STAT6 degraders

Abstract

The present disclosure provides 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

IgE and IgGl producing cells (Walford). In epidermal                . , . x.,,.. 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 may be beneficial in preventing, treating or ameliorating a variety of diseases which involve upregulation or de-regulation of STAT-6. Furthermore, the compounds and pharmaceutically 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, the present disclosure provides a compound according to formula (I) R9 is -A-L-LBM; X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N; X4 is selected from CR4R4 and CO; X3 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 NHR°; R° is selected from hydrogen, Ci-4alkyl, C3-4 cycloalkyl, C3.4 cycloalkyl-Ci-4alkyl, phenyl- Cmalkyl, halo- Ci-4alkyl, -(CHz / n-O-CMalkyl, -(CH2)n-CO-R’, and -(CH2)n-CO2R’, wherein said phenyl is optionally substituted one or more times with a substituents independently selected from halogen, Cwalkyl, halo-Ci-4alkyl, C3-4cycloalkyl,                               ,.xx , -CONR’R”, and -CO2R’, and 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, Cusalkyl, -SO2-C i.4alkyl and deuterated Ci-4alkyl, wherein said Ci-salkyl may optionally he substituted one or more times with halogen; R3 is selected from hydrogen, Ci ialkyl, and deuterated Ci ialkyl; each of R4 and R6 is independently selected from hydrogen, Ci-4alkyl, and C1-4 alkoxy, said Ci-4alkyl and Ci-4alkoxy may optionally be substituted with one or more halogen; R3 is selected from hydrogen, halogen, Ci-4alkyl and Ci-4alkoxy, wherein said Ci-4alkyl 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 carbons 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 R3C are each independently selected from hydrogen and fluoro; R7, R8, and R17 are each independently selected from hydrogen, halogen, cyano, Ci-4alkyl and Cu 4alkoxy,and C3-4cycloalkyl, wherein said Ci-4alkyl and Ci-4alkoxy may optionally be substituted with one or more halogen; R11, R12, and R13 are each independently selected from hydrogen, halogen, Ci-4alkyl, C3-4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, and -CO-(CH2)mOH, wherein saidCi. 4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci.4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; 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-Ci-4alkyl, C3-4 cycloalkyl, hydroxy, Ci^alkoxy, cyano, -COCF3, -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 Cm alkyl; R12 and R13 are each independently selected from hydrogen, halogen, Ci_4alkyl, C3-4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2),nOH, wherein said Ci.4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; A is CO; L is selected from /  \6—(CH2)ni R18 R20 -(CH2)n1—| 5            wherein nl is selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen, fluoro, Ci-4alkyl substituted one or more times with fluoro or Ci- ialkoxy; R19 is independently selected from hydrogen, Ci.4alkyl and fluoro; R20 is selected from hydrogen and Ci-4alkyl; X6 is C; X7 is CR24 or N; R24 is selected from hydrogen and hydroxy; X8 and X9 are independently CH or N; and LBM is wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and Cm cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3-4 cycloalkyl; each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; or both R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O; or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the present disclosure provides a compound according to formula (I’) A-L-LBM Wherein: X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N; X4 is CR4R4 or CO; 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, C3-4 cycloalkyl, C3-4 cycloalkyl-Ci-4alkyl, phenyl-Ci-4alkyl, halo-Ci-4alkyl, -(CH2)n-O-Ci-4alkyl, -(CFhVCO-R’, and -(CHjX-COiR’, wherein said phenyl is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C3 4 cycloalkyl, hydroxy, C Maikoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, and wherein R’ and R” are each independently selected from hydrogen and CMalkyl, and n is 0, 1, or 2; Rla is hydrogen; R2 is selected from hydrogen, CMalkyl, and deuterated CMalkyl; wherein said CMalkyl may optionally be substituted one or more times with halogen; R3 is selected from hydrogen, CMalkyl, and deuterated CMalkyl; R4 and R6 are independently selected from hydrogen and CMalkyl, wherein said CMalkyl may optionally be substituted with one or more halogens; R5 is selected from hydrogen, halogen, CMalkyl, and CMalkoxy, wherein said CMalkyl and CMaikoxy 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 carbons to which they are attached; R5a is hydrogen; or R5 and R3:‘ are both fluoro; R7 and R8 are independently selected from hydrogen, halogen, CMalkyl, C34 cycloalkyl, and CMalkoxy, wherein said CMalkyl and CMalkoxy may independently optionally be substituted with one or more halogen; R11 is selected from hydrogen, halogen, CMalkyl, C3-4cycloalkyl, CMalkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, - CO2R’, -CO-(CH2)mOH, wherein said CMalkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and CMalkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; or R11 and R° together with the atoms attached thereto may form a 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N, wherein said 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted one or more times with a substituent independently selected from halogen, CMalkyl, halo-Ci-4alkyl, C3.4cycloalkyl, hydroxy, CMalkoxy, cyano, -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; R12 and R13 are independently selected from hydrogen, hax^^.x, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2)mOH, wherein said Ci.4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and Cm alkoxy, and wherein m is 1, 2 or 3 and wherein R' and R" are 5           each independently selected from hydrogen and Ci.4alkyl; A is CO; L is selected from R18 R20 -(CH2)n1—| R18 R20 wherein nl is selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen, fluoro, Ci-4alkyl wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Ci-4alkoxy; R19 is independently selected from hydrogen, Ci.4alkyl and fluoro; R20 is selected from hydrogen and Ci-4alkyl; X6 is C; X7 is CR24 or N; R24 is selected from hydrogen and hydroxy; X8 and X9 are independently CH or N; and LBM is O wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci4alkyl, deuterated Ci4alkyl, and Csi cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3.4 cycloalkyl; each R23 is independently selected from hydrogen, halogen, and Ci-lalkyl; or both R23 together with the carbon they are attached to form a C3.6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O; 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 disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound . 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 or stereoisomer thereof, or a pharmaceutical composition of the present disclosure. In one 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 or stereoisomer thereof, for use in therapy. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the results of anHiBit Assay, dose-response curve for Examples 3u208, 3u246, 3ull8, 3ull9, 3ul20, and 3u74 (where percent degradation is plotted vs. test compound concentration in M on a log-scale). FIG. 2 shows data from the human whole blood 3ull8, 3ull9, 3ul20, and 3u74 (where the effect in % is plotted against the test concentration in M on a log scale). DETAILED DESCRIPTION Definitions Whenever the compound of formula (I) is mentioned herein it should be understood that the compound of formula (I’), (I”), (II), (IT), (III), (IV), (IV’), (VII), (VIII), (VIII’), (IX), (IXa), and (IXb), 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, “Ci-4 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 “Chalky!” 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, / / -butyl, isobutyl, sec.-butyl, and tert, -butyl. The term “(Ci-C4)alkoxy” is used herein to refer to a radical of the formula -OR’, wherein R’ 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 (-OCH3), 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                          ,, monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. An aryl may have 6 to 20 ring carbon atoms (i.e., CAui aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., Ce-io 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., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., Cj.s 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 (=O) or N-oxide (-O ) moieties. Any non-aromatic ring containing                                   „ 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., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 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-Cwalkyl” or “halo-Ci-4alkoxy” is used herein to refer to an “Ci.4alkyl” 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 Ci-4alkyl” is used herein to refer to an “Ci^alkyl” group in which one or more hydrogen atoms have been replaced by deuterium. Examples of “deuterated Cwalkyl” include -CH2D2, -CHD2 or -CD3. The term “Ci.4alkoxyl-Ci.4alkyl” is used herein the refer to “Ci.4alkyl” group in which one hydrogen atom have been replaced by (Ci-C4)alkoxy. Examples of “Ci-4alkoxyl-Ci-4alkyl” “ include methoxymethyl or methoxyethyl. The term “(C3-C4)cycloalkyl-Ci.4alkyl” is used herein the refer to “Ci.4alkyl” group in which one hydrogen atom have been replaced by (C3-C4)cycloalkyl. Examples of “(C3-C4)cycloalkyl-Ci.4alkyr include cyclopropylmethyl. The term “phenyl-Ci-4alkyl” is used herein the refer to “Ci-4alkyl” group in which one hydrogen atom has been replaced by phenyl. Examples of “phenyl-Ci^alkyl” 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 “unsubst.,,,             . ... 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 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-hydroxyethane sulfonic acid, toluenesulfonic, sulfamic or fumaric acid. In some embodiments, pharmaceutically acceptable salts of compounds of formula (I) 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, 1-(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. 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 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 ons^t . 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 embodiment the disclosure provides a compound of formula (I) R wherein: R9 R9 R9 R9 R9           R9 R9 is -A-L-LBM; X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N; X4 is selected from CR4R4 and CO; X3 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 NHR°; R° is selected from hydrogen, Ci-4alkyl, C3.4 cycloalkyl, C3.4cycloalkyl-Ci-4alkyl, phenyl- Ci.4alkyl, halo-Ci-4alkyl, -(CH2)n-O-Ci-4alkyl, -(CH2)n-CO-R’, and -(CH2)n-CO2R’, wherein said phenyl is optionally substituted one or more times with a substituents independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C3.4cycloalkyl, hydroxy, Ci-4alkoxy, cyano, -NR’R”, -CONR’R”, and -CO2R’, and 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-4alkyl and deuterated Ci-4alkyl, wherein said Ci-salky 1 may optionally be substituted one or more times with halogen; R3 is selected from hydrogen, Ci-4alkyl, and deuterated Ci-4alkyl; each of R4 and R6 is independently selected from hydrogen, Ci.4alkyl, and Cm alkoxy, said Ci-4alkyl and Ci-4alkoxy may optionally be substituted with one or more halogen; R5 is selected from hydrogen, halogen, Ci-4alkyl and Ci-4alkoxy, wherein said Ci-4alkyl 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 carbons to which they are attached; R3a is hydrogen; or R3 and R5a are both fluoro or R3 and R5a together with the atom attached thereto form a CO group; R3b 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 C3-4cycloalkyl, wherein said Chalky I and Ci.4alkoxy may optionally be substituted with one or more halogen; R11, R12, and R13 are each independently selected from hydrogen, halogen, Ci-4alkyl, C 3-4 cycloalkyl, Ci_ 4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, and -CO-(CH2)mOH, wherein said Ci-4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and C Maikoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; or R11 and R° together with the atoms attached thereto form a 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, C3-4 cycloalkyl, 5          hydroxy, Ci^alkoxy, cyano, -COCF3, -NR’R”, -CONR’R”, and -CO?R’, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen and Ci^alkoxy, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; and R12 and R13 are each independently selected from hydrogen, halogen, Ci-4alkyl, C3.4 cycloalkyl, Ci- 10          4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2)mOH, wherein said Ci-4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; A is CO; 15 L is selected from R18 R20 N    X6—(CH2)n1 ^R- wherein nl is selected from 0 and 1; n2 is selected from 1 and 2; 5            R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen, fluoro, Ci-4alkyl wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Cwalkoxy; R19 is independently selected from hydrogen, Ci.4alkyl and fluoro; R20 is selected from hydrogen and Ci-4alkyl; 10            X6 is C; X7 is CR24 or N; R24 is selected from hydrogen and hydroxy; X8 and X9 are independently CH or N; and LBM is 15 wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci-4alkyl, deuterate^ Cwalkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or Cm cycloalkyl; each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; or both R23 together with the carbon they are attached to form a C3.6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment the disclosure provides a compound of formula (I’) A-L-LBM wherein: X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N; X4 is CR4R4 or CO; 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, C3-4 cycloalkyl, C3-4cycloalkyl-Ci-4alkyl, phcnyl-Ci-4alkyl, halo-Ci-4alkyl, -(CH2)n-O-Ci-4alkyl, -(CH2)n-CO-R’, and -(CHzX-COzR’, wherein said phenyl is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C3.4cycloalkyl, hydroxy, Ci.4alkoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl, and n is 0, 1, or 2; Rla is hydrogen; R2 is selected from hydrogen, Ci.4alkyl, and deuterated Ci.4alkyl; wherein said Ci.4alkyl may optionally be substituted one or more times with halogen; R3 is selected from hydrogen, Ci.4alkyl, and deuterated Ci.4alkyl; R4 and R6 are independently selected from hydrogen and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted with one or more halogens; R5 is selected from hydrogen, halogen, Ci-4alkyl, and Cm^v^, 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 carbons to which they are attached; RM is hydrogen; or R5 and R5a are both fluoro; R7 and R8are independently selected from hydrogen, halogen, Ciialkyl, Cui cycloalkyl, and Ci.4alkoxy, wherein said Ciialkyl and Ci. alkoxy may independently optionally be substituted with one or more halogen; R11 is selected from hydrogen, halogen, Ci-ialkyl, C3.4 cycloalkyl, Ci.4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, - CO2R’, -CO-(CH2)mOH, wherein said Ci ialkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Cioalkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ciialkyl; or R11 and R° together with the atoms attached thereto may form a 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N, wherein said 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted one or more times with a substituent independently selected from halogen, Ciialkyl, halo-Ci-ralkyl, C3-4cycloalkyl, hydroxy, Cwalkoxy, cyano, -NR’R”, -CONR’R” and -CO2R’, wherein said Chalky 1 may optionally be substituted one or more times with a substituent independently selected from halogen and Cwalkoxy, and wherein R’ and R” are each independently selected from hydrogen and Ciialkyl; R12 and R13 are independently selected from hydrogen, halogen, Ciialkyl, C3-4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2)mOH, wherein said Ciialkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ciialkyl; A is CO; L is selected from R18 R20 |-N    X6—(CH2)n1 R17 —(CH2)ni—| R18 R20 wherein nl is selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen, fluoro, Ci-4alkyl substituted one or more times with fluoro or Ci- ialkoxy; R19 is independently selected from hydrogen, Ci.4alkyl and fluoro; R20 is selected from hydrogen and Ci-4alkyl; X6 is C; X7 is CR24 or N; R24 is selected from hydrogen and hydroxy; X8 and X9 are independently CH or N; and LBM is wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and Cm cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3-4 cycloalkyl; each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; or both R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment the disclosure provides a compound of formula (II) or (IIO A-L-LBM wherein X1, X2, X3, X4, Y1, Y2, Z, R, Rla, R2, R5, R5a, R6, A, L, and LBM are as defined anywhere herein; and R3 is Ci-4alkyl; or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, X1 is N, X2is CR12, X3 is CR13, and X4 is CR14. In some embodiments, X1 is CR11, X2is CR12, X3 is CR13, and X4 is CR14. In one embodiment the disclosure provides a compound of formula (III) 10 wherein Y1, Y2, X4, Z, R, Rla, R2, R3, R5, R5a, R6, R11, R12, R13, A, L, and LBM are as defined anywhere herein; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment the disclosure provides a compound of formula (IV) 15 wherein Y1, Y2, X4, Z, R, Rla, R2, R5, R5a, R6, R11, R12, R13, A, L, and LBM are as defined anywhere herein; and R3 is Ci^alkyl; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment the disclosure provides a compound of formula (IV’) wherein Y1, Y2, X4, Z, R, Rla, R2, R5, R5a, R6, R11, R12, R13, A, L, and LBM are as defined anywhere herein; and R3 is Ci.4alkyl; or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, each of R11, R12, R13, and R14, when present, is independently selected from hydrogen, halogen, and Ci.4alkoxy. In some embodiments, R12 and R13 are both hydrogen. In some embodiments, R11, R12, and R13 are all hydrogen. In some embodiments, X1 is CR11; X2is CR12; X3 is CR13; X4 is CR14; and R11 and R° together with the atoms attached thereto may form a 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N, wherein said 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Ci.4alkyl, 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 C1.4alkyl.In some embodiments, the 5-6 membered hetero aromatic ring containing one or two N atoms is a pyrazole ring. In some embodiments, the 5-6 membered heterocyclic ring containing one or two N atoms is a pyrrolidine ring. 