermal growth factor receptor antagonist, Epidermal growth factor receptor modulator, Estradiol agonist, Estrogen receptor agonist, Extracellular signal related kinase-2 inhibitor, Facilitated glucose transporter-1 modulator, Fatty acid synthase inhibitor, FGF receptor antagonist, FGF-2 ligand, FGF-4 ligand, FGF3 receptor antagonist, Filaggrin stimulator, Flt3 tyrosine kinase inhibitor, FMLP related receptor I agonist, FMLP related receptor II agonist, Free fatty acid receptor 2 agonist, Free fatty acid receptor 3 agonist, Fyn tyrosine kinase inhibitor, FXR agonist, G-protein coupled bile acid receptor 1 agonist, G-protein coupled receptor-44 antagonist, G-protein coupled receptor-44 modulator, GABA A receptor agonist, GABA A receptor alpha-2 subunit modulator, GABA A receptor alpha-3 subunit modulator, GABA A receptor alpha-5 subunit modulator, Galectin-10 modulator, GATA 3 transcription factor inhibitor, Glucagon-like peptide 1 receptor agonist, Glucocorticoid receptor agonist, Glutamate dehydrogenase modulator, Glutamate receptor modulator, Glutathione dependent PGD synthase inhibitor, Glutathione independent PGD synthase inhibitor, Glutathione reductase inhibitor, GroEL protein 2 inhibitor, Guanylate cyclase stimulator, H-i- Ki- ATPase inhibitor, Heat shock protein inhibitor, Heme oxygenase 1 modulator. Heparin agonist, High mobility group protein Bl inhibitor. Histamine Hl receptor antagonist, Histamine H4 receptor antagonist, Histamine receptor antagonist, Histone deacetylase-1 inhibitor, Histone deacetylase-2 inhibitor, Histone deacetylase-2 stimulator, Histone deacetylase-3 inhibitor, Histone deacetylase-6 inhibitor, Histone H2A modulator, Histone H4 modulator, HMG CoA reductase inhibitor, Hsp 90 inhibitor, Hsp70 binding protein 1 inhibitor, Hyaluronidase stimulator, Hypoxia inducible factor stimulator, I-kappa B kinase beta inhibitor, I-kappa B kinase epsilon inhibitor, IgG receptor FcRn large subunit p51 modulator, IL-1 receptor accessory protein inhibitor, IL-1 receptor antagonist, IL-10 receptor agonist, IL-10 receptor antagonist, IL-12 receptor antagonist, IL-13 receptor antagonist, IL-13 receptor modulator, IL-15 receptor antagonist, IL-17 antagonist, IL-18 antagonist, IL-2 receptor alpha subunit stimulator, IL-2 receptor antagonist, IL-2 receptor modulator, IL-22 antagonist, IL-23 antagonist, IL-3 receptor modulator, IL-4 receptor antagonist, IL-4 receptor modulator, IL-5 receptor antagonist, IL-6 receptor antagonist, IL-7 receptor antagonist, IL-8 receptor antagonist, IL17RA gene inhibitor, IL2 gene stimulator, Immunoglobulin E antagonist, Immunoglobulin E modulator. Immunoglobulin G agonist, Immunoglobulin G1 modulator, Immunoglobulin agonist, Immunoglobulin kappa modulator, Immunoglobulin modulator, Inducible nitric oxide synthase inhibitor, Insulin receptor substrate-1 inhibitor, Insulin-like growth factor 1 receptor antagonist, Integrin alpha-2 / beta-l antagonist, Integrin alpha-4 / beta-l antagonist, Integrin alpha-4 / beta-7 antagonist, Integrin alpha-5 / beta-l antagonist, Integrin alpha-5 / beta-3 modulator, Integrin alpha-V / beta-1 antagonist, Integrin beta 1 binding protein modulator, Interferon alpha 14 ligand. Interferon alpha ligand inhibitor, Interferon beta ligand, Interferon beta ligand inhibitor, Interferon gamma ligand inhibitor, Interferon gamma receptor antagonist, Interferon type I receptor antagonist, Interleukin 1 delta ligand inhibitor, Interleukin 1 like receptor (IL33R) antagonist, Interleukin 1 like receptor 1 modulator, Interleukin 1 like receptor 2 inhibitor, Interleukin 13 ligand inhibitor, Interleukin 13 receptor alpha 1 antagonist, Interleukin 15 ligand inhibitor, Interleukin 17 ligand inhibitor, Interleukin 17A ligand inhibitor, Interleukin 17A ligand modulator, Interleukin 17E ligand inhibitor, Interleukin 17E ligand modulator. Interleukin 17F ligand inhibitor, Interleukin 17F ligand modulator, Interleukin 18 ligand inhibitor, Interleukin 23A inhibitor, Interleukin 31 ligand inhibitor, Interleukin 31 ligand modulator, Interleukin 33 ligand inhibitor, Interleukin 33 ligand modulator, Interleukin receptor 17A antagonist, Interleukin receptor 17B antagonist, Interleukin-1 alpha ligand inhibitor, Interleukin-1 beta ligand modulator, Interleukin-1 ligand inhibitor, Interleukin-2 ligand, Interleukin-2 ligand inhibitor, Interleukin-31 receptor modulator, Interleukin-4 ligand inhibitor, Interleukin-5 ligand inhibitor, Interleukin-6 ligand inhibitor, Interleukin-8 ligand inhibitor, Interleukin-9 ligand inhibitor, IRAK-4 protein kinase inhibitor, IRAK-4 protein kinase degrader, Itk tyrosine kinase inhibitor, JAK tyrosine kinase inhibitor, Jaki tyrosine kinase inhibitor, Jak2 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, Jun N terminal kinase inhibitor, Kallikrein 2 inhibitor, Kallikrein 5 modulator, Kallikrein 7 inhibitor, Kallikrein 7 modulator, Kallikrein inhibitor, KCNA voltage-gated potassium channel-3 inhibitor, Kelch like ECH associated protein 1 inhibitor, Kelch like ECH associated protein 1 modulator, Kit tyrosine kinase inhibitor, LanC like protein 2 stimulator, Lanosterol-14 demethylase inhibitor, Lek tyrosine kinase inhibitor, Lectin mannose binding protein inhibitor, Leukocyte Ig like receptor A4 modulator, Leukocyte elastase inhibitor, Leukotriene A4 hydrolase inhibitor, Leukotriene BLT receptor antagonist, Leukotriene C4 antagonist, Leukotriene C4 synthase inhibitor, Leukotriene D4 agonist, Leukotriene D4 antagonist, Leukotriene E4 antagonist, Leukotriene receptor antagonist. Liver X receptor agonist, L0XL2 gene inhibitor, Lung surfactant associated protein D stimulator, Lyn tyrosine kinase inhibitor, Lysophosphatidate-1 receptor antagonist, Lysophospholipase inhibitor, Macrophage migration inhibitory factor inhibitor, Major allergen I polypeptide chain 2 inhibitor, Major allergen inhibitor, MALT protein 1 inhibitor, Mannan-binding lectin serine protease inhibitor, MAP kinase modulator, MAPKAPK2 inhibitor, MARCKS protein inhibitor, Mas-related G-protein receptor X2 antagonist, Mas-related G-protein receptor X2 inhibitor, MEK protein kinase inhibitor, MEK-1 protein kinase inhibitor, Melanocortin MCI receptor agonist, Melanocortin MC5 receptor antagonist, Melanocortin receptor agonist, Melanocyte stimulating hormone ligand, Membrane copper amine oxidase inhibitor, Metalloprotease-12 inhibitor, MEX3B gene inhibitor, Mineralocorticoid receptor antagonist, MIP 3 alpha ligand inhibitor, Mite allergen modulator, Mitochondrial 10 kDa heat shock protein stimulator, MKL myocardin like protein inhibitor, MMP1 gene stimulator, MNK protein kinase inhibitor, Monocyte chemotactic protein 1 ligand inhibitor, MS4A2 gene modulator, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, MUC5AC gene inhibitor, Muscarinic Ml receptor antagonist, Muscarinic M2 receptor antagonist, Muscarinic M3 receptor antagonist, Muscarinic M4 receptor antagonist, Muscarinic M5 receptor antagonist, Muscarinic receptor agonist, Muscarinic receptor antagonist, Muscarinic receptor modulator, Myeloperoxidase inhibitor, Myosin heavy chain inhibitor, NACHT LRR PYD domain protein 3 inhibitor, NEDD4 family interacting protein 1 stimulator, Neuropilin 2 modulator, Neutral endopeptidase inhibitor, NFE2L2 gene stimulator, Nicotinic ACh receptor alpha 7 subunit stimulator, Nicotinic acetylcholine receptor agonist, NK1 receptor antagonist, NKG2 D activating NK receptor antagonist, NLR family member XI stimulator, Non receptor tyrosine kinase TYK2 antagonist. Nuclear erythroid 2-related factor 1 stimulator, Nuclear erythroid 2-related factor 2 stimulator, Nuclear erythroid 2-related factor inhibitor, Nuclear factor kappa B gene inhibitor, Nuclear factor kappa B inducing kinase inhibitor, Nuclear factor kappa B inhibitor, Nuclear factor kappa B modulator, Oncostatin M receptor subunit beta inhibitor, Opioid growth factor receptor agonist, Opioid receptor delta antagonist, Opioid receptor kappa agonist, Orexin 1 receptor antagonist, Orexin 2 receptor antagonist, Orphan nuclear receptor antagonist, Outer membrane protein modulator, OX-40 receptor agonist, OX-40 receptor antagonist, OX40 ligand inhibitor, OX40 ligand modulator, Oxoeicosanoid receptor 1 antagonist, P-Glycoprotein inhibitor, P-selectin glycoprotein ligand-1 inhibitor, P2X2 purinoceptor antagonist, P2X3 purinoceptor antagonist, P2X7 purinoceptor modulator, P2Y6 purinoceptor modulator, p38 MAP kinase inhibitor, p53 tumor suppressor protein stimulator, PcrV protein type III inhibitor, PDE 3 inhibitor, PDE 4 inhibitor, PDE 4b inhibitor, PDE 4d inhibitor, PDE 5 inhibitor, PDGF receptor antagonist, Peptidase 1 inhibitor, PGD2 antagonist, PGI2 agonist, Phosphatidylinositol 4 kinase beta inhibitor, Phosphoinositide 3-kinase inhibitor, Phosphoinositide-3 kinase delta inhibitor, Phospholipase A2 inhibitor, Phospholipase C inhibitor, PIM-1 protein kinase inhibitor, PIM-2 protein kinase inhibitor, PIM-3 protein kinase inhibitor, Placenta growth factor ligand inhibitor, Plasminogen activator inhibitor 1 inhibitor, Platelet activating factor receptor antagonist, Poly ADP ribose polymerase 14 inhibitor, PPAR gamma agonist, PPAR gene modulator, Progesterone receptor agonist, Programmed cell death ligand 1 modulator, Programmed cell death protein 1 modulator, Programmed cell death protein 1 stimulator, Prostaglandin E synthase inhibitor, Prostaglandin E synthase-1 inhibitor, Protease inhibitor, Protease-activated receptor-2 antagonist, Proteasome beta-8 subunit modulator, Proteasome inhibitor, Protein kinase C theta inhibitor, Protein kinase inhibitor, Protein NOV homolog modulator, Protein tyrosine kinase inhibitor, Protoporphyrinogen oxidase modulator, Pyruvate kinase muscle isozyme stimulator, Raf B protein kinase inhibitor, Ras gene inhibitor, Reactive oxygen species modulator inhibitor. Ret tyrosine kinase receptor inhibitor, Retinoic acid receptor agonist, Retinoic acid receptor antagonist, Retinoic acid receptor gamma agonist, Retinoic acid receptor gamma antagonist, Retinoic acid receptor gamma inverse agonist, Retinoic acid receptor modulator, Retinoid receptor agonist, Retinoid X receptor agonist, Retinoid X receptor modulator, Retinoid Z receptor gamma antagonist, Retinoid Z receptor gamma inverse agonist, Rev protein modulator, Rho associated protein kinase 1 inhibitor, Rho associated protein kinase 2 inhibitor, Ribonuclease P inhibitor, Ribonuclease stimulator, RIP-1 kinase inhibitor, SI00 calcium binding protein A4 inhibitor, S100A8 gene inhibitor, S100A9 gene inhibitor, SARS coronavirus 3C protease like inhibitor, Secretory phospholipase A2 receptor antagonist, Serine protease inhibitor, Serine threonine protein kinase TBK1 inhibitor, Serum amyloid A protein modulator, SH2 domain containing protein inhibitor, Sialic acid-binding Ig-like lectin 8 inhibitor, SIRT3 gene stimulator, SMAD inhibitor, SNAI1 transcription factor inhibitor, SOD3 gene stimulator. Sodium channel inhibitor, Sphingosine 1 phosphate phosphatase 1 stimulator, Sphingosine-1-phosphate receptor-1 agonist, Sphingosine-1-phosphate receptor-1 antagonist, Sphingosine-1-phosphate receptor-1 modulator, Sphingosine-1-phosphate receptor-3 modulator, Sphingosine-1-phosphate receptor-4 antagonist, Sphingosine-1-phosphate receptor-4 modulator, Sphingosine-1-phosphate receptor-5 modulator, Sphingosylphosphorylcholine receptor antagonist, Src tyrosine kinase inhibitor, STAT inhibitor, STAT-1 modulator, STAT-3 inhibitor, STAT-5 inhibitor, STAT-6 inhibitor, STAT-6 degrader, Stearoyl CoA desaturase-1 inhibitor, Stress induced secreted protein 1 stimulator, Superoxide dismutase modulator, Superoxide dismutase stimulator, Syk tyrosine kinase inhibitor, Synuclein alpha inhibitor, T cell receptor antagonist, T cell receptor modulator, T cell surface glycoprotein CD28 inhibitor, T-cell antigen CD7 modulator, T-cell differentiation antigen CD6 inhibitor, T-cell surface glycoprotein CD8 inhibitor, T-cell transcription factor NF AT modulator, Tau aggregation inhibitor, Tau deposition inhibitor, Tec tyrosine kinase inhibitor, TGF beta 1 ligand inhibitor, TGF beta 3 ligand inhibitor, TGF beta 3 ligand modulator, TGF beta ligand inhibitor, TGF beta receptor agonist, TGF beta receptor antagonist, TGF-beta activated kinase-1 inhibitor, TGF-beta type II receptor antagonist, TGF-beta type II receptor modulator, TGF-beta type III receptor antagonist, Thromboxane A2 antagonist, Thromboxane synthetase inhibitor, Thymic stromal lymphopoietin ligand, Thymic stromal lymphopoietin ligand inhibitor, Thymic stromal lymphopoietin ligand modulator. Thymic stromal lymphopoietin receptor antagonist. Thymic stromal lymphopoietin receptor modulator, TLR agonist, TLR modulator, TLR-2 agonist, TLR-2 antagonist, TLR-4 antagonist, TLR-6 agonist, TLR-7 antagonist, TLR-8 antagonist, TLR-9 agonist, TLR-9 antagonist, TNF agonist, TNF alpha ligand inhibitor, TNF alpha ligand modulator, TNF antagonist, TNF binding agent, TNF related apoptosis inducing ligand, TNF-like receptor-2 modulator, Tumor necrosis factor 15 ligand inhibitor, Topoisomerase IV inhibitor, TRAIL receptor agonist, Transcription factor inhibitor, Transcription factor modulator, Transthyretin modulator, Trk tyrosine kinase receptor inhibitor, TRP cation channel Al inhibitor, TRP cation channel Al modulator, TRP cation channel Cl inhibitor, TRP cation channel VI antagonist, TRP cation channel VI modulator, TRP cation channel V2 modulator, Tsi protein kinase inhibitor, Tubulin binding agent, Tubulin receptor antagonist, Tumor necrosis factor 13B receptor modulator, Tumor necrosis factor 13C receptor modulator, Tumor necrosis factor 14 ligand inhibitor, Tumor necrosis factor 15 ligand modulator, Tumor necrosis factor ligand inhibitor, Txk tyrosine kinase inhibitor, Tyk2 tyrosine kinase inhibitor, Tyk2 tyrosine kinase modulator, Type I IL-1 receptor antagonist. Type I TNF receptor antagonist, Type II TNF receptor modulator, Tyrosine phosphatase substrate 1 inhibitor, Ubiquitin inhibitor, Ubiquitin ligase modulator, Ubiquitin ligase stimulator, Ubiquitin thioesterase-4 inhibitor, Unspecified GPCR antagonist, Unspecified GPCR modulator, Unspecified ion channel inhibitor, Uteroglobin stimulator, V-set transmembrane domain protein 1 stimulator, Vascular cell adhesion protein 1 antagonist, VEGF ligand inhibitor, VEGF receptor modulator, VEGF-2 receptor modulator, Vimentin inhibitor, Vitamin D3 receptor agonist, Wnt 5A ligand inhibitor, Wnt ligand modulator or YSK-4 protein kinase inhibitor. Kits Provided herein are also kits that include a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes 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 compounds in the treatment of the indications, including the diseases or conditions, described herein. Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag. EXAMPLES Experimental procedures Intermediates were obtained sufficiently pure for the next step from the procedures outlined in the specification. Reactions were performed at room temperature unless stated otherwise. When a compound whose synthesis is described herein was used at a larger scale than its reported synthesis, it is to be implicitly understood that more material had been prepared similarly. Microwave reactions were performed in dedicated MW instruments in closed vials. 'H NMR spectra were recorded at 250-600 MHz in d6-DMSO unless stated otherwise. Reactions performed above the boiling point of the solvent took place in sealed tubes or screw-cap vials. Some of the final compounds (Examples) were obtained in pure form and the yield provided accordingly while others were obtained as DMSO solutions for which the concentration and volume are specified. “Dried” refer to drying an organic solution over Na^SOr, MgSOr. or CaCh and filtering off the drying agent. “Degassed” refers to air-sensitive reactions being flushed with inert atmosphere via evacuation and back-filling or by bubbling inert atmosphere through the mixture for several minutes. NaH was used as a 60% oil dispersion. “Filtration” of mixtures refers to the removal / isolation of solid material from mixture by filtration through a paper filter, PFTE septum, or through a pad of celite. Additional solvent was used to wash the solid. Unless noted otherwise hydrogenations were performed at 1 bar from a balloon. ‘Purification by SCX’ refers to the loading of the material onto a SCX column, washing with MeOH, eluting with NH3 in MeOH, and concentrating the fractions containing the product. Catalytic hydrogenations were performed using a catalyst such as 10% Pd / C and a H2 balloon unless stated otherwise. The mixture after the reaction was typically filtered through celite to remove the catalyst. ‘Partitioned (A / B)’ refers to the partitioning of a mixture between solvents A and B. OL (A / B) refers to the organic layer after partitioning the mixture between solvents A and B. 5            AL (A / B) refers to the aq. layer after partitioning the mixture between solvents A and B. Crude reaction mixtures after reductions with iron / zinc power and AcOH / NH4Cl were typically filtered through celite before work-up of the filtrate. HPLC Methods Several Intermediates and final compounds were purified using the HPLC methods listed below. Column Eluent Flow rate XBridge Prep Cl8 OBD, 150x19 mm 5 pm A: 50 mM aq. NH4HCO2, B: ACN, 10-100% ACN 30 mL / min XTerra®RP-18 OBD, 150x19 mm 5 pm A: 0.1% aq. NH4HCO2, B: ACN, 10-100% ACN 30 mL / min PRINCETONE ULTIMA Cl8 250x20 mm, 5 pm A: 0.05% aq. HCO2H, B: ACN 0 min 20% B, 1 min 20% B, 10 min 70% B, 10.1 min 99% B, 12 min 99% B, 12.1 min, 20% B, 15 min 20% B 12.1 / 20,15 / 20 16 mL / min PRINCETONE ULTIMA Cl8 250x20 mm, 5 pm A: 0.1% aq. HCO2H, B: ACN 0 min 20% B, 2 min 20% B, 10 min 50% B 16 mL / min LUNA OMEGA Cl8 250x21.2 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 0 min 40% B, 1 min 40% B, 10 min 85% B, 10.1 min 99% B, 12 min 99% B, 12.1 min 40% B, 15min 40% B 18 mL / min COGENT C18 250x21.2 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 0 min 30% B, 2 min 30% B, 10 min 50% B 16 mL / min COGENT Cl8 250x21.2 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 0 min 30% B, 1 min 30% B, 10 min 80% B, 10.1 min 99% B, 12 min 99% B, 12.1 min 30% B, 15 min 30% B 20 mL / min LUNA Cl8 150x21.2 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 18 mL / min 0 min 40% B, 1 min 40% B, 10 min 80% B, 10.1 min 99% B, 12 min 99% B, 12.1 min 40% B, 15 min 40% B X-SELECT PHENYL HEXYL 250x19 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 0 min 30% B, 1 min 30% B, 10 min 55% B 16 mL / min X-SELECT PHENYL HEXYL 250x19 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 0 min 55% B, 1 min 55% B, 10 min 70% B, 15 min 90% B, 15.1 min 100% B, 19 min 100% B, 19.1 min 55% B 18 mL / min AZZOTA 250x20mm, 10 um A: 10 mM aq. NH4HCO2, B: ACN 0 min 40% B, 1 min 40% B, 10 min 85% B, 10.1 min 99% B, 12 min 99% B, 12.1 min 40% B, 15 min 40% B 18 mL / min AZZOTA 250x20 mm, 5 pm A: 10 mM aq. ABC, B: ACN 0 min 30% B 1 min 30% B, 10 min 85% B 17 mL / min PRINCETONE ULTIMA Cl8 250x20 mm, 10 pm A: 0.1% aq. HCO2H, B: ACN 0 min 10% B, 1 min 10% B, 10 min 90% B, 10.1 min 99% B, 13 min 99% B, 13.1 min 10% B, 16 min 10% B 17 mL / min XSELECT CSHC18 250x19 mm 5 pm A: 0.1% aq. HCO2H, B: ACN 0 min 10% B, 1 min 10% B, 10 min 90% B, 10.1 min 99% B, 13 min 99% B, 13.1 min 10 % B, 16 min 10% B 17 mL / min YMC-PACK-ODS-AQ Cl8 250x20 mm 5 pm A: 0.1% aq. HCO2H, B: ACN 0 min 25% B, 2 min 25% B, 10 min 35% B 15 mL / min HICHROMEC18 250x20 mm 5 pm A: 10mM aq. ABC, B: ACN 0 min 40% B, 2 min 40% B, 10 min 80% B 18 mL / min X SELECTCI8 250x19 mm 5 pm A: 10 mM aq. ABC, B: ACN 0 min 40% B, 1 min 40% B, 10 min 80% B, 11 min 80% B, 11.1 min 99% B, 15 min 99% B, 15.1 min 40% B, 19 min 40% B 16 mL / min LC / MS Method The compounds of disclosure were characterized by the LC / MS methods listed below. Method Column and eluent Gradient Flow rate 1 Agilent Poroshell 120 SB-C18 4.6x30 mm 2.7 pm operated at 60 °C A: 0.1% aq. HCO2H B: 0.1% HCO2H in ACN 0 min 1% B, 1.5 min 100% B, 1.73 min 100% B 3 mL / min 2 Acquity BEH Cl8 50x2.1 mm 1.7 pm operated at 35 °C A: 0.05% aq. HCO2H B: 0.05% HCO2H in ACN 0 min 3% B, 0.4 min 3% B, 2.5 min 98% B, 3.5 min 98%. 