SLC15a4-TASL pathway inhibitors

Abstract

Provided herein are certain substituted quinoline derivatives of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising one or more such compounds, and methods for their preparation and use, as inhibitors of SLC15A4 (endolysosomal solute carrier family 15 member 4), and their use in the treatment of a variety of diseases, conditions, or disorders that are mediated, at least in part, by SLC15A4.

Description

SLC15A4-TASL PATHWAY INHIBITORSTECHNICAL FIELD

[0001] This disclosure relates generally to small molecule inhibitors of SLC15A4-TASL pathway.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to US Provisional Application No.63 / 774,527 filed March 19, 2025, the disclosure of which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0003] Innate immunity is the first line of defense against invading pathogens, and pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) are a key element of the innate immune system. TLRs recognize pathogens by binding to structural shapes or patterns called PAMPs (pathogen-associated molecular patterns), e.g., lipopolysaccharide (LPS), that are present in whole groups of pathogens, but not in the host. At least ten different TLRs are known. Among these, TLRs 1, 2, 4, 5, and 6 bind to components of microbial cell walls and membranes unique to pathogens, and TLRs 3, 7, 8, and 9 bind to microbial nucleic acids, including double and single-stranded RNA from RNA viruses and DNA from most organisms (Christmas, P., 2010, Nature Education 3(9):85). Recognition of foreign nucleic acids by TLRs 3, 7, 8, and 9 largely depends on the location of the nucleic acids in the cell since these TLRs cannot differentiate between host cell and foreign nucleic acids based only on structural differences. TLRs 3, 7, 8, and 9 are located in the membranes of endosomes and lysosomes with their extracellular domain ligand-binding site projecting into the interior of these organelles (Christmas, P. (2010), Nature Education 3(9): 85). Degradation of pathogens in these organelles following internalization releases the pathogen DNA and RNA, allowing their interaction with the TLRs and activation of NF-KB and IRF transcription factors, which induces the production of inflammatory cytokines, such as IL6, tumor necrosis factor alpha (TNFa), and type I interferons (IFN-I), which help the body fight infection.

[0004] Aberrant activation of nucleic acid-sensing pathways, however, can lead to a broad spectrum of pathologies, ranging from interferonopathies to autoimmune conditions such as systemic lupus erythematosus (SLE) (Crow, Y. J., and Stetson, D. B., 2022, Nat. Rev. Immunol.22, 471-483; Pelka, K. et al., 2016, Immunol. Rev. 269, 60-75).

[0005] SLC15A4 (endolysosomal solute carrier familyl5 member 4) is a 12-transmembrane domain protein resident in lysosomes. It is a proton-coupled amino-acid transporter with high gene expression in antigen-presenting cells (APCs), such as plasmacytoid dendritic cells (pDCs) and B cells. It transports histidine and certain oligopeptides from inside the lysosome to the cytosol of eukaryotic cells. SLC15A4 is required for TLR 7 and 9-mediated production of type I interferon (IFN-I) and other pro-inflammatory cytokines and is involved in the pathogenesis of certain diseases including lupus-like autoimmunity.

[0006] SLC15A4 forms a complex with the protein, TASL (TLR adaptor interacting with SLC15A4 on the lysosome), recruiting TASL from the cytosol to endolysosomes (Heinz, L. X. et al., 2020, Nature, vol. 581, 316-321; Zhang, H. et al., 2023, Cell Reports 42, 112916). TASL is an adaptor protein that has a pLxIS motif. It is believed that the pLxIS motif is phosphorylated by a kinase activated by the activation of TLR7-9 by their respective ligands. This is followed by recruitment of the transcription factor, interferon regulatory factor (IRF5) through pLxIS motif, triggering phosphorylation and activation of IRF5 (Chen, X. et al., 2023, Nature Communications, 14:6627, 1-13). Activated IRF5 enters nucleus and drives expression of downstream inflammatory factors and type I interferon. Pharmacological inhibition of SLC15A4-TASL pathway may inhibit the production of these downstream inflammatory factors and type I interferon, and thereby provide therapeutic benefit in systemic lupus erythematosus (SLE) and, possibly, other autoimmune and inflammatory conditions. These are areas in which there is a need for new treatments. The present invention addresses this and other needs.SUMMARY OF THE INVENTION

[0007] In one aspect, the invention disclosed herein provides compounds (hereinafter referred to as compounds of the invention) which have been found to disrupt the interaction of SLC15A4 with TASL, thereby inhibiting the IRF5 signaling pathway and preventing downstream proinflammatory responses. The compounds of the invention have a structure in accordance with Formula (I) or Formula (II):or a pharmaceutically acceptable salt thereof, wherein A, B, C, Wi, W2, and Ri-Rs are as defined below.

[0008] In another aspect, the invention provides pharmaceutical compositions comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier or diluent. Such compositions according to the invention may optionally further include one or more additional therapeutic agents as described herein.

[0009] In another aspect, the invention provides a method for treating or preventing a disease, condition, or disorder including a disease, condition, or disorder that is mediated, at least in part, by the interaction of SLC15A4 with TASL in a subject (e.g., an animal or a human) in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional therapeutic agents. These and other aspects and embodiments of the invention are described more fully below.DETAILED DESCRIPTION OF THE INVENTION

[0010] For each of the following embodiments, any variable not explicitly defined in the embodiment is as defined in Formula (I) or Formula (IA), as applicable. In each of the embodiments described herein, each variable is selected independently of the other unless otherwise noted.

[0011] In embodiment 1, provided herein is the compound having the structural Formula (I):R6or a pharmaceutically acceptable salt thereof, wherein:Ri at each occurrence, Rs, and R2, are independently selected from the group consisting of H, F, Cl, Br, CN, OH, NR4R5, -(CH2)pNR4R5, NO2, SH, S(Ci-C4)alkyl, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)aminoalkyl, O(Ci-Ce)alkyl, O(Ci-C6)haloalkyl, -(CH2)pO(Ci-C6)alkyl, -(CH2)pO(Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, -SO3H (sulfonic acid)), -PO(OH)2(phosphonic acid), -COOH, -(CH2)PCOOH, -COO(Ci-C4)alkyl, -COO(Ci-C4)haloalkyl, -OCO(Ci-C4)alkyl, -OCO(Ci-C4)haloalkyl, CONR4R5, -CH2CONR4R5, -SO2NR4R5, formyl; and phenyl, benzyl, -OCH2CeHs, -NHCeHs, pyridinyl, 4-morphonyl, indolyl, pyrrolidinyl, piperidinyl, thienyl, or furyl, each of which is optionally substituted at 1 to 4 carbon atoms with a group independently selected from CH3, OCH3, CF3, OCF3, OH, SH, NR4R5, -COOH, F, and Cl;each of R3, R4, and Rs is independently selected from the group consisting of H, (Ci-C4)alkyl, phenyl, and -COCH3;Ring A is an aryl, or a heteroaryl having 1-3 ring nitrogen atoms, each optionally substituted with 1 to 4 R7;Re, when present, is H or NR4R5;R7, at each occurrence is independently selected from the group consisting of H, F, Cl, Br, CN, OH, SH, NR4RS,-COOH, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl;Y is C or N, wherein when Y is C, it is substituted with 1 Re;m is 1, 2, or 3;p is 0, 1, 2, or 3;n is 0, 1, 2, or 3; ando is 0 or 1.

[0012] In embodiment 2, provided herein is the compound having the structural Formula (IA):or a pharmaceutically acceptable salt thereof, wherein:Ri at each occurrence, Rs, and R2, are independently selected from the group consisting of H, F, Cl, Br, CN, OH, NR4R5, -(CH2)pNR4R5, NO2, SH, S(Ci-C4)alkyl, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)hydroxyalkyl, (Ci-C6)aminoalkyl, O(Ci-Ce)alkyl, O(Ci-C6)haloalkyl, -(CH2)pO(Ci-C6)alkyl, -(CH2)pO(Ci-C6)haloalkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, -SO3H (sulfonic acid)), -PO(OH)2(phosphonic acid), -COOH, -(CH2)PCOOH, -COO(Ci-C4)alkyl, -COO(Ci-C4)haloalkyl, -OCO(Ci-C4)alkyl, -OCO(Ci-C4)haloalkyl, CONR4R5, -CH2CONR4R5, -SO2NR4R5, formyl; and phenyl, benzyl, -OCH2CeHs, -NHCeHs, pyridinyl, 4-morphonyl, indolyl, pyrrolidinyl, piperidinyl, thienyl, or furyl, each of which is optionally substituted at 1 to 4 carbon atoms with a group independently selected from CH3, OCH3, CF3, OCF3, OH, SH, NR4R5, -COOH, F, and Cl;each of R3, R4, and Rs is independently selected from the group consisting of H, (Ci-C4)alkyl, phenyl, and -COCH3;Re, when present, is H or NR4R5;Ring A is an aryl, or a heteroaryl having 1-3 ring nitrogen atoms, each optionally substituted with 1 to 4 R7;R7, at each occurrence is independently selected from the group consisting of H, F, Cl, Br, CN, OH, SH, NR4RS,-COOH, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl;Y is C or N, wherein when Y is C, it is substituted with 1 Re;m is 1, 2, or 3; andp is 0, 1, 2, or 3.

[0013] In embodiment 3, provided herein is the compound of embodiments 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is N.

[0014] In embodiment 4, provided herein is the compound of embodiments 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is C.

[0015] In embodiment 5, provided herein is the compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6- membered aryl or heteroaryl.

[0016] In embodiment 6, provided herein is the compound of any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of:

[0017] phenyl, pyridyl,, each optionally substituted with 1 to 4 R7.

[0018] In embodiment 7, provided herein is the compound of any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each of Ri at each occurrence, Rs, and R2, are independently selected from the group consisting of H, F, Cl, Br, CN, OH, NR4R5, -(Ci-C6)alkyl, (Ci-C6)haloalkyl, O(Ci-C6)alkyl, O(Ci-C6)haloalkyl, (C3-C6)cycloalkyl, -COOH, CONR4R5; and phenyl, benzyl, pyridinyl, 4-morphonyl, indolyl, pyrrolidinyl, piperidinyl, thienyl, or furyl, each of which is optionally substituted at 1 to 4 carbon atoms with a group independently selected from CH3, OCH3, CF3, OCF3, OH, F, and Cl; and wherein R4 and R5 are H or CH3.

[0019] In embodiment 8, provided herein is the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ri at each occurrence, Rs, and R2, are independently selected from the group consisting of H, F, Cl, NH2, NHCH3, N(CH3)2, CH3, CH2F, CHF2, and CF3; and n (when present) and p are each 1 or 2.