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-Ci-4alkyl, phenyl-Ci.4alkyl, halo-Ci-4alkyl, -(CH2)n-O-Ci-4alkyl, -(CHzVCO-R’, and -(CH2)n-CO2R’, wherein said phenyl is optionally substituted one or more times with a substituent independently selected from halogen, Ci.4alkyl, halo-Ci.4alkyl, C3.4 cycloalkyl, hydroxy, Ci.4alkoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl, and n is 0, 1, or 2; In some embodiments, R is NHR° and R° is selected from hydrogen and Ci^alkyl. In some embodiments, R is NHR° and R° is Ci.4alkyl (e.g., methyl). In one embodiment the disclosure provides a compound of formula (VII) wherein Y1, Y2, X4, Z, Rla, R2, R3, R5, R5a, R6, R12, R13, A, L and LBM are as defined anywhere herein, R16 is selected from hydrogen and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen. In one embodiment the disclosure provides a compound of the formula (VIII) wherein Y1, Y2, X4, Z, Rla, R2, R3, R5, R3a, R6, R12, R13, A, L and LBM are as defined anywhere herein, and R16 is selected from hydrogen and Ci^alkyl, wherein said Cwalkyl may optionally be substituted one or more times with a substituent independently selected from halogen. In one embodiment the disclosure provides a compound of the formula (VIII') wherein Y1, Y2, X4, Z, Rla, R2, R3, R5, R5a, R6, R12, R13, A, L and LBM are as defined anywhere herein, and R16 is selected from hydrogen and Chalky!, wherein said Ci.4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen. In some embodiments, R16 is hydrogen. In one embodiment the disclosure provides a compound of the formula (IX): wherein R16 and R16a are selected from hydrogen and Ci ^alkyl, wherein said Ci ,alkyl may optionally be substituted one or more times with a substituent independently selected from halogen; or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment the disclosure provides a compound of the formula (IXa) or (IXb): (IXa) or wherein R16 and R16a are selected from hydrogen and Cwalkyl, wherein said Ci-4alkyl may 10 optionally be substituted one or more times with a substituent independently selected from halogen; or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, R16 and R16a are both hydrogen. In some embodiments, Z is N. In some embodiments, Z is CR10 and R5 and R10 together form a bond between the two carbons to which they are attached. In some embodiments, Z is CR10 and R10 is hydrogen. In some embodiments, Raa is hydrogen. In some embodiments, X4 is CR4 and R4 is selected from hydrogen and Ci.4alkyl. In some embodiments, the                moiety is           or          . In some embodiments, Y1 is N and Y2 is CR8. In some embodiments, Y1 is N and Y2 is N. In some embodiments, Y1 is CR7 and Y2 is CR8. In some embodiments, the disclosure provides a compound as described herein, wherein (a)both of R7 and R8 is Ci.4alkyl; (b)both of R7 and R8 is halogen; (c)one of R7 and R8 is C ialkyl and the other is halogen; (d)one of R7 and R8 is Ci-ialkyl and the other is hydrogen; or (e)one of R7 and R8 is halogen and the other is hydrogen. In some embodiments, the disclosure provides a compound as described herein, wherein (a)both of R7 and R8 is Ci.4alkyl; (b)both of R7 and R8 is halogen; (c)one of R7 and R8 is Ci-ialkyl and the other is halogen; (d)one of R7 and R8 is Ci ialkyl and the other is hydrogen; (e)one of R7 and R8 is halogen and the other is hydrogen; and (f) both of R7 and R8 are hydrogen; In some embodiments, both of R7 and R8 are halogen; or one of R7 and R8 is Ci.4alkyl and the other is halogen; or both of R7 and R8 are hydrogen. In some embodiments, both of R7 and R8 are halogen, or one of R7 and R8 is Ciialkyl and the other is halogen. In some embodiments, R7 is halogen and R8 is methyl. In some embodiments, the halogen in b) c) and e) is fluoro. In some embodiments, the disclosure provides a compound as described herein, wherein R2 is methyl. In some embodiments, the disclosure provides a compound as described herein, wherein R3 is hydrogen or Ciialkyl. In some embodiments, the disclosure provides a compound as described herein, wherein R3 is methyl. 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). No. labl lab2 Structure No.               Structure lab 3 lab4 lab5 lab6 No. Structure lad8 laf62 lad9 laf63 ladlO laf65 ladll laf82 laf9 1aflO laf61 laf83 Idl ld2 Idll No. Idl9 Structure Ull UVIU1 V ld20 ld21 ld22 ld23 ld24 ld32 ld40 1d41 ld42 ld43 ld44 Ifl lf2 \ No. Tb lf4 Structure Ull UVIU1 V lf5 No.               Structure No. Im67 Structure lm75 lm69 lm76 lm77 lm70 lm71 lm78 lm72 lm73 XNH '2 lm79 CONMe2 lm74 ^NH lm80 lm81 PONHMe CONMe2 CONMe2 PON(CD3)2 con(cd3)2 CONMe2 pONMe2 lm89 lm90 lm91 lm93 lm94 1m95 lm96 n-nh 0' PON(PD3)2 \ CONMe2 \ pONMe2 PON(CD3)2 PON(PD3)2 \ pONMe2 \ PON(CD3)2 lmll8 1ml 19 lml20 lml21 lml22 lml23 lml24 No. Structure lml25 lml26 lnil27 lml32 lml33 lml34 lml35 lml28 lml29 lml30 lnil31 lml36 lml37 lml38 \ CONMe2 CONMe2 CONMe2 \ CONMe2 \ QONMe2 \ CONMe2 \ CONMe2 No. Iml39 Structure lml40 lml41 lml42 lml43 lml44 Moiety A and Moiety L 5          In some embodiments, A is CO. In some embodiments, L is selected from R18   R20 10 wherein nl is selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; R18 is selected from hydrogen, fluoro, Ci-4alkyl wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Ci-4alkoxy; R19 is independently selected from hydrogen, Ci.4alkyl and fluoro; R20 is selected from hydrogen and Ci-4alkyl; X6 is C; X7 is CR24 or N; R24 is selected from hydrogen and hydroxy; and X8 and X9 are independently CH or N. In some embodiments, L is selected from: R18 R20 In some embodiments, L is selected from: R18 R20 In some embodiments, at least one of tbe 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 hydrogen. In some embodiments, A is CO and A-L is selected from: In some embodiments, A is CO. In some embodiments, A is In some embodiments, L is selected from: —(CH2)n1—| pN \6—(CH2)n1 R17 —(CH2)nl—| -(CH2)n1—| , and R18 R20 wherein each nl is independently selected from 0 and 1; n2 is selected from 1 and 2; R17 is selected from hydrogen and fluoro; 5            R18 is selected from hydrogen, fluoro, and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Cwalkoxy; each R19 is independently selected from hydrogen, Ci-4alkyl, and fluoro; R20 is selected from hydrogen and Ci-4alkyl; X6 is C; and 10           X9 is CH or N. In some embodiments, L is selected from: R18 R20 and K'“ K" (CH2)ni—N   N—(CH2)n1—I R17 In some embodiments, L is R19 R19 R18  r20 In some embodiments, L is R19 R19 |-N    X6—(CH2)n1 R17 In some embodiments, L is In some embodiments, L is R18 R20 In some embodiments, at least one of the R17, R18, R19, and R20 of L moiety is not hydrogen. 10           In some embodiments, R17 is hydrogen and at least one of the R18, R19, and R20 of L moiety is not hydrogen. Moiety LBM 5          In some embodiments, LBM is wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci-4alkyl, deuterate^ Cwalkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or Cm cycloalkyl; and each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; or both R23 together with the carbon they are attached to form a Cu, cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O. In some embodiments, X7 is NR22; R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and C3-4 cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-ialkoxy, or C3-1 cycloalkyl. In some embodiments, X7 is NR22; R22 is selected from Ci.4alkyl, deuterated Ci.4alkyl, and C3.4 cycloalkyl, wherein said Ci.4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3-1 cycloalkyL In some embodiments, X7 is NR22; R22 is selected from Ci.4alkyl and C3.4 cycloalkyl. In some embodiments, X7 is NR22 and R22 is methyl. In some embodiments, X7 is NR22 and R22 is cyclopropyl. In some embodiments, X7 is CR23R23; each R23 is independently selected from halogen and Ci-4alkyl; or both R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O. In some embodiments, X7 is CR23R23; each R23 is independently selected from hydrogen and Ci-4alkyl. In some embodiments, X7 is CR23R23, and both R23 are methyl or both R23 are fluoro. In some embodiments, X7 is CR23R23, and both R23 are methyl. In some embodiments, X7 is CR23R23; both R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O. In some embodiments, X7 is CR23R23, and both R23 together with the carbon they are attached to form a C3.6 cycloalkyl. In some embodiments, X7 is CR23R23, and both R23 together with the carbon they are attached to form a 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one heteroatom that is O. In some embodiments, R21 is hydrogen or fluoro. In some embodiments, LBM is selected from: In some embodiments, LBM is 5           wherein X7 is O, NR22, or CR23R23; R21 is selected from hydrogen, fluoro, and chloro; R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and Cm cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3-4 cycloalkyl; 10            each R23 is independently selected from hydrogen and Ci-4alkyl, or both instances of R23 together with the atom to which they are attached form a 3 or 4 membered carbocyclic ring which may be optionally substituted one or more times with a Ci-4alkyl, fluoro, or hydroxy; and R24 is selected from hydrogen and Ci-4alkyl. In some embodiments, X7 is NR22; R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and C3.4 cycloalkyl; and wherein said Ci.4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci.4alkoxy, or C3-4 cycloalkyl. In some embodiments, X7 is NR22; R22 is selected from Ci-4alkyl, deuterated Ci-4alkyl, and C3-4 cycloalkyl; and wherein said Chalky! may optionally be substituted one or more times with fluoro, hydroxy, Ci^alkoxy, or C3-4 cycloalkyl. In some embodiments, X7 is NR22; R22 is selected from Ci-4alkyl and deuterated Ci-4alkyl; and wherein said Ci.4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-ialkoxy, or C3.4 cycloalkyl. In some embodiments, X7 is NR22; and R22 is C3.4 cycloalkyl. In some embodiments, X7 is CR23R23; both R23 are Ci.4alkyl; or two R23 together with the atom to which they are attached form a 3 or 4 membered carbocyclic ring which may be optionally substituted one or more times with a Ci.4alkyl, fluoro, or hydroxy. In some embodiments, X7 is CR23R23; each R23 is independently selected from hydrogen and Ci.4alkyl. In some embodiments, X7 is CR23R23; two R23 together with the atom to which they are attached form a 3 or 4 membered carbocyclic ring which may be optionally substituted one or more times with a Ci-4alkyl, fluoro, or hydroxy. In some embodiments, R24 is hydrogen. In some embodiments, R21 is hydrogen, chloro, or fluoro. In some embodiments, R21 is hydrogen or fluoro. In some embodiments, LBM is selected from: In some embodiments, LBM is selected from: fluoro. In some embodiments, LBM is selected from: In some embodiments, LBM is of the formula: , wherein R21 is hydrogen or Moiety A-L-LAM In some embodiments, A-L-LBM is O wherein R17 is as defined anywhere herein. 10 In some embodiments, A-L-LBM is O wherein R17 is as defined anywhere herein, and n3 is 0, 1, 2 or 3. 5           In some embodiments, A-L-LBM is of the formula: 0 and wherein A is CO, nl is 1, and R18 and R21 are as defined anywhere herein. In some embodiments, A-L-LBM is of the formula: 0 10 and wherein A is CO, nl is 1, and X7, R18, and R21 are as defined anywhere herein. In some embodiments, A-L-LBM is of the formula: 0 and wherein A is CO, n is 1, R18 is hydrogen or Ci-4alkyl, and R21 is hydrogen and fluoro. In some embodiments, A-L-LBM is of the formula: 0 and wherein A is CO, n is 1, R18 is hydrogen or Ci-4alkyl, .- defined anywhere herein. In some embodiments, provided is a compound selected from Table 1, or a pharmaceutically 5 acceptable salt or stereoisomer thereof. Table 1 No. Structure 3e39 o ti 7“\ / “A / NH         / =<        N—\     \ / \ \= / h ° N * 3e44 0    / --X / -NH        / =(       / “(    \ j n / \ \= / / \ rryx              h ° N 3hl0 O  y—v X N 3hl2 ° / —\ HN^       / =(       X ~X <7 BX f-Q   Q _>y0 >\h k ITw                0 N 3ul °   / —V VNH       / =\       / -(    \ rn      z-\       '-n / =^ i o X JI / =(  F 0 । C /                 t^nh 03^            0 N N 3ul0 ° ^NH       / =\      P~\    \ a       q / =<Vo 0   1        \ /                              / NH UEM N 3ul00 and 3u99 3ul01 3ul02 3ulO3 3ul04 and 3ulO5 3ul09 3ull and 3ul2 3ullO 3ul21 3ul22 3ul23 and 3ul24 3ul41 and 3ul42 3ul43 3ul44 and 3ul45 No. Sil UVIULC 0 / -NH       7=\ 'I4—\ f-Q Q w o'      Ck 0 3ul49 0 X --Q Q o’ & ° H 3ul5O and 3ul51 O ^NH        / =\       .N“\ 0 N \                         0 0 H 0   / —v / N / A ^nh        / =\       / N—\ F-w w l5^ ll        Z\         ^“N ° H 3ul52 °   / —V A# 3ul53 and 3ul54 °   / —V / N / A ''NH         / =\        N—V     -7 ~V / )     \ /   Z^0 KO      Z“\       '-N   / =( r 0 X JJ / =( f       H 0 1      ( 7                 r-^ / “nh r[TV-( 3ul93 3ul94 and 3ul95 3u20 and 3u21 3u200 3u201 3u202 and 3u203 3u204 3u217 and 3u218 3u222 3u244 3u245 3u246 3u247 3u248 3u249 No. Sil UVIULC 3u250 V / y-N / -NH        / =( CL F-w w O O X° 3u251 V / / N <x -6 b °^i          F 3u252 OcH 3u253 Q y—k / N / -NH        / =( & zR 0- / '"T"^ ° H 3u254 r— -ox* 3u255 0 / —\ 3   0^0 \ N—•                       X—A. OCM.              0 n *r 3u256 Q / —k ^NH        / =< X f-Q q f Xp X N i         liA 0 H 3u257 3u258 3u259 3u26 3u260 3u261 3u262 3u263 3u264 3u265 3u267 3u268 3u269 3u27 and 3u28 3u270 3u271 3u272 3u273 3u274 3u275 3u302 3u303 3u304 3u305 3u306 3u307 and 3u308 3u35 3u36 3u37 and 3u38 3u39 3u4 3u40 and 3u41 3u71 3u72 and 3u73 3u77 3u93 3u94 and 3u95 3u96 In one or more embodiments of the present disclosure, the compounds of formula (I) have an (ECso) value in the 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 (DCso) value in the STAT6 assay describe below of less than 100 micromolar, or of less than 10 micromolar, or less than 100 nanomolar, or less than 10 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 steroisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (5)-. 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 chrc,..^,^^.^ 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 occurs 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 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 'H, 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 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 art, for example by employing starting 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 one 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 one 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 stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors. In an embodiment the disclosure provides the use ,,. „ 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 stand-alone 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 discl<..,„,^ ,,                                . 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 some embodiments, a dosage unit of a formulation contain 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 embodiment, a compound of the disclosure is provided in combination with one or more therapeutically active compounds. If the treatment involves administration of another therapeutically active compound Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th Ed., J.G. Hardman and L.E. Limbird (Eds.), McGraw-Hill 1995, may be consulted 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 may be 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 soL, 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 incorporated by reference,            .,.               , 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 beta^ 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                  ,            ., j 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,   ____ 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, BBL6000, BCG polysaccharide + nucleic acid , BCL332, 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, BI-1291583, BL 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, BSL502, 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, DBL 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, .                     , 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 fumarate + 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 Nano Ab, 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 + glycopyrronium bromide + mometasone furoate, Indamet, inebilizumab, infliximab, Integrin alpha-2 / beta-l 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, J / 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, KINE-201, KITCL-27, KN-002, KP-470, KT-294, KT-474, KT-621, KX-826, KYV-101, L-608, LABA + LAMA therapy, Langopept, larsucosterol, LAS-200019, LBG-1600M, LCK 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, MDL1228, 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, PBL100, PC-114, PDC-APB, PDE4 inhibitor, pegtarazimod, pemirolast, peresolimab, PF-07264660, PF-07275315, PG011, 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, QBKPN, QLM-3003, QN-02, QP-CO1, ___,                    .,, 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, UL010, 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, vunakizu^, , ...     , 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, a407 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 mod„,ul„.,, hydrocarbon receptor modulator, B and T lymphocyte attenuator stimulator, B-lymphocyte antigen CD19 inhibitor, B-lymphocyte antigen CD19 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, BMP 15 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, CD122 agonist, CD122 modulator, CD19 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, COVID19 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, Filaggr...            . ,,., 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+ K+ ATPase inhibitor, Heat shock protein inhibitor, Heme oxygenase 1 modulator, Heparin agonist, High mobility group protein B1 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-1 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 23 A 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 lifeU.^                       . 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, LOXL2 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 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-l-phosphate receptor-4 modulator, Sphingosine-l-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          .                         . 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 tL,,                                        „ 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 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 c?6-DMSO unless stated otherwise. Reactions performed above the boiling point of the solvent took place in sealed tubes or screwcap vials. “Dried” refers to drying an organic solution over Na^SO i, MgSO4, or CaCE 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. “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. “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. 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 / NH4CI were typically filtered through celite before work-up of the filtrate. Catalytic hydrogenations were performed using a catalyst such as 10% Pd / C and a Hz balloon unless stated otherwise. The mixture after the reaction was typically filtered through celite to remove the catalyst. Intermediates were obtained sufficiently pure for the next step from the procedures outlined in the specification. 