3.6 min 3% B, 4 min 3% B 0.6 mL / min 3 Acquity BEH Cl8 50x2.1 mm 1.7 pm operated at 35 °C A: 0.05% aq. HCO2H B: 0.05% HCO2H in ACN 0 min 3% B, 2.5 min 3% B, 7.5 min 98% B, 9.6 min 3% B, 10 min 3% B 0.6 mL / min 4 Acquity BEH C18 100x2.1 mm 1.7 pm operated at 50 °C A: 0.05% aq. HCO2H B: 0.05% HCO2H in ACN 0 min 3% B, 8.5 min 100% B, 9 min 100% B, 9.5 min 3% B, 10 min 3% B 0.55 mL / min 5 Acquity BEH Cl 8 50x2.1 mm 1.7 pm operated at 35 °C A: 0.05% aq. TFA B: 0.05% TFA in ACN 0 min 3% B, 0.4 min 3% B, 2.5 min 98% B, 3.5 min 98% B, 3.6 min 3% B, 4 min 3% B 0.6 mL / min 6 Acquity BEH Cl8 50x2.1 mm 1.7 pm operated at 35 °C A: 0.05% aq. TFA B: 0.05% TFA in ACN 0 min 3% B, 2.5 min 3% B, 7.5 min 98% B, 9.5 min 98% B, 9.6 min 3% B, 10 min 3% B 0.6 mL / min 7 Acquity BEH C18 100x2.1 mm 1.7 pm operated at 50 °C A: 0.05% aq. TFA 0 min 3% B, 16 min 100% B, 18 min 100% 0.45 mL / min B: 0.05% TFA in ACN B, 18.5 min 3% B, 20 min 3% B 8 Xbridge Cl8 75x4.6 mm 3.5 pm operated at 35 °C A: 10 mM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B, 1 min 15% B, 4 min 98% B, 7 min 98% B, 7.5 min 5% B, 8 min 5% B 1.3 mL / min 9 X Bridge C18 150x4.6 mm 3.5pm operated at 35 °C A: 10 mM aq. NH4HCO3 B: ACN 0 min 5% B, 1 min 5% B, 3 min 15% B, 7 min 55% B, 11 min 98% B, 16 min 98% B, 16.1 min 5% B, 20 min 5% B 1.0 mL / min 10 X SELECT C18 150x4.6 mm 3.5pm operated at RT A: 10 mM aq. NH4HCO3 B: ACN 0 min 5% B, 1 min 5% B, 3 min 15% B, 7 min 55% B, 11 min 98% B, 16 min 98% B, 16.1 min 5% B, 20 min 5% B 1.0 mL / min 11 Acquity UPLC HSS T3 50x2.1 mm 1.8 pm operated at 30 °C A: 10 mM aq. NH4OAc + 0.1% HCO2H B: 0.1% HCO2H in ACN 0 min 1% B, 0.5 min 6% B, 1 min 6% B, 2.6 min 95% B, 3.8 min 95% B, 3.81 min 1% B,4.8 min 1% B 0.7 mL / min 12 Acquity UPLC HSS T3 50x2.1 mm 1.8 pm operated at 60 °C A: 10 mM aq. NH4OAc + 0.1% HCO2H B:0.1%HCO2H in ACN 0 min 5% B, 0.9 min 95% B, 1.2 min 95% B, 1.4 min 5% B 1.2-1.3 mL / min 13 X Brigde BEH C18 (3x100) mm, 2.5pm operated at 35 °C A: 0.05 % TFA in ACN B: 0.05% aq. TFA 0 min 5% A, 5 min 98% A, 9 min 98% A, 9.01 min 5% A, 12 min 5% A 1 mL / min 14 ACQUITY UPLC BEH Cl 8 (2.1x100) mm, 1.7 pm operated at 60 °C 0 min 10% A, 2.5 min 10% A, 7.5 min 98% 0.4mL / min A: 0.05 % TFA in ACN B: 0.05 % aq. TFA A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A 15 YMC-Triart Cl8 ExRS (75x4.6mm, 3 pm) operated at 45 °C A: lOmM aq. NH4HCO3 B: 100% ACN 0 min 5% B, 0.8 min 5% B, 2 min 25% B, 5 min 90% B, 7 min 95% B, 8.5 min 95% B, 8.6 min 5% B, 10 min 5% B LOmL / min 16 X-BRIDGE C8 (4.6X75mm) 3.5pm operated at 50 °C A: 0.05% aq. HCO2H B: 0.05% HCO2H in ACN 0 min 5% B, 3 min 98% B, 5 min 98% B, 5.5 min 5% B, 6 min 5% B LOmL / min 17 Xbridge Cl8 (75x4.6mm, 3 pm) operated at 50 °C A: lOmM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B, 1 min 15% B, 4 min 98% B, 7 min 98% B, 7.5 min 5% B, 8 min 5% B 1.0 mL / min 18 Acquity BEH C18 (50mmx2.1mm, 1.7um) operated at 35 °C A: 0.05% aq. HCO2H B: 0.05 % TFA in ACN 0 min 5% B, 5 min 98% B, 9 min 98% B, 9.01 min 5% D, 12 min 5% B 0.6 mL / min 19 ACQUITY UPLC BEH C18 (2.1x100) mm, 1.7 pm operated at 45 °C A: 0.05 % TFA in ACN B: 0.05 % aq. TFA 0 min 10% A, 2.5 min 10% A, 7.5 min 98% A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A 0.4mL / min 20 ACQUITY UPLC BEH Cl 8 (2.1x100) mm, 1.7pm operated at 35 °C A: 0.05 % TFA in ACN B: 0.05 % aq. TFA 0 min 10% A, 2.5 min 10% A, 7.5 min 98% A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A 0.4mL / min 21 ACQUITY UPLC BEH Cl 8 (2.1x100) mm, 1.7pm operated at 50 °C 0 min 10% A, 2.5 min 10% A, 7.5 min 98% 0.55mL / min A: 0.05 % TFA in ACN B: 0.05 % aq. TFA A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A 22 ACQUITY UPLC BEH Cl 8 (2.1x100) mm, 1.7 pm operated at 35 °C A: 0.05 % TFA in ACN B: 0.05 % aq. TFA 0 min 10% A, 2.5 min 10% A, 7.5 min 98% A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A 0.65mL / min 23 X Bridge C18 (50nmix4.6mm, 3.5 pm) operated at 45 °C A: lOmM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B , 5 min 98% B, 7.5 min 98% B, 7.6 min 5% B, 9 min 5% B 0.8 mL / min 24 YMC-Triart Cl8 ExRS (50x2.1mm, 1.9 pm) operated at 35 °C A: 0.05% aq. TFA B: 0.05 % TFA in ACN 0 min 5% B, 5 min 98% B, 9 min 98% B, 9.01 min 5% B, 12 min 5% B 0.6 mL / min 25 X Bridge C18 50x4.6 mm 3.5pm operated at 35 °C A: 10 mM aq. NH4HCO3 B: ACN 0 min 2% B, 0.5 min 2% B, 3 min 98% B, 6 min 98%B, 8 min 2% B 0.8 mL / min 26 X Bridge C18 50x4.6 mm 3.5pm operated at 30 °C A: 10 mM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B, 1.0 min 15% B, 4.0 min 98% B, 7.0 min 98% B, 7.5 min 5% B, 8.0 min 5% B 1.3 mL / min 27 X Bridge C18 50x4.6 mm 3.5pm operated at 45 °C A: 10 mM aq. NH4HCO3 B: ACN 0 min 2% B, 0.5 min 2% B, 2.5 min 98% B, 5 min 98% B, 5.1 min 2% B, 6 min 2% B 1.0 mL / min 28 YMC Triart Cl8 (75x4.6mm, 3 urn) operated at 45 °C A: 5mM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B, 1 min 15% B, 6 min 55% B, 9 min 95% B, 12 min 95% B, 13 1.3 mL / min min 5% B, 14 min 5% B 29 YMC Triart Cl8 (75x2.1mm, 1.9 um) operated at 35 °C A: 0.05 % aq. TFA B: 0.05 % TFA in ACN 0 min 3% B, 0.4 min 3% B, 2.5 min 98% B, 3.5 min 98% B, 3.6 min 3% B, 4 min 3% B 0.6 mL / min 30 YMC Trial! Cl8 (50x2.1mm, 1.9 um) operated at 60 °C A: 0.05 % aq. TFA B: 0.05 % TFA in ACN 0 min 3% A, 2.5 min 3% A, 7.5 min 98% A, 9.5 min 98% A, 9.6 min 3% A, 10 min 3% A 0.6 mL / min 31 YMC Trial! Cl8 (50x2.1mm, 1.9 um) operated at 60 °C A: 0.05 % aq. TFA B: 0.05 % TFA in ACN 0 min 3% A, 0.4 min 3% A, 2.5 min 98% A, 3.5 min 98% A, 3.6 min 3% A, 4 min 3% A 0.6 mL / min 32 YMC Trial! Cl8 (50x4.6mm, 1.9 um) operated at 60 °C A: 0.05 % TFA in ACN B: 0.05% aq. TFA 0 min 5% A, 0.5 min 5% A, 3 min 95% A, 6 min 95% A, 6.1 min 5% A, 8 min 5% A 1.0 mL / min 33 X Bridge C18 75x4.6 mm 3.5pm operated at 45 °C A: 5 mM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5% B, 1 min 15% B, 6 min 55% B, 9 min 95% B, 12 min 95% B, 13 min 5% B, 14 min 5% B 1.0 mL / min 34 X Bridge C18 75x4.6 mm 3.5pm operated at 35 °C A: lOmM aq. NH4HCO3 B: ACN 0 min 5% B, 0.5 min 5 % B, 1.0 min 15% B, 4.0 min 98% B, 7.0 min 98% B, 7.5 min 5% B, 8.0 min 5% B 1.3 mL / min 35 X Brigde BEH C18 (3x100) mm, 2.5pm operated at 35 °C A: 0.05 % TFA in ACN B: 0.05% aq. TFA 0 min 3% A, 4 min 98% A, 5 min 98% A, 5.01 min 3% A, 6 min 3% A 1 mL / min 36 X Bridge C18 (100mmx3mm, 2.5 pm) operated at 50 °C A: 0.05 % aq. TFA B: 0.05 % TFA in ACN 0 min 3% A, 4 min 98% A, 5 min 98% A, 5.01 min 3% A, 6 min 3% A 1 .OmL / min 37 X Bridge C18 (75mmx4.6mm, 3.5 pm) operated at 45 °C A: 10 mM aq. NH4HCO3 B: 100% ACN 0 min 5% B, 0.8 min 5% B, 2 min 25% B, 5 min 90% B, 7 min 95% B, 8.6 min 5% B, 10 min 5% B l.OmL / min 38 Acquity BEH C18 100x2.1 mm 1.7 pm operated at 60 °C A: 0.05 % TFA in ACN B: 0.05% aq. TFA 0 min 3% A, 1 min 10% A. 8.5 min 100% A, 9 min 100% A, 9.5 min 3% A, 10 min 3% A 0.55 mL / min 39 Acquity BEH C18 100x2.1 mm 1.7 pm operated at 60 °C A: 0.05 % aq. TFA B: 0.05 % TFA in ACN 0 min 3% A, 8 min 100% A, 9 min 100% A, 9.5 min 3% A, 10 min 3% A 0.45 mL / min 40 Acquity BEH C18 100x2.1 mm 1.7 pm operated at 45 °C A: 0.05% aq. TFA B: 0.05% TFA in ACN 0 min 10% B, 2.5 min 10% B, 7.5 min 98% B, 9.5 min 98% B, 9.6 min 10% B, 10 min 10% B 0.4mL / min 41 Agilent Poroshell 120 SB-Cl 8 4.6x30mm 2.7 pm operated at 45 °C A: 0.1% aq HCO2H B 0.1% HCO2H in ACN 0 min 1% B, 1.5 min 100% B, 2.2 min 100% B 3 mL / min 42 Waters HSS T3 1.8 pm ,1.0x 50mm column operated at 50 °C A: 0.01% aq HCO2H B 0.01% HCO2H in AC 0 min 10%B, 0.1 min 10% B, 0.6 min 95% B, 1.5 min 95% B, 1.51 min 10% B 0.475 mL / min Abbreviations ABPR = automated back pressure regulator ACN = acetonitrile AcOH = acetic acid AdBrettPhos Pd G3 = [2-(di-l-adamantyl-phosphino)-2’,4’,6’-tri-Ao-propyl-3,6-dimethoxybiphenyl] [2-(2’ -amino-1,1’ -biphenyl)]palladium(II) methanesulfonate aq = aqueous Boc = tert-butoxycarbonyl BOC2O = di-tert-butyl dicarbonate BOP = (benzotriazol-l-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate B2Pin2 = 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) Brettphos Pd G3 = [(2-Di-cvc / o-hexylphosphino-3,6-dimethoxy-2’,4’,6’- tri-Ao-propyl-1,1’-biphenyl)-2-(2’ -amino-1,1’ -biphenyl)]palladium(II) methanesulfonate methanesulfonate BrettPhos Pd G4 = [2'-(methylamino)-[l,r-biphenyl]-2-yl]palladio methanesulfonate di-cyc / o-hexyl[3,6-dimethoxy-2',4',6'-tris(propan-2-yl)-[l,r-biphenyl]-2-yl]phosphane brine = saturated aqueous sodium chloride cataCXium Pd G4 = [di(adamantan-l-yl)(butyl)phosphine](methanesulfonato- kO)[2’-(methylamino)-2-biphenylyl]palladium CBz = benzyloxycarbonyl CBz-Cl = benzyl chloroformate CDI= l,l'-carbonyldiimidazole DAST = diethylaminosulfur trifluoride dba = dibenzylideneacetone DCC = di-cyc / o-hexylcarbodiimide DCE = 1,2-dichloroethane DCM = dichloromethane DEA =diethylamine DEAD = diethyl azodicarboxylate Deoxo-Fluor = bis(2-methoxyethyl)aminosulfur trifluoride DIAD = di-Ao-propyl azodicarboxylate DIPEA = di-Ao-propyl ethyl amine DMAP = 4-(dimethylamino)pyridine DME = 1,2-dimethoxyethane DMF = dimethyl formamide DMDCH = tran^-A,A-dimethyl-cyc / o-hexane-l,2-diamine DMEDA = A7.A2-dimethylethane- 1,2-diamine DMP = Dess-Martin periodinane DMS = dimethyl sulfide DMSO = dimethyl sulfoxide DPPF = l,l’-bis(diphenylphosphino)ferrocene EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodi-imide EtOAc = ethyl acetate EtOH = ethanol FC = flash chromatography on silica gel unless stated otherwise from the eluent described in the brackets h = hour(s) HATU = (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU = N,N,N’,N’-tetramethyl-O-(lH-benzotriazol-l-yl)uronium hexafluorophosphate HFIP = l,l,l,3,3,3-hexafluoro-2-propanol HOBt = hydroxybenzotriazole HPLC = high performance liquid chromatography Int. / Ints. = intermediate / in termediates IPA = zko-propyl alcohol KO Ac = potassium acetate KOtBu = potassium tert-butoxide LCMS = liquid chromatography-mass spectrometry LDA = lithium di-Ao-propylamide LiHMDS = lithium bis(trimethylsilyl)amide mCPBA = m-chloro-perbenzoic acid MeOH = methanol 2MeTHF = 2-methyl-tetrahydrofuran MHz = megahertz MS = molecular sieves MsCl = methanesulfonyl chloride (mesyl chloride) MTBE = methyl tert-butyl ether MW = micro wave NaOtBu = sodium tert-butoxide NBS = A-bromosuccinimide NMP = A-methyl-2-pyrrolidon NMR = nuclear magnetic resonance ON = overnight Pdzdbas = tris(dibenzylideneacetone)dipalladium(0) PdDPPFCh-DCM = [l,l'-bis(diphenylphosphino)-ferrocene]dichloropalladium(H) DCM complex Pd G3 SPhos = (2-Di-cyc / o-hexylphosphino-2’,6’-dimethoxybiphenyl) f2-(2’-amino-l,l’-biphenyl)]palladium(II) methanesulfonate Pd G3 tert-butyl-Xphos = methanesulfonato (di-tert-butyl) phenylphosphino (2’-amino-1,1’-biphenyl-2-yl) palladium(II) ppm = parts per million PyBOP = (benzotriazol-l-yloxy)tripyrrolidino-phosphonium hexafluorophosphate RT = room temperature RU = response units RuPhos = 2-di-cyc / o-hexylphosphino-2’ ,6' -di-iso-propoxy bi phenyl Ruphos Pd-G2 = Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II) sat. = saturated SCX = strong cation exchange SEM = 2-(trimcthylsilyl)cthoxymcthyl SFC = supercritical fluid chromatography SPR = Surface plasmon resonance STAB = sodium triacetoxy borohydride TBAF = tetra / j-butyl ammonium fluoride TBAI = tetra n-butyl ammonium iodide TFA = trifluoro acetic acid TfzO = trifluoromethanesulfonic anhydride THF = tetrahydrofuran TLC = thin layer chromatography TMEDA = tetramethylethylenediamine Ts = tosyl TsOH = p-toluenesulfonic acid T3P = propanephosphonic acid anhydride VCD = Vibrational circular dichroism XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos = 2-di-cyc / o-hexylphosphino-2',4',6'-tri-zTo-propylbiphenyl Synthesis Methods The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of synthesis. The compounds of the disclosure could for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. Not all compounds falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used. The compounds of the present disclosure or any intermediate could be purified, if required, using standard methods well known to a synthetic organist chemist, e.g. methods described in “Purification of Laboratory Chemicals”, 6th ed. 2009, W. Amarego and C. Chai, Butterworth-Heinemann. Starting materials are either known or commercially available compounds, or may be prepared by routine synthetic methods well known to a person skilled in the art. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. The organic solvents used were usually anhydrous. The solvent ratios indicated refer to vol:vol unless otherwise noted. Thin layer chromatography was performed using Merck 6OF254 silica-gel TLC plates. Visualization of TLC plates was performed using UV light (254 nm) or by an appropriate staining technique. The compounds of the disclosure can be prepared according to the key bond formations outlined below. Xb and W = Cl, Br, I, OTf, B(OH)2 or BPin □5c R5b A' r5 R6- / B VR ' „ c xo5a xa_x5 R Alkylation or reductive amination Xa1 = Br, I, Cl, OTf, OMs, OTs Xb and W = Cl, Br, I, OTf, B(OH)2 or BPin Xa1 = Br, I, Cl, OTf, OMs, OTs Xa1 = Br, I, Cl, OTf, OMs, OTs Linking -A-L-LBM can be achieved according to conditions as described below. 5           Linking the A’ and B rings can be achieved in palladium-mediated couplings reactions wherein either an amine (Z=N) is reacted with an aryl (pseudo)halide based on ring A’ or by coupling ring B in which Z is a carbon atom linked to a boronic acid or boronate to aryl (pseudo)halide based on ring A’. Such reactions can be performed as described for the syntheses of Ints. 1M51 and 1S3. The bond connecting the B ring to the azaindole core (C-C) can be formed either by alkylation 10 of the B ring amine or lactam with an alkyl (pseudo)halide liked to the azaindole core (C-C) or by reductive amination of the B ring amine to the ketone / aldehyde liked to the azaindole core (C-C). Such reactions can be performed as described for the synthesis of Ints. 1AB2 / 1AB3, Example ln7 from Int. 104, Example lq2 from Int. 1Q1. R2 can be attached to the parent azaindole core (C-C) by alkylation with a suitable alkylation 15 agent. Such reactions can be performed as described for the syntheses of Int. 1K3. Compounds wherein R1 is not hydrogen can be prepared from precursors like Int. 1H2 or 1Y3. Attaching ring D to the azaindole core (C-C) can be done either by copper-mediated coupling of a boronic acid or boronate linked to the azaindole (C-C) core and the heteroaromatic ring D bearing a (pseudo)halogen or by the inverted set of Suzuki reaction partners. Such reactions can be performed as described for the synthesis of Example laf50 from Int. 1AF75 or Example laf52 from 1AF76’. 5 Compounds in which ring D is a part of a bicyclic system can be prepared similarly as described for the synthesis of Example 2f4 from Int. 3E261 via Int. 3E8 or Example 2c7 from Int. 2C38. x and w = Cl, Br, I, OTf, B(0H)2 or BPin x and w = Cl, Br, I, OTf, B(OH)2 or BPin x = Br, I, Cl, OTf, OMs, OTs HN —X5 R5 RSa Linking the A and B rings can be achieved in palladium-mediated couplings reactions wherein either an amine (Z=N) is reacted with an aryl (pseudo)halide based on ring A or by coupling ring B in 10 which Z is a carbon atom linked to a boronic acid or boronatc to aryl (pscudo)halidc based on ring A. Such reactions can be performed as described for the syntheses of Ints. 1M51 and 1S3. The bond connecting the B ring to the azaindole core (C-C) can be formed either by alkylation of the B ring amine or lactam with an alkyl (pseudo)halide liked to the azaindole core (C-C) or by reductive amination of the B ring amine to the ketone / aldehyde liked to the azaindole core (C-C). Such 15 reactions can be performed as described for the synthesis of Ints. 1AB2 / 1AB3, Example ln7 from Int. 104, Example lq2 from Int. 1Q1. R2 can be attached to the parent azaindole core (C-C) by alkylation with a suitable alkylation agent. Such reactions can be performed as described for the syntheses of Int. 1K3. Compounds wherein RI is not hydrogen can be prepared from precursors like Int. 1H2 or 1Y3. Attaching ring D to the azaindole core (C-C) can be done either by copper-mediated coupling of a boronic acid or boronate linked to the azaindole (C-C) core and the heteroaromatic ring D bearing a (pseudo)halogen or by the inverted set of Suzuki reaction partners. Such reactions can be performed as described for the synthesis of Example laf50 from Int. 1AF75 or Example laf52 from 1AF76’. 