[0020] In embodiment 9, provided herein is the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ri at each occurrence, Rs, and R2, are independently selected from the group consisting of H, F, Cl, NH2, NHCH3, N(CH3)2, CH3, CH2F, CHF2, and CF3; and n (when present) is 1 or 2, and each of p and m is 2.

[0021] In embodiment 10, provided herein is the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ri at each occurrence, Rs, and R2, areindependently selected from the group consisting of H, F, Cl, NH2, NHCH3, N(CHs)2, CH3, CH2F, CHF2, and CF3; o (when present) is 0; and n (when present), m, and p, each, is 1 or 2.

[0022] In embodiment 11, provided herein is the compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein, each of Ri and Rsis Cl, CH3, or CF3.

[0023] In embodiment 12, provided herein is the compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein each of Ri and Rs is Cl, CH3, or CF3; and R2is H.

[0024] In embodiment 13, provided herein is the compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R7 is independently selected from the group consisting of F, Cl, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl.

[0025] In embodiment 14, provided herein is the compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R7 is independently selected from F, Cl, CH3, -CH2CH3, CF3,-CH2CF3, -0CH3, -OCH2CH3, -OCH2CH2CH3, -OCF3-OCH2CF3, -OCH2CH2CF3, and -OCH2CH2CH2F.

[0026] In embodiment 15, provided herein is the compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each of Ri and Rs is Cl, CH3, or CF3.

[0027] In embodiment 16, provided herein is the compound of any one of embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Re is NH2, and m, n, and p, each is 1 or 2.

[0028] In embodiment 17, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each of Ri and Rs is independently Cl, CF3, or CH3, and ring A is phenyl, optionally substituted with 1 or 2 R7 independently selected from F, Cl, -OCH2CH3, and -OCH2CF3.

[0029] In embodiment 18, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Y is N, each of Ri and Rs is independently Cl, CF3, or CH3, and ring A is phenyl, optionally substituted with 1 or 2 R7 independently selected from F, Cl, -OCH2CH3, and -OCH2CF3.

[0030] In embodiment 19, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each of Ri and Rs is independently Cl,CF3, or CH3, and ring Ais, optionally substituted with 1 or 2 R7 independently selected from CFFand -CH2CH3.

[0031] In embodiment 20, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Y is N, each of Ri and Rs is independentlyCl, CF3, or CH3, and ringA is, optionally substituted with 1 or 2 R7 independently selected from CHsand -CH2CH3.

[0032] In embodiment 21, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each of Ri and Rs is independently Cl,CF3, or CH3, and ringA is, optionally substituted with 1 or 2 R7 independently selected from CH3, CH2CH3, CF3,-OCH3, and -OCH2CH2F.

[0033] In embodiment 22, provided herein is the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Y is N, each of Ri and Rs is independentlyCl, CF3, or CH3, and ringA is, optionally substituted with 1 or 2 R7 independently selected from CH3, CH2CH3, CF3,-OCH3, and -OCH2CH2F.

[0034] In embodiment 23, provided herein is the compound embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:26143261432614326143

[0035] In embodiment 24, provided herein is a pharmaceutical composition comprising the compound of any one of embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0036] In embodiment 25, provided herein the compound of any one of embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, for use in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.

[0037] In embodiment 26, provided herein the use of the compound of any one of embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim2614324, in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.

[0038] In embodiment 27, provided herein the use of the compound of any one of embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, in the manufacture of a medicament for use in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.

[0039] In embodiment 28, provided herein the use according to any one of embodiments 25-27, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

[0040] In embodiment 29, provided herein is a method of treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or a method of treating an inflammatory condition, in each instance the method comprising administering an effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, to a person in need thereof.

[0041] In embodiment 30, provided herein is the method of embodiment 29, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

[0042] In embodiment 31, provided herein is the method of preceding embodiments 29 or 30, wherein said compound or a pharmaceutically acceptable salt thereof is administered in combination with an effective amount of an additional therapeutic agent.

[0043] In embodiment 32, provided herein is the method of embodiment 31, wherein the additional therapeutic agent is selected from the group consisting of upadacitinib, deucravacitinib, litifilimab, and dapirolizumab.

[0044] In embodiment 33, provided herein is a compound having the structural Formula (I) or Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Wi and W 2, each is C or N, provided that one and only one of Wi and W2 is N;Ri at each occurrence is independently selected from the group consisting of H, F, Cl, Br, (Ci-C6)alkyl, (Ci-C6)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, CN, OH, and NR4R5;A is selected from the group consisting of:(i) an aryl, a heteroaryl having 1-3 ring nitrogen atoms and 0-1 other hetero atoms independently selected from S and O, a pyrazol-O(Ci-C4)alkyl, a pyrazol-S(Ci-C4)alkyl, or an N(pyrazol-(Ci-C4)alkyl)R4, wherein each of aryl and heteroaryl is optionally substituted with 1 to 4 R7; pyrazol ring is optionally substituted with 1 to 3 R7; and one or more H atoms in the (Ci-C4)alkyl is optionally substituted with deuterium;(ii) a monocyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally fused to an aryl or a heteroaryl having 1-2 hetero atoms independently selected from N, O, and S, or optionally in a spiro linkage with a (C3- C6)cycloalkyl; wherein the monocyclic heterocyclyl and the fused aryl or heteroaryl, each is optionally substituted with 1 to 4 R7; and wherein the (C3-C6)cycloalkyl is optionally substituted with 1 to 2 groups selected independently from F, Cl, Br, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, CN, OH, and NR4Rs; and(iii) a bicyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally substituted with 1 to 4 R7;wherein each of (i)-(iii) is optionally linked to in Formula (I)orn(Rl) un Formula (II) through a linker selected from -(CH2)m, -0(CH2)m. - (CH2)m0, - S(CH2)m, and -N(R3)(CH2)m, wherein the (CH2)mgroups are optionally independently substituted with 1-4 halogen, deuterium, (Ci-C4)alkyl or (Ci-C4)haloalkyl;B is selected from the group consisting of:R2A(B-c) ^ 'Rs2614326143(B-k)26143R.2 is absent or present; when present, when Y is C, R2 is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, R2 is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;R3, R4, and Rs, at each occurrence is independently selected from H, (Ci-C4)alkyl and (Ci-C4)haloalkyl;Re is absent or present; when present, when Y is C, Re is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, Rs is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;26143R.7, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, OH, SH, NR4R5, phenyl, pyridyl, thiazolyl, -COOH, O, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-Ce)alkynyl, (C2-C6)haloalkynyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, O(C3-C6)cycloalkyl, and O(C3-C6)halocycloalkyl; the phenyl, pyridyl and thiazolyl being optionally substituted with 1-3 groups independently selected from F, Cl, Br, CN, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl;Rs, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, -(CH2)nOH, NR4R5, CONR4R5, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, and (Ci-C4)alkyl-O-(Ci-C4)alkyl optionally substituted independently with 1-4 halogen;Y is C or N;m at each occurrence is independently 1, 2, or 3; andn and p, at each occurrence is independently 0, 1, 2, or 3;with the proviso that the compound is notN-((lR,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carb oxami de,2-(4-ethoxyphenyl)-N-((lR, 4R)-2-(2 -hydroxy ethyl)-2-azabicyclo[2.2. l]heptan-5-yl)quinoline-4-carboxamide,N-((lR,4R)-2-benzyl-2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carb oxami de,2-(4-ethoxyphenyl)-N-((lR,5S,6s)-3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[3.1.0]hexan-6-yl)quinoline-4-carboxamide,N-(3-azabicyclo[3.1.0]hexan-6-yl)-2-(4-ethoxyphenyl)quinazoline-4-carboxamide.

[0045] In embodiment 34, provided herein is the compound of embodiment 33 having the structural Formula (I), or a pharmaceutically acceptable salt thereof.

[0046] In embodiment 35, provided herein is the compound of embodiment 33 having Formula (II), or a pharmaceutically acceptable salt thereof.

[0047] In embodiment 36, provided herein is the compound of embodiment 34, wherein W2 is C, or a pharmaceutically acceptable salt thereof.

[0048] In embodiment 37, provided herein is the compound of any one of embodiments 33, 34, and 36, wherein B is selected from the group consisting of:2614326143optionally substituted with (Rs)P

[0049] In embodiment 38, provided herein is the compound of any one of embodiments 33, 34, and 36, wherein B is selected from the group consisting of:2614326143

[0050] In embodiment 39, provided herein is the compound of any one of embodiments 33, 34, 36, and 37, wherein A is selected from the group consisting of:26143acceptable salt thereof.

[0051] In embodiment 40, provided herein is the compound of any one of embodiments 33, 34, 36, and 37, wherein A is selected from the group consisting of:261432614326143

[0052] In embodiment 41, provided herein is the compound of embodiment 33 having theFormula (I), wherein Bis, or a pharmaceutically acceptable salt thereof.

[0053] In embodiment 42, provided herein is the compound of embodiment 41, wherein A is,, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

[0054] In embodiment 43, provided herein is the compound of embodiment 41, wherein A is, optionally substituted independently with 1 to 4 R7, and wherein one or both H atoms in -OCH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.

[0055] In embodiment 44, provided herein is the compound of embodiment 41, wherein A is,HN, optionally substituted independently with 1 to 4 R7, and wherein one or both H atoms in -N(R4)CH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.

[0056] In embodiment 45, provided herein is the compound of embodiment 41, wherein B is, optionally substituted with (Rs)P, or a pharmaceutically acceptable salt thereof.26143

[0057] In embodiment 46, provided herein is the compound of embodiment 41 or embodiment45, wherein A is selected from the group consisting of

[0058] In embodiment 47, provided herein is the compound of any one of embodiments 33, 34,pharmaceutically acceptable salt thereof.

[0059] In embodiment 48, provided herein is the compound of any one of embodiments 33, 34,3and 36, wherein Bis, optionally substituted with (Rs)P, or a pharmaceutically acceptable salt thereof.

[0060] In embodiment 49, provided herein is the compound of any one of embodiments 33, 34, and 36-38, wherein A is phenyl or pyridyl, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

[0061] In embodiment 50, provided herein is the compound of any one of embodiments 33, 34,and 36-38, whereinA is optionally substituted independently with 1 to 5 R7, or a pharmaceutically acceptable salt thereof.26143

[0062] In embodiment 51, provided herein is the compound of any one of embodiments 33, 34,and 36-38, wherein Ais, optionally substituted independently with 1 to 6 R7, or a pharmaceutically acceptable salt thereof.