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. HPLC Methods Several Intermediates and final compounds (ExamK 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 C18 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 C18 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 C18 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 Cl 8 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 C18 150x21.2 mm, 5 pm A: 10 mM aq. NH4HCO2, B: ACN 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 18 mL / min 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 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, 15 min 40% B 18 mL / min AZZOTA 250x20 mm, 5 pm A: 10 mM aq. ABC, L. 0 min 30% B 1 min 30% B, 10 min 85% B ± / mi— / / mm PRINCETONE ULTIMA C18 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 CSH C18 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 C18 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 HICHROME C18 250x20 mm 5 pm A: 10 mM aq. ABC, B: ACN 0 min 40% B, 2 min 40% B, 10 min 80% B 18 mL / min X SELECTC18 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 Methods The compounds of the disclosure (Examples) 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 C18 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 C18 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 v 111111 / u        min 100% B, 9 min 100% B, 9.5 min 3% B, 10 min 3% B mi— / / mm 5 Acquity BEH C18 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 C18 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 B: 0.05% TFA in ACN 0 min 3% B, 16 min 100% B, 18 min 100% B, 18.5 min 3% B, 20 min 3% B 0.45 mL / min 8 Xbridge C18 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 0 min 1% B, 0.5 min 6% B, 1 min 6% B, 2.6 min 95% B, 3.8 0.7 mL / min A: 10 mM aq. NH4OAc + 0.1% HCOzH B: 0.1% HCO2H in ACN mm y / v >- / .     mm 1%B, 4.8 min 1% B 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 Cl8 (2.1x100) mm, 1.7pm operated at 60 °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 15 YMC-Triart C18 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 1 .OmL / 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 1 .OmL / min 17 Xbridge C18 (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, 1.7pm operated at 45 °C A: 0.05 % TFA in ACN B: 0.05 % aq. TFA v 111111 xv / v ri,     111111 10% A, 7.5 min 98% A, 9.5 min 98% A, 9.6 min 10% A, 10 min 10% A <7.-mix- / / 111111 20 ACQUITY UPLC BEH C18 (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 C18 (2.1x100) mm, 1.7pm operated at 50 °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 0.55mL / min 22 ACQUITY UPLC BEH C18 (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 0.65mL / min 23 X Bridge C18 (50mmx4.6mm, 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 C18 ExRS (50x2.1mm, 1.9pm) 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 3.5gm operated at 45 °C A: 10 mM aq. NH4HCO3 B: ACN v linn / v         111111 2% B, 2.5 min 98% B, 5 min 98% B, 5.1 min 2% B, 6 min 2% B liLLj / llUU 28 YMC Triart C18 (75x4.6mm, 3 um) 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 min 5% B, 14 min 5% B 1.3 mL / min 29 YMC Triart C18 (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 Triart C18 (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 Triart C18 (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 Triart C18 (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 0 min 5% B, 0.5 min 5 % B, 1.0 min 15% B, 4.0 min 98% B, 7.0 1.3 mL / min B: ACN mm yu / v j_ / , /  mm 5% B, 8.0 min 5% B 35 X Brigde BEH Cl 8 (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 l.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 1 .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-C18 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 1.8pm ,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-phosphi no) -2 ’, 4 ’, 6 ’ - tri - Ao -propy 1 - 3,6-dimethoxybiphenyl] [2-(2’ -amino-1,1’ -biphenyl)]palladium(II) methanesulfonate aq = aqueous Boc = tert-butoxycarbonyl BoczO = di-tert-buty 1 dicarbonate BOP = (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate BzPim = 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) Brettphos Pd G3 = [(2-Di-cyclo-hexylphosphino-3,6-dimethoxy-2’,4’,6’- tri- / Isopropyl - 1,1’ -biphenyl)-2-(2’ -amino-1,1 ’ -biphenyl)]palladium(II) methanesulfonate methanesulfonate BrettPhos Pd G4 = [2'-(methylamino)-[l,l'-biphenyl]-2-yl]palladio methanesulfonate di-cvc / o-hexyl[3,6-dimethoxy-2',4',6,-tris(propan-2-y 1) - [ 1,1 -biphenyl] -2-y l]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-hcxylcarbodiimidc 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 = trans-N,N -dimethyl-cyc / o-hexane-1,2-di amine DMEDA = M,2V2-dimethylethane-l,2-dianiine 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 / intermediates IP A = Ao-propyl alcohol KO Ac = potassium acetate KOtBu = potassium tert-butoxide LCMS = liquid chromatography-mass spectrometry LDA = lithium di-rso-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 Pd2dba3 = tris(dibenzylideneacetone)dipalladium(0) PdDPPFCl2-DCM = [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) DCM complex Pd G3 SPhos = (2-Di-cyc / o-hexylphosphino-2’ ,6’ -dimethoxybiphenyl) [2-(2 ’ -amino-1,1’-biphenyl)]palladium(II) methanesulfonate Pd G3 tert-butyl-Xphos = methanesulfonato (ditert-butyl) phenylphosphino (2’-amino-1,1’-biphenyl-2-yl) palladium(II) ppm = parts per million PyBOP = (benzotriazol- 1-ylo xy)tripyrrolidino-phosphonium hexafluorophosphate RT = room temperature RU = response units RuPhos = 2-di-cyc / o-hexylphosphino-2’,6’-di-Ao-propoxybiphenyl Ruphos Pd-G2 = Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'- biphenyl)]palladium(II) sat. = saturated SCX = strong cation exchange SEM = 2-(trimethylsilyl)ethoxymethyl SFC = supercritical fluid chromatography SPR = Surface plasmon resonance STAB = sodium triacetoxy borohydride TBAF = tetra n-butyl ammonium fluoride TBAI = tetra zz-butyl ammonium iodide TFA = trifluoro acetic acid TEO = 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-Ao-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 vohvol 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 as outlined below. R Alkylation Xa = Cl, Br, I, OTf, B(OH)2 or BPin               n Xa1 = Br, I, Cl, OTf, OMs, OTs Xa1 = Br, I, Cl, OTf, OMs, OTs Xa1 = Br, I, Cl, OTf, OMs, OTs Linking A = CO to L-LBM (i.e. of R9) via an amide bond can be performed from the 5 corresponding acid, an appropriate amine, and a suitable coupling agent for example under the conditions used to prepare Int. 1AF84. Linking the A1 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 A1 or by coupling ring B in which Z is a carbon atom linked to a boronic acid or boronate to aryl (pseudo)halide based 10 on ring A1. 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 linked to the azaindole core (CC) or by reductive amination of the B ring amine to the ketone / aldehyde linked to the azaindole core (C-C). Such reactions can be performed as described for the synthesis of Examples ld40 / ld41 from 15 Int. 1T1 or Examples lm6 from Int. 1M1. R2 can be attached to the parent azaindolc core (C-C) by alkylation with a suitable alkylation agent. Such reactions can be performed as described for the syntheses of Int. 1K3. 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 or by copper-mediated Ullmann reaction between an aryl (pseudo)halide derivative of the azaindole core (C-C) and the heteroaromatic ring D. Such reactions can be performed as described for the synthesis 5 of Example laf63 from Int. 1AF1 or Example lab4 from 1AB4. Additionally or alternatively, the compounds of the disclosure can be prepared according to the key bond formations as outlined below. x = Br, I, Cl, OTf, OMs, OTs Linking A = CO to L-LBM via an amide bond can be performed from the corresponding acid, 10 an appropriate amine, and a suitable coupling agent for example under the conditions used to prepare Int. 1AF84. 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 (CC) or by reductive amination of the B ring amine to the ketone / aldehyde liked to the azaindole core 15   (C-C). Such reactions can be performed as described for the synthesis of Examples ld40 / ld41 from Int. 1T1 or Examples lm6 from Int. 1M1. 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 (CC) 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 Examples ld40 / ld41 from Int. 1T1 or Examples lm6 from Int. 1M1. 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. 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 or by copper-mediated Ullmann reaction between an aryl (pseudo)halide derivative of the azaindole core (C-C) and the heteroaromatic ring D. Such reactions can be performed as described for the synthesis of Example laf63 from Int. 1AF1 or Example lab4 from 1AB4. O                                                                                  R,B R22 Compounds in which A = CO the -L- fragment can be introduced via amide bond formation. The prerequisite acids can for example be prepared as described herein for Int. 1M60 from Example lm56. The synthesis Int. 3E274 exemplifies a precursor in which the amide bond linking CO to L-LBM is formed from the prerequisite substrates Ints. 3E275 / 1AC4. The specification exemplifies L-LBM fragments such as Int. 3E68 and their coupling to give the compounds of the disclosure such as described for the reaction of Ints. 3E171 / 3E68 to give Example 3e39. Compounds in which the LBM motif is linked to the rest of the molecule via a triple bond or a C-C to a five-membered aromatic ring can be prepared via cross-coupling reactions from precursors like Ints. 3E240 / 3B1. Compounds in which the LBM motif is linked to the rest of the molecule via a methylene linker can be prepared by reductive amination such as described herein for Int. 3E2. Compounds in which the LBM is linked to the rest of the molecule via the 4-position of a piperidine ring can be prepared from Ints. like 3D1. The LBM motif can be functionalized with Cl or F atoms such as in Ints. 3E50, 3E61, and 3E13L The LBM motif can be functionalized on the benzimidazolone nitrogen atom not bearing the piperidine-2,6-dione unit by functionalized alkyl groups such as (CFFkOH, (CHzhOMe, or CH2CF3 as in Ints. 3E13, 3E159, and 3E106. The LBM motif can be functionalized on the benzimidazolone nitrogen atom not bearing the piperidine-2,6-dione unit by alkyl groups like methyl or cyc / o-propyl as in Ints. 3E3, and 3E20. Compounds in which the LBM motif is an oxindole or benzoxazole can be prepared from Ints. 3E288 and 3E257. Example 1 - Preparation of Intermediates Br            . . _ i        1A5r=ch2oh 1A4r=CH2CI SO2Ph 4-Bromo-l-(phenyl-sulfonyl)-lH-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.27 g) and NaBIL (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 / Et3N (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)-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (0.15 g)- 4-Bromopyridin-2(lH)-one (1.0 g), ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (3.17 g), PdDPPFCL-DCM (0.42 g), and K3PO4 (3.66 g) were degassed in dioxane / water (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), BoczO (0.61 g), and DMAP (23 mg) were stirred ON in DCM / EtjN (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 trans-4-(4-ethoxycarbonylphenyl)-3-methyl-2-oxo-piperidine-l-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. NaHCOa) was dried, and concentrated to give Int. 1A13 ethyl 4-[ / ra / M-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-[tra«y-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, HNMez (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 N,N-Dimethyl-4-[tran5-l-[(4-bromo-l-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]-A,A-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 1AB1 R=NMe2 1AB1'r=n(cd3)2 \=z Br ( ) Int. 1J1 (8 g) and A,A-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-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A,A-dimethylbenzamide (9 g). Int. 1AB1’ 4-(1-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A,A-bis(methyl-(benzamide was prepared similarly from HN(CDs)2. NazCOs (9.2 g), l,l,l-trifhioro-. / V-phenyl-lV-((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-1-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 tert-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-( 1 -((4-Bromo-1 -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)-A^,N-dimethylbenzamide or (R)-4-(l-((4-bromo-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-2-oxopiperidin-4-yl)-A,A-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)-A,A-dimethylbenzamide or (R)-4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-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. HO. .OH jT 1AB4 R=NMe2 1AB4'R=N(CD3)2 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’ A / ,A-Dimethyl-4-[l-[[l-methyL4-(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]-1 -methyl-pyrrolo[2,3-b]pyridin-4-yl]boronic acid and M / V-bisOnethyl-J3)-4-( 1 -((1 -methyl-4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)mcthyl)pipcridin-4-yl)bcnzamidc and (2-((4-(4-(bis-(methyl-£ / 3)carbamoyl)phenyl)piperidin-l-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid. 4-Bromo-AOV,3-trimethylbenzamide (9.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (15.2 g), PdDPPFCh-DCM (0.67 g), and NazCOs (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 Et2O to give Int. 1AB6 AOV,3-trimethyl-4-(l,2,3,6-tetrahydropyridin-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)-l,2,3,6-tetrahydropyridin-4-yl)-A,A,3-trimethylbenzamide (0.10 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. NH4Cl / EtOAc) was washed with water, brine, dried, concentrated, and triturated in EtOAc / pentane to give Int. 1AB8 4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridine-2-carbaldehyde (3-1 g). CONMe2 / TA X— / Int. 1AB10 R=H, single bond / Int. 1AB12 R=H, single bond n / ""X 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 NaiCOs (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 / Hexane 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 EtzO 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. HC1 to give Int. 1AC4 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)mcthyl]-4-pipcridyl]-benzoic acid (0.38 g). Int. 1AC4 (0.5 g) and CDI (0.7 g) were stirred 2h in DMF / EtsN (30:1, 7.2 mL). 25% aq. NEL (1.51 mL) was added followed by water to precipitate a solid that was stirred ON in 1,1-dimethoxy-A, A-dimethylmethanamine (10 mL) to afford Int. 1AC3 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzamide (0-35 g). 4-Bronio-1 -tosy I-1 / 7-pyrrolo[2,3-h]pyridine (1.0 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. NH4Cl / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:0 to 9:1) to give Int. 1AD8 4-bromo-l-(p-tolylsulfonyl)-pyrrolo[2,3-b]-pyridine-2-carbaldehyde (0.6 g). AA-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 (water / DCM) was dried, concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1AD7 4-[l-[f4-bromo-l-(p-tolyl-sulfonyl)-pyrrolof2,3-b]pyridin-2-yl]methyl]-4-piperidyl]-N,N-dimethyl-benzamide (2.3 g). CONMe2 1AE2 R-Boc N—Z   1AE1 R=H O ° N—' r' KOtBu (37 mg), tert-butyl 4-(p-tolylsulfonyloxy)piperidine-l-carboxylate (0.16 g), K2CO3 (83 mg), and ACAMirnethyl-2-oxo-1 H-pyridine-4-carboxamidc (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 tert-butyl 4-[4-(dimethyl-carbamoyl)-2-oxo-l-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 A,A-Dimethyl-2-oxo-l-(piperidin-4-yl)-l,2-dihydropyridine-4-carboxamide (0.15 mg, TFA salt). 4-Bromo-A,A-dimethylbenzamide (25 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (40.7 g), Na2CO3 (34.5 g), and PdDPPFCL-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-1 (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 1AE37r=oh 1AE7' r=n(CD3)2 \— / N—' Bo / 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), NaHCOs (11.7 g), and PdDPPFCh-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 (hexane / 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-(1-(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-f4-[bis-(trideuteriomethyl)-carbamoyl]phenyl]-3,6-dihydro-2H-pyridine-l-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 EtzO / pentane to give Int. 1AE7’ / V, / V-Bis(mcthyLdd-4-( 1,2,3,6-tctrahydropyridin-4-yl)hcnzamidc (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-trimethylbenzamide (20.0 g), NazCOs (21.4 g), and PdDPPFClz-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-methy 1-phenyl]-piperi dine-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 7V,7V,3-trimethyl-(4-piperidin-4-yl)benzamide (9.2 g, TFA salt). CONMe2 HN—f 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 EtzO to give Int. 1AE8’ AOV,3-trimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (1.06 g, HO 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)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methyl-AOV-bis(methyl-< / 3)benzamide (0.45 g). conr2 y—Z 1AE12r=cd3 _ / ”)= 1AE12'R=Me HN—f 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 PdDPPFCP-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-nuoro-4-methoxy-carbonyl-6-methyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (15.5 g). This material and LiOH-H2O (3.72 g) were stirred ON in MeOH / water (1:1, 0.3 L) and acidified to precipitate 4-(l-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-fluoro-5-methyl-benzoic acid (11.8 g). 5.0 g of this material, HNfCDsh (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 tert-butyl 4-[4-[bis(trideuterio-methyl)carbamoyl]-2-fluoro-6-methyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylate (5.1 g). This material was stirred Ih in HFIP / 10M aq. HC1 (31:1, 52 mL) and diluted with MTBE to precipitate Int. 1AE12 3-Fluoro-5-methyl-A,A-bis(methyl-6 / 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 HNfCHsK " \ 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. NaHCO s 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,7V,5-trimethyl-benzamide (0.52 g). \ Int. 1AB1 (0.15 g), Mo(CO)6 (87 mg), Pdjdbas (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-purified give ethyl 2-((4-(4-(dimethylcarbamoyl)phenyl)piperidin-1 -yl)methyl)-1 -methyl- 1H-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-1 H-pyrrolo [2,3-b]pyridine-4-carboxylic acid (0.15 g). Piperazin-2-one (1.0 g), 4-hromo-A',A'-dimethylhenzamide (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 N,N-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. 1J1 (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. 1AE16 4-(4-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-3-oxopiperazin-l-yl)-A,A-dimethylbenzamide (0.20 g). 