5 Compounds in which ring D is a part of a bicyclic system can be prepared similarly as described for the synthesis of Example 2f4 from Int. 3E261 via Int. 3E8 or Example 2c7 from Int. 2C38. Rv Compounds in which A = CO and the -L- fragment can be introduced via amide bond formation. The prerequisite acids can for example be prepared as described herein for Int. 3E83. The specification 10 exemplifies L-LBM fragments such as Int. 3E146 and their coupling to give the compounds of the disclosure such as described for the reaction of Ints. 3E83 / 2Q16 to give Example 2q6. Compounds in which A is a [l,2,4]triazolo[4,3-b]pyridazine unit can be prepared from intermediates like Int. 3E297 by cross-coupling to install the L-LBM fragment as described herein for 15 the synthesis of Example 2rl via Ints. 3E297 / 2C15. Compounds in which the L-LBM motif contains a triple bond can be prepared via alkylation reactions from precursors like Ints. 3A1 / 2T12 to give Example 2t5. The aromatics rings in the L linker can be functionalized with CN, F, or OMe substituents such as in Examples 2i3, 2il, and 2i7 which can be prepared as described herein from Ints. 2117, 211, and 2129. Compounds in which the L contains a six-membered heteroaromatic ring like pyrimidine or pyridine are exemplified herein in Examples 2kl and 2n3 which can be prepared as described herein from Ints. 2K2 and 2N14. The LBM piperidine-2,6-dione unit can be introduced by alkylation with 3-bromopiperidine-2,6-dione under the conditions outlined herein for the synthesis of Int. 2F16 en route to Example 2bL Example 1. Preparation of Intermediates T 1A5 r=ch2oh 1A4r=ch2ci SO2Ph 4-Bromo-l-(phenyl-sulfonyl)-lH-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.27 g) and NaBH4 (33 mg) were stirred 0.5h in THF / MeOH (9:1, 5 mL) at 0 °C. The OL (water / EtOAc) was washed with brine, dried, and concentrated to give Int. 1A5 (4-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methanol (281 mg). Int. 1A5 (0.24 g) and MsCl (0.052 mL) was stirred 0.5h in DCM / EtsN (29:1, 5.2 mL). MsCl (0.014 mL) was added and stirring continued 0.5h. The 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)-1 H-pyrrolo[2,3-b]pyridine (0.15g). 4-Bromopyridin-2(lH)-one (1.0 g), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bcnzoatc (3.17 g), PdDPPFCL-DCM (0.42 g), and K3PO4 (3.66 g) were degassed in dioxanc / watcr (10:1, 11 mL) and stirred 2h at 110 °C under MW conditions. The mixture was filtered, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1A17 ethyl 4-(2-oxo-lH-pyridin-4-yl)benzoate (0.50 g). Int. 1A17 (3.5 g) was hydrogenated 48h using 10% Pd / C (1.5 g) in EtOH / AcOH (4:1, 50 mL), 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 ON in DCM / EhN (25:1, 21 mL) at 0 °C to RT ON. The 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-l-carboxylate (0.40 g). Int. 1A15 (0.30 g) was stirred 0.5h in 0.1M LiHMDS in THF (11 mL) at -78 °C. CH3I (0.16 mL) was added and stirring continued 2h at -25 to -30 °C. The OL (sat. aq. NH4CI / EtOAc) was washed with water and brine, dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1A14 tert-butyl tran^-4-(4-ethoxycarbonylphenyl)-3-methyl-2-oxo-piperidine-1-carboxylate (0.18 g). Int. 1A14 (0.60 g) was stirred ON in DCM / TFA (32:1, 20.6 mL) at 0 °C to RT and concentrated. The OL (10% MeOH in DCM / sat. aq. NaHCOs) was dried, and concentrated to give Int. 1A13 ethyl 4-[tra„.?-3-methyl-2-oxo-4-piperidyl]benzoate (0.38 g). Int. 1A13 (0.20 g) and NaH (28 mg) were stirred 0.5h in THF (10 mL) at 0 °C to RT. Int. 1J1 (0.22 g) and TBAI (25 mg) were added and stirring continued ON. The OL (aq. citric acid / EtOAc) was dried and concentrated to give Ints. 1A12 / 1A11 ethyl 4-[trans-l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidyl]benzoate and 4-[trans-l-[(4-bromo- l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidyl]benzoic acid (0.30 g). 20 mg of this mixture, HNMe2 (0.11 g, HC1 salt), and HATU (0.25 g) were stirred ON in DMF / DIPEA (28.6:1, 10.4 mL). The mixture was combined with another batch prepared similarly on 30 mg scale, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1A10 TV, / V-Dimethyl-4-[trans-1 -[(4-bromo-1 -methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-methyl-2-oxo-4-piperidyl]benzamide (0.20 g). Int. 1A18 4-[l-[(4-Chloro-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-2-oxo-4-piperidyl]-AOV-dimethyl-benzamide was prepared similarly to Int. 1A10 from Int. 1A16 and 4-chloro-2-(chloromethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridine (prepared similarly to Int. 1J1). COR Int. 1J1 (8 g) and A,N-dimethyl-4-(4-piperidyl)benzamide (9.9 g, HC1 salt) were stirred ON in DMF / DIPEA (0.7:1, 47 mL) at 0°C to RT. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:3) to give Int. 1AB1 4-(l-((4-Bromo-l-methyl- 1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-7V,7V-dimethylbenzamide (9 g). Int. 1AB1’ 4-(1-((4-bromo-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-AOV-bis(methyl-c / 3)benzamide was prepared similarly from HNtCDih. Na2COs (9.2 g), 1,1 ,l-trifluoro-A-phenyl-A-((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 3h at 100 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 2:3) to give Int. 1AB14 tert-butyl 4-[4-(dimethylcarbamoyl)phenyl]-6-oxo-2,3-dihydropyridine-l-carboxylate (5.1 g). Int. 1AB14 (4.4 g) was hydrogenated ON using 10% Pd / C (0.45 g) in MeOH (100 mL), filtered, and concentrated to give Int. 1AB13 te / t-butyl 4-(4-(dimethylcarbamoyl)-phenyl)-2-oxopiperidine-l-carboxylate (3.9 g). Int. 1AB13 (8.1 g) was stirred ON in DCM / 4M HC1 in dioxane (4.2:1, 124 mL) and concentrated. The OL (sat. aq. NaHCO3 / 10% MeOH in DCM) was dried and concentrated to give Int. 1AB12 A,A-dimethyl-4-(2-oxo-piperidin-4-yl)-benzamide (2.9 g). This material was resolved by SFC using a Chiralpak IG 250x25 5pm column operated at 30 °C and an eluent of 50% CO? and 50% MeOH (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 0.25h in DMF (1 mL). Int. 1J1 (0.10 g) was added and stirring continued 0.5h. The OL (DCM / water) was washed with water and brine, dried, concentrated, and triturated in ACN to give Int. 1AB3 (S)-4-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)-A0V-dimethylbenzamide or (R)-4-(l-((4-bromo-l-methyl- 1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)-AOV-dimethyl-benzamide (31 mg). Int. 1AB2 (S)-4-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)-AOV-dimethylbenzamide or (R)-4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)mcthyl)-2-oxopiperidin-4-yl)-A,A-dimethyl-benzamide (35 mg) was prepared similarly from Ints. 1AB11 / 1J1 (95 mg / 0.10 g). The absolute configurations of these compounds were not determined. Int. 1AB1 (0.15 g), B2Pin2 (0.13 g), KOAc (81 mg), and PdDPPFCl2-DCM (27 mg) were degassed in dioxane (3 mL) and stirred at 90 °C, filtered and concentrated to give Ints. 1AB4 / 1AB4’ A0V-Dimethyl-4-[l-[[l -methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidyl]benzamide and [2-[[4-[4-(dimethylcarbamoyl)phenyl]-l-piperidyl]methyl]-l-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid and AOV-bis(methyl-6 / 3)-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzamide and (2-((4-(4-(bis-(methyl-d3)carbamoyl)phenyl)piperidin-1 -yl)methyl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid. 4-Bromo-A^3-trimethylbenzamide (9.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (15.2 g), PdDPPFClz-DCM (0.67 g), and Na^COs (9.62 g) were degassed in dioxane (180 mL) and stirred ON at 90 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 2:3) to give Int. 1AB7 tert-butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (11.0 g). Int. 1AB7 (0.6 g) was stirred ON in DCM / TFA (30:1, 15.5 mL), concentrated, and triturated in Et20 to give Int. 1AB6 ACV,3-trimcthyl-4-( 1.2.3.6-letrahydropyridin-4-yl (benzamide (TFA salt). Ints. 1AB6 / 1AB8 (0.23 g, TFA salt / 0.1 g) were stirred ON in DCE / DIPEA (11.4:1, 5.4 mL) at 0 °C to RT. STAB (26 mg) was added and stirring continued 2h at 0 °C to RT. The OL (water / DCM) was dried, concentrated, and purified by FC (MeOH / DCM 1:9) to give Int. 1AB5 4-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-y 1 )-N, N, 3-tri methyl benzamide (0.10 g). Br 4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridine (5.0 g) was stirred 2h in 1.1M LDA in THF (33 mL) at -78 °C. DMF (3.46 g in THF (20 mL)) was added and stirring continued ON at -78 °C to RT ON. The OL (sat. aq. NELCl / EtOAc) was washed with water, brine, dried, concentrated, and triturated in EtOAc / pentane to give Int. 1AB8 4-Bromo-l-methyl-IH-pyrrolo [2,3-b]pyridine-2-carbaldehyde (3.1 g)- CONMe2 \— / Int. 1AB10 R=H, single bond / Int 1AB12 R=H, single bond Int 1AB14 R=Boc, double bond ° \    / Int 1AB13 R=Boc, single bond r' PdDPPFCL-DCM (1.1 g), tert-Butyl 6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-l(2H)-carboxylate (10.2 g), (4-(dimethylcarbamoyl)phenyl)boronic acid (5.7 g), and NazCOj (9.4 g) were stirred 3h in toluene / water (150 / 40 mL) at 100 °C. The mixture was filtered. The filtrate was concentrated and purified by FC (EtOAc / Hcxanc 3:2) to give Int. 1AB14 tert-butyl 4-(4-(dimethyl-carbamoyl)-phenyl)-6-oxo-3,6-dihydropyridine-l(2H)-carboxylate (5.2 g). Int. 1AB14 (5 g) and 10% Pd / C (2.5 g) were hydrogenated 48h under a hydrogen pressure of 60 psi in EtOAc (100 mL). The mixture was filtered and concentration to give Int. 1AB13 tert-butyl 4-(4-(dimethylcarbamoyl)phenyl)-2-oxopiperidine-l-carboxylate (4.0 g). Int. 1AB13 (0.1 g) was stirred 12h in DCM / 4M HC1 in dioxane (5 / 0.4 mL). The residue after concentration was triturated in Et2O to give Int. 1AB10 / 1AB12 N,N-dimethyl-4-(2-oxopiperidin-4-yl)benzamide (78 mg). Int. 1AB8 (6.0 g) and methyl 4-(l-piperidin-4-yl)benzoate (7.1 g, HC1 salt) were stirred 4h in DCE / DIPEA (7.7:1, 113 mL). STAB (11.0 g) was added and stirring continued ON at 0 °C to RT. The OL (water / EtOAc) was washed with brine, dried, concentrated, and triturated in EtOAc / MeOH give Int. 1AC5 methyl 4-(l-((4-bromo-l-methyl- lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoate. Int. 1AC5 (0.4 g) and NaOH (0.18 g) were stirred ON in THF / MeOH (2:1, 9 mL), concentrated, and triturated in dilute aq. HO to give Int. 1AC4 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidyl]-benzoic acid (0.38 g). Int. 1AC4 (0.5 g) and GDI (0.7 g) were stirred 2h in DMF / EtsN (30:1, 7.2 mL). 25% aq. NFL (1.51 mL) was added followed by water to precipitate a solid that was stirred ON in I, I -dimethoxy-A'jV-dimethylmethanamine (10 mL) to afford Int. 1AC3 4-(1-((4-bromo-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzamide (0.35 g). 4-Bromo-l-tosyl-lH-pyrrolo[2,3-£’]pyridine (i.O g) was stirred Ih in 0.6M LDA in THF (14.2 mL) at -78 °C. DMF (1.3 mL) was added and stirring continued 2h at -78 °C. The OL (sat. aq. NHiCl / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:0 to 9:1) to give Int. 1AD8 4-bromo-1 -(p-tolylsulfonyl)-pyrrolo[2,3-b]-pyridine-2-carbaldehyde (0.6 g). MAl-Dimethyl-4-(4-piperidinyl)-benzamide (1.4 g, HC1 salt) and Int. 1AD8 (1.3 g) were stirred ON in DCE / DIPEA (20:1, 21 mL) at 0 °C to RT. STAB (1.1 g) was stirring continued 2h at 0 °C to RT. The OL (watcr / DCM) was dried, concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AD7 4-[l-[[4-bromo-l-(p-tolyl-sulfonyl)-pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidyl]-N,N-dimethyl-benzamide (2.3 g). CONMe2 1AE2 R=Boc N-Z 1AE1 R=H N—' r' KOtBu (37 mg), tert-butyl 4-(p-tolylsulfonyloxy)piperidine-l-carboxylate (0.16 g), K2CO3 (83 mg), and A,A-dimethyl-2-oxo-lH-pyridine-4-carboxamide (50 mg) were degassed in DME (5 mL) and stirred ON at 120 °C. The OL (water / MeOH / DCM) was dried and concentrated to give Int. 1AE2 tertbutyl 4-[4-(dimethyl-carbamoyl)-2-oxo-1 -pyridyl]-piperidine-l -carboxylate. Int. 1AE2 (0.25 g) was stirred in DCM / TFA (8.6:1, 5.6 mL). The mixture was concentrated to give Int. 1AE1 7V, / V-Dimethyl-2-oxo-l-(piperidin-4-yl)-l,2-dihydropyridine-4-carboxamide (0.15 mg, TFA salt). 4-Bromo-A,A-dimethylbenzamide (25 g), Zert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (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 at 90 °C ON and filtered. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 55:45) to give tert-butyl 4-(4-(dimethyl-carbamoyl)-phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (36.0 g). 5.0 g of this material was stirred ON in DCM / TFA (6.9:1, 46 mL) and concentrated. The OL (sat. aq. NaHCO3 / 10% MeOH in DCM) was washed with brine, dried, concentrated, and triturated in Et2O to give Int. 1AE7 4-(3,6-dihydro-2H-pyridin-4-yl)-A,A-dimethyl-benzamide (2.80 g). 1AE14R=OMe __COR 1AE37 R=OH 1AE7' r=n(CD3)2 \— / N—' Boe' Methyl 4-bromobenzoic acid ester (10 g) tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (14.4 g), NaHCO3 (11.7 g), and PdDPPFCl2-DCM (1.2 g) were degassed in dioxane (300 mL) and stirred at 100 °C ON. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hcxanc / EtOAc 9:1) to give Int. 1AE14 tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (11 g). 4.5 g of this material and LiOH-H2O (3.0 g) were stirred 4h in MeOH / THF / water (4:2:1, 35 mL) at 0 °C to RT. The mixture was partially concentrated and diluted with aq. citric acid to precipitate Int. 1AE37 4-(l-(tert-butoxycarbonyl)-l,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, HC1 salt) were stirred ON in DMF / DIPEA (2.5:1, 42 mL). The OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give tert-butyl 4-[4-[bis-(trideuteriomethyl)-carbamoyl]phenyl]-3,6-dihydro-2H-pyridine-1 -carboxylate (3.5 g). 2.5 g of this material was stirred ON in DCM / TFA (1:1, 30 mL) at 0 °C to RT and concentrated. The OL (aq. NaHCO3 / 10% MeOH in DCM) was dried, concentrated, and triturated in Et2O / pentane to give Int. 1AE7’ A,A-Bis(methyl-d3)-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (1.7 g). tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (33.7 g), 4-bromo-A(A(3-trimcthylbcnzamidc (20.0 g), Na2CO3 (21.4 g), and PdDPPFCL-DCM (1.48 g) were degassed in dioxane / water (9:1, 200 mL) and stirred ON 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-l-carboxylate (25 g). 15 g of this material was hydrogenated ON using 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). 10 g of this material was stirred ON in DCM / TFA (1:1, 200 mL) at 0 °C to RT, concentrated, and triturated in EtzO to give Int. 1AE8 A,A,3-trimethyl-(4-piperidin-4-yl)benzamide (9.2 g, TFA salt). tert-Butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (4.0 g) was stirred 0.5h in 4M HC1 in dioxane (40 mL), concentrated, and triturated in Et2O to give Int. 1AE8’ A,A,3-trimethyl-4-( 1,2,3,6-tetrahydropyridin-4-yl)benzamide (1.06 g, HC1 salt). Ints. 1J1 / 1 (0.70 g / 0.49 g, HC1 salt) and KI (0.11 g) were stirred ON in DMF / DIPEA (8.3:1, 11.2 mL) at 0 °C to RT. The OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (EtOAc / hexane 7:3) to give Int. 1AE9 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-y 1 )-3-fluoro-5-methyl-A,A-bis(methyl-r / 3)benzamide (0.45 g). conr2 / 1AE12r=cd3 _\ 1AE12'R=Me HN—' Methyl 4-bromo-3-fluoro-5-methyl-benzoate (20 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (27.5 g), K2CO3 (44.8 g), and PdDPPFCL-DCM (3.31 g) were degassed in dioxane / water (4:1, 0.5 L) and stirred at 100 °C ON. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane to EtOAc) to give tert-butyl 4-(2-fluoro-4-methoxy-carbonyl-6-methyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (15.5 g). This material and LiOH-HjO (3.72 g) were stirred ON in MeOH / water (1:1, 0.3 L) and acidified to precipitate 4-(l-te / 7-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-fluoro-5-methyl-benzoic acid (11.8 g). 5.0 g of this material, HN(CD3)z (1.44 g, HC1 salt), and HATU (6.8 g) were stirred ON in DMF / DIPEA (6.4:1, 58 mL), concentrated, and purified by FC (hexane to EtOAc) to give tertbutyl 4-[4-[bis(trideuterio-methyl)carbamoyl]-2-fluoro-6-niethyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (5.1 g). This material was stirred Ih in HFIP / 10 M aq. HO (31:1, 52 mL) and diluted with MTBE to precipitate Int. 1AE12 3-Fluoro-5-methyl-A,A-bis(methyl-t / 3)-4-( 1,2,3,6-tetrahydropyridin-4-yl)benzamide (3.45 g, HO salt). Int. 1AE12’ 3-fluoro-5-methyl-A,A-bis(methyl)-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide was prepared in a similar manner from HNtCHfiz. Int. 1J3 (0.50 g) was stirred Ih in DCM (20 mL) and MsCl (0.8 mL) at 0 °C. The OL (water / DCM) was washed with sat. aq. NaHCO3 and concentrated to give (4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl methanesulfonate (0.52 g). 0.5 g of this material, KI (0.13 g), and Int. 1AE12’ (0.51 g) were stirred ON in DMF / DIPEA (14:1, 21.5 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AE13 4-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-A,A,5-trimethyl-benzamide (0.52 g). Int. 1AB1 (0.15 g), Mo(CO)e (87 mg), Pd2dba3 (8 mg), and XantPhos (10 mg) were degassed in EtOH (5 mL) and stirred 0.5h at 120 °C under MW conditions. The mixture was filtered and HPLC-purificd give ethyl 2-((4-(4-(dimcthylcarbamoyl)phenyl)piperidin-l-yl)mcthyl)-l-mcthyl-lH-pyrrolo[2,3-b]pyridine-4-carboxylate (0.25 g). This material and LiOH (69 mg) were stirred in water / EtOH (2:1, 1.5 mL), concentrated, and HPLC-purified to give Int. 1AE15 2-((4-(4-(Dimethylcarbamoyl)phenyl)piperidin-1-yl)methyl)-1-methyl-lH-pyrrolo[2,3-b]pyridine-4-carboxylic acid (0.15 g). Piperazin-2-one (1.0 g), 4-bromo-A,A-dimethylbenzamide (1.14 g), K3PO4 (6.4 g), Pd(OAc)2 (0.22 g), and RuPhos (0.93 g) were degassed in tert-butyl alcohol (15 mL) and stirred ON at 80-90 °C. The mixture was filtered, concentrated, and purified by FC (DCM / MeOH 9:1) to give A,A-dimethyl-4-(3-oxopiperazin-l-yl)benzamide (0.70 g). 0.25 g of this material and NaH (81 mg) were stirred Ih in THF / DMF (10:1, 5.5 mL) at 0 °C to RT. Int. UI (0.25 g) was added and stirring continued ON at 0 °C to RT. The OL (10% MeOH in DCM / water) was dried, concentrated, and purified by FC (DCM / MeOH 9:1} to give Int. LAE16 4-(4-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-oxopiperazin-1 -yl)-7V,N-dimethylbenzamide (0.20 g). R' 1AE19r=h 6-Bromo-5-methyl-pyridine-3-carboxylic acid (4.5 g), HATU (9.5 g), and HN(CHs)2 (8.4 g, HC1 salt) were stirred ON in DMF / DIPEA (2.5:1, 45 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated and purified by FC (hexane / EtOAc 3:7) to give Int. 1AE21 6-bromo-7V,A,5-trimethylnicotinamide (4.2 g). 3.2 g of this material, NaHCO ? (3.9 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-pyridine-l(2H)-carboxylate (6.1 g), and PdDPPFCl2-DCM (0.27 g) were degassed in dioxane / water (3.7:1, 14 mL) and stirred ON at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1AE20 tert-butyl 5-(dimethylcarbamoyl)-3-methyl-3',6'-dihydro-[2,4'-bipyridine]-l'(2'H)-carboxylate (4.0 g). 0.25 g of this material was stirred ON in DCM / TFA (8.4:1, 5.6 mL) at 0 °C to RT, concentrated, and triturated in Et2O / pentane to give Int. 1AE19 A, / V,5-trimethyl-6-( 1,2,3,6-tetrahydro-pyridin-4-yl)pyridine-3-carboxamide (0.28 g, TFA salt). CONMe2 1AF22 R=Br       — 1AF23 R=B(OH)2 / BPin \=| / R N Ints. 1AE19 / 1J1 (0.5 g / 0.5 g) were stirred ON ACN / EtsN (18:1, 26 mL), concentrated, and HPLC-purified to give Int. 1AE22 6-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-ACV,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 ON at 80 °C. The OL (water / EtOAc) was dried and concentrated to give Int. 1AE23 (2-((5-(dimethylcarbamoyl)-3-methyl-3',6'-dihydro-[2,4'-bipyri din]-l'(2'H)-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid / A,A,3-trimethy 1-1'-((1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (1.0 g). CONMe2 ( / A   1AE27 R=Boc, double bond )=(    1AE26 R=Boc, single bond / =(        1AE25 R=H, single bond N—' d 4-Bromo-3-fluoro-A,A-dimethyl-benzamide (1.0 g), tert-butyl 4-(4,4,5,5-tetramethyL 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (1.51 g), Na2COs (1.72 g), and PdDPPFClz-DCM (0.17 g) were degassed in dioxane / water (4:1, 10 mL) and stirred at 100 °C ON. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AE27 tert-butyl 4-[4-(dimcthyl-carbamoyl)-2-fluoro-phcnyl]-3,6-dihydro-2H-pyridinc-l-carboxylate (1.2 g). This material was hydrogenated ON using 10% Pd / C (40 mg) in MeOH (10 mL) under an atmosphere of Hz in a sealed tube, filtered, and concentrated to give Int. 1AE26 tert-butyl 4-[4-(dimethylcarba-moyl)-2-fluoro-phenyl]piperidine-l-carboxylate (0.60 g) that was stirred in 4M HC1 in dioxane (10 mL) ON, concentrated, and HPLC-purified to give Int. 1AE25 3-fluoro-A,A-dimethyl-4-(piperidin-4-yl)benzamide (63 mg). CONMe2 sr                               / Br      / -\ L IT y-cHo             n- / n—p iTy— Ts                    1AE34 1AE35                  Ts 4-Bromo-l-tosyl-lH-pyrrolo[2,34]pyridinc (1.0 g) was stirred Ih in 0.6 M LDA in THF (14 mL) at -78 °C. DMF (1.3 mL) was added and stirring continued 2h at -78 °C. The OL (sat. aq. NH4Cl / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 1AE35 4-bromo-l-(p-tolyl-sulfonyl)pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.6 g). Int. 1A35 (1.5 g) and N,N-dimethyl-4-(piperidin-4-yl)benzamide (1.6 g, HC1 salt) were stirred ON in DCM / DIPEA (5:1, 24 mL). STAB (2.5 g) was added and stirring continued 2h at 0 °C to RT. The OL (DCM / water) was dried, concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AE34 4-[l-[[4-bromo-l-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-2-yl]methyl]-4-piperidyl]-A,A-dimethyl-benzamide (1.0 g). Int. 1AC4 (0.10 g), HATU (164 mg), and (3,4-dimethoxybenzyl)(methyl)-amine (58 mg) were stirred 3h in DMF / DIPEA (25:1, 3.1 mL). The OL (sat. aq. NaHCO7DCM) was dried, concentrated, and purified by FC (DCM to DCM / MeOH 93:7) to give Int. 1AE36 4-(l-((4-bromo-l-methyl-lH-pyrrolo-[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A-(3,4-dimethoxybenzyl)-A-methylbenzamide (0.12 g). CONMe2 HN—' tert-Butyl 4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (4.0 g) was stirred 0.5h in 4M HC1 in dioxane (40 mL), concentrated, and triturated in Et2O to give Int. 1AE38 A,A,3-trimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (1.06 g, HC1 salt). tert-Butyl 3-oxopiperazine-l-carboxylate (0.50 g), 4-bromo-A,A-dimethylbenzamide (0.68 g), K3PO4 (1.06 g), Cui (71 mg), DMDCH (36 mg), were degassed in dioxane (10 mL) and was stirred at 100 °C ON. The OL (water / EtOAc) was dried, concentrated, and purified by FC (EtOAc / MeOH 1:0 to 9:1) to give tert-butyl 4-(4-(dimethylcarbamoyl)-phenyl)-3-oxopiperazine-l-carboxylate (0.80 g). 0.23 g of this material was stirred Ih in DCM / TFA (1:1,6 mL) and concentrated to give Int. 1AE39 N,N-Dimethyl-4-(2-oxo-piperazin-l-yl)benzamide (0.24 g, TFA salt). \ Int. 1J1 / 1AE7’ (0.33 g / 0.30 g), and KI (21 mg) were stirred ON in DMF / DIPEA (7.3:1, 9 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AF1 4-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-A,A-bis(methyl-t / 3)benzamide (0.20 g). CON(CD3)2 Methyl 2-bromopyrimidine-5-carboxylate (10.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (15.6 g), K2CO3 (25.5 g), and PdDPPFCL-DCM (1.88 g) were degassed in dioxane / water (4:1, 0.25 L) and stirred ON at 100 °C. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give methyl 2-(l-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrimidine-5-carboxylate (14.7 g). This material and LiOH-H2O (2.15 g) were stirred ON in MeOH / water (1:1, 200 mL) and acidified to precipitate 2-(l-tert-butoxy-carbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrimidine-5-carboxylic acid (8.0 g). 4.0 g of this material, HNfCDsh 11.21 g, HC1 salt), 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-fbis(tri-deuteriomethyl)carbamoyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyridine-l-carboxylate (2.20 g). This material was stirred in Ih HFIP / 10M aq. HO (30:1, 23 mL), concentrated, and triturated in MTBE to give Int. 1AF2 A,A-bis(methyl-r / 3)-2-( 1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide (1.40 g, Ints. 1AF2 / 1J1 (0.5 g / 0.5 g) were stirred in ACN / EhN (19:1, 26 mL), concentrated, and HPLC-purified to give Int. 1AF3 2-[l-[(4-Bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-A,A-bis(trideuteriomethyl)pyrimidine-5-carboxamide (0.3 g). 4-Bromo-3-fluoro-A,A-dimethyl-benzamide (1 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.5 g), Na2CO3 (1.7 g), PdPDDFCL-DCM (0.17 g) were deassed in dioxane / water (4:1, 10 mL) and stirred ON at 100 °C. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give Int. 1AF11 tert-butyl 4-[4-(dimethylcarbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (1.2 g). Int. 1AF11 (0.6 g) was stirred ON in 4M HC1 in dioxane (10 mL). The residue after concentration was HPLC-purified to give Int. 1AF10 3-fluoro-A,A-dimethyl-4-( 1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g). Ints. 1AF10 / 1J1 (0.5 g / 0.5 g) were stirred ON in ACN / Et3N (19:1, 26 mL), concentrated, and HPLC-purified to give Int. 1AF9 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)-methyl]-3,6-dihydro-2H-pyridin-4-yl]-A,A,3,5-tetramethyl-benzamide (0.3 g). Int. 1AF9 (3 g), B2pin2 (5 g), KOAc (5 g), and PdDPPFCh-DCM (50 mg) were degassed in dioxane and stirred ON at 80 °C. The OL (EtOAc / water) was dried and concentrated to give Int. 1AF8 3-chloro-A,A-dimethyl-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide / (2-((4-(2-chloro-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyridin-l(2H)-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (1 g). Ints. 1S5 / 1J1 (0.5 g / 0.5g, as the HC1 salt) were stirred ON in ACN / Et3N (19:1, 26 mL), concentrated, and HPLC-purified to give Int. 1AF13 6-[l-[(4-bromo-l-methyl-pyrrolo-[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-A,A-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 at 80 °C ON. The OL (water / EtOAc) was concentrated to give Example 1AF12 AOV-Dimethyl-l'-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-I'.2'.3',6'-tetrahydi'o-[2.4'-bipyridine]-5-carboxamide / (2-((5-(dimethylcarbamoyl)-3',6'-dihydro-[2,4'-bipyridin]-l'(2'H)-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (1.0 g). Methyl 5-bromopyrazine-2-carboxylate (11.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (17.2 g), K2CO3 (28.0 g), PdPDDFCl2-DCM (2.07 g) were deassed in dioxane / water (5:1, 250 mL) and stirred ON at 100 °C. The aq. layer (water / EtOAc) was acidified to precipitate 5-(l-tert-butoxy-carbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (12.0 g). 4.5 g of this material, HN(CD3)2 (1.40 g, HC1 salt), and HATU (6.20 g) were stirred ON in DMF / DIPEA (2.6:1, 28 mL), concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-[5-[bis(trideuteriomethyl)-carbamoyl]pyrazin-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.0 g). This material was stirred in Ih HFIP / 10M aq. HC1 (29:1, 21 mL), concentrated, and triturated in MTBE to give Int. 1AF14 5-(1,2,3,6-Tetrahydropyridin-4-yl)-A,A-bis(trideuteriomethyl)pyrazine-2-carboxamide (0.88 g, HC1 salt). Ints. 1AF14 / 1J1 (0.5 g / 0.5 g), and Et3N (1.2 mL) were stirred ON in ACN (25 mL), concentrated, and HPLC-purificd to give Int. 1AF15 5-(l-((4-Bromo-l-mcthyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-A,A-bis(methyl-£ / 3)pyrazine-2-carboxamide (0.3 g)- 1.0M MeMgBr in THF (185 mL) was added to a solution of Int. 1AB8 (29.5 g) in THF (1.2 L) at 0 °C and stirring continued 3h. The OL (sat. aq. NH,;CI / EtOAc) was washed with brine, dried, concentrated and purified by FC (pentane / EtOAc 3:1) to give Int. 1AF21 l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethan-l-ol (25.5 g). 0.30 g of this material was stirred in toluene / SOCF (12.5:1, 10.8 mL) at 0 °C before stirring 0.5h at 110 °C. The mixture was concentrated. The residue, CS2CO3 (1.15 g), KI (0.98 g), and 7V,7V-dimethyl-4-(4-piperidyl)-benzamide (0.41 g) were stirred ON in ACN (10 mL) at 0 °C to RT. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1AF17 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b] py ridi n-2-y 1 )ethy l)-piperid in-4-y 1 )-A,A-di methyl benzamide (0.28 g). Int. 1AF17 (0.70 g), BjPim (0.51 g), KO Ac (0.4 g), and Pd^PhsECL (0.1 g) were degassed in THF (50 mL) and stirred ON at 100 °C, filtered, concentrated, and triturated in pentane to give Int. 1AF24 (2-(1 -(4-(4-(dimethyl-carbamoyl)phenyl)piperidin-1 -yl)ethyl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g). CONMe2 1AF24 \= / B(OH)2 / ~\ N—' uCH N Int. 1AF17 (0.70 g), BzPinz (0.51 g), KO Ac (0.4 g), and Pd^PhsEClz (0.1 g) were degassed in THF (50 mL) and stirred ON at 100 °C, filtered, concentrated, and triturated in pentane to give Int. 1AF24 (2-(1 -(4-(4-(dimcthyl-carbamoyl)phcnyl)pipcridin-1 -yl)cthyl)-1 -methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g). Int. 1AF17 (0.70 g), BzPinz (38 mg), KOAc (45 mg), and PdDPPFCL-DCM (25 mg) were degassed in dioxane (10 mL) and stirred ON at 110 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF27 A,7V-dimethyl-4-(l-(l-(l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo-[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzamide (0.85 g). l-(4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethan-l-ol (0.20 g) was stirred 1.5h in toluene / SOCT (29:1, 5.2 mL) at 0 °C to 110 °C and concentrated. The residue, KI (10 mg), and Int. 1AF5 (0.23 g) were stirred ON in DMF / DIPEA (2.5:1,2.8 mL) at 0 °C to RT. The 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-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-7V,A-dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), BzPinz (24 mg), KOAc (25 mg), and PdC12(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred ON at 90 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(l-(4-(4-(dimethylcarbamoyl)-phenyl)-3,6-dihydropyridin-l(2H)-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-boronic acid (0.50 g). l-(4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethan-l-ol (0.20 g) was stirred 1.5h in toluene / SOCL (29:1, 5.2 mL) at 0 °C to 110 °C and concentrated. The residue, KI (10 mg), and Int. 1AF5 (0.23 g) were stirred ON in DMF / DIPEA (2.5:1, 2.8 mL) at 0 °C to RT. The 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-[l-[l-(4-bromo-l-methyl-pyrrolo-[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-ACV-dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), B2Pin2 (24 mg), KOAc (25 mg), and PdC12(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred ON at 90 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(l-(4-(4-(dimethyl-carbamoyl)-phenyl)-3,6- dihydropyridin-l(2H)-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-boronic acid (0.50 g). Int. 1AF40 4-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-A,A,3-trimethyl-benzamide (0.15 g) was prepared similarly to Int. 1AF17 from Int. 1AF21 (0.20 g) and Int. 1AE38 (0.37 g, TFA salt). Int. 1AF39 (2-(l-(4-(4-(dimethylcarbamoyl)-2- methylphenyl)-3,6-dihydropyridin-l(2H)-yl)-ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (40 mg) was prepared similarly to Int. 1AF33 from Int. 1AF40 (50 mg). Int. 1AF44 4-[1 -[1 -(4-bromo-l -meihyl-pyrrolo[2,3-b]pyridin-2-yl)elhyl]-4-piperidyl]-M / V:3-trimethyl-benzamide (0.15 g) was prepared similarly to Int. 1AF17 from Ints. 1AF24 / 1AE38 (0.20 g / 0.42 g, TFA salt). Int. 1AF43 (2-(1-(4-(4-(dimethylcarbamoyl)-2-methylphenyl)-3,6-dihydropyridin-l(2H)-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]-pyridin-4-yl)boronic acid (0.60 g) was prepared similarly to Int. 1AF39 from Int. 1AF44 (0.50 g). Int. 1AF50 4-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-4-piperidyl]-A,A-bis(trideuterio-methyl)benzamid (0.65 g) was prepared similarly to Int. 1AF17 from Ints. 1AF21 / 1D7 (0.35 g / 0.53 g, TFA salt). Int. 1AF49 [2-[l-[4-[4-[bis(trideuterio-methyl)carbamoyl]phenyl]-l-pipcridyl]cthyl]-l-mcthyl-pyrrolo[2,3-b]-pyridin-4-yl]-boronic acid (0.41 g) was prepared similarly to Int. 1AF25 from Int. 1AF50 (0.32 g) and B2Pin2 (0.34 g). Int. 1AF56 4-( 1 -(1 -(4-bromo-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-A,A-bis(methyl-r / 3)benzamide (0.60 g) was prepared similarly to Int. 1AF34 from Int. 1AF21 (0.50 g) and Int. 1AE7’ (0.69 g). Int. 1AF55 [2-[l-[4-[4- 5 [bis(trideuteriomethyl)carbamoyl]phenyl]-3,6-dihydro-2H-pyridin-l-yl]ethyl]-l-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (0.55 g) was prepared similarly to Int. 1AF39 from Int. 1AF56 (0.50 g). CON(CD3)2 1AF62R=Br 1AF61 r=b(OH)2 / r (= / N W Int. 1AF62 4-(1-(1-(4-bromo-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-7V,7V-bis(methyl-d3)benzamide (0.46 g) was prepared similarly to Int. 1AF17 from 10 Ints. 1AF24 / 1S20 (0.50 g / 0.70 g). Int. 1AF61 (2-(1-(4-(4-(bis(methyl-<73)carbamoyl)-2-methylphenyl)-3,6-dihydropyridin-l(2H)-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.75 g) was prepared similarly to Int. 1AF55 from B2Pin2 (0.52 g) and Int. 1AF62 (0.5 g). Int. 1AF72 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3- 15 methyl-A,A-bis-(methyl-c?3)benzamide (90 mg) was prepared similarly to Int. 1AF17 from Ints. 1AF24 / 1S22 (0.10 g / 0.19 g, TFA salt). Int. 1AF71 (2-(l-(4-(4-(bis(methyl-J3)carbamoyl)-2- methylphenyr)piperidin-l-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.10 g) was prepared similarly to Int. 1AF55 from Int. 1AF72 (90 mg) and B2Pin2 (0.12 g). R Int. 1AF21 (1.20 g) was stirred Ih in toluene / SOCl2 (5.9:1, 23.5 mL) at 0 °C to 110 °C and concentrated. The residue, CS2CO3 (4.60 g), KI (0.39 g), and Int. 1AE7 (1.30 g) were stirred ON in ACN (30 mL) at 0 °C to RT. The 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-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-A,A-dimethyl-benzamide (1.0 g). Int. 1AF74 4-(1-(1-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-AOV-bis(methyl-<i3)benzamide (0.60 g) was prepared similarly from Ints. 1AE7’ / 1AF21 (0.69 g / 0.50 g). ” \ 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) and stirred 6h at 90 °C, filtered, concentrated, and triturated in Et2O to give Int. 1AF75 (S)-A,A-bis(methyl-Js)-4-(l-(1-(1-methyl-4-(4,4,5,5-tetramethyL 1,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)benzamide (1.30 g). R 1AF76 X=Br, R=C0NMe2 1AF76'X=Br, R=CON(CD3)2 c y 1AF77 X=l, R=CON(CD3)2   )—' X Int. 2C36 (0.35 g), HATU (0.3 g), and HN(CD3)2 (77 mg, HC1 salt) were stirred ON in DMF / DIPEA (14.7:1, 10.7 mL) at 0 °C to RT and diluted with water to precipitate Int. 1AF76 (0.30 g). Int. 1AF76’ (3.5 g) was prepared similarly 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) and stirred at 110 °C ON and filtered. The OL (DCM / aq. NH3) was dried, concentrated, and purified by FC (DCM / McOH 97:3) to give Int. 1AF77 (S)-4-(l-(l-(4-iodo-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-AOV-bisimethyl-^ j-henzamide (50 mg). The absolute configuration of 1AF76 (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo-[2,3-b]pyridin-2-yl)-ethyl)piperidin-4-yl)-A0V-dimethylbenzamide and 1AF76’ (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo-[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)-AOV-bis(methyl-<A)benzamide was determined to S by VCD. CDI (7.04 g) was added to a solution of 4-bromo-3-fluoro-5-methyl-benzoyl chloride (11.0 g)in DCM (50 mL) at 0 °C and stirring continued 0.5h. HN(CH3)z (7.1 g, HC1 salt) was added before refluxing 5h. The mixture was washed with water, dried, and concentrated to give Int. 1AF7 4-bromo-3-fluoro-V,V,5-trimethyl-benzamide (12.4 g). This material, tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (15.0 g), K2CO3 (18.3 g), and PdDPPFCL-DCM (0.73 g) were degassed in dioxane (100 mL) and stirred 48h at 90 °C. The OL (water / MTBE) was dried and concentrated to give Int. 1AF6 tert-butyl 4-(2-chloro-4-(dimethylcarbamoyl)-6-fluorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate (11.0 g). Int. 1AF6 (0.6 g) was stirred 0.5h in THF / 4M HC1 in dioxane (1:1, 2 mL). The OL (water / EtOAc) was dried and concentrated to give Int. 1AF5 3-chloro-5-fluoro-7V,A-dimethyl-4-( 1,2,3,6-tetrahydro-pyridin-4-yl)benzamide (0.25 g, HC1 salt). This material, K2CO3 (0.37 g), and Int. 1J1 (0.23 g) were stirred in DMF (5 mL) ON. The OL (water / MTBE) was layer was dried and concentrated to give Int. 1AF4 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)-methyl]-3,6-dihydro-2H-pyridin-4-yl]-3-chloro-5-fluoro-ACV-dimethyl-benzamide (0.17 g). This material, B2Pin2 (0.17 g), KO Ac (0.10 g), and PdDPPFCl2-DCM (6 mg) were degassed in dioxane (5 mL) and stirred 48h at 100 °C. The OL (water / MTBE) was layer was dried and concentrated to give Int. 1AF82 3-Chloro-5-fluoro-V,V-dimcthyl-4-(l-((l-mcthyl-4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide / (2-((4-(2-chloro-4-(dimethyl-carbamoyl)-6-fluorophenyl)-3,6-dihydropyridin-l(2H)-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-boronic acid (0.19 g). Int. 1AF21 (8 g) was stirred 0.5h in toluene / SOCL (4:1, 123 mL) at 0 °C to 80 °C and concentrated to give Int. 1AF88 (7.5 g). Ints. 1AF88 / 1AF90 (7.5 g, 7.8 g, HC1 salt), Cs2CO3 (31 g), and KI (23 g) were stirred ON in ACN (100 mL) at 0 °C to RT. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 41:9) to give Int. 1AF87 methyl 4-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5-methyl-benzoate (3.9 g). Int. 1AF87 (0.2 g) was resolved by SFC using a Chiralpak AD-H 250x21 mm 5pm column operated at 30 °C and an eluent of 70% CO2 and 30% MeOH (70 g / min) and a back pressure of 100 bar to give Int. 1AF86 methyl (S)-4-( 1-(1-(4-bromo-l-methyl-lH-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 was determined by VCD for Int. 1AF86. Int. 1AF86 (2.5 g) and LiOH (1.1 g) were stirred Ih in THF / MeOH / water (2:1:1, 20 mL) at 0 °C to RT. The mixture was concentrated and triturated in aq. citric acid to precipitate Int. 1AF85 4-[l-[(lS)-l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5- methyl-benzoic acid (2.3 g). 4-[l-[(lS)-l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-5-methyl-benzoic acid (1.8 g), HATU (2.2 g), and HNMe2 (0.93 g, HC1 salt) were stirred ON in DMF / DIPEA (6.1:1, 23.3 mL) at 0 °C to RT. The mixture was diluted with water to precipitate Int. 1AF84 4-[l-[(lS)-l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-3-fluoro-A,A,5-trimethyl-benzamide (1.5 g). Int. 1AF84’ (S)-4-(l-(1-(4-bromo-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methyl-A,A-bis(methyl-t / 3)benzamide was prepared similarly using the HC1 salt of HNlCDs)?. Int. 1AF84 (1.1 g), KOAc (0.86 g), B2Pin2 (1.1 g), and PdDPPFCl2-DCM (0.18 g) stirred Ih in dioxane (10 mL) at 110 °C under MW conditions. The mixture was filtered, concentrated, and triturated 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]-l-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (1.3 g). CO2Me / 1AF91 r=boc 1AF90r=h 1AF93 R=NH; 1AF92 R=Br 2-Fluoro-4-iodo-6-methyl-aniline (20 g) and PdDPPFCL-DCM were stirred ON in MeOH / EtsN (23:1, 522 mL) under an atmosphere of CO (200 psi) at 80 °C. The mixture was filtered. The OL (EtOAc / 10% aq. EDTA) was dried and concentrated to afford Int. 1AF93 methyl 4-amino-3-fluoro-5-methyl-benzoate (14 g). Int. 1AF93 (25 g), tert-butyl nitrite (21.1 g), and CuBr2 (152 g) were stirred ON in ACN (500 mL) at 0 °C to 80 °C. The mixture was cooled to 0 °C, diluted with sat. aq. NaHCO?, and filtered. The OL (EtOAc / 10% aq. NH3) was concentrated and purified by FC (hexane / EtOAc 9:1) to give Int. 1AF92 methyl 4-bromo-3-fluoro-5-methyl-benzoate (21 g). Int. 1AF92 (1.