[0063] In embodiment 52, provided herein is the compound of any one of embodiments 33, 34,NHand 36-38, wherein Ais, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

[0064] In embodiment 53, provided herein is the compound of any one of embodiments 33, 34,and 36-38, wherein Ais, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

[0065] In embodiment 54, provided herein is the compound of any one of embodiments 33, 34,HNand 36-38, wherein Ais, wherein the pyrazole ring is optionally substituted independently with 1 to 3 R7, and one or more H atoms in -OCH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.

[0066] In embodiment 55, provided herein is the compound of any one of embodiments 33, 34,N N-,and 36, whereinB is orR3, optionally substituted with (Rs)Pand A is phenyl optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.26143

[0067] In embodiment 56, provided herein is the compound of any one of embodiments 33, 34,R3and 36, wherein Bis, optionally substituted with (Rs)P, and A is, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

[0068] In embodiment 57, provided herein is the compound of any one of embodiments 33, 34,N NR3and 36, wherein Bis, optionally substituted with (Rs)P, and A is HN, wherein the pyrazole ring is optionally substituted with up to two groups independently selected from (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocycloalkyl, and one or more H atoms in the -OCH2- linker is optionally substituted with deuterium, or a pharmaceutically acceptable salt thereof.

[0069] In embodiment 58, provided herein is the compound of any one of embodiments 33, 34,R3and 36, wherein Bis, optionally substituted with (Rs)Pand A isNH, optionally substituted with up to two groups independently selected from (Ci- Ce)alkyl, (Ci-C6)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocycloalkyl, or a pharmaceutically acceptable salt thereof.26143

[0070] In embodiment 59, provided herein is the compound of any one of embodiments 33, 34,N NR3and 36, wherein Bis, optionally substituted with (Rs)P, and A is, optionally substituted with up to three groups independently selected from (Ci-C6)alkyl, (Ci-C6)haloalkyl, F, Cl, Br, CN, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3- C6)cycloalkyl, (C3-C6)halocycloalkyl, and (C2-Ce)alkynyl, (C2-C6)haloalkynyl, or a pharmaceutically acceptable salt thereof.

[0071] In embodiment 60, provided herein is the compound of embodiment 33 having the Hmstructural Formula (II), wherein Cis, or a pharmaceutically acceptable salt thereof.

[0072] In embodiment 61, provided herein is the compound of embodiment 33 having the R6structural Formula (II), wherein Cis, or a pharmaceutically acceptable salt thereof.

[0073] In embodiment 62, provided herein is the compound of embodiment 33 selected from the group consisting of:2614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143or a pharmaceutically acceptable salt thereof.

[0074] In embodiment 63, provided herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of embodiments 33 to 62, and a pharmaceutically acceptable carrier.

[0075] In embodiment 64, provided herein is a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 33 to 62, or the pharmaceutical composition of embodiment 63, for use in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.

[0076] In embodiment 65, provided herein is use of the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 33 to 62, or the pharmaceutical composition of embodiment 63, in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.

[0077] In embodiment 66, provided herein is use of the compound or a pharmaceutically acceptable salt thereof of any one of embodiments 33 to 62, or the pharmaceutical composition of embodiment 63 in the manufacture of a medicament for use in treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL. In a specific example, the use is in treating an inflammatory condition.26143

[0078] In embodiment 67, provided herein is the use in treating according to any one of embodiments 64-66, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

[0079] In embodiment 68, provided herein is a method of treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, or a method of treating an inflammatory condition, in each instance the method comprising administering an effective amount of a compound of any one of claims 33 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63, to a person in need thereof.

[0080] In embodiment 69, provided herein is the method of embodiment 68, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

[0081] In embodiment 70, provided herein is the method of embodiment 68 or embodiment 69, or the use in treating of embodiments 64-67, wherein said compound or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

[0082] In embodiment 71, provided herein is the method of embodiment 70, wherein said additional therapeutic agent is selected from the group consisting of upadacitinib, deucravacitinib, litifilimab, and dapirolizumab.

[0083] In embodiment 72, provided herein is a compound having the structural Formula (I) or Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Wi and W 2, each is C or N, provided that one and only one of Wi and W2 is N;Ri at each occurrence is independently selected from the group consisting of H, F, Cl, Br, (Ci-C6)alkyl, (Ci-C6)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, CN, OH, and NR4R5;A is selected from the group consisting of:26143(i) an aryl, a heteroaryl having 1-3 ring nitrogen atoms and 0-1 other hetero atoms independently selected from S and O, a pyrazol-O(Ci-C4)alkyl, a pyrazol-S(Ci-C4)alkyl, or an N(pyrazol-(Ci-C4)alkyl)R4, wherein each of aryl and heteroaryl is optionally substituted with 1 to 4 R7; pyrazol ring is optionally substituted with 1 to 3 R7; and one or more H atoms in the (Ci-C4)alkyl is optionally substituted with deuterium;(ii) a monocyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally fused to an aryl or a heteroaryl having 1-2 hetero atoms independently selected from N, O, and S, or optionally in a spiro linkage with a (C3- C6)cycloalkyl; wherein the monocyclic heterocyclyl and the fused aryl or heteroaryl, each is optionally substituted with 1 to 4 R7; and wherein the (C3-C6)cycloalkyl is optionally substituted with 1 to 2 groups selected independently from F, Cl, Br, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, CN, OH, and NR4R5; and(iii) a bicyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally substituted with 1 to 4 R7;wherein each of (i)-(iii) is optionally linked to in Formula (I)or n(R1) in Formula (II) through a linker selected from -(CH2)m, -O(CH2)m. - (CH2)mO, - S(CH2)m, and -N(R3)(CH2)m, wherein the (CH2)mgroups are optionally independently substituted with 1-4 halogen, deuterium, (Ci-C4)alkyl or (Ci-C4)haloalkyl;B is selected from the group consisting of:2614326143(B-k)2614326143R.2 is absent or present; when present, when Y is C, R2 is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, R2 is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;R3, R4, and Rs, at each occurrence is independently selected from H, (Ci-C4)alkyl and (Ci-C4)haloalkyl;Re is absent or present; when present, when Y is C, Re is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, Re is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;R7, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, OH, SH, NR4R5, phenyl, pyridyl, thiazolyl, -COOH, =O, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-Ce)alkynyl, (C2-Ce)haloalkynyl, (C3-Ce)cycloalkyl, (C3-Ce)halocycloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, O(C3-Ce)cycloalkyl, and O(C3-Ce)halocycloalkyl; the phenyl, pyridyl and thiazolyl being optionally substituted with 1-3 groups independently selected from F, Cl, Br, CN, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl;Rs, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, -(CH2)nOH, NR4R5, CONR4R5, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-26143C4)haloalkyl, and (Ci-C4)alkyl-O-(Ci-C4)alkyl optionally substituted independently with 1-4 halogen;Y is C or N;m at each occurrence is independently 1, 2, or 3; andn and p, at each occurrence is independently 0, 1, 2, or 3;• wherein B is selected from (B-a)-(B-h), (B-j)-(B-k) and (B-m)-(B-s);• wherein: (i) when B is (B-i), Y is N, and R2 is -(CH2)nOH or -(CH2)nphenyl, then A cannot be phenyl having one substituent which is O(Ci-C4)alkyl or O(Ci- C4)haloalkyl; and (ii) when B is (B-i), Y is N, R2 is H, and A is phenyl having one substituent which is O(Ci-C4)alkyl or O(Ci-C4)haloalkyl, then n of (Ri)nof Formula (I) is 1; or• wherein: (i) when B is (B-l), Y is N, and R2 is -(CH2)nOH, then A cannot be phenyl having one substituent which is O(Ci-C4)alkyl or O(Ci-C4)haloalkyl; and (ii) when B is (B-l), Y is N, R2 is H, and A is phenyl having one substituent which is O(Ci-C4)alkyl or O(Ci-C4)haloalkyl, then n of (Ri)nof Formula (I) is 1.

[0084] In embodiment 73, provided herein is the compound of embodiment 62, wherein thecompound isDefinitions

[0085] As used herein, unless otherwise specified, the following terms have the following meanings.

[0086] Unsatisfied valences in the text, schemes, examples, structural formulae, and any Tables herein are assumed to have a hydrogen atom or atoms of sufficient number to satisfy the valences.26143

[0087] When a variable appears more than once in any moiety or in any compound of the invention (e.g., aryl, heterocycle, N(R)2), the selection of moieties defining that variable for each occurrence is independent of its definition at every other occurrence unless specified otherwise in the local variable definition.

[0088] As described herein, unless otherwise indicated, the use of a compound in treatment means that an amount of the compound, generally presented as a component of a formulation that comprises other excipients, is administered in aliquots of an amount, and at time intervals, which provide and maintain at least a therapeutic serum level of at least one pharmaceutically active form of the compound over the time interval between dose administrations.

[0089] The phrase “at least one” used in reference to the number of components comprising a composition, for example, "at least one pharmaceutical excipient" means that one member of the specified group is present in the composition, and more than one may additionally be present. Components of a composition are typically aliquots of isolated pure material added to the composition, where the purity level of the isolated material added into the composition is the normally accepted purity level for a reagent of the type.

[0090] Whether used in reference to a substituent on a compound or a component of a pharmaceutical composition the phrase "one or more", means the same as "at least one".

[0091] “Concurrently” and "contemporaneously" both include in their meaning (1) simultaneously in time (e.g., at the same time); and (2) at different times but within the course of a common treatment schedule.

[0092] “Consecutively” means one following the other.

[0093] " Sequentially" refers to a series administration of therapeutic agents that awaits a period of efficacy to transpire between administering each additional agent; this is to say that after administration of one component, the next component is administered after an effective time period after the first component; the effective time period is the amount of time given for realization of a benefit from the administration of the first component.

[0094] “Effective amount” or “therapeutically effective amount” is meant to describe the provision of an amount of at least one compound or of a composition comprising at least one compound which is effective in treating or inhibiting a disease or condition described herein, and thus produce the desired therapeutic, ameliorative, inhibitory or preventative effect. For example, in treating a cancer as described herein with one or more of the compounds of the invention optionally in combination with one or more additional agents, “effective amount” (or “therapeutically effective amount”) means, for example, providing the amount of at least one compound of the invention that results in a therapeutic response in a patient afflicted with the26143disease, condition, or disorder, including a response suitable to manage, alleviate, ameliorate, or treat the condition or alleviate, ameliorate, reduce, or eradicate one or more symptoms attributed to the condition and / or long-term stabilization of the condition, for example, as may be determined by the analysis of pharmacodynamic markers or clinical evaluation of patients afflicted with the condition.

[0095] “Patient” and "subject" means an animal, such as a mammal (e.g., a human being) and is preferably a human being.