1AE19r=h 6-Bromo-5-methyl-pyridine-3-carboxylic acid (4.5 g), HATU (9.5 g), and HN(CHs)2 (8.4 g, HO 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-A'.A'.5-trimethylnicotinamide (4.2 g). 3.2 g of this material, NaHCOs (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 PdDPPFCL-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 ACV,5-trimethy 1-6-(1,2,3,6-tetrahydro-pyridin-4-yl)pyridinc-3-carboxamidc (0.28 g, TFA salt). 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]-7V,A,5-trimethyl-pyridine-3-carboxamide (0.3 g). Int. 1AE22 (3 g), BzPinz (5.0 g), KOAc (5.0 g), and PdDPPFCL-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'-bipyridin]-r(2'H)-yl)methyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid / A,A^3-trimethyl-r-((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'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (1.0 g). CONMe2 / /       1AE27 R=Boc, double bond )=(    1AE26 R=Boc, single bond / =< F 1AE25 R=H, single bond N—f r' 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), NazCOs (1.72 g), and PdDPPFCB-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-(dimethyl-carbamoyl)-2-fluoro-phenyl]-3,6-dihydro-2H-pyridine-1 -carboxylate (1.2 g). This material was hydrogenated ON using 10% Pd / C (40 mg) in MeOH (10 mL) under an atmosphere of FL 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). 4-Bromo-1 -tosy 1-1 H-pyrrolo[2,3-£>]pyridine (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 A,A-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. NaHCOj / DCM) 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). 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-( 1,2,3,6-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 A,A-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)- / V,A-bis(methyl-J3)benzamide (0.20 g). CON(CD3)2 Methyl 2-bromopyrimidine-5-carboxylate (10.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,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, HN(CD3)2 (1.21 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-[bis(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. HC1 (30:1, 23 mL), concentrated, and triturated in MTBE to give Int. 1AF2 A,A-bis(methyl-t / 3)-2-(l,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide (1.40 g, HO salt). CON(CD3)2 Ints. 1AF2 / 1J1 (0.5 g / 0.5 g) were stirred in ACN / EtiN (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]-7V,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-l,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-(l,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), Bipin? (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 I (2-((4-(2-chloro-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyri din-l(2H)-yl)methyl)-1 -methyl- 1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (1 g). CONMe2 1AF13R=Br 1AF12 R=B(OH)2 / BPin \=N' R N—' n m Ints. 1S5 / 1J1 (0.5 g / 0.5g, as the HC1 salt) were stirred ON in ACN / EhN (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 PdDPPFCh-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 N,N-Dimethyl-l'-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yhmethylhr^'^'^’-tetrahydro-P^'-bipyridinel-S-carboxamide / (2-((5-(dimethylcarbamoyl)-3',6'-dihydro-[2,4,-bipyridin]-T(2'H)-yl)methyl)-l-methyl-lH-pyrrolof2,3-b]pyridin-4-yl)boronic acid (1.0 Methyl 5-bromopyrazine-2-carboxylate (11.0 g), / e / 7-hutyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (17.2 g), K2CO3 (28.0 g), PdPDDFCh-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-( 1 -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(tridcutcriomcthyl)-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-(l,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-purified to give Int. 1AF15 5-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-Ar,A-bis(methyL<i3)pyrazine-2-carboxamide 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. NFLCl / EtOAc) was washed with brine, dried, concentrated and purified by FC (pcntanc / EtOAc 3:1) to give Int. 1AF21 1 -(4-bromo-l -methyl- 1H-pyrrolo[2,3-b]pyridin-2-yl)ethan-l-ol (25.5 g). 0.30 g of this material was stirred in toluene / SOCl2 (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 A,A-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 I MeOH 95:5) to give Int. 1AF17 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)-A,A-dimethylbenzamide (0.28 g). CONMe2 B(OH)2 / ~\ N—' uCH n rf Int. 1AF17 (0.70 g), B2Pin2 (0.51 g), KO Ac (0.4 g), and Pd(PPh3)2Cl2 (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-(l-(4-(4-(dimethyl-carbamoyl)phenyl)piperidin-l-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g). CONMe2 1AF24 \= / B(OH)2 / \ -X   N—' N * Int. 1AF17 (0.70 g), B2Pin2 (0.51 g), KO Ac (0.4 g), and Pd(PPh3)2Cl2 (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-(l-(4-(4-(dimethyl-carbamoyl)phenyl)piperidin-l-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid (0.85 g). CONMe2 1AF27 BPin Int. 1AF17 (0.70 g), B2Pin2 (38 mg), KOAc (45 mg), and PdDPPFCl2-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-dimethyL4-(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 tolucnc / SOCl2 (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- [ 1 - [ 1 -(4-bromo-1 -methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl] -3,6-dihydro-2H-pyridin-4-yl]-A,A-dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), B2Pin2 (24 mg), KOAc (25 mg), and PdCl2(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred ON at 90 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(1-(4-(4-(dimethylcarbamoyl)-phenyl)-3,6-dihydropyridin-l (2H)-yl)ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-boronic acid (0.50 g). CONMe2 1AF34R=Br 1AF33 R=B(OH)2\= / R A N—' N 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 / SOC12 (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]-A,A-dimethyl-benzamide (80 mg). Int. 1AF34 (0.32 g), B2Pin2 (24 mg), KOAc (25 mg), and PdCl2(PPh3)2 (48 mg) were degassed in THF (5 mL) and stirred ON at 90 °C. The mixture was filtered, concentrated, and purified by FC (pentane / EtOAc 95:5) to give Int. 1AF33 (2-(1-(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). CONMe2 1AF44R=Br 1AF43 R=B(OH)2 / R n Int. 1AF44 4-[l-[l-(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)ethyl]-4-piperidyl]-A,A,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-(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 (0.60 g) was prepared similarly to Int. 1AF39 from Int. 1AF44 (0.50 g). ., .   „                 CON(CD,), 1AF50RBr __ /   ' 3,2 1AF49R-BPin vy R        \ N—' rm. 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-piperidyl]ethyl]-l-methyl-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-1 H-pyrrolo [2,3-b]pyridin-2-yl)ethy 1)-1,2,3,6- tetrahydropyridin-4-yl j-A'jV-bisi'methyl-Jjhenzamide (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- [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). Int. 1AF62 4-(1-( 1 -(4-bromo-1 -methyl-1 H-pyrrolo [2,3-b]pyridin-2-y l)e thy I)-1,2,3,6- tetrahydro-pyridin-4-yl)-3-methyl-A,A-bis(methyl-d3)benzamide (0.46 g) was prepared similarly to Int. 1AF17 from Ints. 1AF24 / 1S20 (0.50 g / 0.70 g). Int. 1AF61 (2-(l-(4-(4-(bis(methyl- J3)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 EFPim (0.52 g) and Int. 1AF62 (0.5 g). Int. 1AF72 4-(1-( 1 -(4-bromo-1 -methyl-1 H-pyrrolo [2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-methyl-A,A-bis-(methyl-<73)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-c / 3)carbamoyl)-2-methylphenyl)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 1AF73 R=C0NMe2 1AF74 R=CON(CD3)2 \ 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-dimethy 1-benzamide (1.0 g). Int. 1AF74 4-(1-(1 -(4-bromo- 1-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethy 1)-1,2,3,6-tetrahydropyridin-4-yl)-A,A-bis(methyl-r / 3)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), KO Ac (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)-AOV-bis(methyl-r / 3)-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 (1.30 g). R 1AF76 X=Br, R=CONMe2 .__ / 1AF76' X=Br, R=CON(CD3)2 e y 1AF77 x=i, r=con(CD3)2 / =, X / ~\ N * 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 / MeOH 97:3) to give Int. 1AF77 (S)-4-(l-(l-(4-iodo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-A,A-bis(methyl-r / 3)-benzamide (50 mg). The absolute configuration of 1AF76 (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo-f2,3-b]pyridin-2-yl)-ethyl)piperidin-4-yl)-A,A-dimethylbenzamide and 1AF76’ (S)-4-(l-(l-(4-bromo-1-methyl-1 H-pyrrolo-[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)-A,A-bis(methyl-<L)henzamide 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)2 (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-7V,A,5-trimethyl-benzamide (12.4 g). This material, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-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-A,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-f(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)-methyl]-3,6-dihydro-2H-pyridin-4-yl]-3-chloro-5-fluoro-A,7V-dimethyl-benzamide (0.17 g). This material, B2Pin2 (0.17 g), KOAc (0.10 g), and PdDPPFCL-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-A, / V-dimethyl-4-(1 -((l-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l H-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-1 (2H)-yl)methyl)-1 -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-(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-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-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methyl-A,A-bis(methyl-<: / ■,) benzamide was prepared similarly using the HC1 salt of HN(CD3)2. hit. 1AF84 (1.1 g), KO Ac (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). 2-Fluoro-4-iodo-6-methyl-aniline (20 g) and PdDPPFCl2-DCM were stirred ON in MeOH / EtjN (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-niethyl-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. NaHCOa, and filtered. The OL (EtOAc / 10% aq. NIL) was concentrated and purified by FC (hcxanc / EtOAc 9:1) to give Int. 1AF92 methyl 4-bromo-3-fluoro-5-nicthyl-benzoatc (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 PdDPPFCl2-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). 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), KOAc (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, A-bis(trideuteriomethyl) benzamide (0.6 g). \ Int. 1AB1 (0.29 g), Cui (0.12 g), and NaN3 (83 mg) were degassed in DMSO / DMEDA (14.4:1, 1.4 mL) and stirred at 100 °C. The OL (sat. aq. NH iCI / EtOAc) was washed with water, brine, dried, concentrated, HPLC-purified, and triturated in MTBE to give Int. 1C1 4-[l-[(4-Amino-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidyl]-A,A-dimethyl-benzamide (0.22 g). 1D1or1D2 1D2or1D1 1D3OI-1D4 1D4or1D3 2.0M LDA in THF (28.1 mL) was added to a solution of tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (10.0 g) in THF (200 mL) -78 °C. The mixture was stirred for 0.3h at -78 °C. l,l,l-Trifluoro-A-phenyl-A-((trifluoro-methyl)sulfonyl)methane-sulfonamide (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), Na2CO3 (7.67 g), (4-(dimethyl-carbamoyl)phenyl)boronic acid (8.38 g), and PdDPPFCL-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-1-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 ALV-dirnethy l-442-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% NH3 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 A,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% NH3 (30 mL / min) and a back pressure of 100 bar to give Int. 1D3 A,A-dimethyl-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide (0.70 g, first peak) and Int. 1D4 A,A-dimethyl-4-((2S,4S)-2-methyl-piperidin-4-yl)benzamide (0.90 g, second peak). The absolute configuration was determined by VCD for Int. 1D3 and 1D4. 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-(l-((4-Bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-7V,A-diethylbenz amide (30 mg). Int. 1D6 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-A,N-dipropyl-benzamide (37 mg, was prepared similarly from HNPr2. R 1 D7 R=CON(CD3)2 1D7' R=CONMe2 \_ / HN—• 1-(1,1-Dimethylethyl) 4-(4-carboxyphenyl)-l-piperidinecarboxylate (5.1 g), HATU (13 g), and HN(CD3)2 (2.5 g, HO 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-1 -carboxylate (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 EtzO to give Int. 1D7 A,A-Bis(methyl-c / 3)-4-(H2-piperidin-4-yl)- benzamide (0.81 g, TFA salt). Int. 1D7’ / V, / V-dimethyl-4-(4-piperidyl)benzamide (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-t / 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. NaHCO3 / DCM) was dried and concentrated. The residue was stirred Ih 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-l-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-(1-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-<73)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 / pentane to give Int. 1D18 4-(2-methyl-4-piperidyl)-A,7V-bis(trideuteriomethyl)benzamide (3.50 g, TFA salt). Int. 1D18 was separated into Ints. 1D14 AJV-bis(methyl-<i)-4-((2S,4R)-2-methylpiperidin-4-yl)benzamide, Int. 1D15 N,.N-bis-(methyl-J3)-4-((2R,4S)-2-methylpiperidin-4-yl)benzamide, Int. 1D16 A,A-bis(methyl-<f3)-4-((2R,4R)-2-methylpiperidin-4-yl)benzamide, and Int. 1D17 N,A-bis(methyl-<f3)-4-((2S,4S)-2-methyl-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), PdDPPFCl2-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 ds-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, HC1 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 czs-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% zso-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-yl)-A,A-dimethylbenzamide and 4-((3R,4S)-3-fluoropiperidin-4-y 1 )-N,N-dimethyl-benzamide. 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 tert-butyl 3-hydroxy-4-(4-(methoxy-carbonyl)phenyl)piperidine-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. NaHCOVDCM) 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-difluoro-piperidine-l-carboxylate (4.5 g). Int. 1F11 (4.2 g) was stirred ON inDCM / TFA (27:1, 83 mL) at 0 °C to RT and concentrated. The OL (5% MeOH in DCM / sat. aq. NaHCO3) was dried and concentrated to give Int. 1F10 4-(3,3-difluoro-4-piperidyl)-A,A-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-dimethyl benzamide and (S)-4-(3,3-difluoropiperidin-4-yl)- A,A-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 (luoropiperidin-4-y I )-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. NH4CI / 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 7V,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. NaHCOs / DCM.) was washed with brine, dried, concentrated, and purified by FC (DCM / MeOH 1:0 to 9:1) to give Int. 1H1 4-[l-f(4-bromo-l,3-dimethyl-pyrrolof2,3-b]pyridin-2-yl)methyl]-4-piperidyl]-A'.A'-dimethyl-henzamide (30 mg). CONMe2 Br          \ N Int. Ill 4-(l-((4-bromo-l,5-dimethyl-lH-pyrrolof2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)- ALV-dimethylbenzamide (0.16 g) as prepared similarly to Int. 1H1 from 4-bromo-5-methyl-lH-pyrrolo[2,3-b]pyridine (0.51 g) and A,A-dimethyl-4-(piperidin-4-yl)benzamide (0.18 g). Br Int. 1AB8 (30 g) and NaBH4 (19 g) were stirred 2h in MeOH (300 mL) at 0 °C to RT. The OL (aq. NaiSiOVEtOAc) 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 / Et3N / MsCl (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- 1H-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)pyrrolo[2,3-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 HNtCHih (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^^ A / =< 1M23 Double bond / 1M24 Single bond 4-Bromo-3-mcthoxybcnzoic acid (3.0 g), HN(CHs)2 (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-AOV-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.17 g). NaNO2 (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-fluoro-5-methyl-benzoic acid (15.0 g) was stirred 5h in DCM / SOCh (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-A'jV.5-trimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.22 g). Int. 1M26 3-chloro-7V,7V,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-A,A-dimethyl-benzamide (1.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (1.41 g), Na2COs (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 / EtOAc) was washed with brine, dried, concentrated, and purified by FC (hexane to EtOAc) to give tert-butyl 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-A,A-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 tert-butyl 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,A-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(CHs)2 (1.36 g, HC1 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,A-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-dioxaborolan-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-1-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 A,A-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoro-mcthyl)bcnzamidc (0.14 g). tert-Butyl 4-[4-(dimcthyl-carbamoyl)-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 N,N-dimethyl-4-(piperidin-4-yl)-3-(trifluoromethyl)benzamide (0.23 g). 