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.9 g), NaHCOs (1.29 g), and PdDPPFCL-DCM (0.33 g) were degassed in dioxane / water (5:1, 18 mL) and stirred ON at 110 °C. The mixture was filtered. The 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-l(2H)-carboxylate (0.65 g). Int. 1AF91 (10 g) was stirred in 1.5 M HC1 in dioxane (160 mL) at 0 °C to RT. The residue after concentration was triturated in Et2O to give Int. 1AF90 methyl 3-fluoro-5-methyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzoate (13 g, HC1 salt). CON(CD3)2 CON(CD3)2 1AF95R=Br 1AF94 R=BPin 1AF96 Ints. 1AF88 / 1AE12 (4.5 g, 5.5 g, HC1 salt), Cs2CO3 (27 g), and KI (1.4 g) were stirred ON in ACN (50 mL) at 0 °C to RT. The mixture was diluted with water, filtered, and concentrated. The OL (EtOAc / water) was dried and concentrated. The residue was mixed with another batch prepared similarly on 1.5 g scale 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 250x30 mm 5pm column operated at 30 °C and an eluent of 70% CO2 and 30% IPA (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), KO Ac (0.29 g), and PdDPPFCl2-DCM (81 mg) were degassed in dioxane (5 mL) and stirred Ih at 120°C under MW conditions. The mixture was concentrated and triturated in pentane / Et2O to give Int. 1AF94 3-fluoro-5-methyl-4-[l-[(lS)-l-[l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]-pyridin-2-yl]ethyl]-3,6-dihydro-2H-pyridin-4-yl]-A,7V-bis(trideuteriomethyl)benzamide (0.6 g). Int. 1 .ABI (0.29 g), Cui (0.12 g), and NaNs (83 rag) were degassed in DMSO / DMEDA (14.4:1, 1.4 mL) and stirred at 100 °C. The OL (sat. aq. NHiCl / EtOAc) was washed with water, brine, dried, concentrated, HPLC-purified, and triturated in MTBE to give Int. 1CI 4-[l-[(4-Amino-l-methyl-pyrrolo[2.3-b]pyridin-2-yl)methyl]-4-piperidyl]-iVJV-dimelhyl-benzamide (0.22 g). 1D1or1D2 1D2or1D1 1D3or1D4 1D4or1D3 2.0M LDA in THF (28.1 mL) was added to a solution of tert-butyl 2-methyl-4-oxo-piperidine-l-carboxylate (10.0 g) in THF (200 mL) -78 °C. The mixture was stirred for 0.3h at -78 °C. 1,1,1-Trifluoro-A-phcnyl-A-((trifluoro-mcthyl)sulfonyl)mcthanc-sulfonamidc (20 g in THF (10 mL)) was added and stirring continued 3h at -78 °C to RT. The OL (aq. NH4Cl / EtOAc) was washed with water and brine, dried, and concentrated to give Int. 1D13 tert-butyl 6-methyl-4-(trifluoromethyl-sulfonyloxy)-3,6-dihydro-2H-pyridine-l-carboxylate (18.0 g). Int. 1D13 (10 g), Na2COs (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 ON. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1D12 tert-butyl 4-[4-(dimethyl-carbamoyl)phenyl]-6-methyl-3,6-dihydro-2H-pyridine-l-carboxylate (5.2 g). 5.0 g of this material was hydrogenated ON using 10% Pd / C (2.50 g) and H2 (50-60 psi) in EtOH (75 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 35:65) to give Int. 1D11 tert-butyl 4-[4-(dimethylcarbamoyl)phenyl]-2-methyl-piperidine-l-carboxylate (4.0 g). 5.0 g of this material was stirred ON in DCM / TFA (3.6:1, 26 mL) at 0 °C to RT, concentrated, and triturated in Et2O / pentane to give Int. 1D10 A,A-dimethyl-4-(2-methyl-4-piperidyl)benzamide (4.0 g, TFA salt). Int. 1D10 (10.8 g) was separated into the racemic cis and trans diastereomers by SFC using a Chiral Art Cellulose SC 250x30 5pm column operated at 30 °C and an eluent of 60% CO2 and 40% MeOH containing 0.5% HNEt2 (90 g / min) and a back pressure of 120 bar to give the cis racemate (first two peaks; 3.0 g) and the trans racemate (last two peaks; 7.0 g). The trans racemate (7.0 g) was resolved by SFC on a Sepiatec instrument fitted with a Chiralpak IK 250X30 5pm column operated at 30 °C and an eluent of 70% CO2 and 30% MeOH containing 0.5% NH s at a (90 g / min) and a back pressure of 100 bar to give Int. 1D1 A,A-dimethyl-4-((2S,4R)-2-methylpiperidin-4-yl)benzamide (0.95 g, first peak) and Int. 1D2 7V,A-dimethyl-4-((2R,4S)-2-methylpiperidin-4-yl)benzamide (1.2 g, second peak). The absolute configuration was determined by VCD for Int. 1D1 and 1D2. The cis racemate (3.0 g) was resolved by SFC using a Chiralpak IGK 250x30 5pm column operated at 30 °C and an eluent MeOH containing 0.5% NHj (30 mL / min) and a back pressure of 100 bar to give Int. 1D3 A, / V-dimethyl-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide (0.70 g, first peak) and Int. 1D4 A',A'-dimethyl-4-C2S,4S)-2-methyl-piperidin-4-yl)benzamide (0.90 g, second peak). The absolute configuration was determined by VCD for Int. 1D3 and 1D4. conr2 Br / \ N—' 1D5 R - Et ' 1D6R = Pr Int. 1CA4 (20 mg), HNEt2 (24 pL), and HATU (27 mg) were stirred 0.25h in DMF (1 mL). The OL (sat. aq. NaHCOs / EtOAc) was washed with brine, dried, and concentrated to give Int. 1D5 4-(1-((4-Bromo-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl )methyl)piperidin-4-yl)-A,,A'-diethy I benzamide (30 mg). Int. 1D6 4-(1-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)W,7V-dipropyl-benzamide (37 mg, was prepared similarly from HNPr2. R 1D7 R=CON(CD3)2 1D71 R=CONMe2 \_ / HN—' 1-( 1,1-Dimethylethyl) 4-(4-carboxyphenyl)-l-piperidinecarboxylate (5.1 g), HATU (13 g), and HN(CDs)2 (2.5 g, HC1 salt) were stirred ON in DMF / DIPEA (1.8:1, 47 mL). Water was added to precipitate solid that was dissolved in DCM / MeOH (9:1), dried, concentrated, and purified by FC (hexane / EtOAc 2:3) to give tert-butyl 4-[4-[bis-(trideuteriomethyl)carbamoyl]phenyl]piperidine-l-carboxylatc (4.8 g). 1.1 g of this material was stirred ON in DCM / TFA (3.6:1, 26 mL) at 0 °C to RT, concentrated, and triturated in EfO to give Int. 1D7 V,A-Bis(methyl-< / 3)-4-( 112-piperidin-4-y 1)-benzamide (0.81 g, TFA salt). Int. 1D7’ A,,A,-dimethyl-4-t4-pipcridyl)bcnzamidc (9 g, HC1 salt) was prepared similarly from 1-(1,1-dimethylethyl) 4-(4-carboxyphenyl)-l-piperidine-carboxylate (17 g) and HN(CH3)2 (13.6 g, HC1 salt). Int. 1AC4 (4.0 g), EDC (4.7 g, HC1 salt), HOBt (2.5 g), and HN(CD3)2 (1.4 g, HC1 salt) were stirred ON in DMF / DIPEA (8.2:1, 89 mL). The residue after concentration was purified by FC (EtOAc / hexane) to give Int. 1D8 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A,A-bis(methyl-r / 3)benzamide (2.7 g). Int. 1AB1 (1 g) mCPBA (0.59 g) were stirred 2h in DCM (10 mL) at 0 °C. The OL (sat. aq. NaHCOs / DCM) was dried and concentrated. The residue was stirred 1h in TFA, concentrated, and purified by FC (DCM / MeOH 1:0 to 4:1) to give Int. 1D9 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-l-oxido-piperidin-l-ium-4-yl]-A,,A-dimethyl-benzamide (0.77 g). 1D20 R=H, single bond                1D14or1D15 1D15or1D14 1D16or1D17 1D17or1D16 Int. 1D21 tert-butyl 4-(4-(methoxycarbonyl)phenyl)-6-methyl-3,6-dihydropyridine-l(2H)-carboxylate (5.20 g) was prepared similarly to Int. 1D12 from Int. 1D13 (10.0 g) and (4-(methoxycarbonyl)phenyl)boronic acid (7.82 g). Int. 1D20 tert-butyl 4-(4-(methoxycarbonyl)phenyl)-2-methylpiperidine-1-carboxylate (3.0 g) was prepared similarly to Int. 1D11 from Int. 1D21 (3.5 g). Int. 1D20 (3.0 g) and LiOH-H2O (1.50 g) were stirred 4h in THF / MeOH / water (1.3:1:1, 50 mL) at 0 °C to RT and concentrated. The OL (aq. citric acid / EtOAc) was dried and concentrated to give 4-(l-tert-butoxy-carbonyl-2-methyl-4-piperidyl)benzoic acid (1.50 g) 6.0 g of this material, HN(CD)3)2 (2.47 g, HC1 salt), HOBt (1.90 g), and EDC-HC1 (2.70 g) were stirred ON in DMF / DIPEA (1.9:1, 46 mL) at 0 °C to RT. The OL (water / EtOAc) was dried and concentrated to give Int. 1D19 tert-butyl 4-(4-(bis(methyl-<i)carbamoyl)-phenyl)-2-methylpiperidine-l-carboxylate (4.50 g). 3.5 g of this material was stirred 4h in DCM / TFA (2.5:1, 70 mL) at 0 °C to RT, concentrated, and triturated in Et2O / pcntanc to give Int. 1D18 4-(2-methyl-4-piperidyl)-A,A-bis(trideuteriomethyl)benzamide (3.50 g, TFA salt). Int. 1D18 was separated into Ints. lD147V,7V-bis(methyl-i / 3)-4-((2S,4R)-2-methylpiperidin-4-yl)benzamide, Int. 1D15 A,7V-bis-(methyl-i / 3)-4-((2R,4S)-2-methylpiperidin-4-yl)benzamide, Int. 1D16 ALV-bislrnethy 1-1 / ()-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide, and Int. 1D17 ;V,'V-bis(mcthyl-i / ()-4-t(2S.4S)-2-mclhyl-piperidin-4-yl)benzamide as described for Ints. 1D1-1D4. The absolute configurations of these compounds were not determined. The absolute configurations of these compounds were determined by comparison to RT on chiral chromatography vs. Int. 1D1-1D4. Methyl 4-bromobenzoate (25 g), PdDPPFCh-DCM (4.7 g), NaHCOs (49 g), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (39 g) were degassed in 1,4-dioxane / water (5:1, 0.6 L) and stirred ON at 110 °C. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 99:1) to give Int. 1F9 tert-butyl 4-(4-(methoxycarbonyl)-phenyl)-3,6-dihydro-pyridine-l(2H)-carboxylate (18 g). Int. 1F9 (38 g) and SelectFluor (7.2 g) were stirred Ih in ACN / water (3:1, 0.64 L). SelectFluor (2.1 g) was added and stirring continued Ih. The OL (EtOAc / sat. aq. NaHCOs) was dried, 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-l-carboxylate (6.0 g). Int. 1F8 (4.8 g) was hydrogenated ON using 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-l-carboxylate (3.2 g). Int. 1F7 (3.5 g) and LiOH-H2O (1.4 g) were stirred ON in MeOH / THF / H2O (3:2:1; 25 mL) at 0 °C to RT and concentrated. The OL (10% MeOH in DCM / aq. citric acid) was dried and concentrated to give cis-4-(l-(tert-butoxycarbonyl)-3-fluoro-piperidin-4-yl)benzoic acid (2.1 g). 2.5 of this compound, HATU (4.4 g), and HN(CH3)2 (1.9 g, HO salt) were stirred ON in DMF / DIPEA (2.4:1, 35 mL) at 0 °C to RT. The OL (water / 5% MeOH in DCM) was dried, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 1F6 cis-tert-butyl-4-[4-(dimethylcarbamoyl)-phenyl]-3-fluoro-piperidine-l-carboxylate (2.4 g). Int. 1F6 (1.5 g) was stirred ON in DCM / TFA (3,8:1, 13 mL) at 0 °C to RT and concentrated. The OL (aq. NaHCO3 / Et2O and 10% MeOH in DCM) was dried and concentrated to give Int. 1F5 A,A-dimethyl-4-[czs-3-fluoro-4-piperidyl]-benzamide (1.19 g). This material was resolved by SFC using a Lux Cellulose-4 250x30 5pm column operated at 30 °C and an eluent of 70% CO2 and 30% 0.5% iso-propyl amine in IPA (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-y 1 )-A,A-di methyl benzamide and 4-((3R,4S)-3-fluoropipcridin-4-yl)-A,A-dimcthyl-bcnzamidc. The absolute configurations of these compounds were not determined. Int. 1F9 (10 g) was stirred ON in THF / 2M BH3-DMS in THF (11.6:1, 217 mL) at 0 °C to RT. 2M aq. NaOH (38 mL) and 30% aq. H2O2 (5.9 mL) were added and stirring was continued at 0 °C to RT over Ih. The OL (sat. aq. NaS2O3 / EtOAc) was washed with water and brine, dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 1F14 zc / 7-hutyl 3-hydroxy-4-(4-(methoxy-carbonyl)phcnyl)pipcridinc-l-carboxylate (7.4 g). Int. 1F14 (8.0 g) and DMP (5.1 g) were stirred ON in DCM (200 mL) at 0 °C to RT. The 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-l-carboxylate (5.2 g). Int. 1F13 (5.0 g) was stirred ON in DCM / 50% Deoxo-Fluor in THF (12.2:1, 108 mL) at -78 °C to RT ON. The OL (aq. NaHCO3 / DCM) was washed with sat. aq. citric acid, dried, concentrated, and purified by FC (hexane) to give Int. 1F12 tert-butyl 3,3-difluoro-4-(4-methoxycarbonyl-phenyl)piperidine-l-carboxylate (2.5 g). This material and LiOH-HzO (1.5 g) were stirred in MeOH / THF / HzO (3:3:1; 60 mL) at 0 °C to RT over 4h, concentrated, and triturated in dilute aq. citric acid to give Int. lF12a 4-(1 -tert-butoxycarbonyl-3,3-difluoro-4-piperidyl)benzoic acid (2.3 g). Int. lF12a (4.8 g), HATU (6.4 g), and HN(CH3)2 (2.3 g, HC1 salt) were stirred ON in DMF / DIPEA (13.2:1, 108 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1F11 tert-butyl 4-(4-(dimethylcarbamoyl)-phenyl)-3,3-difiuoro-piperidine-1-carboxylate (4.5 g). Int. 1F11 (4.2 g) was stirred ON in DCM / TFA (27:1, 83 mL) at 0 °C to RT and concentrated. The OL (5% MeOH in DCM / sat. aq. NaHCO q was dried and concentrated to give Int. 1F10 4-(3,3-difluoro-4-piperidyl)-7V,7V-dimethyl-benzamide (3 g). This material was resolved by SFC using a Chiralpak IG 250x30 5pm column operated at 30 °C and an eluent of 60% CO2 and 40% MeOH (80 g / min) and a back pressure of 60 bar to give Int. 1F3 (1.1 g) and Int. 1F4 (1.0 g) (R)-4-(3,3-Difluoropiperidin-4-yl)- A,A-dimethylhenzamide and (S)-4-(3,3-difluoropiperidin-4-yl)- N,N-dimethylbenzamide. The absolute configurations of these compounds were not determined. Ints. 1J1 / 1F3 (45 mg / 60 mg), Cs3CO3 (169 mg), Nai (26 mg) were stirred in DMF (1 mL) for 0.5 h and HPLC-purified to give Int. 1F15 (48 mg). Int. 1F16 was prepared similarly from Int. 1F4. Ints. 1F15 and 1F16 (R)-4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3,3-di fl uoropi peridin-4-y 1 )-A,A-di methyl benzamide and (S)-4-(l-((4-bromo-l -methyl- lH-pyrrolo[2,3- b]pyridin-2-yl)methyl)-3,3-difluoropiperidin-4-yl)-A,A-dimethylbenzamide. The absolute configurations were not determined for these compounds. 4-Bromo-3-methyl-lH-pyrrolo[2,3-b]pyridine (0.51 g) and NaH (0.12 g) were stirred Ih in DMF (5 mL) at 0 °C before Mel (0.3 mL) was added and stirring continued for 0.3h. The OL (water / EtOAc / Et2O) was washed with brine, dried, concentrated to give Int. 1H3 4-bromo-l,3-dimethyl-pyrrolo[2,3-b]pyridine (0.53 g). This material was stirred 2h in THF / 1.0 M LDA in THF (2.9:1, 13.5 mL) -78 °C before DMF (1 mL) was added and stirring continued 2h at -78 °C to RT. The OL (sat. aq. NHiCl / EtOAc) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 1:0 to 1:1) to give Int. 1H2 4-bromo-l,3-dimethyl-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.17 g). Int. 1H2 (30 mg) and A,A-dimethyl-4-(piperidin-4-yl)benzamide (42 mg) were stirred 0.5h in DCE (2 mL) . STAB (57 mg) was added and stirring continued ON. The OL (sat. aq. NaHCOj / DCM.) was washed with brine, dried, concentrated, and purified by FC (DCM / MeOH 1:0 to 9:1) to give Int. 1H1 4-[l-[(4-bromo-l,3-dimethyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidyl]- N,A-dimethyl-benzamide (30 mg). CONMe2 Br      / -\ -\   N—' n * Int. Ill 4-(l-((4-bromo-l,5-dimethyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A,A-dimethylbenzamide (0.16 g) as prepared similarly to Int. 1H1 from 4-bromo-5-methyl-lH-pyrrolo[2,3-b]pyridinc (0.51 g) and A,A-dimcthyl-4-(pipcridin-4-yl)bcnzamidc (0.18 g). Br r^l]-^ / U3r=oh 1J1R=ci Int. 1AB8 (30 g) and NaBH4 (19 g) were stirred 2h in MeOH (300 mL) at 0 °C to RT. The OL (aq. Na2S2O3 / EtOAc) was dried, concentrated, and purified by FC (pentane / EtOAc 1:1 to 2:3) to give Int. 1J3 (4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methanol. Int. 1J3 (2.5 g) was stirred ON in DCM / Et iN / MsCI (21.4:5.2:1, 39 mL) at 0 °C to RT and filtered. The OL layer (EtOAc / water) was washed with brine, dried, and concentrated to give Int. 1J1 4-bromo-2-(chloromethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridine (2.0 g). R 4-Bromo-l-(trideuteriomethyl)pyrrolo[2,3-b]pyridine (0.40 g) was stirred 2h in THF / 2M LDA in THF (7.1:1, 11.4 mL) at -78 °C. DMF (0.7 mL) was added and stirring continued 2h at -78 °C to RT and diluted with water to precipitate Int. 1K3 4-bromo-l-(trideuterio-methyl)pyrrolof2,3-b]pyridine-2-carbaldehyde (0.35 g). Int. 1K3 (0.17 g) and methyl 4-(piperidin-4-yl)benzoate (0.16 g) were stirred 3h in DCE / DIPEA (28.3:1, 15.5 mL). STAB (0.26 g) was added and stirring continued ON. The OL (water / DCM) was washed brine, dried, concentrated, and purified by FC (pentane / EtOAc 4:1) to give Int. 1K2 methyl 4-[l -[[4-bromo-l -(trideuteriomethyl)pyrrolo-[2,3-b]pyridin-2-yl]methyl]-4-piperidyl]-benzoate (0.14 g). Int. 1K2 (50 mg) was stirred 0.25h in THF / MeOH / 2M aq. NaOH (7.1:3.6:1, 3.3 mL). pH was adjusted to 5 with IM aq. HC1. The mixture was concentrated. The residue and HATU (85 mg) were dissolved in DMF / DIPEA (25.6:1, 2.1 mL) before HN(CHs)2 (14 mg; HC1 salt) was added and stirring continued 72h. The OL (water / DCM) was dried, concentrated, and purified by FC (DCM / MeOH 1: to 9:1) to give Int. IKI 4-[l-[[4-bromo-l-(trideuteriomethyl)pyrrolo[2,3-b]pyridin-2-yl]-methyl]-4-piperidyl]- A / A-dimethyl-benzamide (39 mg). CONMe2 MeO—G A / =< 1M23 Double bond / 1M24 Single bond 4-Bromo-3-methoxybenzoic acid (3.0 g), HNfCHaL (1.6 g, HC1 salt), and HATU (5.92 g) were stirred ON in DCM / DIPEA (7.4:1, 57 mL), concentrated, and HPLC-purified to give 4-bromo-3-methoxy-A,A-dimethyl-benzamide (2.5 g). 1.0 g of this material, tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.44 g), K2CO3 (2.14 g), and PdDPPFCL-DCM (0.16 g) were degassed in dioxane / water (4:1, 10 mL) and stirred at 100 °C ON. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-(4-(dimethylcarbamoyl)-2-methoxy-phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (1.10 g). 0.6 g of this material was hydrogenated ON using 10% Pd / C (0.2 g) in MeOH (10 mL), filtered, concentrated, stirred in 4M HC1 in dioxane (10 mL) ON, concentrated, and HPLC-purified to give Int. 1M24 3-methoxy-A,A-dimethyl-4-(piperidin-4-yl)benzamide (0.23 g). tert-Butyl 4-(4-(dimethylcarba-moyl)-2-methoxyphenyl)-3,6-dihydropyridine-l(2H)-carboxylate (0.50 g) was stirred ON in 4M HC1 in dioxane (10 mL), concentrated, and HPLC-purified to give Int. 1M23 3-methoxy-A,A-dimcthyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.17 g). NaNOz (6.1 g) and 4-amino-3-fluoro-5-methyl-benzoic acid (15.0 g) were stirred 0.3h in 48% aq. HBr (150 mL) at 0 °C. CuBr (13.0 g) was added and stirring continued 4h. The OL (aq. NaHCOs / MTBE) was washed with water and concentrated to give 4-bromo-3-fluoro-5-methyl-benzoic acid (8.50 g). 4-Bromo-3-lluoro-5-niethyl-benzoic acid (15.0 g) was stirred 5h in DCM / SOCB (83:1, 150 mL), and concentrated. The residue and HNMe2 (3.1 g, HC1 salt) were stirred 5h DCM / EtsN (13.6:1, 160 mL) The OL (water / DCM) was concentrated. The residue, K2CO3 (7.3 g), PdPDPPFCL-DCM (0.15 g), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-pyridine-l(2H)-carboxylate (6.0 g) were degassed dioxane (150 mL) and stirred 48h at 90 °C. The OL (water / dioxane) was concentrated, stirred 0.5h in THF / 4M HC1 in dioxane (1:1, 100 mL), concentrated, and HPLC-purified to give Int. 1M25 3-fluoro-AOV,5-trimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g). Int. 1M26 3-chloro-AOV,5-trimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.11 g) was prepared similarly to Int. 1M25 from 4-bromo-3-chloro-5-methyl-benzoic acid (15 g). 