[0096] “Prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of a compound of the invention to a compound of the invention, or to a pharmaceutically acceptable salt thereof. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference; the scope of this invention includes prodrugs of the novel compounds of this invention.

[0097] The term “substituted” means that one or more of the moieties enumerated as substituents (or, where a list of substituents are not specifically enumerated, the substituents specified elsewhere in this application) for the particular type of substrate to which said substituent is appended, provided that such substitution does not exceed the normal valence rules for the atom in the bonding configuration presented in the substrate, and that the substitution ultimately provides a stable compound, which is to say that such substitution does not provide compounds with mutually reactive substituents located geminal or vicinal to each other; and wherein the substitution provides a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0098] Where optional substitution by a moiety is described (e.g., "optionally substituted") the term means that if substituents are present, one or more of the enumerated (or default) moieties listed as optional substituents for the specified substrate can be present on the substrate in a bonding position normally occupied by the default substituent, for example, a hydrogen atom on an alkyl chain can be substituted by one of the optional substituents, in accordance with the definition of "substituted" presented herein.

[0099] " Alkyl" means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 10 carbon atoms. "(Ci-Cejalkyl" means an aliphatic hydrocarbon group, which may be straight or branched, comprising 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. Non-26143limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, and t-butyl.

[0100] “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl (up to and including each available hydrogen group) is replaced by a halogen atom. As appreciated by those of skill in the art, “halo” or “halogen” as used herein is intended to include chloro (Cl), fluoro (F), bromo (Br) and iodo (I). Chloro (Cl) and fluoro (F) halogens are generally preferred.

[0101] “Aryl” means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. “Monocyclic aryl” means phenyl.

[0102] “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more substituents, which may be the same or different, as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. “Heteroaryl” may also include a heteroaryl as defined above fused to an aryl as defined above. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl (which alternatively may be referred to as thiophenyl), pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thi enopyridyl, quinazolinyl, thienopyrimidyl, pyrrol opyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term “monocyclic heteroaryl” refers to monocyclic versions of heteroaryl as described above and includes 4- to 7-membered monocyclic heteroaryl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, O, and S, and oxides thereof. The point of attachment to the parent moiety is to any available ring carbon or ring heteroatom. Non-26143limiting examples of monocyclic heteroaryl moieties include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridazinyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl), imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

[0103] “Cycloalkyl” means a non-aromatic fully saturated monocyclic or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms. The cycloalkyl can be optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of multicyclic cycloalkyls include [l.l.l]-bicyclopentane, 1-decalinyl, norbomyl, adamantyl and the like.

[0104] “Heterocycloalkyl” (or "heterocyclyl") means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocycloalkyl groups contain 4, 5 or 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-di oxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S, S-di oxide. “Heterocyclyl” also includes rings wherein =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such =0 groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (orI / npyrrolidone):. As used herein, the term “monocyclic heterocycloalkyl” refers to monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)2. The point of attachment to the parent moiety is to any available ring26143carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. Non-limitingexamples of lower alkyl-substituted oxetanyl include the moiety:

[0105] It is noted that in hetero atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, and there are no N or S groups oncarbon adjacent to another heteroatom.H, there is no -OH attached directly to carbons marked 2 and 5.

[0106] The line -, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry. For example:

[0107] H H H

[0108] The wavy line ~~~, as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:, indicate that the indicated line (bond) may be attached to any of the substitutable ring atoms.

[0109] as used herein indicates a single stereoisomer of unknown configuration (R or S). For example, the single stereoisomer is obtained using chiral chromatography.

[0110] “ Oxo” is defined as an oxygen atom that is double bonded to a ring carbon in a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or other ring described herein, e.g.,

[0111] As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:26143

[0113] One or more compounds of the invention may also exist as, or optionally be converted to, a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J.Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, and hemisolvate, including hydrates (where the solvent is water or aqueous based) and the like are described by E. C. van Tonder et al., AAPS PharmS ci Tech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the compound of the invention in desired amounts of the desired solvent (for example, an organic solvent, an aqueous solvent, water or mixtures of two or more thereof) at a higher than ambient temperature, and cooling the solution, with or without an antisolvent present, at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (including water) in the crystals as a solvate (or hydrate in the case where water is incorporated into the crystalline form).

[0114] The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, and in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.

[0115] This invention also includes the compounds of the invention in isolated and purified form obtained by routine techniques. Polymorphic forms of the compounds of the invention, and of the salts, solvates and prodrugs of the thereof, are intended to be included in the present invention. Certain compounds of the invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropisomers). The compounds of the invention include all isomeric forms thereof, both in pure form and admixtures of two or more, including racemic mixtures.

[0116] In similar manner, unless indicated otherwise, presenting a structural representation of any tautomeric form of a compound which exhibits tautomerism is meant to include all such tautomeric forms of the compound. Accordingly, where compounds of the invention, their salts, and solvates and prodrugs thereof, may exist in different tautomeric forms or in equilibrium26143among such forms, all such forms of the compound are embraced by, and included within the scope of the invention. Examples of such tautomers include, but are not limited to, ketone / enol tautomeric forms, imine-enamine tautomeric forms, and for example heteroaromatic forms such as the following moieties:NH

[0117] Where a reaction scheme appearing in an example employs a compound having one or more stereocenters, the stereocenters are indicated with an asterisk, as shown below:

[0118] Accordingly, the above depiction consists of the following pairs of isomers: (i) Transisomers ((2R,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-1) and ((2S,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC-2); and (ii) Ci s-i somers ((2R,7aR)-2-methylhexahydro-lH-pyrrolizin-7a-yl)m ethanamine (Compound ABC-3) and ((2S,7aS)-2-methylhexahydro-lH-pyrrolizin-7a-yl)methanamine (Compound ABC- 4).ABC-4 IvieABC'2IVIe

[0119] All stereoisomers of the compounds of the invention (including salts and solvates of the compounds of the invention and their prodrugs), such as those which may exist due to asymmetric carbons present in a compound of the invention, and including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may be isolated in a pure form, for example, substantially free of other isomers, or may be isolated as an admixture of two or more stereoisomers or as a racemate. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”,26143“solvate” “prodrug” and the like, is intended to equally apply to salts, solvates and prodrugs, respectively, of isolated enantiomers, stereoisomer pairs or groups, rotamers, tautomers, or racemates of the compounds of the invention.

[0120] Where diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by known methods, for example, by chiral chromatography and / or fractional crystallization, simple structural representation of the compound contemplates all diastereomers of the compound. As is known, enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individually isolated diastereomers to the corresponding purified enantiomers.

[0121] As the term is employed herein, salts of the compounds of the invention, whether acidic salts formed with inorganic and / or organic acids, basic salts formed with inorganic and / or organic bases, salts formed which include zwitterionic character, for example, where a compound contains both a basic moiety, for example, but not limited to, a nitrogen atom, for example, an amine, pyridine or imidazole, and an acidic moiety, for example, but not limited to a carboxylic acid, are included in the scope of the compounds of the invention described herein. The formation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D. C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference.

[0122] The present invention contemplates all available salts, including salts which are generally recognized as safe for use in preparing pharmaceutical formulations and those which may be formed presently within the ordinary skill in the art and are later classified as being “generally recognized as safe” for use in the preparation of pharmaceutical formulations, termed herein as “pharmaceutically acceptable salts”. Examples of pharmaceutically acceptable acid salts include, but are not limited to, acetates, including trifluoroacetate salts, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemi sulfates, heptanoates, hexanoates,26143hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3 -phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like.

[0123] Examples of pharmaceutically acceptable basic salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N, N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine, phenylcyclohexyl-amine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogencontaining groups may be converted to an ammonium ion or quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0124] All such acid and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and basic salts are considered equivalent to the free forms of the corresponding compounds for purposes of the scope of the invention.

[0125] A functional group in a compound termed “protected” means that the group is in modified form to preclude undesired side reactions at the protected site when the protected compound is subjected to particular reaction conditions aimed at modifying another region of the molecule. Suitable protecting groups are known, for example, as by reference to standard textbooks, for example, T. W. Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York.

[0126] In the compounds of the invention, 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 predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (XH) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched26143compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0127] The present invention also embraces isotopically-labeled compounds of the present invention which are structurally identical to those recited herein, but for the fact that a statistically significant percentage of one or more atoms in that form of the compound are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number of the most abundant isotope usually found in nature, thus altering the naturally occurring abundance of that isotope present in a compound of the invention. Examples of isotopes that can be preferentially incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine and chlorine, for example, but not limited to:2H,3H,nC,13C,14C,13N,15N,15O,170,180,31P,32P,35S,18F, and36C1,123I and125I. It will be appreciated that other isotopes also may be incorporated by known means.

[0128] Certain isotopically-labeled compounds of the invention (e.g., those labeled with3H,nC and14C) are recognized as being particularly useful in compound and / or substrate tissue distribution assays using a variety of known techniques. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detection. Further, substitution of a naturally abundant isotope with a heavier isotope, for example, substitution of protium with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the reaction Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent, or by well-known reactions of an appropriately prepared precursor to the compound of the invention which is specifically prepared for such a “labeling” reaction. Such compounds are included also in the present invention.

[0129] The term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0130] The term “pharmaceutical composition” as used herein encompasses both the bulk composition and individual dosage units comprised of one, or more than one (e.g., two), pharmaceutically active agents such as, for example, a compound of the present invention (optionally together with an additional agent as described herein), along with any26143pharmaceutically inactive excipients. As will be appreciated by those of ordinary skill in the art, excipients are any constituent which adapts the composition to a particular route of administration or aids the processing of a composition into a dosage form without itself exerting an active pharmaceutical effect. The bulk composition and each individual dosage unit can contain fixed amounts of the aforesaid one, or more than one, pharmaceutically active agents. The bulk composition is material that has not yet been formed into individual dosage units.

[0131] It will be appreciated that pharmaceutical formulations of the invention may comprise more than one compound of the invention (or a pharmaceutically acceptable salt thereof), for example, the combination of two or three compounds of the invention, each present in such a composition by adding to the formulation the desired amount of the compound in a pharmaceutically acceptably pure form. It will be appreciated also that in formulating compositions of the invention, a composition may comprise, in addition to one or more of compounds of the invention, one or more other agents which also have pharmacological activity, as described herein.