6-Chloro-5-fluoro-pyridine-3-carboxylic acid (3.0g), HNtCHji (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-7V,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,A-dimethyl-6-(l,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, HC1 salt), HOBt (0.42 g), and EDC (0.60 g, HC1 salt) were stirred ON in DCM / DIPEA (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-1-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-1 -yl)-benzamide (0.20 g). Int. 1M59 (S)-A,A,3-trimethyl-4-(3-methylpiperazin-1 -yl)-benzamide was prepared similarly from tert-butyl (R)-2-mcthylpipcrazinc-l-carboxylate. CONMe2 CONMe2 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-di methyl benzamide (3.1 g) were degassed in dioxane (30 mL) and stirred ON at 100 °C. The OL (Et2O / 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-l-carboxylate (0.46 g) was prepared similarly from tert-butyl (R)-2-methylpiperazine-l-carboxylate (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. NaHCO3) 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,A-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-1 -y 1 )-N,N-dimethylbenzamide (30 mg). CONMe2 0 D Boc-piperazine (0.40 g), 6-bromo-A,A-dimethylnicotinamide (0.59 g), NaOtBu (0.41 g), Xphos (0.10 g), and Pd2dba3 (0.1 g) were degassed in dioxane (4 mL) and stirred 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 HC1 in dioxane (3 mL) at 0 °C to RT and concentrated to give Int. 1M55 A,A-dimethyl-6-(piperazin-l-yl)nicotinamide (0.14 g, HO salt). :onr2 1M56 r=cd3 ( \ 1M57r=mg HN—' 4-(4-tert-Butoxycarbonylpiperazin-l-yl)benzoic acid (1.0 g), HN(CDj)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 tert-butyl 4-(5-(bis(methyl-J3)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(A'-his(mcthyl-J3)-6-(piperazin-l -yljnicotinamidc (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 tertbutyl 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 EtiO to give Int. 1M57 7V,A-dimethyl-6-(piperidin-4-yl)nicotinamide (0.50 g, TFA salt). Ints. 1M1 / 1S7 (15 mg / 22 mg, HO 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 7V,7V,3-Trimethyl-4-(4-((l-methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperazin-1-yl)benzamide (6.6 mM in DMSO (0.70 mL). Example lm56 3-Fluoro-A,A,5-trimethyl-4-(l-((l-methyl-4-(4-(methylamino)-2-oxopyridin-1 (2H)-yl)-1H-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-FLO (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-methyl-4-(l-((l-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 t 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-1 -methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]piperazine-1 -carboxylate (0.20 g). Int. 1AB8 (0.35 g) and A,A-dimethyl-4-(piperazin-l-yl)benzamide (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)-7V,A-dimethyl-benzamide (0.44 g). Int. 1N4 (25 mg), KO Ac (11 mg), PdDPPFCl2-DCM (4 mg), and B2Pin2 (15 mg) were degassed in dioxane (3 mL) and stirred 4h at 70 °Ch. KOAc (11 mg), and B2Pin2 (15 mg), and PdDPPFCl2-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,A-dimethyl-4-[4-[[l-methyl-4-(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- 1H-pyrrolo[2,3-b]pyridin-4-yl)boronic acid. b(ohj2 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 I2 (50 mg) were refluxed Ih in THF (50 mL). l-Benzylpiperidin-4-onc (8.0 mL) was added before refluxing 3h. The OL (sat. aq. NH4CI / 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. NaHCO3 / DCM) was dried, concentrated, and purified by FC (DCM / 2M NH3 in MeOH 1:0 to 4:1) to give Int. 1R5 ethyl 4-(l-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)-A,A-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-(mcthoxycarbonyl)phcnyl)-piperidine-1-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-(l-(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 I 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)-A,A-dimethyl-benzamide (14.5 g). This material was resolved by SFC using a Chiralpak IG 250x25 5pm 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)-AOV-dime thy Ibenz amide and 4-((3S,4S)-3-fluoropiperidin-4-yl)-AOV-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)-1 -[(4-bromo-1 -methyl-pyrrolo[2,3-b]-pyridin-2-yl)methy l]-3-fluoro-4-piperidyl]benzamide (0.12 g). Int. 1R13 A, / V-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). KOtBu (74 mg), K2CO3 (0.17 g), A,A-dimethyl-2-oxo-lH-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 A0V-Dimethyl-2-oxo-1-(4-piperidyl)pyridine-4-carbox-amide and Int. 1S2’ N,N-dimethyl-2-(4-piperidyloxy)pyridine-4-carboxamide (0.15 g, TFA salt). 4-Bromo-AOV,3,5-tetramethylbenzamide (5.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-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 HC1 in dioxane (7 mL) at 0 °C to R, concentrated, and triturated in EtzO. The solid was treated with sat. aq. NaHCOj and concentrated. The residue was dissolved in DCM, dried, and concentrated to give Int. 1S3 7V,7V,3,5-tetramethyl-4-(l,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 PdDPPFCE-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 NaHCOs). The mixture was purified by FC (reverse-phase C18 column; 8% ACN in 0.001% aq. formic acid) to give Int. lS4A,A-dimethyl-r,2',3,,6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.60 g). 6-Bromo-A,A,5-trimethyl-pyridine-3-carboxamide (3.2 g), NaHCOs (3.9 g), PdDPPFCE-DCM (0.27 g), and tert-butyl 4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridinc-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 Et2O / pentane to give Int. 1S5 A,A,3-trimethyl-l',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.35 g, TFA salt). conr2 O1S7 R=Me ....       1S7'R=CD: tert-Butyl piperazine-1-carboxylate (5.0 g), 4-bromo- / V,A,3-trimethylbenzamide (7.1 g), Pd2dbas (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 HC1 in dioxane / DCM (1.8:1, 55 mL) at 0 °C to RT, concentrated, and triturated in Et2O / pentane to give Int. 1S7 A,A,3-trimethyl-4-(piperazin-l-yl)benzamide (5.0 g, HC1 salt). Int. 1S7’ 3-methyl-N,N-bis(methyl-cO)-4-(piperazin-1 -yl)benzamide was prepared similarly from 4-bromo-3-methyl-N,N-bis(methyl-<73)benzamide. 6-Bromo-A,A,5-trimethyl-pyridine-3-carboxamide (3.2 g), NaHCOi (3.9 g), and PdDPPFCL-DCM (0.27 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-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 N,N,5-Trimethyl-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-dihydropyridinc-l(2H)-carboxylatc (1.51 g), NazCOj (1.72 g), and PdDPPFCL-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-fIuoro-phenyl]-3,6-dihydro-2H-pyridine-l-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-7V,A-dimethyl-4-(piperidin-4-yl)benzamide (63 mg). CO2H             CON(CD3)2 / \           / \ 1S20r=boc n—'           N—' 1S19r=h Boc' 1S21        f( 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. NaHCOs / 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-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (14.8 g), NhvCOi (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-1-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-<73)-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-methy l-A,A-bis-( methy 1-^ / ()-4-( pi peridi n-4-yl)benzamide (0.45 g) was prepared similarly to Int. 1S7 from Int. 1S23 (0.90 g). Int. 1A6 (0.30 g), A,A-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-[[l-(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]-A,A-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 A,A-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-[(4-bromo-3-lIuoro-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-4-piperidyl]-A,A-dimethyl-benzamide (0.38 g). Int. 1Y2 (0.25 g), B2Pin2 (0.17 g), KO Ac (0.16 g), and PdDPPFCh-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-(l-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-4-yl)-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-yl)methyl]-4-hydroxy-4-piperidyl]-AOV-dimethyl-benzamide (0.15 g). Int. 1J1 (0.97 g), KI (12 mg), Int. 1AE7 (1 g), and K2CO3 (1.6 g) were stirred llh 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)-l,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethylbenzamide (0.67 g). Int. 1Z9 (0.67 g), KOAc (0.44 g), PdDPPFCh-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 PdDPPFCh-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 (CHCh / 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,l,l,3,3,3-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 / EtsN (48:1, 20.4 mL). The mixture was concentrated and HPLC-purified to give Int. 1Z14 6-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,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(methyl-t / 3)amine hydrochloride (0.61 g) in DCM (20 mL) and Et3N (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-<73)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 PdDPPFCh-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 (CHCI3 / MTBE 1:0 to 0:1) to give Int. 1Z19 tert-butyl 4-(6-(bis-(methyl-t73)carbamoyl)-pyridazin-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.55 g). Int. 1Z19 (0.55 g) was stirred Ih in l,l,l,3,3,3-hexafluoro-2-propanol / 10M HC1 (26:1, 5.2 mL). The mixture was diluted with MTBE to precipitate Int. 1Z20 N,N-bis(methyl-J3)-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 / EtsN (48:1, 20.4 mL). The mixture was concentrated and HPLC-purified to give Int. 1Z17 6-( 1 -((4-bromo-1 -methyl-lH-pyrrolo[2,3-b]-pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-bis(methyl-t / 3)pyridazine-3-carboxamide (50 mg). CONMe2 CONMe2 Int. 1Z27 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), tert-butyl 4-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridinc-l(2H)-carboxylatc (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 (CHCI3 / ACN 1:0 to 4:1) to give Int. 1Z25 / ert-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). CONMe2 Int. 1Z29 R=Br Int. 1Z30 R=BPin Ints. 1J1 / RR44 (0.3 g / 0.3 g) were stirred 12h in ACN / Et3N (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), PdDPPFCh-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), PdDPPFCh-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 PdDPPFCh-DCM (0.22 g) were stirred ON in dioxane / FhO (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-(dimcthylcarbamoyl)pyrimidin-5-yl)-3,6-dihydropyridinc-l(2H)-carboxylatc (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), PdDPPFCh-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), PdDPPFCL-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-J3)-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), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-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 / H2O (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 tertbutyl 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-dimethyl-r,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (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 T-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-N,N-dimethyl-r,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.4 g). 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(methyl-Jj)-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 (0.40 g). PdDPPFCh-DCM (0.25 g), 4-bromo-2-fluoro-N,N-dimethylbenzamide (1.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-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 tertbutyl 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-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,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 Et iN (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-trimethylpyridazine-3-carboxamide (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). PdDPPFCL-DCM (0.3 g), Int. 1Z59 (0.9 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,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 HO 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, HO salt). STAB (0.30 g) and Ints. 1AB8 / 1Z61 (0.1 g / 0.1 g) were stirred ON in DCE / EtsN (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). PdDPPFCk-DCM (1.1 g), 4-bromo-N,N,2-trimcthylbcnzamidc (3.3 g), K2CO3 (5.7 g), and tert-butyl 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 / HiO (15:4, 190 mL) under an inert atmosphere. The OL (aq. NaHCO3 / 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 / Et3N (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-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,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-(l-(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)-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluoro-N,N-dimethylbenzamide (0.35 g). COR LiOHH2O (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-methylbenzoic acid (68 g). Int. 1Z70 (70 g), dimethylamine hydrochloride (36 g), and HATU (84 g) were stirred 12h in DMF (300 mL) and DIPEA (180 mL) at 0 °C to RT. The mixture was diluted with water to precipitate a solid that was dried to give Int. 1Z69 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-N,N,5-trimethylbenzamide (63 g). Ints. 1AF88 / 1S4 (1.5 g / 1.5 g), KI (91 mg), and Cs2CO3 (8.9 g) were stirred 16h in ACN (15 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (DCM / MeOH 19:1) to give Int. 1Z71 r-(l-(4-bromo-l-mcthyl-lH-pyrrolo[2,3-b]pyridin-2-yl)cthyl)-N,N-dimcthyl-r,2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (0.50 g). 3Tluoro-5-methyl-N,N-bis(methyl-c?3)-4-(l-((l-methyl-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)benzamide Int. 1AE9 (0.45 g), bis(pinacolato)diboron (0.35 g), PdDPPFCl2-DCM (75 mg), and KOAc (0.27 g) were stirred Ih in dioxane (5 mL) at 110 °C under MW conditions. The mixture was filtered through celite and concentrated to give Int. 1Z73 3-fluoro-5-methyl-N,N-bis(methyl-J3)-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-tctrahydropyridin-4-yl)bcnzamidc (0.40 g). Int. 1AE38 (3.2 g) and Cs2CO3 (18 g) were stirred 0.3h in ACN (20 mL). Int. 1AF88 (3 g) and KI (0.91 g) were added and stirring continued 12h at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 1:9) to give Int. 1Z75 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide (0.90 g). Int. 1Z75 (0.90 g) was resolved by SFC on a SFC-150-022 instrument fitted with a Chiral ART Amylose-C NEO 250x30 mm 5pm column operated at 30 °C and an eluent of 80% CO2 and 20% MeOH at a (100 g / min) and a back pressure of 100 bar to give Int. 1Z76 (0.15 g, first peak) and Int. 1Z77 (0.15 g, second peak) (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide and (R)-4-(l-(1-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-N,N,3-trimethylbenzamide. The absolute configurations of these compounds were not determined. Br bo2Ph 3M CH.MgCI in THF (32 mL) was added slowly to a solution of Int. 1A6 (11.5 g) in THF (310 mL) at -78 °C. The mixture was stirred 0.5h at -78 °C to RT. The OL (aq. NH4Cl / EtOAc) was dried, and concentrated to give Int. 1Z79 l-(4-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethan-l-ol (12 g). SOCI2 (0.18 mL) was added to a solution of Int. 1Z79 (0.1 g) in toluene (3 mL). The mixture was stirred 0.5h and concentrated. Int. 1AE12' (90 mg), KI (20 mg), and CS2CO3 (0.40 g) were stirred ON in a solution of the residue in ACN (5 mL). The mixture was HPLC-purified to give Int. 1Z80 4-(l-(l-(4-bromo-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (13 mg). LiOHH2O (9.8 g) and Int. 3C17 (16.5 g) were stirred 16h in THF / MeOH / H2O (2:1:1, 600 mL) at 0 °C to RT. The residue after concentration was stirred in aq. citric acid, filtered, and dried to give Int. 1Z87 4-(l-(tert-butoxycarbonyl)piperidin-4-yl)-3,5-difluorobenzoic acid (11.5 g). HATU (8.3 g), Int. 1Z87 (5 g), and dimcthylaminc hydrochloride (1.8 g) were stirred 16h in DMF (30 mL) and DIPEA (13 mL) 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to give Int. 1Z86 tert-butyl 4-(4-(dimethylcarbamoyl)-2,6-difluorophenyl)piperidine-1-carboxylate (3.2 g). Int. 1Z86 (3.2 g) was stirred 16h in 2M HC1 in dioxane (60 mL) at 0 °C to RT. The mixture was concentrated to give Int. 1Z85 3,5-difluoro-N,N-dimethyl-4-(piperidin-4-yl)benzamide (2.3 g, HC1 salt). Ints. 1J1 / 1Z85 (0.35 g / 0.36 g) and K2CO3 (0.93 g) were stirred 16h in ACN (10 mL) at 0 °C to RT. The mixture was filtered, concentrated, and purified by FC (PE / EtOAc 1:4) to give Int. 1Z84 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3,5-difluoro-N,N-dimethyl-benzamide (0.40 g). Int. 1Z66 (5 g), hisimcthyl-JOamirie hydrochloride (1.5 g), and HATU (8.4 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. 1Z94 tert-butyl 4-(4-(bis(methyl-r / 3)carbamoyl)-2,6-difluoro-phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (3.5 g). Int. 1Z94 (3.6 g) was stirred 16h in 2M HC1 in dioxane (60 mL) at 0 °C to RT. The mixture was concentrated to give Int. 1Z93 3,5-difluoro-N,N-bis-(methyl-<i3)-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (2.7 g, HC1 salt). Ints. 1J1 / 1Z93 (0.40 g / 0.57 g), KI (77 mg), and K2CO3 (0.64 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. 1Z92 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluoro-N,N-bis(methyl-J3)benzamide (0.41 g). PdDPPFCh-DCM (0.2 g), methyl 5-bromo-4,6-dimethylpicolinate (1.1 g), K2CO3 (2 g), and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1.5 g) were stirred 12h in dioxane (8:1, 45 mL) at 80 °C under an inert atmosphere. The mixture was filtered and concentrated to give Int. 1Z99 r-(tert-butoxycarbonyl)-2,4-dimethyl-l',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid (1.4 g). LiOHH2O (0.3 g) and Int. 1Z99 (1.4 g) were stirred 12h in MeOH / H2O (1:1, 60 mL). The mixture was concentrated to give Int. 1Z98 l'-(tert-butoxycarbonyl)-2,4-dimethyl-T,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxylic acid (1.3 g, Li salt). Int. 1Z98 (1.4 g), dimethylamine hydrochloride (0.4 g) and HATU (1.7 g) were stirred 12h in DMF (50 mL) and EhN (2.8 mL). The mixture was concentrated. The OL (water / EtOAc) was concentrated to give Int. 1Z97 tert-butyl 6-(dimethylcarbamoyl)-2,4-dimethyl-3',6'-dihydro-[3,4'-bipyridine]-l'(2'H)-carboxylate (0.95 g). Int. 1Z97 (0.95 g) was stirred ON in MeOH / 2.8M HC1 in dioxane (1:1, 40 mL). The mixture was concentrated to give Int. 1Z96 N,N,2,4-tetramethyl-r,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.7 g, HO salt). Int. 1AF89 (0.3 g) was stirred 0.5h in toluene (20 mL) and SOCI2 (0.61 mL) at 80 °C. The mixture was concentrated. The residue, Int. 1Z96 (0.5 g), and CS2CO3 (0.3 g) were stirred 12h in DMF (10 mL). The OL (water / EtOAc) was concentrated and HPLC-purified to give Int. 1Z95 r-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-N,N,2,4-tetramethyl-r,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (0.5 g). Int. 1Z87 (2 g), bis(methyl-d3)amine hydrochloride (0.62 g), and HATU (3.3 g) were stirred 16h in DMF (30 mL) and DIPEA (5.1 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 2:1) to give Int. 1Z103 tert-butyl 4-(4-(bis(methyl-< / 3)carbamoyl)-2,6-difluorophenyl)-piperidine-l-carboxylate (1.4 g). Int. 1Z103 (1.4 g) was stirred 16h in 2.2M HO in dioxane (18 mL) at 0 °C to RT. The mixture was concentrated to give Int. 1Z102 3,5-difluoro-N,N-bis(methyl-<i)-4-(piperidin-4-yl)benzamide (1.1 g, HO salt). Ints. 1J1 / 1Z102 (0.50 g / 0.60 g), KI (0.16 g), and K2CO3 (1.3 g) were stirred 16h in ACN (20 mL) at 0 °C to RT. The OL (water / EtOAc) was concentrated and purified by FC (hexane / EtOAc 1:4) to give Int. 1Z101 4-(1-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3,5-difluoro-N,N-bis(methyl-c / jhenzamide (0.45 g). NaIO4 (2.6 g) was added portion-wise to a mixture of Iz (8.9 g) in sulfuric acid (100 mL). The mixture was stirred 0.5h before 4-bromo-N,N-dimethylbenzamide (17 g) was added and stirring continued for 18h. The mixture was diluted with water to precipitate a solid that was dried and crystallized from CCI4 to give Int. 1Z105 4-bromo-3-iodo-N,N-dimethylbenzamide (17 g). PdDPPFCh-DCM (2.0 g), Int. 1Z105 (17 g), cyclopropylboronic acid (5.0 g), and K2CO3 (20 g) were refluxed ON in dioxane / H2O (3:1, 200 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCh to CHCh / ACN 1:1) to give Int. 1Z106 4-bromo-3-cyclopropyl-N,N-dimethylbenzamide (12 g). PdDPPFCh-DCM (1.9 g), Int. 1Z106 (12 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (21 g), and K2CO3 (19 g) were refluxed ON in dioxane / FhO (6:1, 140 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCh to CHCI3 / ACN 1:1) to give Int. 1Z107 tert-butyl 4-(2-cyclopropyl-4-(dimethylcarbamoyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (4.1 g). Int. 1Z107 (4.1 g) was stirred in ON 4M HC1 in dioxane (50 mL). The mixture was concentrated and triturated in EtOAc to give Int. 1Z108 3-cyclopropyl-N,N-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.10 g, HO salt). STAB (0.30 g) and Ints. 1AB8 / 1Z108 (0.1 g / 0.1 g) were stirred ON in DCE / EtsN (73:1, 10.1 mL) at 0 °C to RT. The mixture was