4-Bromo-3-fluoro- / V, / V-dimethyl-benzamide (1.0 g), tert-butyl 4-(4,4,5,5-tetramethyL 1,3,2-dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (1.41 g), NazCOj (1.61 g), and PdDPPFCL-DCM (0.16 g) were degassed in dioxane / water (4:1, 10 mL) and stirred ON at 100 °C. The OL (water I EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give tertbutyl 4-[4-(dimethylcarbamo-yl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (1.20 g). 0.6 g of this material was stirred ON in 4M HC1 in dioxane (10 mL). The mixture was concentrated and HPLC-purified to give Int. 1M29 3-fluoro-A,A-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)-benzamide (0.22 g). 4-Bromo-3-chloro- / V, / V-dimethyl-benzamide (5.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.71 g), NazCOs (8.1 g), and PdDPPFCL-DCM (0.78 g) were degassed in dioxane / water (4:1, 10 mL) and stirred at 100 °C ON. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-[2-chloro-4-(dimethylcarbamoyl)phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (1.10 g). This material was hydrogenated ON using 10% Pt / C (1.1 g) in MeOH (10 mL), filtered, and concentrated to give tertbutyl 4-[2-chloro-4-(dimethylcarbamoyl)phenyl]-piperidine-l-carboxylate (0.60 g). This material was stirred ON in 4M HC1 in dioxane (10 mL), concentrated, and HPLC-purified to give Int. 1M44 3-chloro-A,7V-dimethyl-4-(piperidin-4-yl)benzamide (0.15 g). tert-Butyl 4-[2-chloro-4-(dimethyl-carbamoyl)phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (0.60 g) was stirred ON in 4M HC1 in dioxane (10 mL), concentrated, and HPLC-purified to give Int. 1M43 3-chloro-A,A-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g). 4-Bromo-3-(trifluoromethyl)benzoic acid (3.0 g), HN(CH3)2 (1.36 g, HO salt) and HATU (5.1 g) stirred ON in DCM / DIPEA (8.6:1, 56 mL), concentrated, and HPLC-purified to give 4-bromo-A'jV-dimethyl-3-(trifluoro-methyl)benzamide (2.40 g). 1.0 g of this material, tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxahorolan-2-yl)-3,6-dihydro-pyridine-l(2H)-carboxylate (1.25 g), K2CO3 (1.87 g), and PdDPPFCL-DCM (0.14 g) were degassed in dioxane / water (4:1, 10 mL) and stirred ON at 100 °C. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to obtain tert-butyl 4-[4-(dimethyl-carbamoyl)-2-(trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (1.04 g). 0.50 g of this material was stirred ON in 4M HC1 in dioxane (10 mL), filtered, and HPLC-purified to give Int. 1M45 / V,A-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoro-methyl)benzamide (0.14 g). tert-Butyl 4-[4-(dimethyLcarbamoyl)-2-(trifluoromethyl)phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (0.50 g) was hydrogenated ON using 10% Pd / C (0.5 g) in MeOH (10 mL). The mixture was filtered. The residue after concentration was stirred ON in 4M HC1 in dioxane (10 mL), concentrated, and HPLC-purified to give Int. 1M46 A,A-dimcthyl-4-(pipcridin-4-yl)-3-(trifluoromethyl)benzamide (0.23 g). 6-Chloro-5-fluoro-pyridine-3-carboxylic acid (3.0 g), HN(CH3)2 (1-53 g, HC1 salt), and HATU (7.15 g) were stirred ON in DCM / DIPEA (5.6:1, 59 mL), concentrated, and purified by FC (hexane to EtOAc) to give 6-chloro-5-fluoro-A,A-dimethyl-pyridine-3-carboxamide (3.1 g). This material, tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (5.20 g), K3CO3 (8.50 g), and PdDPPFCl2-DCM (0.62 g) were degassed in dioxane / water (4:1, 50 mL) and stirred ON at 100 °C. The 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-l-carboxylate (3.10 g). 0.13 g of this material was stirred 1.5h in DCM / 4M HC1 in dioxane (3.6:1, 6.4 mL) and concentrated. The OL (DCM / aq. NaHCOs) was dried, concentrated, and HPLC-purified to give Int. 1M47 5-fluoro-A,N-dimethyl-6-( 1,2,3,6-tetrahydropyridin-4-yl)pyridine-3-carboxamide (20 mg). CONMe2 CONMe2 tert-Butyl (S)-2-methylpiperazine-l-carboxylate (1.0 g), ethyl 4-bromo-3-methyl-benzoate (1.46 g), CS2CO3 (4.88 g), Pd2dba3 (0.23 g), and XPhos (0.24 g) were degassed in dioxane (20 mL) and stirred at 110 °C ON. The OL (EtOAc / water) was concentrated and purified by FC (hexane to EtOAc) to give tert-butyl (2R)-4-(4-ethoxy-carbonyl-2-methyl-phenyl)-2-methyl-piperazine-l-carboxylate (0.85 g). 0.70 g of this material and LiOH-H2O (0.22 g) were stirred 6h in THF / water / MeOH (10 mL), concentrated, and triturated in dilute aq. citric acid to give 4-[(3R)-4-tert-butoxy-carbonyl-3-methyl-piperazin-l-yl]-3-methyl-benzoic acid (0.45 g). 4-[(3R)-4-tert-butoxycarbonyl-3-methyl-piperazin-l-yl]-3-methyl-benzoic acid (0.70 g), HNMe2 (0.26 g, HO salt), HOBt (0.42 g), and EDC (0.60 g, HO salt) were stirred ON in DCM / D1PEA (10:1, 11 mL) at 0 °C to RT. The OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 3:2) to give tert-butyl (2R)-4-[4-(dimethylcarbamoyl)-2-methyl-phenyl]-2-methyl-piperazine-l-carboxylate (0.45 g). This material was stirred 6h in DCM / TFA (6:1, 7 mL) at 0 °C to RT, concentrated, and triturated in Et2O to give Int. 1M49 (R)-A,A,3-trimethyl-4-(3-methylpiperazin-l-yl)-benzamide (0.20 g). Int. 1M59 (S)-A,A,3-trimethyl-4-(3-methylpiperazin-l-yl)-benzamide was prepared similarly from tert-butyl (R)-2-methylpiperazine-l-carboxylate. CONMe2 CONMe; tert-Butyl (S)-2-methylpiperazine-l-carboxylate (2.5 g), NaOtBu (2.4 g), Pd2dba3 (0.57 g), Xphos (0.59 g), and 4-bromo-A,A-dimethylbenzamide (3.1 g) were degassed in dioxane (30 mL) and stirred ON at 100 °C. The OL (Et2OZ water) was washed with brine, dried, concentrated, and purified by FC (hexane / EtOAc 1:4) to give Int. 1M50 tert-butyl (S)-4-(4-(dimethylcarbamoyl)phenyl)-2-methyl-piperazine-1-carboxylate and tert-butyl (2.4 g). Int. 1M52 (R)-4-(4-(dimethylcarbamoyl)phenyl)-2-methyl-piperazine-1 -carboxylate (0.46 g) was prepared similarly from tert-butyl (R)-2-methylpiperazine-Lcarboxylate (0.50 g). Int. 1M50 (46 mg) was stirred Ih in DCM / TFA (1:1, 1 mL) and concentrated. The residue and 4A MS were stirred ON in DCM / DIPEA (19.5:1, 1.6 mL). Int. 1J1 (23 mg) was added and stirring was continued ON. The OL (DCM / sat. aq. NaHCO s) was dried, concentrated, and purified by FC (DCM / MeOH 1:0 to 95:5) to give Int. 1M51 (S)-4-(4-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-methylpiperazin-l-yl)-A,7V-dimethylbenzamide (40 mg). CONMe2 Int. 1M52 (46 mg) was stirred Ih in DCM / TFA (1:1, 1 mL) and concentrated. The residue, Int. 1AB8 (21 mg), and 4A MS were stirred 2h in DCM / DIPEA (19.5:1, 1.6 mL). STAB (56 mg) was added and stirring continued ON. The OL (water / DCM) was dried, concentrated, and purified by FC (DCM / MeOH 1:0 to 95:5) to give Int. 1M53 (R)-4-(4-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-methylpiperazin-l-yl)-A,A-dimethylbenzamide (30 mg). CONMe2 Boc-piperazine (0.40 g), 6-bromo-A,7V-dimethylnicotinamide (0.59 g), NaOtBu (0.41 g), Xphos (0.10 g), and Pdidba ? (0.1 g) were degassed in dioxane (4 mL) and stirred at 110 °C ON. The 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)-piperazine-l-carboxylate. 0.26 g of this material was stirred Ih in 3M HO in dioxane (3 mL) at 0 °C to RT and concentrated to give Int. 1M55 / V, / V-dimethyl-6-(piperazin-l-yl)nicotinamide (0.14 g, HC1 salt). conr2 0 N' 1M56r=cd3 (  \   1M57 R-Me HN—' 4-(4-tert-Butoxycarbonylpiperazin-l-yl)benzoic acid (1.0 g), HN(CDs)2 (0.43 g, HC1 salt), HOBt (0.66 g), and EDC (0.94 g, HC1 salt) were stirred ON in DCM / DIPEA (15.4:1, 21 mL). The OL (water / DCM) was washed with brine, dried, concentrated, and purified by FC (pentane / EtOAc 1:1) to give terr-butyl 4-(5-(bis(methyl-6 / 3)carbamoyl)-pyridin-2-yl)piperazine-l-carboxylate (0.95 g). This material was stirred in DCM / TFA (6.7:1, 35 mL), concentrated, and triturated in EtzO to give Int. 1M56 A'jV-bis(mcthyl-J;)-6-(pipcrazin-l -yl)nicotinamide (0.85 g). Int. 1AE20 (14 g) was hydrogenated ON using 10% Pd / C (3.5 g) in MeOH (200 mL), filtered, and concentrated to give tert-butyl 4-[5-(dimethyl-carbamoyl)-2-pyridyl]piperidine-l-carboxylate (11 g). 0.9 g of this material was stirred in DCM / TFA (10:1, 11 mL) at 0 °C to RT, concentrated, and triturated in EtzO to give Int. 1M57 A,A-dimethyl-6-(piperidin-4-yl)nicotinamide (0.50 g, TFA salt). Ints. 1M1 / 1S7 (15 mg / 22 mg, HC1 salt) were stirred 0.5h in DCE (0.5 mL). STAB (25 mg) was added and stirring was continued ON. The mixture was filtered. The filtrate was stirred 0.5h in TFA (0.5 mL), concentrated, and purified by HPLC to give Example lm6 A,A,3-Trimethyl-4-(4-((l-methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperazin-l-yl)benzamide (6.6 mM in DMSO (0.70 mL). Example lm56 3-Fluoro-A,A,5-trimethyl-4-(l-((l-methyl-4-(4-(methy lamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l, 2,3,6-tetrahydropyridin-4-yl)benzamide (10 mM in DMSO (1.2 mL)) was prepared similarly to Example lm6 from Int. 1M25 (17 mg). Example lm56 (2.4 g) and LiOH-HzO (1.1 g) were stirred 3h in THF / water (2.5:1, 28 mL) at 0 °C to 60 °C. The residue after concentration was triturated in aq. HC1 to give Int. 1M60 3-fluoro-5-methy 1-4-(1-((1-methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzoic acid (2.4 g). FMoc Int. 1AB8 (0.25 g) and 9H-fluoren-9-ylmethyl piperazine-1-carboxylate (0.48 g) were stirred 2h in DCE / AcOH (100:1,10 mL). STAB (0.44 g) was added and stirring continued 2h at 0 °C to RT. The OL (sat. aq. NaHCOs / DCM) was washed with brine, dried, and concentrated to give Int. 1N2 9H-fluoren-9-ylmethyl 4-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]piperazine-l-carboxylate (0.20 g). Int. 1AB8 (0.35 g) and A',A'-dimethyl-4-( piperazin-1 -yljbenzamide (0.40 g, HC1 salt) were stirred 4h in DCE / DIPEA (6.5:1, 11.6 mL). STAB (0.94 g) was added and stirring continued ON. The 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-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperazin-l-yl)-ACV-dimethyl-benzamide (0.44 g). ■N BPin /  \ N—' " \ Int. 1N4 (25 mg), KOAc (11 mg), PdDPPFCh-DCM (4 mg), and BiPin, (15 mg) were degassed in dioxane (3 mL) and stirred 4h at 70 °Ch. KOAc (11 mg), and B2Pin2 (15 mg), and PdDPPFCh-DCM (4 mg) were added and stirring continued 4h at 70 °C and ON at RT. KOAc (11 mg), B2Pin2 (15 mg), and PdDPPFCl2-DCM (4 mg) were added and stirring continued 6h at 90 °C. The mixture was filtered and HPLC-purified to give Int. 1N5 7V,N-dimethyl-4-[4-[[l-methyL4-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)pyrrolo[2,3-b]pyridin-2-yl]methyl]piperazin-l-yl]benzamide and (2-((4-(4-(dimethyl-carbamoyl)-phenyl)piperazin-l-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid. B(OH), Int. 1J3 (1.0 g), B2Pin2 (1.58 g), Pd(PPh3)2Cl2 (0.29 g), and KOAc (1.02 g) were degassed dioxane (10 mL) and stirred 3h at 100 °C and concentrated. The residue decanted with pentane and concentrated to give Int. 103 [2-(hydroxymethyl)-l-methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid (0.8 g)- 2-(4-Bromophenyl)-4,4-dimethyl-4,5-dihydrooxazole (10 g) and Mg turnings (1.1 g) and 12 (50 mg) were refluxed Ih in THF (50 mL). l-Benzylpiperidin-4-one (8.0 mL) was added before refluxing 3h. The OL (sat. aq. NEhCJ / MTBE) was washed with water, brine, dried, and concentrated to give Int. 1R6 l-benzyl-4-(4-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)phenyl)piperidin-4-ol. Int. 1R6 (7.0 g) was stirred ON in EtOH / 96% H2SO4 (10:1, 400 mL) at 90 °C and concentrated. The OL (sat. aq. NaHCOs / DCM) was dried, concentrated, and purified by FC (DCM / 2M NIL in MeOH 1:0 to 4:1) to give 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 stirring continued 2h at -78 °C to RT over 2h. The OL (DCM / water) was washed with brine, dried, concentrated, and HPLC-purified to give Int. 1R4 ethyl 4-(l-benzyl-4-fluoro-piperidin-4-yl)benzoate. Int. 1R4 (2.0 g) was stirred 3h in DCM (40 mL) and 1-chloroethyl carbono-chloridate (0.76 mL) at 0 °C to RT and concentrated. The residue was refluxed 0.5h in MeOH (20 mL) and concentrated. The residue and Boc2O (1.56 g) were stirred ON in DCM / Et3N (14.7:1, 27 mL). The OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (heptane / EtOAc 1:0 to 1:1) to give 4-(l-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)benzoic acid. 0.77 g of this material, HATU (1.18 g), and HN(CH3)2 (0.29 g, HC1 salt) were stirred Ih in DMF / DIPEA (5:1, 10 mL). The OL (EtOAc / water) was dried, concentrated, and purified by FC (heptane to EtOAc / MeOH 95:5) to give Int. 1R2 tert-butyl 4-(4-(dimethylcarbamoyl)-phenyl)-4-fluoropiperidine-l-carboxylate. Int. 1R2 (0.55 g) was stirred Ih in MeOH / 4M HC1 in dioxane (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). Int. 1AE14 (10.0 g) was stirred ON in THF / 2.0 M BH3-Me2S in THF (11:6:1, 218 mL) at 0 °C to RT. 2.0 M aq. NaOH (38 mL) and 30% aq. H2O2 (5.9 mL) were added and stirring continued Ih. The OL (sat. aq. Na2S2O3 / 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-l-carboxylate (7.4 g). 7.0 g of this material was dissolved in DCM (140 mL) at -78 °C. 50% Deoxo-Fluor in THF (4.5 mL) was added and stirring continued 6h at -78 °C to RT. The OL (sat. aq. NaHCO3 / DCM) were washed with sat. aq. citric acid, dried, concentrated, and purified by FC (hexane / EtOAc 85:15) to give Int. 1R11 tert-butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)-piperidine-l-carboxylate (4.8 g). Int. 1R11 (10.0 g) and LiOH-H2O (6.1 g) were stirred ON in MeOH / THF / water (2:4:1, 230 mL) at 0 °C to RT and concentrated. The OL (aq. citric acid / 10% MeOH in DCM) was dried and concentrated to give 4(1 -(tert-butoxy-carbonyl)-3-fluoropiperidin-4-yl)benzoic acid (8.0 g). 22 g of this material, HATU (39 g), and HN(CH3)2 (16.5 g, HC1 salt) were stirred ON in DMF / DIPEA (6:7:1, 0.46 L) at 0 °C to RT. The OL (water / MeOH / DCM (5:95)) was dried, concentrated, and purified by FC (hexane / EtOAc 2:3) to give tert-butyl 4-(4-(dimethylcarbamoyl)phenyl)-3-fluoropiperidine-l-carboxylate (20 g). This material was stirred ON in DCM / TFA (37:1, 513 mL) at 0 °C to RT ON and concentrated. The aq. layer (water / Et2O) was basified with sat. aq. NaHCO3 and extracted with MeOH / DCM (5:95). The OLs were dried and concentrated to give 4-(3-fluoropiperidin-4-yl)-N,N-dimethyl-benzamide (14.5 g). This material was resolved by SFC using a Chiralpak IG 250x25 5 pm column operated at 30 °C using an 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)- / V,A'-dimethylbenzamide and 4-((38,4S)-3-fluoropiperidin-4-yl)-A,A-dimethylbenzamide. The absolute configurations of these compounds were not determined. Int. 1F1 (0.10 g), DIPEA (0.21 mL), KI (20 mg), and Int. 1J1 were stirred ON in DMF (5 mL). The OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane / EtOAc 3:7) to give Int. 1R12 A,A-Dimethyl-4-[(3R,4S)-l-[(4-bromo-l-methyl-pyrrolo[2,3-b]-pyridin-2-yl)methyl]-3-fluoro-4-piperidyl]benzamide (0.12 g). Int. 1R13 A,A-dimethyl-4-[(3S,4R)-l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3-fluoro-4-piperidyl]benzamide (0.12 g) was prepared similarly from Ints. 1F2 / 1J1 (0.10 g / 0.16 g). CONMe2 N-A 0 KOtBu (74 mg), K2CO3 (0.17 g), A',A'-dimcthyl-2-oxo-1 H-pyridine-4-carboxamide (0.10 g), and tert-butyl 4-(p-tolylsulfonyloxy)piperidine-l-carboxylate (0.24 g) were stirred ON in DME (5 mL) at 110 °C ON. The OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4-[4-(dimethyl-carbamoyl)-2-oxo-l-pyridyl]piperidine-l-carboxylate (70 mg). tert-Butyl 4-[4-(dimethylcarbamoyl)-2-oxo-l-pyridyl]piperidine-l-carboxylate (0.20 g) was stirred in DCM / TFA (10:1, 5.5 mL) and concentrated to give Int. 1S2 7V,A-Dimethyl-2-oxo-l-(4-piperidyl)pyridine-4-carbox-amide and Int. 1S2’ N,N-dimethyl-2-(4-piperidyloxy)pyridine-4-carboxamide (0.15 g, TFA salt). CONMe2 \    / 1S3 Double bond HN—'  doe JOO Single bond 4-Bromo-A,A,3,5-tetramethylbenzamide (5.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (7.3 g), PdDPPFCL-DCM (0.88 g), and NaHCOs (5.4 g) were degassed in dioxane / water (3:1, 47 mL) and stirred ON at 100 °C. The OL (EtOAc / water) was dried, concentrated, and purified by FC (pentane / EtOAc 1:1) to give tert-butyl 4-[4-(dimethylcarbamoyl)-2,6-dimethyl-phenyl]-3,6-dihydro-2H-pyridine-l-carboxylate (4.5 g). 0.3 g of this material was stirred ON in 2.9M HO in dioxane (7 mL) at 0 °C to R, concentrated, and triturated in Et20. The solid was treated with sat. aq. NaHCO? and concentrated. The residue was dissolved in DCM, dried, and concentrated to give Int. 1S3 AUV,3,5-tetramethyl-4-( 1,2,3,6-tetrahydro-pyridin-4-yl)benzamide (0.15 g). tert-Butyl 4-[4-(dimethylcarbamoyl)-2,6-dimethyl-phenyl]-3,6-dihydro-2H- pyridine-1-carboxylate (50 mg) was hydrogenated 48h using PtO2 (15 mg) in AcOH (3 mL), filtered, and concentrated to give Int. 1S6 A,A,3,5-tetramethyl-4-(piperidin-4-yl)benzamide (35 mg). 6-Bromo-A,A-dimethylnicotinamide 20.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (27.0 g), NaHCOs (25.7 g), and PdDPPFClz-DCM (0.71 g) were degassed in dioxane / water (4:1, 0.5 L), refluxed ON, and filtered. The OL (water / EtOAc) was dried, concentrated, and purified by FC (pentane / EtOAc 45:55) to give tert-butyl 4-[5-(dimethyl-carbamoyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylate (17 g). 1.0 g of this material was stirred ON in DCM / 4M HC1 in dioxane (2.6:1, 14 mL) at 0 °C to RT. The mixture was combined with another two batches prepared on 0.1 g scale and concentrated. The residue was stirred in water at pH 8 (adjusted with NaHCOz). The mixture was purified by FC (reverse-phase C18 column; 8% ACN in 0.001% aq. formic acid) to give Int. 1S4 A^,A-dimethyl-l ',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.60 g). 6-Bromo-A,M5-trimethyl-pyridine-3-carboxamide (3.2 g), NaHCOz (3.9 g), PdDPPFClz-DCM (0.27 g), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (6.1 g) were degassed in dioxane / water (4:1, 13 mL) and stirred ON at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give tert-butyl 4-[5-(dimethyl-carba-moyl)-3-methyl-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylate (4.0 g). 0.35 g of this material was stirred ON in DCM / TFA (10:1, 9 mL) at 0 °C to RT, concentrated, and triturated in EtzO / pentane to give Int. 1S5 A(M3-trimethyl-l',2',3',6'-tetrahydro-[2,4'-bipyridirie]-5-carboxamide (0.35 g, TFA salt). O1S7 R=Me 1S7' r=cd3 tert-Butyl piperazine-1-carboxylate (5.0 g), 4-bromo-A,7V,3-trimethylbenzamide (7.1 g), Pdzdbaz (1.19 g), XPhos (1.29 g), and NaOtBu (5.19 g) were degassed in dioxane (50 mL) and stirred ON at 100 °C and filtered. The OL (water / EtOAc) was dried, concentrated, and purified by FC (pentane / EtOAc 3:7) to give tert-butyl 4-[4-(dimethyl-carbamoyl)-2-methyl-phenyl]piperazine-l-carboxylate (6.1 g). 7.2 g of this material was stirred ON in 4M HO in dioxane / DCM (1.8:1,55 mL) at 0 °C to RT, concentrated, and triturated in EtzO / pentane to give Int. 1S7 AOV,3-trimethyl-4-(piperazin-l-yl)benzamide (5.0 g, HC1 salt). Int. 1S7’ 3-methyl-N,N-bis(methyl-d3)-4-(piperazin-1 -yl)benzamide was prepared similarly from 4-bromo-S-methyl-N.N-bislmcthyl-t / Obcnzamidc. 