[0132] While formulations of the invention may be employed in bulk form, it will be appreciated that for most applications the formulations of the invention will be incorporated into a dosage form suitable for administration to a patient, each dosage form comprising an amount of the selected formulation which contains an effective amount of one or more compounds of the invention. Examples of suitable dosage forms include, but are not limited to, dosage forms adapted for: (i) oral administration, e.g., a liquid, gel, powder, solid or semi-solid pharmaceutical composition which is loaded into a capsule or pressed into a tablet and may comprise additionally one or more coatings which modify its release properties, for example, coatings which impart delayed release or formulations which have extended release properties; (ii) a dosage form adapted for intramuscular administration (IM), for example, an injectable solution or suspension, and which may be adapted to form a depot having extended release properties; (iii) a dosage form adapted for intravenous administration (IV), for example, a solution or suspension, for example, as an IV solution or a concentrate to be injected into a saline IV bag; (iv) a dosage form adapted for administration through tissues of the oral cavity, for example, a rapidly dissolving tablet, a lozenge, a solution, a gel, a sachets or a needle array suitable for providing intramucosal administration; (v) a dosage form adapted for administration via the mucosa of the nasal or upper respiratory cavity, for example a solution, suspension or emulsion formulation for dispersion in the nose or airway; (vi) a dosage form adapted for transdermal administration, for example, a patch, cream or gel; (vii) a dosage form adapted for intradermal administration, for26143example, a microneedle array; and (viii) a dosage form adapted for delivery via rectal or vaginal mucosa, for example, a suppository.

[0133] For preparing pharmaceutical compositions comprising compounds of the invention, generally the compounds of the invention will be combined with one or more pharmaceutically acceptable excipients. These excipients impart to the composition properties which make it easier to handle or process, for example, lubricants or pressing aids in powdered medicaments intended to be tableted, or adapt the formulation to a desired route of administration, for example, excipients which provide a formulation for oral administration, for example, via absorption from the gastrointestinal tract, transdermal or transmucosal administration, for example, via adhesive skin "patch" or buccal administration, or injection, for example, intramuscular or intravenous, routes of administration. These excipients are collectively termed herein "a carrier". Typically, formulations may comprise up to about 95 percent active ingredient, although formulations with greater amounts may be prepared.

[0134] Pharmaceutical compositions can be solid, semi-solid or liquid. Solid form preparations can be adapted to a variety of modes of administration, examples of which include, but are not limited to, powders, dispersible granules, mini-tablets, beads, which can be used, for example, for tableting, encapsulation, or direct administration. Liquid form preparations include, but are not limited to, solutions, suspensions and emulsions which for example, but not exclusively, can be employed in the preparation of formulations intended for parenteral injection, for intranasal administration, or for administration to some other mucosal membrane. Formulations prepared for administration to various mucosal membranes may also include additional components adapting them for such administration, for example, viscosity modifiers.

[0135] Aerosol preparations, for example, suitable for administration via inhalation or via nasal mucosa, may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable propellant, for example, an inert compressed gas, e.g., nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to a suspension or a solution, for example, for oral or parenteral administration. Examples of such solid forms include, but are not limited to, freeze dried formulations and liquid formulations adsorbed into a solid absorbent medium.

[0136] The compounds of the invention may also be deliverable transdermally or transmucosally, for example, from a liquid, suppository, cream, foam, gel, or rapidly dissolving solid form. It will be appreciated that transdermal compositions can take also the form of creams, lotions, aerosols and / or emulsions and can be provided in a unit dosage form which includes a transdermal patch of any know in the art, for example, a patch which incorporates either a matrix comprising the26143pharmaceutically active compound or a reservoir which comprises a solid or liquid form of the pharmaceutically active compound.

[0137] Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions mentioned above may be found in A. Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20thEdition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

[0138] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparations subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0139] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill in the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.

[0140] In accordance with the present invention, treating a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, treating an inflammatory condition, or disrupting the interaction of SLC15A4 with TASL is accomplished by administering to a patient in need of such intervention an effective amount of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0141] In some embodiments it is preferred for the compound to be administered in the form of a pharmaceutical composition comprising the compound of the invention, or a salt thereof, and at least one pharmaceutically acceptable carrier (described herein). It will be appreciated that pharmaceutical composition of the invention may comprise more than one compound of the invention, or a salt thereof, for example, the combination of two or three compounds of the invention, or, additionally or alternatively, another active agent such as those described herein, each present by adding to the formulation the desired amount of the compound or a salt thereof (or agent, where applicable) which has been isolated in a pharmaceutically acceptably pure form.

[0142] As mentioned above, administration of a compound of the invention to effect treatment of a disease, condition, or disorder, including a disease, condition or disorder that is mediated, at least in part by the interaction of SLC15A4 with TASL, treatment of an inflammatory condition, or disruption of the interaction of SLC15A4 with TASL is preferably accomplished by incorporating the compound into a pharmaceutical composition incorporated into a dosage form, for example, one of the above-described dosage forms comprising an effective amount of at least one compound of the invention (e.g., 1, 2 or 3, or 1 or 2, or 1, and usually 1 compound of the26143invention), or a pharmaceutically acceptable salt thereof. Methods for determining safe and effective administration of compounds which are pharmaceutically active, for example, a compound of the invention, are known to those skilled in the art, for example, as described in the standard literature, for example, as described in the “Physicians’ Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), the Physician’s Desk Reference, 56thEdition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742), or the Physician’s Desk Reference, 57thEdition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosures of which is incorporated herein by reference thereto. The amount and frequency of administration of the compounds of the invention and / or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Compounds of the invention can be administered at a total daily dosage of up to 1,000 mg, which can be administered in one daily dose or can be divided into multiple doses per 24-hour period, for example, two to four doses per day.

[0143] As those of ordinary skill in the art will appreciate, an appropriate dosage level for a compound (or compounds) of the invention will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day or may be administered once or twice per day.

[0144] Those skilled in the art will appreciate that treatment protocols utilizing at least one compound of the invention can be varied according to the needs of the patient. Thus, compounds of the invention used in the methods of the invention can be administered in variations of the protocols described above. For example, compounds of the invention can be administered discontinuously rather than continuously during a treatment cycle.

[0145] In general, in whatever form administered, the dosage form administered will contain an effective amount of at least one compound of the invention, or a salt thereof, which will provide a therapeutically effective serum level of the compound in some form for a suitable period of time such as at least 2 hours, more preferably at least four hours or longer. In general, as is26143known in the art, dosages of a pharmaceutical composition providing a therapeutically effective serum level of a compound of the invention can be spaced in time to provide serum level meeting or exceeding the minimum therapeutically effective serum level on a continuous basis throughout the period during which treatment is administered. As will be appreciated the dosage form administered may also be in a form providing an extended-release period for the compound of the invention which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals. As mentioned above, a composition of the invention can incorporate additional pharmaceutically active components or be administered simultaneously, contemporaneously, or sequentially with other pharmaceutically active agents as may be additionally needed or desired in the course of providing treatment. As will be appreciated, the dosage form administered may also be in a form providing an extended-release period for the compound of the invention which will provide a therapeutic serum level for a longer period, necessitating less frequent dosage intervals.Preparative Examples

[0146] The compounds of invention described herein can be prepared according to the following schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. The specific examples illustrate details for the preparation of the compounds. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in detail. For instance, in some cases, the order of carrying out the steps of reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes and descriptions. These examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure.

[0147] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated: s: singlet, d: doublet, t: triplet, q: quartet, sep: septet, dd: double doublet, dt: double triplet, td: triple doublet, tt: triple triplet, ddd: double double doublet, ddt: double double triplet, dtd: double triple doublet, tdd: triple double doublet, m: multiplet, br: broad, brs: broad singlet, tert: tertiary, h: hours, ACN / ABC:Acetonitrile / Ammonium Bicarbonate, DMSO-de: deuterated dimethyl sulfoxide, LCMS: liquid chromatography-mass spectrometry, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, DCM: dichloromethane, EtOAc: ethyl acetate, TFA: trifluoroacetic26143acid, MeOH: methanol, EtOH: ethanol, EtrN: tri ethylamine, DIPEA: N, N-diisopropylethylamine, m-CPBA: meta-Chloroperoxybenzoic acid, pet ether: petroleum ether, RT: room temperature, Pd(dppf)C12: [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), and HATU: 1-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate, K2CO3: potassium carbonate.

[0148] The reagents used in the Examples are commercially available products unless indicated otherwise. Prepacked columns manufactured by BIOTAGE (Company providing support services in drug discovery and development, Headquarter, Uppsala, Sweden) were used in silica gel column chromatography and basic silica gel column chromatography. AVANCE NEO 400 spectrometer (400 MHz; BR KER) and AVANCE III HD 500 spectrometer (500 MHz;BRUKER) were used for NMR spectra. For a deuterated solvent containing tetramethylsilane, tetramethylsilane was used as the internal reference. For other cases, measurement was performed using an NMR solvent as the internal reference. All 6 values are indicated in ppm. Microwave reaction was performed using an Initiator (trademark) manufactured by BIOTAGE.Intermediate A5: 2-chloro-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Int-A5)POCI3LiOH H2O DIPEA, HATU 0 °C to rt, 5h THF, MeOH, H2O DMF, 0 °C to rt, 3h 0°C to rt, 4h Step C Step D Step E26143Step A: 2-[(acetyloxy)methyl]prop-2-en-l-yl acetate (Int-Al)

[0149] To a stirred solution of methyl 7-bromoquinoline-4-carboxylate (4 g, 0.02 mol) in 1, 4-dioxane (40 mL), potassium carbonate (6 g, 0.05 ml) was added at room temperature. The reaction mixture was degassed and purged with nitrogen gas. Then, to this reaction mixture 1,1'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (0.5 g, 0.8 mmol) and 2,4,6-Trimethyl-1,3,5,2,4,6-trioxatriborinane (5 mL, 0.04 mol) were added at room temperature in a sealed vial. The reaction mixture was stirred at 100 °C. The reaction mixture was cooled to room temperature, quenched with water (200 mL) and extracted with EtOAc (2 x 150 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (13% EtOAc / petroleum ether) to afford 2-[(acetyloxy)methyl]prop-2-en-l-yl acetate (Int-Al) as a solid. MS: 202 (M+H)+.StepB: 4-(methoxycarbonyl)-7-methylquinoline 1 -oxide (Int-A2)

[0150] To a stirred solution of Int-Al (2 g, 0.01 mol) in DCM (30 mL), m-CPBA (2 g, 0.01 mol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature. The reaction was quenched with water (150 mL), basified with aqueous saturated NaHCOs (pH=8) and extracted with DCM (2 x 80 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (34% EtOAc / petroleum ether) to afford 4-(methoxycarbonyl)-7-methylquinoline 1 -oxide (Int-A2) as a solid. MS: 218 (M+H)+.Step C: Methyl 2-chloro-7-methylquinoline-4-carboxylateacetate (Int-A3)