concentrated, dissolved in THF, filtered through silica, and concentrated to give Int. 1Z109 4-( l-((4-bromo-1-methyl-1H-pyrrolo [2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-cyclopropyl-N,N-dimethylbenzamide (0.19 g)- NaIO4 (2.3 g) was added to a mixture of h (8.0 g) in sulfuric acid (100 mL) portion-wise and stirred 0.5h. 4-Bromo-3-fluoro-N,N-dimethylbenzamide (17 g) was added and stirring continued 18h. The reaction mixture was diluted with water to precipitate a solid that was dried and precipitated from CCh to give Int. 1Z122, a mixture of 4-bromo-5-fluoro-2-iodo-N,N-dimethylbenzamide and 4-bromo-3-fluoro-5-iodo-N,N-dimethylbenzamide mixture (13 g). PdDPPFCh-DCM (1.4 g), Int. 1Z122 (13 g), cyclopropylboronic acid (3.6 g), and K2CO3 (14 g) were refluxed ON in dioxane / FhO (3:1, 200 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCh to CHCh / ACN 1:1) to give Int. 1Z121, a mixture of 4-bromo-2-cyclopropyl-5-fluoro-N,N-dimethyIbenzamide and 4-bromo-3-cyclopropyl-5-fluoro-N,N-dimethylbenzamide mixture (7 g). PdDPPFCh-DCM (1.0 g), Int. 1Z121 (7 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (11 g), and K2CO3 (10 g) were refluxed ON in dioxane / H2O (6:1, 140 mL) under an inert atmosphere. The mixture was concentrated and purified by FC (CHCh to CHCh / ACN 1:1) to give Int. 1Z120, a mixture of tert-butyl 4-(5-cyclopropyl-4- (dimethylcarbamoyl)-2-fluorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate and tert-butyl 4-(2-cyclopropyl-4-(dimethylcarbamoyl)-6-fluoro-pheny 1)-3,6-dihydropyridine-l(2H)-carboxylate mixture (2.6 g). Int. 1Z120 (2.6 g) was stirred in ON 4M HC1 in dioxane (50 mL). The mixture was concentrated and triturated in EtOAc to give Int. 1Z119 2-cyclopropyl-5-fluoro-N,N-dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)benzamide and 3-cyclopropyl-5-fluoro-N,N-dimethyl-4-( 1,2,3,6-tetrahydropyridin-4-yl)benzamide mixture (2.0 g, HC1 salt). STAB (0.30 g) and Ints. 1AB8 / 1Z119 (0.1 g / 0.1 g) were stirred ON in DCE / Et3N (73:1, 10.1 mL) at 0 °C to RT. The residue after concentration dissolved in THF, filtered through silica, and concentrated to give a mixture of Ints. 1Z123 / 1Z124 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-cyclopropyl-5-fluoro-N, N-dimethyIbenzamide and 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-cyclopropyl-5-fluoro-N,N-dimethylbenzamide (0.17 g). N-Iodosuccinimidc (196 g) and 2-fluoro-6-mcthylanilinc (100 g) were stirred 2h in ACN (2.0 L) at 0 °C to RT. The OL (aq. Na2S2O3 / EtOAc) was dried, and concentrated to give Int. 1Z131 2-fluoro-4-iodo-6-methylaniline (180 g). Int. 1Z131 (30 g), dimethylamine hydrochloride (24 g), and PdDPPFCl2-DCM (4.9 g) were stirred 16h in dioxane / Et3N (14:3, 364 mL) at 85 °C under 200 psi of CO. The mixture was filtered and concentrated. The OL (IM HCl / EtOAc) was neutralized to pH ~8 with Na2CO3. The OL (water / EtOAc) was dried, and concentrated to give Int. 1Z130 4-amino-3-fluoro-N,N,5-trimethylbenzamide (17 g). CuBr2 (85 g) and 1Z130 (15 g) were stirred 16h in ACN (300 mL) and 'BuONO (14 mL) at 0-85 °C. The OL (aq. NH3 / PE) was dried, filtered and concentrated to give Int. 1Z129 4-bromo-3-fluoro-N,N,5-trimethylbenzamide (14 g). Int. 1Z129 (1 g), PdDPPFCl2-DCM (0.31 g), bis(pinacolato)diboron (2.0 g), and KOAc (1.1 g) were stirred Ih in dioxane (10 mL) at 110 °C under MW conditions. The mixture was filtered through celite, concentrated, and washed with pentane to give Int. 1Z128 3-fluoro-N,N,5-trimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.80 g). PdDPPFCl2-DCM (0.11 g), Ints. 3E284 / 1Z128 (0.50 g / 0.77 g), and Na2CO3 (0.43 g) were stirred 1.5h in dioxane / H2O (4:1, 10 mL) at 110 ° C under MW conditions. The mixture was filtered. The OL (water / EtOAc) was concentrated and purified by FC (hexane / EtOAc 3:7) to give Int. 1Z127 tert-butyl 4-(4-(dimethylcarbamoyl)-2-fluoro-6-methylphenyl)-3,3-difluoro-3,6-dihydro-pyridine-l(2H)-carboxylate (65 mg). Int. 1Z127 (0.50 g) was stirred 16h in DCM / 4M HC1 in dioxane (2:1, 6 mL) at 0 °C to RT. The mixture was concentrated to give Int. 1Z126 4-(3,3-difluoro-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.40 g, HC1 salt). Ints. 1AF88 / 1Z126 (0.40 g / 0.59 g), KI (0.17 g), and Cs2CO3 (3.3 g) were stirred 12h in ACN (10 mL) at 0 °C to RT. The mixture was filtered, concentrated, and purified by FC (hexane / EtOAc 4:1) to give Int. 1Z125 4-(1-(1-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]-pyridin-2-yl)ethyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.13 g). \ Int. 1Z127 (0.40 g) and PtO2 (0.80 g) were hydrogenated 75h at 70 psi in THF / EtOH / AcOH (8:8:1, 17 mL). The mixture was filtered and concentrated to give Int. 1Z132 tert-butyl 4-(4-(dimethyl-carbamoyl)-2-fluoro-6-methylphenyl)-3,3-difluoropiperidine-l-carboxylate (0.40 g). Int. 1Z133 4-(3,3-difluoropiperidin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (0.20 g, HC1 salt) was prepared similarly to Int. 1Z126 from Int. 1Z132 (0.25 g). Ints. 1AF88 / 1Z133 (0.15 g / 0.18 g), KI (64 mg), and Cs2CO3 (0.12 g) were stirred 16h in ACN (10 mL) at 0 °C to RT. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 1:1 to 1:2) to give Int. 1Z134 4-(1-(1-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-3,3-difIuoropiperidin-4-yl)-3-fIuoro-N,N,5-trimethyl-benzamide (0.13 g). Di(lH-imidazol-l-yl)methanone (1.0 g) and 4-bromo-3-(trifluoromethoxy)benzoic acid (1.8 g) were refluxed 0.3h in dioxane (50 mL). Dimethylamine hydrochloride (0.51 g) and Et3N (5.2 mL) was added and stirring continued lOh. The mixture was concentrated. The OL (aq. NaHSOVCHCh) was concentrated to give Int. 1Z139 4-bromo-N,N-dimethyl-3-(trifluoro(oxo)-X6-methyl)benzamide (1.5 g). Int. 1Z139 (1.5 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 (2.0 g), and PdDPPFCl2-DCM (0.20 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 to give Int. 1Z138 tert-butyl 4-(4-(dimethylcarbamoyl)-2-(trifluoromethoxy)phenyl)-3,6-dihydro-pyridine-l(2H)-carboxylate (0.78 g). Int. 1Z138 (0.78 g) was stirred ON in 2.8M HC1 in dioxane (10 mL). The mixture was concentrated to give Int. 1Z137 N,N- dimethyl-4-(l,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethoxy)benzamide (0.43 g, HC1 salt). Ints. 1J1 / 1Z137 (0.36 g / 0.43 g) and K2CO3 (0.57 g) were stirred 1 Ih in DMF (10 mL). The mixture was diluted with water to precipitate Int. 1Z136 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N,N-dimethyl-3-(trifluoromethoxy(benzamide (0.14 g). Int. C3. 4-( 1-(1 -(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (0.11 g) was prepared similarly to Int. 2C9 from Int. 3E37 (0.12 g). Methyl 4-bromo-3-methylbenzoate (2.5 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (4.0 g), NaHCO? (2.8 g), and PdDPPFCL-DCM (0.45 g) were degassed in dioxane / water (10:1, 30 mL) and stirred ON at 100 °C. The mixture was diluted with EtOAc (100 mL), filtered, concentrated, and purified by FC (hexane / EtOAc 9:1 to 85:15) to give Int. 2C41 tert-butyl 4-(4-methoxy-carbonyl-2-methyl-pheny 1)-3,6-dihydro-2H-pyridine-1-carboxylate (3.2 g). Int. 2C41 (0.25 g) was stirred ON in DCM / 4M HC1 in dioxane (4:1, 10 mL) and concentrated. The residue was triturated in pentane to give Int. 2C42 methyl 3-methyl-4-(l,2,3,6-tetra-hydropyridin-4-yl)benzoate (0.19 g, HC1 salt). Ints. 1AB8 / 2C42 (1.2 g / 1.2 g, HC1 salt) were stirred 4h in DCE / DIPEA (2:2:1, 7.3 mL) at 0 °C to RT. STAB (1.9 g) was added and stirring continued ON. The OL (EtOAc / water) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 2C43 methyl 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-methyl-benzoate (1.0 g). Methyl 6-bromonicotinate (5.0 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (7.8 g), K2CO3 (3.0 g) and PdDPPFCL-DCM (1.9 g) were stirred in dioxane / H2O (4:1, 100 mL) ON at 100 °C under an inert atmosphere. The OL (water / EtOAc) was dried, concentrated and purified by FC (hexane / MTBE 1:0 to 0:1) to give Int. 2C65 1'-(tert-butyl) 5-methyl 3',6'-dihydro-[2,4'-bipyridine]-l',5(2'H)-dicarboxylate (5.9 g). Int. 2C65 (2.0 g) was stirred 16h in 2M HC1 in dioxane (40 mL), concentrated, and washed with Et3O to give Int. 2C64 methyl r,2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (1.8 g, HC1 salt). Ints. 1AB8 / 2C64 (616 mg / 750 mg) and 4A MS were stirred ON in DCE / Et3N (9:1, 11.1 mL). (AcO)3BHNa (1.6 g) was added and stirring continued for 3h before it was concentrated and HPLC-purified to give Int. 2C63 methyl l'-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-r,2',3',6,-tetrahydro-[2,4,-bipyridine]-5-carboxylate (0.57 g). Int. 2C63 (0.29 g), bis(pinacolato)diboron (0.18 g), KO Ac (0.19 g), and PdDPPFCL-DCM (53 mg) were stirred ON in dioxane (10 mL) at 80 °C under an inert atmosphere. The residue after concentration was dissolved in THF, filtered through silica, and concentrated to give Int. 2C62 methyl l'-((l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)-methyl)-r,2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (0.30 g). CO2Me Int. 2C77 R=Br Int. 2C76 R=BPin Ints. 1AB8 / 2C78 (0.50 g / 1.0 g) and 4A MS were stirred ON in DCE / Et3N (15:1, 15.9 mL). (AcO)3BHNa (1.0 g) was added and stirring continued 3h. The mixture was concentrated and HPLC-purified to give Int. 2C77 methyl r-((4-bromo-l-methyl-lH-pyrrolof2,3-b]pyridin-2-yl)methyl)-3-methyl-l',2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (0.61 g). Int. 2C77 (0.30 g), bis(pinacolato)diboron (0.30 mg), KOAc (0.30 mg) and PdDPPFCL-DCM (30 mg) were stirred ON in dioxane (3 mL) at 80 °C under an inert atmosphere. The residue after concentration was dissolved in THF, filtered through silica and concentrated to give Int. 2C76 methyl 3-methyl-l'-((l-methyl-4-(4,4,5,5-tetramethyLl ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridin-2-yl)methyl)-1', 2',3 ',6'-tetrahydro-[2,4'-bipyridine]-5-carboxylate (0.30 g). CO2Me Int. 3C31 Ints. 1AB8 / 3C25 (8.0 g / 12.6 g) were stirred 16h in DCE (80 mL) and DIPEA (35 mL) at 0 °C to RT under an inert atmosphere. STAB (28 g) was added in portions at 0 °C and stirring was continued for 12h. The OL (water / DCM) was dried, filtered, concentrated, and purified by FC (PE / EtOAc 3:2) to give Int. 3C31 methyl 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.3 g). Ints. 1AF88 / 2G97 (2.0 g / 2.3 g), KI (0.85 g) and Cs2CO3 (9.5 g) were mixed in ACN (20 mL) at 0 °C and stirred for 16h at RT filtered and concentrated. The residue was purified by FC (hexane / EtOAc 4:1) to give Int. 2G85 methyl 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2 yl)ethyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (2.0 g). Int. 1AF89 (1.5 g) was stirred 0.3h in tolucnc / SOCl2 (7:3, 14.3 mL) at 90 °C. The residue after concentration, Cs2CO3 (7.7 g), KI (0.49 g), and Int. 3C16 (2.1 g) were stirred 16h in ACN (10 mL) at 0 °C to RT under an inert atmosphere. The reaction mixture was concentrated and triturated in water to precipitate a solid that was washed with water, dried, and purified by FC (PE / EtOAc 9:1 to 17:3) to give Int. 2G96 methyl 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3,5-difluorobenzoate (1.5 g). Int. 1AF90 (15 g), Boc2O (17 g) and DMAP (0.64 g) were mixed in DCM / Et3N (4:1, 187 mL) at 0 °C and stirred 16h and filtered. The OL (water / DCM) was dried, concentrated, and purified by FC (hexane / EtOAc 2:1) to give Int. 2G105 tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)-6-methylphenyl)-3,6-dihydropyridine-l(2H)-carboxylate (14 g). Int. 2G105 (14 g) and Pd / C (7 g) was hydrogenated 16h in MeOH (140 mL), filtered, concentrated to give Int. 2G104 tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)-6-methylphenyl)piperidine-l-carboxylate (13.2 g). Int. 2G104 (13.2 g) was stirred 16h in DCM / 4M HC1 in dioxane (2:5, 105 mL) at 0 °C to RT. The mixture was concentrated and washed with pentane to give Int. 2G97 methyl 3-fluoro-5-methyl-4-(piperidin-4-yl)benzoate (9.0 g, HC1 salt). Ints. 1AF88 / 2G97 (2.0 g / 2.3 g), KI (0.85 g), and Cs2CO3 (9.5 g) were stirred 16h in ACN (20 mL) at 0 °C to RT. The mixture was filtered and concentrated. The residue was purified by FC (hexane / EtOAc 4:1) to give Int. 2G85 methyl 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (2.0 g). DIPEA (15 mL) was added to a solution of Ints. 1AB8 / 2G97 (8.0 g / 12.5 g) in DCE / DMSO (5:1, 600 mL) at 0 °C and stirred for 16h at RT. STAB (28 g) was added and stirring continued for 16h. The OL (water / DCM / MeOH) was dried, filtered, concentrated and purified by FC (hexane / MeOH 4:1 to 2:1) to give Int. 2G115 methyl 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3-fluoro-5-methylbenzoate (8.0 g). Methyl 4-bromo-3,5-difluorobenzoate (100 g), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (160 g), PdDPPFCb-DCM (16 g), and NaHCOs (100 g) were stirred 16h in dioxane / HiO (10:3, 1.3 L) at 100 °C under an inert atmosphere. The mixture was filtered. The OL (brine / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 1:0 to 9:1) to give Int. 3C18 tert-butyl 4-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (45 g). Int. 3C18 (100 g) and 5% wet Pd / C(20 g) were stirred 16h in MeOH (0.7 L) under an atmosphere of hydrogen. The mixture was filtered and concentrated to give Int. 3C17 tert-butyl 4-(2,6-difluoro-4-(methoxycarbonyl)phenyl)piperidine-l-carboxylate (90 g). Int. 3C17 (20 g) was stirred 16H in DCM / 4M HC1 in dioxane (2:1, 600 mL) at 0 °C to RT. The mixture was concentrated and washed with EtiO to give Int. 3C16 methyl 3,5-difluoro-4-(piperidin-4-yl)benzoate (12 g, HC1 salt). Ints. 1AB8 / 3C16 (3.5 g / 3.6 g) were stirred 16h in DCE / DMSO / DIPEA (7:3:1, 112 mL). STAB (12 g) was added atO °C and the mixture was stirred 16h atO °C to RT. The OL (water / DCM) was dried, concentrated, and purified by FC (hexane / EtOAc 9:1) to give Int. 3C15 methyl 4-( l-((4-bromo-l -methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)-3,5-difluorobenzoate (4.0 g). F Int. 3C25. methyl 3,5-difluoro-4-(l,2,3,6-tetrahydropyridin-4-yl)benzoate (16 g, HC1 salt) was prepared similarly to Int. 3C16 from Int. 3C18 (20 g). CO2Me F-O / = / ^F Br       /  \ I          \   /  Int. 3C26 (racemate) / Int. 3C27 (S-enantiomer) |l      z\     Int. 3C28 (R-enantiomer) ^N'  N   ' Int. 1AF89 (9.0 g) was stirred 0.5h in toluene / SOCL (6:1, 174 mL) at 90 °C. The residue after concentration, CS2CO3 (43 g), KI (2.7 g), and Int. 3C25 (10 g) were stirred 16h in ACN (250 mL) at 0 °C to RT under an inert atmosphere. The mixture was concentrated. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 4:1) to give Int. 3C26 methyl 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.1 g). Int. 3C26 (0.85 g) was resolved by SFC on a SFC-150-008 instrument fitted with a Chiralpak-AD-H 150x25 mm 5pm column operated at 30 °C and an eluent of 65% CO2 and 35% MeOH (80 g / min) and a back pressure of 100 bar to give Int. 3C27 (0.30 g, first peak) and Int. 3C28 (0.30 g, second peak) methyl (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate and methyl (R)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate. The absolute configurations of these compounds were not determined. CO2Me f-Q Br / =) N— / N * Ints. 1AB8 / 3C25 (8.0 g / 12.6 g) were stirred 16h in DCE (80 mL) and DIPEA (35 mL) at 0 °C to RT under an inert atmosphere. STAB (28 g) was added in portions at 0 °C and stirring was continued for 12h. The OL (water / DCM) was dried, concentrated, and purified by FC (PE / EtOAc 3:2) to give Int. 3C31 methyl 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorobenzoate (7.3 g). ZnCL (IM in Et2O, 31 mL) was added to a solution of Int. 1AB8 (2.7 g) and ethyl 4-(piperazin-l-yl)-benzoate (2.4 g) in THF (30 mL) at 0 °C and stirred 16h at RT. NaCNBFR (3.4 g) was added and stirring continued for 16h. The OL (water / EtOAc) was dried, concentrated, and purified by FC (PE / EtOAc 1:1) to give Int. 3C59 ethyl 4-(4-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-piperazin-l-yl)benzoate (2.2 g). DIPEA (7.3 mL) was added to a solution of Ints. 1AB8 / 1AF90 (2.0 g / 2.9 g) at 0 °C and 5 stirred in DCE (10 mL) for 16h at RT under an inert atmosphere. STAB (5.2 g) was added at 0 °C and stirring continued for 2h. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 3:2) to give Int. 3C73 methyl 4-(l-((4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-fluoro-5-methylbenzoate (1.3 g). 10          Int. 3E35 (1.7 g) and LiOH-H2O (1.1 g) were stirred 3h in THF / MeOH / H2O (4:2:1, 25 mL) at 0 °C to RT and concentrated. The AL (water / Et2O) was acidified with KHSO i to precipitate Int. 2C36 (S)-4-( 1 -(1 -(4-bromo-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (1.5 g). The absolute configuration was determined for derivatives 1AF76 and 1AF76’. 15          Int. 1AC5 (3.0 g), B2Pin2 (1.1 g), KO Ac (2.0 g), and PdDPPFCl2-DCM (50 mg) were degassed in dioxane (30 mL) and stirred ON at 90 °C. The filtrate after filtration was concentrated and purified by FC (pentane / EtOAc 1:4) to give Int. 2H14 methyl 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]benzoate (1.7 g). 