6-Bromo-ACV,5-trimethyl-pyridine-3-carboxamide (3.2 g), NaHCO3 (3.9 g), and PdDPPFCP-DCM (0.27 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (6.1 g) were degassed in dioxane / water (4:1, 14 mL) and stirred ON at 110 °C. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 1:4) to give tert-butyl 4-(5-(dimethylcarba-moyl)-3-methyl-2-pyridyl]-3,6-dihydro-2H-pyridine-l-carboxylate (4.0 g). 4.2 g of this material was hydrogenated ON using 10% Pd / C (2.0 g) in MeOH (100 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 1:9) to give tert-butyl 4-[5-(dimethyl-carbamoyl)-3-methyl-2-pyridyl]piperidine-l-carboxylate (3.5 g). 4.3 g of this material was stirred ON in DCM / TFA (1.5:1, 25 mL) at 0 °C to RT, concentrated, and triturated in pentane / Et2O to give Int. 1S8 A\A'.5-Trimelhyl-6-(piperidin-4-yl)nicotinamide (5.0 g, TFA salt). 4-Bromo-3-fluoro-A,A-dimethyl-benzamide (1.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.51 g), Na2CO3 (1.72 g), and PdDPPFCP-DCM (0.17 g) were degassed in dioxane / water (4:1, 10 mL) and stirred ON at 100 °C. The OL (water / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 4- [4-(dimethyl-carbamoyl)-2-fluoro-phenyl] -3,6-dihydro-2H-pyridine-1 -carboxylate (1.20 g). This material was hydrogenated ON using 10% Pd / C (45 mg) in MeOH (2 mL), filtered, concentrated, stirred ON in 4M HC1 in dioxane (10 mL), concentrated, and HPLC-purified to give Int. 1S18 3-fluoro-A, / V-dimethyl-4-(piperidin-4-yl)benzamide (63 mg). co2h             CON(CD3)2 ““O / \         \~ / 1S20r=boc N—'          N—' 1S19r=h Bo< / 1S21        r' 96% aq. H2SO4 (2.5 mL) was added to a solution of 4-bromo-3-methyl-benzoic acid (20 g) in MeOH (300 mL). The mixture was stirred at 90 °C ON and concentrated. The organic layer (sat. aq. NaHCO3 / EtOAc) was dried and concentrated to give methyl 4-bromo-3-methyl-benzoate (20 g). 10g of this material, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (14.8 g), Na2CO3 (13.8 g), and PdDPPFCL-DCM (0.84 g) were degassed in dioxane / water (2.3:1, 100 mL), stirred ON at 90 °C, filtered, concentrated, and purified by FC (hexane / EtOAc 95:5) to give tert-butyl 4-(4-methoxycarbonyl-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (7.0 g). 2.5 g of this material and LiOH-H2O (2.0 g) were stirred ON in EtOH / THF / water (2:1:1, 24 mL) at 0 °C to RT, concentrated, and triturated in dilute aq. citric acid to give Int. 1S21 4-(l-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-methyl-benzoic acid (2.0 g). Int. 1S20 (0.70 g) was prepared similarly to Int. 1D8 from Int. 1S21 (2.0 g). Int. 1S19 3-methyl-A,A-bis(methyl-i / 3)-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.31 g) was prepared similarly to Int. 1S7 from Int. 1S20 (0.80 g). Int. 1S20 (0.35 g) was hydrogenated ON using 10% Pd / C (50 mg) in MeOH (10 mL), filtered, and concentrated to give Int. 1S23 (0.21 g). Int. 1S22 3-niethyl-A(AMiis-(melhyl-i / 3)-4-fpiperidin-4-yl)benzamide (0.45 g) was prepared similarly to Int. 1S7 from Int. 1S23 (0.90 g). Int. 1A6 (0.30 g), N,N-dimethyl-4-(4-piperidyl)benzamide (0.34 g), and 4A MS were stirred 0.3h in DCM (5 mL). STAB (0.52 g) was added and stirring was continued ON. The mixture was filtered, concentrated, and purified by FC (heptane to EtOAc / MeOH 1:4) to give Int. 1X2 4-[l-[[ 1-(benzenesulfonyl)-4-bromo-pyrrolo-[2,3-b]-pyridin-2-yl]-methyl]-4-piperidyl]-A,A-dimethyl-benzamide (0.22 g). Int. 1X2 (0.12 g) was stirred 2.5h in EtOH / 4M aq. NaOH (2.5:1, 2.8 mL) at 80 °C and concentrated. The OL (water / DCM) was concentrated to give Int. 1X1 4-[l-[(4-bromo-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidyl]-7V,7V-dimethyl-benzamide (94 mg). 4-Bromo-3-fluoro-l-methyl-pyrrolo[2,3-b]pyridine (1.9 g) was stirred 2h in THF / 2.0 M LDA in THF (5:1, 24 mL) at -78 °C. DMF (1.6 mL in THF (5 mL)) was added and stirring continued 2h at -78 °C to RT. The 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-l-methyl-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.4 g). Int. 1Y3 (0.39 g) and / V, / V-dimethyl-4-(4-piperidyl)benzamide trifluoro acetate (0.38 g) were stirred ON in DCE / DIPEA (3.8:1, 6.3 mL) at 0 °C to RT. STAB (0.64 g) was added and stirring continued ON at 0 °C to RT. The OL (EtOAc / water) was washed brine, dried, concentrated, and purified by FC (pentane to EtOAc) to give Int. 1Y2 4-[l-f(4-bromo-3-fluoro-l-methyl-pyrrolo[2,3-b]pyridin-2-yl )methyl]-4-piperidyl]-A,A-dimethyl-benzamide (0.38 g). Int. 1Y2 (0.25 g), BjPim (0.17 g), KO Ac (0.16 g), and PdDPPFCL-DCM (37 mg) were degassed in THF (20 mL) and ON at 100 °C, concentrated, and triturated in pentane to give Int. 1Y1 (2-((4-(4-(dimethylcarbamoyl)phenyl)-piperidin-l-yl)methyl)-3-fluoro-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.2 g). Int. 1R5 (0.5 g) and LiOH (181 mg) were stirred ON in MeOH / THF / water (3:5:1, 9 mL) and concentrated to give Int. 1Z4 4-(l-benzyl-4-hydroxypiperidin-4-yl)benzoic acid (0.40 g). Int. 1Z4 (0.40 g), HN(CH3)2 (0.31 g, HC1 salt), and HATU (636 mg) were stirred ON in DMF / DIPEA (7:3:1, 9.1 mL). The OL (EtOAc / water) was concentrated, and purified by FC (heptane / EtOAc 5:3 to 3:7) to give Int. 1Z3 4-(1 -benzyl-4-hydroxy-piperidin-4-yl)-A,A-dimethyl-benzamide. Int. 1Z3 (1.0 g) was hydrogenated 32h using 10% Pd / C (0.5 g) in MeOH (20 mL), filtered, and concentrated to give Int. 1Z2 4-(4-hydroxypiperidin-d-ylj-A'.A'-dimethylbenzamide. Int. 1Z2 (0.20 g) and 4-bromo-lH-pyrrolo[2,3-b]pyridine-2-carboxaldehyde (0.19 g) were stirred 4h in DCE / DIPEA (10:1, 3.3 mL). STAB (0.51 g) was added and stirring continued 32h. The OL (water / DCM) was concentrated and purified by FC (hexane / EtOAc 1:0 to 4:1) to give Int. 1Z1 4-[l-[(4-Bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-y I )methyl]-4-hydroxy-4-piperidyl]-A',A'-di methyl-benzamide (0.15 g). Int. 1J1 (0.97 g), KI (12 mg), Int. 1AE7 (1 g), and K2CO3 (1.6 g) were stirred 1 Ih in DMF (10 mL). The OL (water / MTBE) was concentrated to give Int. 1Z9 4-(l-((4-bromo-l-methyl-lH-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), KO Ac (0.44 g), PdDPPFCf-DCM (24 mg), and bis(pinacolato)diboron (0.75 g) were stirred 48h in dioxane (10 mL) at 90 °C under an inert atmosphere. The OL (water / MTBE) was concentrated to give Int. 1Z10 N,N-dimethyl-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo-[2,3-b]pyridin-2-yl)methyl)-l,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 ON in IM LiHMDs in THF (1.9 mL) and THF (5 mL) at 0 °C to RT under an inert atmosphere. The OL (sat. aq. NH4Cl / EtOAc) was dried, and concentrated to give Int. 1Z11 tert-butyl (6-bromopyridazin-3-yl)carbamate (0.15 g). 6-Chloro-N,N-dimethylpyridazine-3-carboxamide (0.85 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.6 g), K2CO3 (2.5 g), and PdDPPFCL-DCM (0.19 g) were stirred ON in dioxane / H2O (4:1, 25 mL) at 100 °C under an inert atmosphere. The OL (water / EtOAc) was dried, concentrated, and purified by FC (CHCL / MTBE 1:0 to 0:1) to give Int. 1Z15 tert-butyl 4-(6-(dimethylcarbamoyl)pyridazin-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 g). Int. 1Z15 (1 g) was stirred Ih in l,LL3,3,3-hexafluoro-2-propanol / 10M HC1 (19:1, 10.5 mL). The mixture was diluted with MTBE to precipitate Int. 1Z16 N,N-dimethyl-6-(l,2,3,6-tetrahydro-pyridin-4-yl)pyridazine-3-carboxamide (0.8 g, HC1 salt). Ints. 1J1 / 1Z16 (0.2 g / 0.3 g) were stirred 12h in ACN / EtjN (48:1, 20.4 mL). The mixture was concentrated and HPLC-purified to give Int. 1Z14 6-( 1 -((4-bromo-1 -methyl- lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylpyridazine-3-carboxamide (70 mg). 6-Chloropyridazine-3-carboxylic acid (1 g) was stirred in DCM / SOCL (40:1, 20.5 mL) for 2h at 40 °C and concentrated. Bis(mcthyl-< / 3)aminc hydrochloride (0.61 g) in DCM (20 mL) and EtaN (2.6 mL) were added and the mixture was stirred ON. The mixture was concentrated and purified by FC (CHCL / ACN 1:0 to 1:1) to give Int. 1Z18 6-chloro-N,N-bis(methyl-<A)pyridazine-3-carboxamide (1.2 g). Int. 1Z18 (1.2 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (2.1 g), K2CO3 (3.5 g), and PdDPPFCL-DCM (0.26 g) were stirred ON in dioxane / H2O (4:1, 25 mL) at 100 °C under an inert atmosphere. The OL (water / EtOAc) was dried, concentrated, and purified by FC (CHCL / MTBE 1:0 to 0:1) to give Int. 1Z19 tert-butyl 4-(6-(bis-(methyl-<A)carbamoyl)-pyridazin-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.55 g). Int. 1Z19 (0.55 g) was stirred Ih in l,LL3,3,3-hexafluoro-2-propanol / 10M HC1 (26:1, 5.2 mL). The mixture was diluted with MTBE to precipitate Int. 1Z20 N,N-bis(methyl-t / 3)-6-(l,2,3,6-tetrahydropyridin-4-yl)-pyridazine-3-carboxamide (0.2 g, HC1 salt). Ints. 1J1 / 1Z20 (0.2 g / 0.2 g) were stirred 12h in ACN / EtjN (48:1, 20.4 mL). The mixture was concentrated and HPLC-purified to give Int. 1Z17 6-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]-pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N-bis(methyl-< / 3)pyridazine-3-carboxamide (50 mg). 4-Chloro-3-cyanobenzoic acid (3.4 g) and di(lH-imidazol-l-yl)methanone (3.0 g) were refluxed 0.3h in dioxane (50 mL). Dimethylamine hydrochloride (1.5 g) was added and stirring continued lOh. The mixture was concentrated. The OL (aq. NaHSOVCHCL) was concentrated to give Int. 1Z24 4-chloro-3-cyano-N,N-dimethyl-benzamide (0.87 g). Int. 1Z24 (1 g), / «7-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.6 g), K2CO3 (2.0 g), and PdDPPFCL-DCM (0.20 g) were stirred in dioxane / H2O (4:1, 20 mL) ON at 100 °C under an inert atmosphere. The mixture was filtered, concentrated, and purified by FC (CHCL / ACN 1:0 to 4:1) to give Int. 1Z25 tert-butyl 4-(2-cyano-4-(dimethyl-carbamoyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (0.44 g). Int. 1Z25 (0.44 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The mixture was concentrated to give Int. 1Z26 3-cyano-N,N-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.3 g, HC1 salt). Ints. 1J1 / 1Z26 (0.3 g / 0.3 g) and K2CO3 (0.5 g) were stirred 1 Ih in DMF (10 mL). The mixture was diluted with water to precipitate Int. 1Z27 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-cyano-N,N-dimethylbenzamide (0.12 g). Ints. 1J1 / RR44 (0.3 g / 0.3 g) were stirred 12h in ACN / EI3N (29:2, 10.7 mL). The mixture was concentrated and HPLC-purified to give Int. 1Z29 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N,3,5-tetramethylbenzamide (0.3 g). Int. 1Z29 (0.3 g), bis(pinacolato)diboron (0.4 g), KOAc (0.5 g), and PdDPPFCL-DCM (50 mg) were stirred 12h in dioxane (10 mL) at 80 °C under an inert atmosphere. The OL (water / EtOAc) was concentrated to give Int. 1Z30 N,N,3,5-tetramethyl-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.3 g). Int. 1Z50 (0.75 g), bis(pinacolato)diboron (0.78 g), PdDPPFCb-DCM (0.13 g), and KO Ac (0.45 g) were stirred 1.3h in dioxane (10 mL) at 110 °C under an inert atmosphere under MW conditions. The mixture was filtered through celite and concentrated to give Int. 1Z31 3-fluoro-N,N,5-trimethyl-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.85 g). Int. 1Z65 (0.50 g), bis(pinacolato)diboron (0.52 g), PdDPPFCb-DCM (83 mg), and KOAc (0.30 g) were stirred Ih in dioxane (10 mL) at 110 °C under an inert atmosphere under MW conditions. The mixture was filtered through celite, concentrated, and washed with pentane to give Int. 1Z33 3,5-difluoro-N,N-dimethyl-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.50 g). 5-Bromo-N,N-dimethylpyrimidine-2-carboxamide (1.3 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.9 g), K2CO3 (2.3 g), and PdDPPFCb-DCM (0.22 g) were stirred ON in dioxane / H2O (4:1, 20 mL) at 100 °C under an inert atmosphere. The mixture was concentrated and purified by FC (MTBE / MeOH) to give Int. 1Z35 tertbutyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.9 g). Int. 1Z35 (0.9 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The mixture was concentrated to give Int. 1Z36 N,N-dimethyl-5-(l,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-carboxamide (0.65 g, HC1 salt). Ints. 1J1 / 1Z36 (0.3 g / 0.3 g) and K2CO3 (0.5 g) were stirred 1 Ih in DMF (10 mL). The mixture was diluted with water to precipitate Int. 1Z37 5-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylpyrimidine-2-carboxamide (0.35 g). Int. 1Z37 (0.35 g), bis(pinacolato)diboron (0.70 g), PdDPPFCb-DCM (10 mg), and KOAc (0.40 g) were stirred 14h in dioxane (10 mL) at 90 °C under an inert atmosphere. The OL (water / chloroform) was concentrated and HPLC-purified to give Int. 1Z38 N,N-dimethyl-5-(l-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)pyrimidine-2-carboxamide (90 mg). Int. 1Z65 (0.50 g), bis(pinacolato)diboron (0.52 g), PdDPPFCh-DCM (82 mg), and KOAc (0.30 g) were stirred Ih in dioxane (6 mL) at 120 °C under MW conditions. The mixture was filtered through celite and concentrated to give Int. 1Z40 3,5-difluoro-N,N-bis(methyl-i / 3)-4-(l-((l-methyl-4-(4,4,5,5-tetra-methyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.60 g). 5-Bromo-N,N-dimethylpicolinamide (1.5 g), te / r-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (2.2 g), K2CO3 (2.7 g), and PdDPPFCL-DCM (0.27 g) were stirred ON in dioxane / FLO (4:1, 20 mL) ON 100 °C under an inert atmosphere. The mixture was concentrated and purified by FC (hexane / MTBE 1:0 to 0:1) to give Int. 1Z52 tert-butyl 6-(dimethyl-carbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-r(2'H)-carboxylate (1 g). Int. 1Z51 (1 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The mixture was concentrated to give Int. 1Z52 N,N-dimcthyl-r,2',3',6'-tctrahydro-[3,4'-bipyridinc]-6-carboxamidc (0.5 g, HC1 salt). Ints. 1J1 / 1Z52 (0.6 g / 0.5 g) and K2CO3 (0.9 g) were stirred 1 Ih in DMF (10 mL). The mixture was diluted with water to precipitate Int. 1Z50 l'-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N,N-dimethyl-T,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.4 g). CON(CD3)2 — Br Int. 1AE9 (0.45 g), bis(pinacolato)diboron (0.35 g), PdDPPFCL-DCM (75 mg), and KOAc (0.27 g) were stirred Ih in dioxane (5 mL) for Ih at 110 °C under MW conditions. The mixture was filtered through celite and concentrated to give Int. 1Z53 3-fluoro-5-methyl-N,N-bis(methy 1-^)-4-( 1-((1-methyl- 4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yf)-lH-pyrrolo[2,3-b]pyridin-2-yf)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.40 g). PdDPPFCE-DCM (0.25 g), 4-bromo-2-fluoro-N,N-dimethylbenzamide (1.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (2.1 g), and K2CO3 (2.5 g) were stirred ON in dioxane / H2O (4:1, 20 mL) at 100 0 C 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-l(2H)-carboxylate (1 g). Int. 1Z55 (1 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The mixture was concentrated to give Int. 1Z56 2-fluoro-N,N-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.5 g, HC1 salt). Ints. 1J1 / PP60 (0.5 g / 0.5 g) and K2CO3 (0.8 g) were stirred 1 Ih in DMF (10 mL). The mixture was diluted with water to precipitate Int. 1Z54 4-(l-((4-bromo-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetra-hydropyridin-4-yl)-2-fluoro-N,N-dimethylbenzamide (0.4 g). CDI (2.6 g) in THF (175 mL) was added dropwise to a mixture of 6-chloro-5-methylpyridazine-3-carboxylic acid (2 g) in THF (175 mL). The mixture was refluxed 3.5h. Dimethylamine hydrochloride (2.8 g) and EtjN (5.2 mL) were added and stirring continued 16h at RT. The OL (brine / EtOAc) was concentrated to give Int. 1Z58 6-chloro-N,N,5-trimcthylpyridazinc-3-carboxamidc (0.8 g). Int. 1Z58 was refluxed ON in bromotrimethylsilane (10 mL). The mixture was concentrated and purified by preparative TLC (hexane / EtOAc, 3:1) to give Int. 1Z59 6-bromo-N,N,5-trimethylpyridazine-3-carbox-amide (0.9 g). PdDPPFCh-DCM (0.3 g), Int. 1Z59 (0.9 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.0 g), and K2CO3 (2.0 g) were refluxed ON in dioxane / H2O (15:4, 190 mL) under an inert atmosphere. The OL (aq. NaHCOs / EtOAc) was dried, and concentrated to give Int. 1Z60 tert-butyl 4-(6-(dimethylcarbamoyl)-4-methylpyridazin-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.3 g). Int. 1Z60 (1.3 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The residue after concentration was triturated in EtOAc to give Int. 1Z61 N,N,5-trimethyl-6-(l,2,3,6-tetrahydropyridin-4-yl)pyridazine-3-carboxamide (0.9, HC1 salt). STAB (0.30 g) and Ints. 1AB8 / 1Z61 (0.1 g / 0.1 g) were stirred ON in DCE / ElN (73:1, 10.1 mL) at 0 °C to RT. The residue after concentration was dissolved in THF, filtered through silica, and concentrated to give Int. 1Z57 6-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N,5-trimethylpyridazine-3-carboxamide (0.19 g). PdDPPFCE-DCM (1.1 g), 4-bromo-N,N,2-trimethylbenzamide (3.3 g), K2CO3 (5.7 g), and tertbutyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (5.9 g) were refluxed ON in dioxane / H2O (15:4, 190 mL) under an inert atmosphere. The OL (aq. NaHCOs / EtOAc) was dried and concentrated to give Int. 1Z63 tert-butyl 4-(4-(dimethylcarbamoyl)-3-methyl-phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (4.1 g). Int. 1Z63 (4.1 g) was stirred ON in 2.8M HC1 in dioxane (30 mL). The residue after concentration was triturated in EtOAc to give Int. 1Z64 N,N,2-trimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (2.3 g, HC1 salt). STAB (0.30 g) and Ints. 1AB8 / 1Z64 (0.1 g / 0.1 g) were stirred ON in DCE / Et ;N (73:1, 10.1 mL) at 0 °C to RT. The residue after concentration was dissolved in THF, filtered through silica, and concentrated to give Int. 1Z62 4-(1-((4-bromo-1 -methyl- lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N, 2-trimethylbenzamide (0.19 g). LiOHH2O (9.5 g) and Int. 3C18 (16 g) were stirred 16h in THF / MeOH / H2O (2:1:1, 300 mL) at 0 °C to RT. The residue after concentration was stirred in aq. citric acid to precipitate Int. 1Z66 4-(1 -(tert-butoxy-carbonyl)-l,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 16h in DMF (40 mL) and DIPEA (13 mL) at 0 °C to RT. The 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-l(2H)-carboxylate (3.7 g). Int. 1Z67 (3.7 g) was stirred 16h in 2M HC1 in dioxane (60 mL) at 0 °C to RT. The mixture was concentrated to give Int. 1Z68 3,5-difluoro-N,N-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (2.9 g, HC1 salt). Ints. 1J1 / 1Z68 (0.35 g / 0.49 g), KI (22 mg), and K2CO3 (0.56 g) were stirred 16h in ACN (20 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 3:7) to give Int. 1Z65 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difIuoro-N,N-dimethylbenzamide (0.35 g). COR LiOH HzO (33 g) and Int. 1AF87 (76 g) were stirred 16h in THF / MeOH / H2O (2:1:1, 1.5 L) at 0 °C to RT. The residue after concentration was stirred in aq. citric acid at 0 °C to precipitate Int. 1Z70 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methylbenz...