[0151] To Int-A2 (1.8 g, 7.1 mmol) in a round bottom flask, POCh (10 mL, 0.11 mol) was added at 0 °C. The reaction mixture was stirred at room temperature. Reaction was quenched with ice and extracted with EtOAc (2 x 100 mL). The organic layers were combined, washed with aqueous saturated NaHCOs, saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (9% EtOAc / petroleum ether) to afford methyl 2-chloro-7-methylquinoline-4-carboxylateacetate (Int-A3) as a solid. MS: 236 (M+H)+.Step D: 2-chloro-7-methylquinoline-4-carboxylic acid (Int-A4)

[0152] To a stirred solution of Int-A3 (1.4 g, 5.8 mmol) in a mixture of THF (15 mL), MeOH (5 mL) and H2O (5 mL), LiOH H2O (0.97 g, 23 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature. The reaction mixture was quenched with water (100 mL), acidified with aqueous saturated KHSO4 solution (pH=3) and extracted with EtOAc (2 x 100 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated26143under reduced pressure to afford 2-chloro-7-methylquinoline-4-carboxylic acid (Int-A4) as a solid. MS: 222 (M+H)+.Step E: 2-chloro-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Int-A5)

[0153] To a stirred solution of Int-A4 (300 mg, 1.25 mmol) and quinuclidin-4-amine (930 mg, 3.74 mmol) in DMF (8 mL), DIPEA (1.74 mL, 9.96 mmol) and HATU (710 mg, 1.87 mmol) were added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature, quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 80 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on Cl 8 silica (60-100% MeCN / water w / 0.1% TFA) to afford 2-chloro-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Int-A5) as a solid. MS: 330 (M+H)+.

[0154] The example compound shown in Table 1 below was prepared in a similar manner to Int-A5 above using the corresponding amine for Step E.Table 1Compound Structure Compound Name [M+H]+[Found] Int-A6 2-chloro-N-(4- 359Q / methoxybicyclo[2.2.2]octan-l- yl)-7-methylquinoline-4- carb oxami deIntermediate AW3: 3-chloro-6-methylisoquinoline-l-carboxylic acid (Int-AW3)Trimethylboroxine Pd(dtbpf)CI2> K2CO31,4-dioxane, 100 °C, 3hStep A lnt-AW1POCI30 °C to rt, 5hStep C26143Step A: ethyl 6-methylisoquinoline-l -carboxylate (Int-AWl)

[0155] To a stirred solution of methyl 6-bromoisoquinoline-l-carboxylate (500 mg, 1.88 mmol), in 1, 4-dioxane (4 mL), potassium carbonate (649 mg, 4.70 mmol) was added at room temperature. The reaction mixture was degassed and purged with nitrogen gas. To this reaction mixture, l,l'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (61.2 mg, 0.094 mmol) and 2,4,6-Trimethyl-l,3,5,2,4,6-trioxatriborinane (0.42 mL, 3.01 mmol) were added at room temperature in a sealed vial. The reaction mixture was stirred at 100 °C, cooled to room temperature, quenched with water (20 mL) and extracted with EtOAc (2 x 15 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (13% EtOAc / petroleum ether) to afford Int-AWl as a solid. MS: 202 (M+H)+.Step B: 1 -(ethoxy carbonyl) -6-methylisoquinoline 2-oxide (Int-AW2)

[0156] To a stirred solution of Int-AWl (150 mg, 745 pmol) in DCM (2 mL), m-CPBA (386 mg, 2.24 mmol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature, quenched with water (5 mL), basified with aqueous saturated NaHCCh (pH=8) and extracted with DCM (2 x 20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-25% MeOH / DCM) to Int-AWl as a solid. MS: 218 (M+H)+.Step C: Ethyl 3-chloro-6-methylisoquinoline-l-carboxylate (Int-AW3)

[0157] To Int-AW2 (40.0 mg, 184 pmol) in a round bottom flask, POCI3 (305 pL, 3.31 mmol) was added at 0 °C. The reaction mixture was warmed to room temperature then heated at 60 °C. Next, the reaction mixture was quenched with ice and extracted with DCM (2 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Int-AW3 as a solid. MS: 236 (M+H)+.26143Intermediate Bl: 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4- carboxylic acid (Int-Bl)lnt-B1

[0158] To a stirred solution of 6-m ethylindoline-2, 3 -di one (1.5 g, 9.3 mmol) and l-(4-(2,2,2-trifluoroethoxy)phenyl)ethan-l-one (2.0 g, 9.3 mmol) in ethanol (19 mL) and water (19 mL), potassium hydroxide (5.2 g, 93 mmol) was added. The reaction was heated at 80 °C. An LCMS of the reaction indicated conversion to the desired product. The reaction mixture was cooled and acidified to a pH of 2 with IM HCl(aq). The precipitate that formed was collected on a frit and dried on a lyophilizer to yield 7-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxylic acid (Int-Bl) as a solid. MS: 362 (M+H)+.

[0159] The example compounds in Table 2 below were prepared in a similar manner to Int-Bl above.Table 2Compound Structure Compound Name [M+H]+[Found]Int-B2 0 OH 7-chloro-2-(3- 400fluoro-4-(2,2,2- trifluoroethoxy)phenFyl)quinoline-4- carboxylic acidInt-B3 0 OH 7-chloro-2-(4- 328ethoxyphenyl)quinoline-4-carboxylicacidInt-B4 0 OH 7-chloro-2-(4-(2,2,2- 382trifluoroethoxy)phenyl)quinoline-4- carboxylic acidF26143Compound Structure Compound Name [M+H]+[Found] Int-B5 0 OH 7-chloro-2-(3- 362 chloro-4- ethoxyphenyl)quinolciine-4-carboxylicacidInt-B6 0 OH 7-chloro-2-(4- 346 ethoxy-3- fluorophenyl)quinoliCl NFne-4-carboxylic acidInt-B7 0 OH 2-(4-ethoxyphenyl)- 3627- (trifluoromethyl)qui noline-4-carboxylicacidInt-B8 o OH 2-(4-ethoxyphenyl)- 3087-methylquinoline- 4-carboxylic acid jfY jIQO^In-B9 o OH 7-methyl-2-(4- 362 (2,2,2- JTY J trifluoroethoxy)phen yl)quinoline-4- carboxylic acidInt-BlO 0 OH 6-methyl-2-(4- 362 (2,2,2- trifluoroethoxy)phen yl)quinoline-4- carboxylic acidInt-Bll 0 OH 6,7-dimethyl-2-(4- 376 (2,2,2- trifluoroethoxy)phen Vo yl)quinoline-4- carboxylic acidu W\y~^F26143Compound Structure Compound Name [M+H]+[Found]Int-B12 O OH 7-chloro-2-(6- 329ethoxypyri din-3 - yl)quinoline-4- carboxylic acidIntermediate Cl: tert-butyl 2-chloro-6,7-dihvdropyrazolo[l,5-a1pyrazine-5(4H)-carboxylate (Int-Cl)Lid, CuCI, t-butyl nitrite Boc^ \- * i rVciMeCN50 °C, 2.5hlnt-C1

[0160] To a mixture of cuprous chloride (0.93 g, 9.4 mmol), Lithium chloride (0.33 g, 7.9 mmol) and MeCN (45 mL), tert-Butyl nitrite (0.97 g, 9.4 mmol) was added and stirred at 23 °C. To the above suspension a solution of tert-butyl 2-amino-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (1.5 g, 6.3 mmol) in MeCN (15 mL) was added and the mixture was stirred at 50 °C. The reaction mixture was diluted with EtOAc (50 mL), and NaHCCh (30 mL) followed by extraction of the aqueous layer with EtOAc (2 x 40 mL). The organic layers were combined, washed with brine (30 mL) and water (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica eluting with 40% heptane / EtOAc and the relevant fractions were combined to afford tert-butyl 2-chl oro-6, 7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (Int-Cl). MS: 258 (M+H)+.Intermediate D2: 2-(prop-l-vn-l-yl)-4,5,6,7-tetrahvdropyrazolo[l,5-a]pyrazine (Int-D2)— = — Sn(nBu)3Pd-PEPPSI-IHept-CICsF, MS (4A) 1,4-dioxane, 80 °C DCM, 25 °Clnt-C1 lnt-D1 Step B lnt-D2 Step A: tert-butyl 2-(prop-l-yn-l-yl)-6, 7-dihydropyrazolo[l,5-a]pyrazine-5(4H)- carboxylate (Int-Dl)

[0161] Tert-butyl 2-chloro-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (Int-Cl) (100 mg, 0.38 mmol) was stirred in dioxane (3.9 mL). N2 was bubbled through the reaction mixture. Tributyl(prop-l-yn-l-yl)stannane (177 pL, 0.58 mmol), cesium fluoride (118 mg, 776 pmol), (SP-4-l)-[l,3-Bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-26143ylidene]dichloro(3-chloropyridine-kappaN)-Palladium (37 mg, 0.038 mmol) and Molecular Sieves 4A (20 mg) were added. N2 was bubbled through the reaction mixture and heated at 80 °C. The reaction was poured into saturated KF solution and extracted with ethyl acetate. The organic layer was washed with saturated KF solution, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica eluting with 5-50% Ethyl Acetate: Heptane to afford tert-butyl 2-(prop-l-yn-l-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (Int-Dl). MS: 262 (M+H)+.Step B: 2-(prop-l-yn-l-yl)-4,5, 6, 7-tetrahydropyrazolo [ 1,5-a]pyrazine (Int-D2)

[0162] Tert-butyl 2-(prop-l-yn-l-yl)-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (Int-Dl) (36 mg, 0.14 mmol) was stirred in anhydrous DCM (1.4 mL) and TFA (0.21 mL, 2.8 mmol) at 25 °C. The reaction mixture was evaporated in vacuo with DCM to afford 2-(prop-l-yn-l-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Int-D2). MS: 162 (M+H)+.Intermediate E2: 7-methyl-2-(2-methyl-6,7-dihydropyrazolo[L5-a]pyrazin-5(4H)- yl)quinoline-4-carboxylic acid (Int-El)Pd-PEPPSI-IHept-CI CS2CO3 THF, 90 °C Step AInt-A3 Step A: Methyl 7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1, 5-a] pyr azin-5 (4H)- yl)quinoline-4-carboxylate (Int-El )

[0163] To a solution of methyl-2-chloro-7-methylquinoline-4-carboxylate (Int-A3) (1.7 g, 7.3 mmol) and pyrazolo[l,5-a]pyrazine,4,5,6,7-tetrahydro-2-methyl (1.0 g, 7.3 mmol) in THF (73 mL), cesium carbonate (7.1 g, 22 mmol) was added and N2 was bubbled through the solution. Then (SP-4-l)-[l,3-Bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-kappaN)-Palladium (0.11 g, 0.11 mmol) was added and the mixture was heated to 100 °C. The reaction was quenched by adding water (100 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography over silica gel (-40% EtOAc / Heptane) to afford Int-El. MS: 336 (M+H)+.26143Step B: 7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinolme-4- carboxylic acid (Int-E2)

[0164] To a solution of methyl 7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylate (Int-El) (775 mg, 2.30 mmol) in THF (7.37 mL) and water (1.84 mL), lithium hydroxide (276 mg, 11.5 mmol) was added and the reaction was stirred at 20 °C. The reaction was quenched by the addition of HC1 (1.92 mL, 6 M) and directly concentrated to afford Int-E2. MS: 323 (M+H)+.