3E37                    3E35and3E36 Int. 1AF21 (1.0 g) was stirred 0.3h in toluene / SOCh (7.1:1, 22.8 mL) at 85-90 °C. The residue after concentration, CS2CO3 (3.8 g), KI (0.33 g), and methyl 4-(piperidin-4-yl)-benzoate (1.3 g, HC1 salt) were stirred ON in ACN (25 mL) at 0 °C to RT. The mixture was concentrated to half volume and diluted with water to precipitate Int. 3E37 methyl 4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-piperidin-4-yl)benzoate (1.4 g). Int. 3E37 (7.4 g) was resolved by SFC using a Chiralpak IA 250X25 5pm column operated at 30 °C using an eluent of 60% CO2 and 40% MeOH at a flow rate of 90 g / min and a back pressure of 100 bar to give Int. 3E35 methyl (S)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoate (3.0 g, first eluting isomer) and Int. 3E36 methyl (R)-4-(l-(l-(4-bromo-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoate (3.0 g, second eluting isomer). The absolute configuration was determined for derivatives 1AF76 and 1AF76’. Methyl 4-bromo-3,5-dimethyl-benzoate (0.50 g), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (0.70 g), Na2CO3 (0.26 g), and PdDPPFCL-DCM (84 mg) were degassed in dioxane / water (9:1; 8 mL) and stirred ON at 90 °C. The OL (water / EtOAc) was concentrated and purified by FC (hexane / EtOAc 7:3) to give Int. 3E45 tertbutyl 4-(4-methoxycarbonyl-2,6-dimethyl-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (0.55 g). This material was stirred 3h in DCM / 4M HO in dioxane (5:4; 9 mL) at 0 °C to RT and concentrated to give Int. 3E44 methyl 3,5-dimethyl-4-(l ,2,3,6-tetrahydro-pyridin-4-yl)benzoate (0.44 g, HO salt). Ints. 1AB8 / 3E44 (0.23 g / 0.30 g) were stirred 4h in DCE / DIPEA (12.5:1, 5.4 mL). STAB (0.41 g) was added and stirring continued ON. The OL (water / EtOAc) was dried, concentrated, and purified by FC (hexane / EtOAc 7:3) to give Int. 3E43 methyl 4-[l-[(4-bromo-l-methyl-pyrrolo[2,3-b]pyridin-2-yl)methyl]-3,6-dihydro-2H-pyridin-4-yl]-3,5-dimethyl-benzoate (0.33 g). Int. 3E35 (2.0 g), B2Pin2 (1.7 g), PdDPPFCL-DCM (0.18 g), KOAc (0.9 g) were degassed in dioxane (15 mL) and stirred 5h at 95-100 °C, filtered, concentrated, and triturated in Et2O to give Int. 3E170 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]-4-piperidyl]benzoate (2.3 g). Int. 3E35 (0.50 g), B2Pin2 (0.41 g), PdDPPFCl2-DCM (44 mg), KOAc (0.21 g) were degassed in dioxane (10 mL) and stirred 5h at 95-100 °C, filtered, concentrated, and triturated in Et2O to give a mixture of Int. 3E170 and 3E177 (S)-(2-(l-(4-(4-(methoxycarbonyl)phenyl)piperidin-l-yl)-ethyl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)boronic acid and methyl (S)-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)benzoate (0.50 g). PdDPPFCl2-DCM (40 mg), Int. 1Z69 (0.24 g), bis(pinacolato)diboron (0.15 g), and KOAc (0.14 g) were stirred ON in dioxane (5 mL) at 100 °C under an inert atmosphere. The mixture was concentrated and purified by FC (THF) to give Int. 1Z47 3-fluoro-N,N,5-trimethyl-4-(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)-l,2,3,6-tctrahydropyridin-4-yl)bcnzamidc (0.27 g). Int. 1AF84’ (0.20 g), bis(pinacolato)diboron (0.20 g), PdDPPFCl2-DCM (32 mg), and KOAc (0.12 g) were stirred 6h in dioxane (10 mL) at 90 °C under an inert atmosphere. The mixture was filtered through celite, concentrated, dissolved in Et2O, filtered, concentrated, washed with pentane, and dried to give Int. 1Z48 (S)-3-fluoro-5-methyl-N,N-bis(methyl-<73)-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)-l,2,3,6-tetrahydropyridin-4-yl)benzamide (0.14 g). CHO Int. 1AB8 (1.0 g), 4-(methylamino)pyridin-2(lH)-one (0.57 g), K3PO4 (1.33 g), Cui (0.40 g), DMDCH (0.60 g) were degassed in dioxane (30 mL) and stirred at 110 °C ON and filtered. The OL (dioxane / water) was washed brine, dried, concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1M1 l-Methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridine-2-carbaldehyde (0.34 g). Int. 1AB9. tert-Butyl (tert-butoxycarbonyl)(6-oxo-l,6-dihydropyridazin-4-yl)carbamate 5-Aminopyridazin-3(2H)-one (0.3 g), DMAP (0.17 g), and BOC2O (2.36 g) were stirred ON in ACN / EhN (6:1, 11.7 mL) at 0 °C to RT ON and purified by FC (EtOAc / pentane 4:1) to give Int. 1AB9 (80 mg). ^n-Boc o^hr 1AD1 0 H 1AD2 (fjT^-CHO N 4-(Methylamino)pyridin-2(lH)-one (0.9 g) was dissolved in 0.3M LiHMDS in THF (28 mL) at 0 °C. BoczO (2.0 g) was added and stirring continued 2h at 0 °C to 45-50 °C and ON at RT. The OL (aq. NH4C1 / 1O% MeOH in DCM) was concentrated and purified by FC (DCM / MeOH 95:5) to give tertbutyl methyl(2-oxo-l,2-dihydropyridin-4-yl)carbamate (0.3 g). A larger portion of this material prepared similarly (2.1 g), Int. 1AB8 (2.0 g), Cui (0.8 g), DMDCH (1.2 g), and K3PO4 (2.7 g) were degassed in dioxane (50 mL) and stirred at 100 °C ON. This mixture was mixed with another batch prepared similarly on 1.0 g scale and filtered. The OL (EtOAc / water) was washed with brine, dried, concentrated, and purified by FC (EtOAc / pentane 3:2) to give Int. 1AD1 tert-Butyl (l-(2-formyl-l-methyl-lH-pyrrolo[2,3-b]pyridin-4-yl)-2-oxo-l,2-dihydropyridin-4-yl)-(methyl)carbamate (2.5 g). COR Int. 1M60. 3-fluoro-5-methyl-4-(l-((l-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 Example lm56 (2.4 g) and LiOH-H2O (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 12.4 g). Int. 1AD1 (0.10 g) and NaBH4 (15 mg) were stirred 2h in MeOH (10 mL) at 0 °C to RT and concentrated. The OL (water / EtOAc) was dried, and concentrated to give Int. 1T2 tert-butyl (1-(2-(hydroxymethyl)-1 -methyl-1 H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxo-1,2-dihydropyri din-4- yl)(methyl)carbamate (60 mg). Int. 1T2 (0.10 g) was stirred ON in DCM / Et3N (45:1, 10.2 mL) and MsCl (60 pL) at 0 °C to RT. The OL (water / DCM) was washed with sat. aq. NaHCO3, dried, and concentrated to give Int. 1T1 tert-Butyl N-[l-[2-(chloromethyl)-l-methyl-pyrrolo[2,3-b]pyridin-4-yl]-2-oxo-4-pyridyl]-7V-methyl-carbamate (50 mg). Ints. 3E35 / 1AD2 (0.40 g / 0.29 g), Cui (0.33 g), K2CO3 (0.36 g), and DMDCH (0.25 g) were degassed in dioxane (10 mL) and stirred ON at 95-100 °C. The OL (water / EtOAc) was dried, concentrated, and purified by FC (DCM / MeOH 95:5) to give Int. 3E172 methyl 4-[1 -[(1S)-1 -[4-[4-[tert-butoxycarbonyl(methyl)amino]-2-oxo-l-pyridyl]-l-methyl-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-4-piperidyl]benzoate (0.33 g). A solution of this material (0.22 g) in dioxane / 6M aq. HC1 (1:1; 8 mL) was stirred ON at 70 °C and concentrated to give Int. 3E171 4-( 1-[(IS)-1-( l-methyl-4-[4-(methylamino)-2-oxo-l-pyridyl]pyrrolo[2,3-b]pyridin-2-yl]ethyl]-4-piperidyl]benzoic acid (0.18 g, HC1 salt). 3,5-Dihydro-2H-furo[3,2-c]pyridin-4-one (2.15 g) was stirred 8h in PMB-NH2 (20 mL) at 180 °C and diluted with Et2O to precipitate Int. 3E181 l-[(4-methoxyphenyl)-methyl]-3,5-dihydro-2H-pyrrolo[3,2-c]pyridin-4-one (2.35 g). Ints. 3E53 / 3E181 (0.30 g / 0.2 g), Cui (0.25 g), K2CO3 (0.27 g), and DMDCH (0.19 g) were degassed in dioxane (10 mL) and stirred 2h at 120 °C. The OL (water / EtOAc) was dried, concentrated, and triturated in Et3O to give Int. 3E180 methyl 4-(1 -[(1S)-1-[4-[l-[(4-methoxyphenyl)methyl]-4-oxo-2,3-dihydropyrrolo-[3,2-c]pyridin-5-yl]-l-methyl-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-4-piperidyl]benzoate (0.40 g). 0.15 g of this material and LiOH-H2O (98 mg) were stirred 5h in MeOH / THF / water (2:2:1; 5 mL), concentrated, and triturated in dilute aq. HC1 to give Int. 3E179 4-[l-[(lS)-l-[4-[l-[(4-methoxyphenyl)-methyl]-4-oxo-2,3-dihydropyrrolo[3,2-c]-pyridin-5-yl]-l -methyl-pyrrolo[2,3-b]pyridin-2-yl]ethyl]-4-piperidyl]-benzoic acid (0.13 g). A solution of Int. 3E179 (0.15 g) in TFA / TfOH (10:1: 1.65 mL) was stirred Ih at 80 °C and concentrated to give Int. 3E178 (S)-4-(l-(l-(l-methyl-4-(4-oxo-l,2,3,4-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (0.15 g, TfOH salt). Cui (0.24 g), Int. 1Z71 (0.30 g), 4-amino-3-fluoropyridin-2(lH)-one (82 mg), and K3PO1 (0.61 g) were stirred 2h in dioxane (5 mL) and rran5-N,N’-dimethylcyclohexane-1,2-diamine amine (0.20 mL) at 120 °C under an inert atmosphere. The OL (aq. NH3 / DCM / MeOH) was dried, filtered, concentrated, and purified by FC (DCM / MeOH 19:1) and HPLC-purified to give Int. 1Z72 l'-(l-(4-(4-amino-3-fluoro-2-oxopyridin-1 (2H)-yl)-1-methyl-1 H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-N,N-dimethyl-r,2',3',6'-tetrahydro-[2,4'-bipyridine]-5-carboxamide (75 mg). 0 H Int. 3E181 (2.3 g) was stirred 6h in TFA (20 mL) at 0-75 °C. The residue after concentration was dissolved in MeOH and concentrated. The residue was dissolved in MeOH and mixed with Amberlyst® A21 ion exchange resin, filtered, and dried to give Int. 1Z74 l,2,3,5-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (0.90 g). NHMe 4-Chloropyridin-2-ol (10 g) was stirred ON in 2M methylamine in MeOH (100 mL) at 100 °C. The mixture was concentrated and purified by FC(ACN / MeOH 1:0 to 3:1) to give Int. 1Z78 4-(methylamino)pyridin-2-ol (8 g). H 2-Methoxy-3-methylpyridin-4-amine (0.75 g), Nai (0.92 g), and (CH3)3SiCl (0.64 mL) were stirred Ih in ACN (2 mL) at 85 °C under MW conditions. The mixture filtered and concentrated. The residue was dissolved in MeOH containing basic Amberlyst ion exchange resin. The mixture was filtered and dried to give Int. 1Z81 4-amino-3-mcthylpyridin-2(lH)-onc (0.30 g). l,5-Dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (2.0 g) and TsOH (1.3 g) were stirred 16h in THF / 3,4-dihydro-2H-pyran (22:3, 34 mL) at 0 °C to RT. The OL (aq. NaHCO3 / DCM) was dried, filtered, concentrated, and purified by FC (DCM / MeOH 19:1) to give Int. 1Z82 l-(tetrahydro-2H-pyran-2-yl)-l,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (1.3 g). Cui (73 mg), Ints. 1Z82 / 1AF77 (63 mg / 0.10 g), and K3PO4 (0.18 g) were stirred 16h in DMF (2 mL) and rrans-N,N’-dimethylcyclohexane-l,2-diamine (60 pL) at 110 °C under an inert atmosphere. The mixture was filtered. The OL (aq. NH3 / DCM) was dried, filtered, concentrated, and purified by FC (DCM / MeOH 49:1) to give Int. 1Z83 N,N-bis(methyl-£ / 3)-4-(l-((lS)-l-(l-methyl-4-(4-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzamide (40 mg). Rxn'r            ^nh Int. 1Z91 R-Boc R'=H Int. 1Z90 R-Boc R-Me K |1    ----► y || Int. 1Z88 Int. 1Z89 R=H, R-Me H Di-terz-butyl dicarbonate (22 g) was added portion-wise to a mixture of 2,6-difluoropyridin-4-amine (12 g) and DMAP (1.1 g) in DCM (200 mL). The mixture was stirred 8h and concentrated to give Int. 1Z91 tert-butyl (2,6-difluoropyridin-4-yl)carbamate (17 g). Int. 1Z91 (21 g) was added portion-wise to a solution of NaH (2.6 g) in DMF (100 mL) at 0 °C. The mixture was stirred Ih before Mel (6.2 mL) was added drop-wise and stirring continued 12h. The OL (water / MTBE) was concentrated to give Int. 1Z90 tert-butyl (2,6-difluoropyridin-4-yl)(methyl)carbamate (22 g). Int. 1Z90 (17 g) was stirred 0.5h in MeOH / 2.8M HO in dioxane (6:1, 350 mL). The mixture was concentrated to give Int. 1Z89 2,6-di-fluoro-N-methylpyridin-4-amine (10 g). Int. 1Z89 (10 g) was refluxed 15h in 1.7M NaOH (0.2 L). The mixture was diluted with aq. citric acid. The OL (water / EtOAc) was concentrated to give Int. 1Z88 6-fluoro-4-(methylamino)pyridin-2(1 H)-one (1.2 g)- Cul (50 mg), Ints. 1Z78 / 1Z95 (30 mg / 80 mg), and K2CO3 (0.1 g) were stirred 12h in DMSO (5 mL) and tran.s-N,N’-dimethylcyclohexane-l,2-diamine (83 pL) at 100 °C under an inert atmosphere. The mixture was filtered and HPLC-purified to give Int. 1Z100 N,N,2,4-tetramethyl-T-(l-(l-methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)-l’,2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (11 mg). Paraformaldehyde (0.29 g) was added to a solution of Int. 1Z81 (0.40 g) in MeOH (10 mL) under an inert atmosphere. 30% NaOMe in MeOH (3 mL) was added drop-wise and stirring continued 4h at 0-55 °C. NaBH4 (0.38 g) was added portion-wise and stirring continued 4h at 0-55 °C. The mixture was diluted with aq. citric acid, concentrated, and purified by FC on neutral alumina (DCM / MeOH 9:1) to give Int. 1Z104 3-methyl-4-(methylamino)pyridin-2(lH)-one (0.30 g). Cui (12 g), Ints. 2G81 / 1Z69 (8.6 g / 32 g), and K3PO4 (40 g) were stirred 16h in dioxane (375 mL) and tran.y-N,N’-dimcthylcyclohcxanc-1,2-diaminc (20 mL) at 107 °C under an inert atmosphere. The mixture was filtered. The OL (aq. NH3 / DCM / MeOH) was dried, filtered, and concentrated. The residue was refluxed Ih in EtOAc / DCM (10:3) and filtered while hot, the filter was washed with EtOAc and Et2O and the filtrate concentrated to give Int. 1Z105 3-fluoro-N,N,5-trimethyl-4-(l-(l-(l-methyl-4-(4-(methylamino)-2-oxopyri din-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethy 1)-1,2,3,6-tetrahydropyridin-4-yl) benzamide (22 g). Cui (1.1 g), Ints. 3E181 / HH10 (1.6 g / 2.8 g), and K3PO4 (3.6 g) were stirred 16h in dioxane (15 mL) and traHs-N,N’-dimethylcyclohexane-l,2-diamine (1.8 mL) at 100 °C under an inert atmosphere. The mixture was filtered. The OL (aq. NHs / DCM / MeOH) was dried, filtered, concentrated, and purified by FC (DCM / MeOH 19:1) to give Int. 1Z114 methyl 3-fluoro-4-(l-(l-(4-(1-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoate (1.8 g). LiOHH2O (1.5 g) and Int. 1Z114 (4.6 g) were stirred 16h in THF / MeOH / H2O (3:1:2, 90 mL) at 0 °C to RT. The residue after concentration was stirred in aq. citric acid to precipitate Int. 1Z113 3-fluoro-4-(l-(l-(4-(l-(4-methoxybenzyl)-4-oxo-l,2,3,4-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoic acid (4.3 g). Int. 1Z113 (0.80 g) was stirred 16h in TFA (7 mL) at 65 °C. The mixture was concentrated and triturated in MTBE to give Int. 1Z112 3-fluoro-5-methyl-4-( 1-(1-(1 -methyl-4-(4-oxo-1,2,3,4-tetrahydro-5H-pyrrolo [3,2-c]pyridin-5 -yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid (0.80 g, TFA salt). Int. 1Z112 (0.80 g) was resolved by SFC on a Sepiatc-200-001 instrument fitted with a (R,R) Whelk-01 250x30 mm 5pm column operated at 30 °C and an eluent of 65% CO? and 35% 30 mM MeONHs in MeOH at a (90 g / min) and a back pressure of 120 bar to give Int. 1Z110 (0.30 g, first peak) and Int. 1Z111 (0.25 g, second peak) (S)-3-fluoro-5-methyl-4-( 1 -(1-(1 -methyl-4-(4-oxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid and (R)-3-fluoro-5- methyl-4-(l-(l-(l-methyl-4-(4-oxo-l,2,3,4-tetrahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzoic acid. The absolute configurations of these compounds were not determined. NH \ Int. 1Z118 R=Me racemate Int. 1Z117 R=H, racemate Int. 1Z115 R=H, enantiomer 1 Int. 1Z116 R=H, enantiomer 2 co2r Cui (0.93 g), Ints. 2G68 / 2G85 (0.42 g / 1.2 g), and K3PO4 (1.6 g) were stirred 16h in dioxane (5 mL) and tran.y-N,N’-dimethylcyclohexane-1,2-diamine (0.78 mL) at 100 °C under an inert atmosphere. The OL (aq. NIL / DCM / MeOH) was dried, filtered, concentrated, and purified by FC (DCM / MeOH 9:1) to give Int. 1Z118 methyl 3-fluoro-4-(l-(l-(4-(5-fluoro-4-(methylamino)-2-oxopyridin-l(2H)-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoate (0.90 g). LiOHH2O (0.34 g) and Int. 1Z118 (0.90 g) were stirred 4h in THF / MeOH / H2O (2:1:1, 10 mL) at 0 °C to RT. The residue after concentration was stirred in aq. citric acid to precipitate Int. 1Z117 3-fluoro-4-( 1-(l-(4-(5-fluoro-4-(methylamino)-2-oxopyridin-1 (2H)-yl)- 1-methyl- 1H-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoic acid (0.50 g). Int. 1Z117 (0.60 g) was resolved by SFC on a Sepiatec-660 instrument fitted with a (R,R) Whelk-01 250x30 mm 5,urn column operated at 30 °C and an eluent of 55% CO2 and 45% 30 mM MeONHs in MeOH at a (100 g / min) and a back pressure of 120 bar to give Int. 1Z115 (0.13 g, first peak) and Int. 1Z116 (0.14 g, second peak) (R)-3-fluoro-4-(l-(l-(4-(5-fluoro-4-(methylamino)-2-oxopyridin-l(2H)-yl)-l-methyl-lH-pyrrolof2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoic acid and (S)-3-fluoro-4-(l-(l-(4-(5-fluoro-4-(methylamino)-2-oxopyridin-l(2H)-yl)-1-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-5-methylbenzoic acid. The absolute configurations of these compounds were not determined. pONMe2 Cui (50 mg) and tran^-N,N’-dimethylcyclohexane-1,2-diamine (82 pL) were added to a solution of Ints. 2G81 / 1Z134 (42 mg / 0.14 g) and K3PO4 (0.17 g) in dioxane (10 mL) and stirred for 16h at 105 °C under an inert atmosphere and filtered. The OL (aq. NHs / DCM / MeOH) was dried, filtered and concentrated to give Int. 1Z135 4-(3,3-difluoro-l-(l-(l-methyl-4-(4-(methylamino)-2-oxopyridin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)-3-fluoro-N,N,5-trimethylbenzamide (95 mg). 2.5M "BuLi in hexane (7 mL) was added to a solution of 2,4-dichloropyridine (2.0 g) in THF (135 mL) at -78 °C. The mixture was stirred 0.5h at -78 °C under an inert atmosphere. Ethyl 2,2,2-trifluoro-acetate (3.2 mL) was added drop-wise and stirring continued 0.75h at -78 °C. The OL (water / EtOAc) was dried, filtered and concentrated. The residue was stirred ON in THF (100 mL) and hydrazine hydrate (4.2 mL) at -40 °C to RT. The mixture was stirred ON min at -40 °C to RT. The residue after concentration was precipitated from MTBE to give Int. 1Z143 4-chloro-3-(trifluoromethyl)-lH-pyrazolo[4,3-c]-pyridine (1.1 g). Int. 1Z143 (1.1 g) was stirred 24h in ACOH / H2O (75:1, 15.2 mL) at 100 °C. The mixture was concentrated. The OL (water / DCM) was dried, filtered, and concentrated to give Int. 1Z142 3-(trifluoromethyl)-lH-pyrazolo[4,3-c]pyridin-4-ol (0.96 g). SEM-C1 (0.84 mL) was added to a stirred mixture of CS2CO3 (3.1 g) and Int. 1Z142 in DMF (7 mL). Stirring was continued 0.3h. The OL (water / DCM) was dried, filtered, concentrated, and triturated in MTBE to give Int. 1Z141 3-(trifluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolo[4,3-c]pyridin-4-ol (0.33 g). Cui (73 mg), Ints. 1Z141 / 1AF77 (96 mg / 0.10 g), and K3PO4 (0.16 g) were stirred 2h in DMF (10 mL) and trans-N,N’-dimethylcyclohexane-1,2-diamine (56 pL) at 120 °C under an inert atmosphere. The mixture was filtered. The OL (water / EtOAc) was concentrated and purified by FC (DCM / MeOH 9:1) to give Int. 1Z140 (S)-N,N-bis(methyl-J3)-4-(l-(l-(l-methyl-4-(4-oxo-3-(trifluoromethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-l,4-dihydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)ethyl)piperidin-4-yl)benzamide (0.10 g). 2-Chloro-5-fluoro-A-methylpyrimidin-4-amine (5 g) was stirred 16h in water / formic acid (0.61 mL / 23 mL) at 90 °C. The mixture was diluted with EtOAc to precipitate Int. 3C12 (3.2 g). Cui (2.4 g), trans-N,N’-dimethylcyclohexane- 1,2-diamine (2.0 mL), K3PO4 (4.0 g), Int. 3C12 (3 g), and 4-(methylamino)-pyrimidin-2(lH)-one (1.0 g) were stirred 16h in DMF / DMSO (5:1, 30 mL) at 110 °C under an inert atmosphere. The mixture was filtered. The OL (aq. NH3 / DCM / MEOH) was filtered, concentrated, and washed with EtzO to give Int. 3C11 methyl 3,5-difluoro-4-(l-((l-methyl-4-(4-(methylamino)-2-oxopyrimidin-l(2H)-yl)-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoate (2.6 g). LiOH H2O (1.0 g) and Int. 3C11 (2.6 g) were stirred 4h in THF / MeOH / H2O (15:7:10, 32 mL) and concentrated. The AL (water / Et2O) was diluted with aq. citric acid to precipitate Int. 3C10 3,5-difluoro-4-( 1 -((1 -methyl-4-(4-(methylamino)-2-oxopyrimidin-1 (2H)-yl)- 1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoic acid (2.4 g). Cui (2.0 g), trans-N,N’-dimethylcyclohexane-l,2-diamine (1.7 mL), K3PO4 (3.3 g), and Ints. 3C12 / 3C15 (0.97 g / 2.5 g) were stirred 12h in dioxane (15 mL) at 100 °C under an inert atmosphere. The mixture was filtered. The OL (water / EtOAc) was concentrated and purified by FC (PE / EtOAc 4:1 to 3:17) to give Int. 3C41 methyl 3,5-difluoro-4-(l-((4-(5-fluoro-4-(methylamino)-2-oxopyrimidin-l(2H)-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoate (1.6 g). LiOH H2O (0.28 g) and Int. 3C41 (1.2 g) were stirred ON in THF / MeOH / H2O (5:5:2, 24 mL). The residue after concentration was stirred in aq. citric acid to precipitate Int. 3C40 3,5-difluoro-4-(l-((4-(5-fluoro-4-(methylamino)-2-oxopyrimidin-l(2H)-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoic acid (0.90 g). o, N Hn' NNHMe 2-Chloro-5-fluoro- / V-methylpyrimidin-4-amine (5 g) was stirred 16h in water / formic acid (0.61 mL / 23 mL) at 90 °C. The mixture was diluted with EtOAc to precipitate Int. 3C12 5-fluoro-4-(methylamino)-pyrimidin-2(lH)-one (3.2 g). co2r xnh       z=\ Af zR / \ r^VN N— R jTy—1 Int. 3C41R=Me Cui (2.0 g) and trans-N,N’-dimethylcyclohexane-l,2-diamine (1.7 mL), K3PO4 (3.3 g), and Ints. 3C42 / 3C15 (0.97 g / 2.5 g) were stirred 12h in dioxane (15 mL) at 100 °C under an inert atmosphere. The mixture was filtered and the OL (water / EtOAc) was concentrated and purified by FC (PE / EtOAc 4:1 to 3:17) to give Int. 3C41 methyl 3,5-difluoro-4-(l-((4-(5-fluoro-4-(methylamino)-2-oxopyrimidin-l(2H)-yl)-l-methyl-lH-pyrrolo[2,3-b]pyridin-2-yl)methyl)piperidin-4-yl)benzoate (1.6 g). LiOH H2O (0.28 g) and Int. 3C41 (1.2 g) were stirred ON in THF / MeOH / H2O (5:5:2, 24 mL). The so...