Claims

1. A compound according to formula (I):X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14 and N, and wherein whenX4 is N the N may be an N-oxide, or X1 is CR11 and taken together with R forms a 5-membered heteroaryl ring which is optionally substituted with C(O)CF3;X5 is selected from CR4R4 and CO;Xa is selected from N and oxidized N;Y1 is selected from N and CR7;Y2 is selected from N and CR8;Y3 is selected from N and CR17;Z is selected from N and CR10;R is selected from NHR° and -CONHR0;R° is selected from hydrogen, Ci-4alkyl, C3.4 cycloalkyl, C3-4cycloalkyl-Ci-4alkyl, phenyl-Ci. 4alkyl, halo-C i-4alkyl, -(CH2)n-O-R', -(CH2)n-CO-Ci-4alkyl and -(CH2)n-CO2R\ wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Ci-4alkyl, halo-C Malkyl, C3-4cycloalkyl, hydroxy, Ci-4alkoxy, cyano, -NR'R", -CONR'R" and -CO2R', wherein R and R" are each independently selected from hydrogen and Ci-4alkyl and n is 0, 1 or 2;R1 and Rla are independently selected from hydrogen, fluoro and Ci-4alkyl;R2 is selected from hydrogen, Ci-salkyl, -SO2-C i^alkyl and deuterated CMalkyl, wherein said Ci. salkyl may optionally be substituted one or more times with fluoro;R3 is independently selected from hydrogen, Ci-4alkyl, and deuterated C Malkyl;each R4 and R6 are independently selected from hydrogen, C Malkyl, and CMalkoxy, wherein said Ci-4alkyl and CMalkoxy may optionally be substituted with one or more halogen;R3 is selected from hydrogen, halogen, CMalkyl and CMalkoxy, wherein said CMalkyl and Ci. 4alkoxy may optionally be substituted with one or more halogen;R10 is selected from hydrogen and fluoro; orR5 and R10 together form a bond between the two carbon atoms to which they are attached;R3a is hydrogen;or R5 and R5a are both fluoro or R3 and R5a together with the atom attached thereto form a CO group;R3b and R3C are each independently selected from hydrogen and fluoro;R7, R8, and R17 are each independently selected from hydrogen, halogen, cyano, Ci.4alkyl and Ci. 4alkoxy,and C3-icycloalkyl, wherein said C । । a I ky I and Ciialkoxy may optionally be substituted with one or more halogen;R9 is -A-L-LBM;R11, R12, R13 and R14 are each independently selected from hydrogen, halogen, Ci- alkyl, C3.4 cycloalkyl, Ciialkoxy, hydroxy, cyano, - NR'R", -CONR'R". -CO2R', -CO-CO2R', -CO-(CH2)„,OH, tetrazolyl and -SO2-Ci-4alkyl, wherein said Ci-alkyl and Ciialkoxy are optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ciialkoxy, wherein m is 1, 2 or 3; orR11 and R° together with the atoms attached thereto form a 5-6 membered hctcroaromatic or heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or heterocyclic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C 3-4 cyclo alkyl, hydroxy, Ci-4alkoxy, cyano, -COF3, -NR'R", -CONR'R" and -CO2R', wherein said Ci-alkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ciialkoxy;wherein5            R17 is selected from hydrogen and fluoro;R18 is selected from hydrogen and fluoro;R19 is selected from hydrogen and Ci-4alkyl, wherein said Ci.4alkyl may optionally be substituted one or more times with fluoro;R20 is independently selected from hydrogen and fluoro;10            nl is selected from 0 and 1;n2 is selected from 1 and 2;X6 is CH or N;X7 is selected from N and CH;and15          LBM is selected fromR21    R23                      R22               R21    R22R22whereinX8 is selected from O, NH, and triazolyl;R21 is selected from hydrogen, fluoro, chloro, cyano, Ci-4alkyl and trifluoromethyl;R22 is selected from hydrogen and fluoro;R23 is selected from hydrogen, fluoro and Ci-4alkoxy;or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A compound according to formula (I’):A-L-LBMwherein:X1 is selected from CR11 and N; X2 is selected from CR12 and N; X3 is selected from CR13 and N, and X4 is selected from CR14 and N, and wherein when X4 is N the N may be oxidized to a N-oxide;X5 is CO or CR4R4;Y1 is selected from N and CR7;Y2 is selected from N and CR8;Z is selected from N and CR10;R is NHR°;R° is selected from hydrogen, Ci^alkyl, Csucycloalkyl, Cuicycloalkyl-Ci.ialkyl. phenyl-Ci.4alkyl, halo-C i.4alkyl, -(CH2)„-O-R', -(CH2)„-CO-Ci.4alkyl and -(CH2)„-CO2R;wherein said phenyl is optionally substituted one or more times with substituents independently selected from halogen, Ci-4alkyl, halo-C i-4alkyl, C3 4 cycloalkyl, hydroxy, Ci alkoxy, cyano, -NR'R", -CONR'R", and -CO2R', wherein R' and R" are each independently selected from hydrogen and Ci-4alkyl and n is 0, 1, or 2;R1 and Rla are independently selected from hydrogen, fluoro, and Ci-4alkyl;R2 is selected from hydrogen, Ci-salkyl, and deuterated Ci-4alkyl, wherein said Ci-salkyl may optionally be substituted one or more times with fluoro;R3 is selected from hydrogen, Ci-4alkyl and deuterated CMalkyl;each of R4 and R6 are independently selected from hydrogen, CMalkyl, and Ci.4alkoxy, wherein said C1-4alkyl and Cm alkoxy may optionally be substituted with one or more halogen;R3 is selected from hydrogen, fluoro, and CMalkyl; wherein said CMalkyl may optionally be substituted with one or more halogen, and R5a and R10 is hydrogen; orR5 and R5a are both selected from fluoro and R10 is hydrogen; orR5 and R10 together form a bond between the two carbon atoms to which they are attached, and R5a is hydrogen;R7 and R8 are independently selected from hydrogen, halogen, CMalkyl, and CMalkoxy, wherein said CMalkyl and CMalkoxy may optionally be substituted with one or more halogen;R11, R12, R13 and R14 arc independently selected from hydrogen, halogen, CMalkyl, C3.4 cycloalkyl, Ci.4alkoxy, hydroxy, cyano, -NR'R", -CONR'R", -CO2R', -CO-CO2R', -CO-(CH2)mOH, tetrazolyl and -SO2-C Malkyl, wherein said CMalkyl and CMalkoxy is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and CMalkoxy, wherein m is 1, 2 or 3;R11 and R° may together form a 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring or 5-6 membered heterocyclic containing one or two N atoms is optionally be substituted one or more times with a substituent independently selected from halogen, CMalkyl, halo-Ci-4alkyl, C3-4 cycloalkyl, hydroxy, CMalkoxy, cyano, -COF3, -NR'R", -CONR'R", and -CO2R', wherein said CMalkyl may optionally be substituted one or more times with a substituent independently selected from halogen and C1-4 alkoxy;A is CO orL is selected from:R17 is selected from hydrogen and fluoro;R18 is selected from hydrogen and fluoro;R19 is selected from hydrogen and Ci.4alkyl, wherein said Ci-4alkyl may optionally be substituted 10 one or more times with fluoro;R20 is independently selected from hydrogen and fluoro;nl is selected from 0 and 1;n2 is selected from 1 and 2;X6 is CH or N;15          X7 is selected from N and CH;andLBM is selected fromwherein5            X8 is selected from O, NH, and triazolyl;R21 is selected from hydrogen, fluoro, chloro, cyano, Ci-4alkyl and trifluoromcthyl;R22 is selected from hydrogen and fluoro;R23 is selected from hydrogen, fluoro and Ci-4alkoxy;or a pharmaceutically acceptable salt or stereoisomer thereof.10        3. The compound according to claim 1 or 2, having the formula (II):A-L-LBMwherein R3 is Ci-4alkyl, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound according to claim 1 or 2, wherein the compound is of formula (I-b), (Il-b), or (Ill-b):A-L-LBMA-L-LBMA-L-LBMwherein R3 is Cwalkyl;5            or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound according to any one of claims 1-4, wherein L isR196. The compound according to any one of claims 1-4, wherein L isr2° r2010        7. The compound according to any one of claims 1-6, wherein LBM isR21    R23y—NH  OR22       < NH48. The compound according to any one of claims 1-4, wherein A-L-LBM is:R21    r2310. The compound according to any one of claims 8 or 9, wherein R21 is fluoro and R22 and R23 are hydrogen.

11. The compound according to any one of claims 2-10, wherein X1 is N, X2is CR12, X3 is CR13 and X4 is CR14.

12. The compound according to any one of claims 1-11, wherein R is NHR° and R° is selected from hydrogen and Ci-4alkyl.

13. The compound according to any one of claims 1-10, wherein R11 and R° together with the atoms attached thereto form a 5-6 membered heteroaromatic ring containing one or two N atoms, wherein said 5-6 membered heteroaromatic ring containing one or two N atoms is optionally substituted one or more times with a substituent independently selected from halogen, Chalky 1, halo-Ci-4alkyl, C3-4cycloalkyl, hydroxy, CMalkoxy, cyano, -COF3, -NR'R", -CONR'R" and -CO2R', wherein said Ci.4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci-4alkoxy.

14. The compound according to any one of claims 2-12, wherein X1 is CH, X2 is CH, X3 is CH and X4 is CH and R° and R11 together form a pyrazole ring or imidazole ring; where said pyrazole or imidazole ring may optionally be substituted by a substituent independently selected from halogen, Ci.4alkyl, halo-Ci-4alkyl, C 3-4 cyclo alkyl, hydroxy, CMalkoxy, cyano, -NR'R", -CONR'R"and -COiR', wherein said Chalky 1 may optionally be substituted one or more times with a substituent independently selected from halogen and CMalkoxy, and wherein R' and R " are each independently selected from hydrogen and Ci-4alkyl.

15. The compound according to claim 14, wherein said pyrazole or imidazole is either unsubstituted or substituted by Ci-4alkoxy-Ci.4alkyl.

16. The compound according to any one of claims 1-15, wherein Z is CR10 and R10 is hydrogen.

17. The compound according to any one of claims 1-16, wherein Y1 is CR7 and Y2 is CR8.

18. The compound according to claim 17, wherein one or both of R7 and R8 is hydrogen.

19. The compound according to any one of claims 1-18, wherein R1 is hydrogen and R2 andR3 is methyl.

20. The compound according to claim 1, which is selected from Table 1 or a pharmaceutically acceptable salt or stereoisomer thereof.

21. A method of treating a disease, disorder or condition in a patient in need thereof, which disease, disorder or condition is responsive of modulation of STAT-6.

22. The method of claim 21, wherein the disease is an autoimmune disease.

23. A method of treating or amelioration of a disease in a patient in need thereof, wherein saiddisease is characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast and solid fibrous cancers either as a stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors.

24. A compound according to any one of claims 1-20 for use in therapy.

25. A compound according to claim 24 for use in the treatment of a disease, disorder orcondition, which disease, disorder or condition is responsive of modulation of STAT-6.

26. A compound according to claim 24 for use in the treatment of autoimmune diseases.

27. A compound according to claim 24 for use in the treatment of prophylaxis, treatment oramelioration of any of the following diseases characterized by Th2-mediated inflammation such as atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease) and different cancers such as lymphomas, triple negative breast and solid fibrous cancers either as a stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors.

27. A pharmaceutical composition comprising a compound according to any one of claims 120 together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

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