[0165] The example compounds in Table 3 below were prepared in a similar manner to Int-E2 above with the appropriate Step A conditions.Table 3Compound Structure Compound Name [M+H]+Alternative [Found] Step A Conditions Int-E3 O OH (R)-7-methyl-2-(7- 323 P(t-Bu)3 Pd G4 methyl-6,7- (0.1 equiv), dihydropyrazolo [1,5- 1,4-dioxanes, a]pyrazin-5(4H)- 100 °C yl)quinoline-4- carboxylic acidInt-E4 0 OH (S)-7-methyl-2-(7- 323 P(t-Bu)3 Pd G4 methyl-6,7- (0.1 equiv), dihydropyrazolo [1,5- 1,4-dioxanes, a]pyrazin-5(4H)- 100 °C yl)quinoline-4- carboxylic acidInt-E5 0 OH 2-( 1,3-dimethyl-l, 4,5,7- 337tetrahydro-6H- pyrazolo [3,4-c]pyridin- 6-yl)-7-methylquinoline- 4-carboxylic acidLInt-E6 O OH 7 -methyl-2-(6-methyl- 320l,3-dihydro-2H- pyrrolo [3,4-c]pyridin-2- yl)quinoline-4- carboxylic acid26143Compound Structure Compound Name [M+H]+Alternative [Found] Step A Conditions Int-E7 O OH (R)-7-methyl-2-(2- 363methyl-2- phenylmorpholino)quinoJCOL line-4-carboxylic acid^0Intermediate F2: 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4- carboxylic acid (Int-F2)Step A: Methyl 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylqumolme-4- carboxylate (Int-Fl)

[0166] Methyl 2-chloro-7-methylquinoline-4-carboxylate (Int-A3) (2 g, 8 mmol) was stirred in dioxane (200 mL) and water (20 mL), and N2 was bubbled through the reaction mixture. Next, (3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (3 g, 10.0 mmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.5 g, 0.6 mmol) and potassium phosphate, tribasic (5 g, 30.0 mmol) were added. N2 was bubbled through the reaction mixture, and the reaction was stirred at 80 °C. The reaction mixture was cooled down to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was loaded onto silica gel and purified by silica gel column chromatography (5% to 50% EtOAc in Heptanes) to afford methyl 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxylate (Int-Fl). MS: 394 (M+H)+.Step B: 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxylic acid (Int-F2)

[0167] Methyl 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxylate (Int-Fl) (500 mg, 1.27 mmol) was stirred in anhydrous THF (5.72 mL) and water (636 pL). LiOH (152 mg, 6.36 mmol) was added, and the reaction mixture was stirred at 25 °C. The26143reaction was quenched with 2M HC1 (3.2 mL), the product extracted in EtOAc, and the organic layer was dried over sodium sulfate and evaporated in vacuo to afford 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxylic acid (Int-F2). MS: 380 (M+H)+.Intermediate II: 2-(3-oxa-8-azabicvclo[3.2.1]octan-8-yl)-7-methylquinoline-4-carboxylic acid (Int-Il)

[0168] To a pressure tube, 2-chloro-7-methylquinoline-4-carboxylic acid (550 mg, 2.48 mmol), cesium carbonate (2.43 g, 7.44 mmol), 3-Oxa-8-azabicyclo[3.2.1]octaneHydrochloride (446 mg, 2.98 mmol) and (SP-4-l)-[l,3-Bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-kappaN)-Palladium (121 mg, 124 pmol) were added. Then 1,4-Dioxane (10 mL) was added, the mixture purged under positive flow of nitrogen, and then the reaction was heated at 105 °C. The reaction was cooled down and the mixture was filtered over celite and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was re-diluted in EtOAc (2 mL), and the desired product was precipitated out using Et2O (2 x 20 mL). The mixture was filtered to afford Int-Il as a solid. MS: 299 (M+H)+.

[0169] The example compounds in Table 4 below were prepared in a similar manner to Int-Il above with the appropriate amine and starting intermediate.Table 4Compound Structure Compound Name M+H]+[Found] Int-I2 O OH 7-methyl-2-(2-(o- 363tolyl)morpholino)quinoline-4- carboxylic acid26143Compound Structure Compound Name M+H]+[Found] Int-I3 O OH (R)-7-methyl-2-(2- 349phenylmorpholino)quinoline-4- carboxylic acidInt-I4 0 OH 0 6-methyl-3-(2-methyl-6,7- 322dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)isoquinoline- 1 - XXA carboxylic acidO-trIntermediate L2: L3,5-trimethyl-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine (Int-L2)trimethylboroxine PddtbpfCI2, K2CO3PtO2, H2, ACOH Dioxane: H2O (3:1), 80 °C MeOH, 23 °CStep AInt-L1 Step B lnt-L2 Step A: l,3,5-trimethyl-lH-pyrazolo[3,4-c]pyridine (Int-Ll)

[0170] To a stirred solution of 5-bromo-l,3-dimethyl-lH-pyrazolo[3,4-c]pyridine (250 mg, 1.11 mmol) in 1,4-Dioxane (2.07 mL), potassium carbonate (382 mg, 2.76 mmol) was added and the resulting mixture degassed with nitrogen gas. Then, l,l'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (28.8 mg, 44.2 pmol) and 2,4,6-Trimethyl-l,3,5,2,4,6-trioxatriborinane (278 mg, 2.21 mmol) were added. The reaction was stirred at 80 °C, cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% 3:1 EtOAc: EtOH / Hexanes) to afford the desired product l,3,5-trimethyl-lH-pyrazolo[3,4-c]pyridine (Int-Ll). MS: 162 (M+H)+.Step B: 1, 3, 5-trimethyl-4, 5, 6, 7-tetrahydro-lH-pyrazolo [ 3, 4-c Jpyridine (Int-L2)

[0171] A solution of l,3,5-trimethyl-lH-pyrazolo[3,4-c]pyridine (16.6 mg, 103 pmol) in MeOH (1.03 mL) and acetic acid (58.9 pL 1.03 mmol) was sparged with nitrogen. Platinic oxide (2.34 mg, 10.3 pmol) was added and H2 was bubbled through the reaction. The reaction mixture was stirred under a H2 atmosphere at room temperature. The reaction was filtered through celite, washed with DCM / MeOH (1:1, 10 x 3 mL), and the filtrate was concentrated to give 1,3,5-trimethyl-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine. MS: 166 (M+H)+.26143Intermediate M2: l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (Int-M2) / Pr-I, NaH DMF, 80 °C THF, 0 °C Step A Step BStep A: ethyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate (Int-Ml)

[0172] A solution of ethyl 3-methyl-lH-pyrazole-5-carboxylate (7.35 g, 47.7 mmol) in DMF (100 mL) was cooled to 0 °C. NaH (1.72 g, 71.5 mmol) was slowly added at 0 °C and the mixture was stirred. Then, 2-iodopropane (14.3 mL, 143 mmol) was added and the reaction mixture was heated to 80 °C and stirred. The reaction was cooled to 0 °C and quenched with water (100 mL). Ethyl acetate (50 mL) was added to the mixture, and the organic layer was separated out. The aqueous layer was re-extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography (0 to 30% ethyl acetate in hexanes), affording ethyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate (Int-Ml). MS: 197 (M+H)+.StepB: (l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (Int-M2)

[0173] Ethyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate (1.0 g, 5.1 mmol) was dissolved in THF (25 mL) and cooled to 0 °C. LiAlEL (0.39 g, 10 mmol) was slowly added to the solution, and the reaction was stirred at 0 °C. The reaction was quenched with MeOH (10 mL) and diluted with water (30 mL) and ethyl acetate (30 mL). The mixture was filtered through a pad of celite. The organic layer was separated out, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford (l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (Int-M2). MS: 155 (M+H)+.

[0174] The example compounds in Table 5 below were prepared in a similar manner to Int-M2 above with the appropriate starting ester and alkyl halide.Table 5Compound Structure Compound Name [M+H]+[Found]Int-M3 (3 -(difluorom ethyl)- 1 - 191HOi sopropy 1 - 1 H-py razol -5 - ^Q yl)methanol / - FF26143Compound Structure Compound Name [M+H]+[Found] Int-M4 (3 -cyclopropyl - 1 -i sopropyl- 1811 H-py razol - 5 -y l)methanolInt-M5 (3 -methyl- 1 -(pentan-3 -yl)- 1831 H-py razol - 5 -y l)methanolInt-M6 (3 -methyl - 1 -propyl - 1 H- 155py razol - 5 -y 1 )m ethanolInt-M7 (l-cyclopropyl-3-methyl- 1531 H-py razol - 5 -y l)methanolHO JXN \TM '7NInt-M8 ( 1 -ethyl -3 -methyl - 1 H- 141py razol - 5 -y 1 )m ethanolInt-M9 (3-cyclopropyl-l-methyl- 153HH6 1 H-py razol - 5 -y l)methanolIntermediate 02: (lR.3R.4R)-4-(trifluoromethyl)-l-azabicyclor2.2.11heptan-3-amine tint- 02)TEA Pd / C, H2DCM, THF 23 °C EtOH, EtOAc, 23 °C Step A Step B lnt-O1 lnt-O2Isomers A-D Step A: benzyl (4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-yl)carbamate (Int-01)

[0175] To 4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-amine, 2HC1 (1.230 g) in THF (36 mL), carbobenzoxy chloride (829.1 mg, 740.9 pL), triethylamine (1.475 g, 2.03 mL, 3 Eq, 14.58 mmol) and DCM (20 mL) were added. The reaction was stirred. Next, carbobenzoxy chloride26143(414.5 mg, 370.4 pL, 0.5 Eq, 2.430 mmol) was added and the reaction was stirred. The reaction mixture was washed with brine (20 ml) and then extracted with DCM (3 x 10ml). The biphasic mixture was passed through a phase separator cartridge and concentrated under reduced pressure. The product was purified by column chromatography on silica column (0-50% MeOH / DCM). The desired fractions were pooled and concentrated under reduced pressure to afford benzyl (4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-yl)carbamate. Chiral resolution of the desired diastereomer was achieved by chiral preparative SFC separation using Chiral SFC column (ADIT, 80%:20% CC>2: IPA+ 0.1% NFUOH modifier) to afford isomers A-C (faster eluting) and desired isomer D (slower eluting).Step B: (lR,3R,4R)-4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-amine (Int-O2)