Claims

1. A compound having the formula (I)R9 is -A-L-LBM;X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N;X4 is selected from CR4R4 and CO;X5 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 NHR°;R° is selected from hydrogen, Cwalkyl, C3.4 cycloalkyl, C3.4cycloalkyl-Ci-4alkyl, phenyl- Ci.4alkyl,halo-Cmalkyl, -(CtDn-O-Cmalkyl, -(CIDn-CO-R’, and -(CH2)n-CO2R’, wherein said phenyl is optionally substituted one or more times with a substituents independently selected from halogen, Ci-4alkyl, halo-Cmalkyl, C3-4cycloalkyl, hydroxy, Ci-4alkoxy, cyano, -NR’R”, -CONR’R”, and -CO2R’, and 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.4alkyl and deuterated Ci.4alkyl, wherein said Ci-salkyl may optionally be substituted one or more times with halogen;R3 is selected from hydrogen, Ci-4alkyl, and deuterated Ci-4alkyl;each of R4 and R6 is independently selected from hydrogen, Cmalkyl, and C1-4 alkoxy, said Cmalkyl and Ci-4alkoxy may optionally be substituted with one or more halogen;R5 is selected from hydrogen, halogen, Ci-4alkyl and Ci-4alkoxy, wherein said Ci-4alkyl and Ci-ialkoxy 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 carbons to which they are attached;R5a is hydrogen;or R5 and R3a are both fluoro or R5 and R5a together with the atom attached thereto form a CO group;R5b 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 C3-4cycloalkyl, wherein said Ci-4alkyl and CMalkoxy may optionally be substituted with one or more halogen;R11, R12, and R13 are each independently selected from hydrogen, halogen, Ci-4alkyl, C3-4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, and -CO-(CH2)mOH, wherein said Ci-4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; orR11 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-Ci-4alkyl, C3-4 cycloalkyl, hydroxy, Ci-4alkoxy, cyano, -COCF3, -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 CMalkoxy, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl; andR12 and R13 are each independently selected from hydrogen, halogen, Ci-4alkyl, C3.4 cycloalkyl, Ci-4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2)mOH, wherein said Ci-4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Chalky 1;A is CO;L is selected fromR18   R20\ / =^ / —\ >wherein nl is selected from 0 and 1;n2 is selected from 1 and 2;R17 is selected from hydrogen and fluoro;R18 is selected from hydrogen, fluoro, Ci-4alkyl wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Ci.4alkoxy;R19 is independently selected from hydrogen, Ci.4alkyl and fluoro;R20 is selected from hydrogen and Ci-4alkyl;X6 is C;X7 is CR24 or N;R24 is selected from hydrogen and hydroxy;X8 and X9 are independently CH or N; andLBM isOwherein X7 is O, NR22, or CR23R23;R21 is selected from hydrogen, fluoro, and chloro;R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and Cm cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or C3-4 cycloalkyl;each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; orboth R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O;or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A compound having the formula (I’)A-L-LBMwherein:X1 is selected from N and CR11; X2 is selected from N and CR12; and X3 is selected from N and CR13, provided that only one of X1, X2 and X3 may be N;X4 is CR4R4 or CO;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, C3-4 cycloalkyl, C3-4cycloalkyl-Ci-4alkyl, phenyl-Cwalkyl, halo-Ci-4alkyl, -(CH2)n-O-Ci4alkyl, -ICtDn-CO-R’, and -(CHiJn-COzR’, wherein said phenyl is optionally substituted one or more times with a substituent independently selected from halogen, Ci-4alkyl, halo-Ci-4alkyl, C3-4cycloalkyl, hydroxy, Ci-4alkoxy, cyano, - NR’R”, -CONR’R”, and -CO2R’, and wherein R’ and R” are each independently selected from hydrogen and Ci-4alkyl, and n is 0, 1, or 2;Rla is hydrogen;R2 is selected from hydrogen, Ci-4alkyl, and deuterated Ci-4alkyl; wherein said Ci-4alkyl may optionally be substituted one or more times with halogen;R3 is selected from hydrogen, Ci^alkyl, and deuterated Ci-talkyl;R4 and R6 are independently selected from hydrogen and Ci ialkyl, wherein said Ci-ialkyl may optionally be substituted with one or more halogens;R3 is selected from hydrogen, halogen, Ci-4alkyl, and Ci-4alkoxy, wherein said Ci-ralkyl 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 carbons to which they are attached;R5a is hydrogen; or R5 and R5a are both fluoro;R7 and R8 are independently selected from hydrogen, halogen, Ciialkyl, C3-4 cycloalkyl, and Ci-4alkoxy, wherein said Chalky 1 and Ci-4alkoxy may independently optionally be substituted with one or more halogen;R" is selected from hydrogen, halogen, Ci-4alkyl, C3.4 cycloalkyl, Ci.4alkoxy, hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-(CH2)mOH, wherein said Ci-jalkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy and Cwalkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R” are each independently selected from hydrogen and Ciialkyl; orR11 and R° together with the atoms attached thereto may form a 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N, wherein said 5-6 membered heterocyclic or heteroaromatic ring containing one to two heteroatoms selected from N is optionally substituted one or more times with a substituent independently selected from halogen, Ciialkyl, halo-Ci-4alkyl, C3-4cycloalkyl, hydroxy, Ci-4alkoxy, cyano, -NR’R”,-CONR’R” and -COzR’, 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 Cwalkyl;R12 and R13 are independently selected from hydrogen, halogen, Ci.4alkyl, C3.4 cycloalkyl, Ci-4alkoxy, 5          hydroxy, cyano, -NR’R”, -CONR’R”, -CO2R’, -CO-CO2R’ and -CO-(CH2)mOH, whereinsaid Ci-4alkyl is optionally substituted one or more times with a substituent independently selected from halogen, hydroxy, and Ci-4alkoxy, and wherein m is 1, 2 or 3 and wherein R’ and R”are each independently selected from hydrogen and Ci-4alkyl;A is CO;10 L is selected from R18 H(CH2)ni—N R17       A R19 F R20                                        R18   R20 N-(CH2)m—I    pl / \6—(CH2)ni--<^N—(CH2)n1—| '--  R17           / \ □ 19                                            R19 R19R18 R20 * 0      W     }    \ |-N   V— (CH2)n1—N.)— (CH2)n1—|        t '---  R17 R19 R19                   , j / --\    f          P /      (CH2)n2--N R18  R20 pN^___---(CH2)n1---\l---(CH2)n1---1 R1^9 R19 R19 Cx9^wherein nl is selected from 0 and 1;n2 is selected from 1 and 2;5            R17 is selected from hydrogen and fluoro;R18 is selected from hydrogen, fluoro, Ci-4alkyl wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro or Ci-4alkoxy;R19 is independently selected from hydrogen, Ci-ralkyl and fluoro;R20 is selected from hydrogen and Cwalkyl;10            X6 is C;X7 is CR24 or N;R24 is selected from hydrogen and hydroxy;X8 and X9 are independently CH or N; andLBM is15wherein X7 is O, NR22, or CR23R23;R21 is selected from hydrogen, fluoro, and chloro;R22 is selected from hydrogen, Ci-4alkyl, deuterated Ci-4alkyl, and C s-i cycloalkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with fluoro, hydroxy, Ci-4alkoxy, or cycloalkyl;each R23 is independently selected from hydrogen, halogen, and Ci-4alkyl; or5           both R23 together with the carbon they are attached to form a C3-6 cycloalkyl or 3-6 memberedheterocyclic ring, wherein the heterocyclic ring contains one to two heteroatoms selected from O;or a pharmaceutically acceptable salt or stereoisomer thereof.10   3. A compound according to claim 2, having the formula (II) or (IT)A-L-LBMA-L-LBMwherein R3 is Ci-4alkyl;or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The compound according to claim 2 having the formula (III)or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound according to claim 4 having the formula (IV)wherein RJ is Ci-4alkyl;or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The compound according to any one of claims 1-5, wherein R is NHR° and R° is selected from hydrogen and C । । alkyl.

7. The compound according to claim 2 having the formula (VII)wherein R16 is selected from hydrogen and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen;or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound according to claim 7 having the formula (VIII)A-L-LBMwherein R16 is selected from hydrogen and Ci-ralkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen;or a pharmaceutically acceptable salt or stereoisomer thereof.5   9. The compound according to claim 2, wherein the compound is of formula (IX):wherein R16 and R16a are selected from hydrogen and Ci-4alkyl, wherein said Ci-4alkyl may optionally be substituted one or more times with a substituent independently selected from halogen;or a pharmaceutically acceptable salt or stereoisomer thereof.1010. The compound according to claim 2, wherein the compound is of formula (IXa), or (IXb):wherein R16 and R16a are selected from hydrogen and Ci.4alkyl, wherein said Ci.4alkyl may optionally15 be substituted one or more times with a substituent independently selected from halogen;or a pharmaceutically acceptable salt or stereoisomer thereof.

11. The compound according to any one of claims 1-10, wherein X7 is NR22 and R22is methyl.

12. The compound according to any one of claims 1-10, wherein X7 is NR22 and R22 is cyclopropyl.

13. The compound according to any one of claims 1-10, wherein X7 is CR23R23, and both R23 aremethyl or both R23 are fluoro.

14. The compound according to any one of claims 1-10, wherein X7 is CR23R23, and both R23 together with the carbon they are attached to form a C3-6 cycloalkyl.

15. The compound according to any one of claims 1-10, wherein X7 is CR23R23, and both R23 together with the carbon they are attached to form a 3-6 membered heterocyclic ring, wherein the heterocyclic ring contains one heteroatom that is O.

16. The compound according to any one of claims 1-10, wherein A-L-LBM is17. The compound according to any one of claims 1-10, wherein A-L-LBM isOwherein n3 is 0, 1,2 or 3.

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

19. The compound according to any one of claims 1-17, wherein Z is CR10 and R5and R10 together form a bond.

20. The compound according to any one of claims 1-17, wherein Z is CR10 and R10 is hydrogen.

21. The compound according to any one of claims 1-20, wherein Y1 is N and Y2 is CR8.

22. The compound according to any one of claims 1-20, wherein Y1 is N and Y2 is N.

23. The compound according to any one of claims 1-20, wherein Y1 is CR7 and Y2 is CR8.

24. The compound according to claim 23, wherein(a)     both of R7 and R8 is Ci^alkyl;(b)     both of R7 and R8 is halogen;(c)     one of R7 and R8 is Ci.4alkyl and the other is halogen;(d)     one of R7 and R8 is Ci-4alkyl and the other is hydrogen; or(e)     one of R7 and R8 is halogen and the other is hydrogen.

25. The compound according to claim 24, wherein R7is halogen and R8is methyl.

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

27. The compound according to any one of claims 1-26, wherein R12 and R13 are hydrogen.

28. The compound according to any one of claims 1-7 and 16-27, wherein R11, R12 and R13 are hydrogen.

29. A compound according to any one of claims 1-28, wherein X4 is CR4R4 and each R4 is independently selected from hydrogen and Ci-4alkyl.

30. A compound according to any one of claims 1-29, wherein R2 is methyl.

31. A compound according to any one of claims 1-30, wherein R3 is hydrogen or Ci-4alkyl.

32. A compound according to any one of claims 1-31, wherein R3 is methyl.

33. A compound according to any one of claims 1-32, wherein R5ais hydrogen.

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

35. A compound according to any one of claims 1-34 for use in therapy.

36. A compound according to any one of claims 1-34 for use in the treatment of a disease, disorder orcondition, which disease, disorder or condition is responsive of modulation of STAT6.

37. A compound according to any one of claims 1-34 for use in the treatment of autoimmune diseases.

38. A compound according to any one of claims 1-34, or a pharmaceutically acceptable salt orstereoisomer thereof, for use in the treatment of 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 stand-alone treatment or in combination with other anticancer drugs such as check point inhibitors.

39. Use of the compound of any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, for the manufacture of a medicament for the treatment of a disease or condition mediated by a signal transducer and activator of transcription 6 (STAT6) protein activity in a subject.

40. A pharmaceutical composition comprising a compound according to any one of claims 1-33, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable vehicle or excipient or pharmaceutically acceptable carrier(s).

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

42. The pharmaceutical composition of claim 40 or 41, further comprising one or more additional therapeutic agents.

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

44. 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 any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of any one of claims 40-42.

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

46. 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 any one of claims 134, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of any one of claims 40-42.

47. The method of claim 46, wherein the STAT6-mediated disorder or disease is from the class of diseases or rheumatology, gastroenterology, pulmonology, hepatology, nephrology, dermatology or an allergic disease.

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

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

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

51. 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 any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of any one of claims 40-42.

52. 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 any one of claims 1-34, or a pharmaceutically acceptable salt or stereoisomer thereof, is used.

Images