[0176] Pd / C (128 mg, 10% Wt, 0.2 Eq, 120 pmol) was placed in a microwave vial. The vial was sealed, and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. A solution of benzyl (4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-yl)carbamate (189 mg, 1 Eq, 601 pmol) (Isomer D from above) in Ethanol (3.01 mL) and EtOAc (3.01 mL) were added. The resulting mixture was stirred under an atmosphere of H2 with an H2 balloon, after which the mixture was filtered through a celite pad. The celite pad was washed with EtOAc (5mL 2x) and the filtrate was concentrated in vacuo to provide (lR,3R,4R)-4-(trifluoromethyl)-l-azabicyclo[2.2.1]heptan-3-amine (Int-O2). 1HNMR (500 MHz, CDC13) 6 3.10 -2.89 (m, 3H), 2.80 (d, J = 10.1 Hz, 1H), 2.50 (dd, J = 39.2, 11.2 Hz, 3H), 1.96 (t, J = 11.0 Hz, 1H), 1.25 (s, 1H). Absolute configuration was assigned based on three-dimensional cryogenic electron microscopy analysis of a ligand containing Int-O2 bound to SLC15A4.26143Intermediate P4: (R / S)-4-(difluoromethyl)quinuclidin-3-amine (Int-P4)lnt-P4 lnt-P3Step A: Methyl 4-(difluoromethyl)-l-(2-ethoxy-2-oxoethyl)piperidine-4-carboxylate (Int- Pl)

[0177] To a vial with methyl 4-(difluoromethyl)piperidine-4-carboxylate, HC1 (500 mg, 1 Eq, 2.18 mmol), potassium carbonate (316 mg, 1.05 Eq, 2.29 mmol) DMF (4.35 mL) and tetrabutylammonium bromide (702 mg, 1 Eq, 2.18 mmol) were added. Next, ethyl 2-bromoacetate (382 mg, 254 pL, 1.05 Eq, 2.29 mmol) was added dropwise and the reaction was stirred, filtered and concentrated. The residue was purified by column chromatography on silica (0- 100%| EtOAc / hexanes). The desired fractions were pooled and concentrated under reduced pressure to afford methyl 4-(difluoromethyl)-l-(2-ethoxy-2-oxoethyl)piperidine-4-carboxylate (Int-Pl). MS: 280 (M+H)+.Steps B and C: 4-(difluoromethyl)quinuclidin-3-one (Int-P3)

[0178] Methyl 4-(difluoromethyl)-l-(2-ethoxy-2-oxoethyl)piperidine-4-carboxylate (0.21 g, 1 Eq, 0.75 mmol) was placed in a vial and the vial was sealed and placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. The vial was brought into the glove box and potassium 2-methylpropan-2-olate (0.13 g, 1.5 Eq, 1.1 mmol) was added followed by toluene (5.0 mL). The vial was sealed and removed from the glovebox. The reaction was stirred at 110 °C. The mixture was cooled to room temperature and extracted by cone. HC1. The aqueous layer was separated, and the aqueous layer was heated to 110 °C to afford decarboxylation. All solvents were evaporated through rotary evaporation to give 4-(difluoromethyl)quinuclidin-3-one (Int-P3). Step B: MS: 248 (M+H)+. Step C: MS: 176 (M+H)+.26143Step D: 4-(difluoromethyl)quinuclidin-3-amine (Int-P4)

[0179] 4-(difluoromethyl)quinuclidin-3-one (0.19 g, 1 Eq, 1.1 mmol) was added to a vial. The vial was sealed, and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. Ammonia (1.5 g, 12 mL, 7 molar, 80 Eq, 87 mmol) was added and the solution was stirred at 70 °C. After that the reaction mixture was cooled down to room temperature and purged with N2. Next, Pd / C (0.12 g, 10% Wt, 0.1 Eq, 0.11 mmol) was added and the reaction was purged further with N2 and then purged with H2 with a H2 balloon. The reaction mixture was stirred under a H2 balloon. Next, the reaction mixture was filtered over celite and then concentrated in vacuo. The crude reaction mixture was placed in a vial, the vial sealed, and its contents placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles. Ammonia (1.5 g, 12 mL, 7 molar, 80 Eq, 87 mmol) was added and the solution was stirred at 70 °C. After that the reaction mixture was cooled down to room temperature and purged with N2. Next, Pd / C (0.12 g, 10% Wt, 0.1 Eq, 0.11 mmol) was added and the reaction was purged further with N2 and then purged with H2 with a H2 balloon. The reaction mixture was stirred under a H2 balloon, filtered over celite and then concentrated in vacuo to give 4-(difluoromethyl)quinuclidin-3 -amine (Int-P4). MS: 177 (M+H)+.Intermediate R2: (l-isopropyl-3-(methylamino)-lH-pyrazol-5-yl)methanol (Int-R2)Me-B(OH)2Cu(OAc)2 pyrdine '^XO DMF, 60 °C Step A / Step Blnt-R1 lnt-R2Step A: Ethyl l-isopropyl-3-(methylamino)-lH-pyrazole-5-carboxylate (Int-Rl)

[0180] Ethyl 3 -amino-l-isopropyl-lH-pyrazole-5-carboxylate (350 mg, 1.77 mmol) was dissolved in DMF (15 mL) and methylboronic acid (319 mg, 5.32 mmol), copper diacetate (645 mg, 3.5 mmol), and pyridine (0.86 mL, 10.6 mmol) were added followed by stirring at 60 °C. Next, the reaction mixture was quenched with water and extracted with EtOAc (2 x 30 mL). The organic layers were combined, dried over anhydrous MgSCh, filtered, and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0 to 60% ethyl acetate in hexanes) to afford ethyl l-isopropyl-3-(methylamino)-lH-pyrazole-5-carboxylate (Int-Rl). MS: 212 (M+H)+.26143Step B: (1 -isopropyl-3-(methylamino)-lH-pyrazol-5-yl)methanol (Int-R2)

[0181] Ethyl l-isopropyl-3-(methylamino)-lH-pyrazole-5-carboxylate (239 mg, 1.13 mmol) was dissolved in THF (11 mL) and cooled to 0 °C. Next, LiAlEU (2.0 M in THF, 1.13 mL, 2.26 mmol) was slowly added to the solution and the reaction was stirred at 0 °C. The reaction was quenched with MeOH (10 mL) and diluted with water (30 mL) and ethyl acetate (30 mL). The mixture was filtered through a pad of celite. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford (l-isopropyl-3-(methylamino)-lH-pyrazol-5-yl)methanol (Int-R2). MS: 170 (M+H)+.Intermediate XI: Ethyl 7-methoxy-2-oxo-L2-dihvdroquinoline-4-carboxylate (Int-Xl)lnt-X1

[0182] To 7-methoxy-2-oxo-l,2-dihydroquinoline-4-carboxylic acid (1.00 g, 4.56 mmol) and ethanol (40 mL), thionyl chloride (8 mL) was added dropwise. The resulting suspension was heated to 90 °C. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was redissolved in DCM, washed with saturated NaHCCh, dried over MgSCh, filtered, and concentrated under reduced pressure to yield ethyl 7-methoxy-2-oxo-l,2-dihydroquinoline-4-carboxylate (Int-Xl). 'H NMR. (500 MHz, CDCh) 88.25 (d, J= 9.1 Hz, 1H), 7.05 (s, 1H), 6.87 (d, J= 9.2 Hz, 1H), 6.71 (s, 1H), 4.45 (q, J= 7.1 Hz, 2H), 3.91 (s, 3H), 1.43 (t, J= 7.1 Hz, 3H). MS: 248 (M+H)+.

[0183] The example compounds in Table 6 below were prepared in a similar manner to Int-Xl above with the appropriate starting building block.Table 6Compound Structure Compound Name [M+H]+[Found] Int-X2 O OEt Ethyl 6-fluoro-2-oxo-l,2- 236dihydroquinoline-4- carb oxy lateT riH26143Compound Structure Compound Name [M+H]+[Found] Int-X3 0 OEt Ethyl 8-chloro-2-oxo-l,2- 252dihydroquinoline-4- carb oxy lateIlHInt-X4 0 OEt Ethyl 6-methyl-2-oxo-l,2- 232dihydroquinoline-4- carb oxy lateHInt-X5 ° OEt Ethyl 8-fluoro-2-oxo-l,2- 236dihydroquinoline-4- carb oxy lateOi l1 HInt-X6 O OEt Ethyl 6-chloro-2-oxo-l,2- 252dihydroquinoline-4- carb oxy lateHInt-X7 O OEt Ethyl 7-fluoro-2-oxo-l,2- 236dihydroquinoline-4- carb oxy lateF'^^^N'^OHInt-X8 0 OEt Ethyl 7-chloroquinoline-4- 236carb oxy lateIntermediate Y2: Ethyl 2,7-dichloroquinoline-4-carboxylate (Int-Y2)mCPBA POCI3DCM, 0 °C~rt, 3 h rt, overnightStep A Step B Step A: 7 -Chlor o-4-(ethoxycarbonyl) quinoline 1-oxide (Int-Yl)

[0184] A solution of ethyl 7-chloroquinoline-4-carboxylate (Int-X8, 1.12 g, 4.77 mmol) in DCM (50 mL) was cooled to 0 °C. Then, mCPBA (1.60 g, 77 wt%, 7.15 mmol) was added portionwise. The resulting solution was stirred at 0 °C, warmed to room temperature and stirred. The reaction mixture was diluted with DCM, washed with saturated NaHCCh, dried over MgSCh, filtered, and26143concentrated under reduced pressure to yield 7-chloro-4-(ethoxycarbonyl)quinoline 1 -oxide (Int-Yl). MS: 252 (M+H)+.Step B: Ethyl 2, 7-dichloroquinoline-4-carboxylate (Int-Y2)

[0185] To 7-chloro-4-(ethoxycarbonyl)quinoline 1-oxide (Int-Yl), POCh (12 mL) was added. The resulting solution was stirred at room temperature and then concentrated under reduced pressure. The crude product was purified via silica gel chromatography (elution: 20-100% DCM / hexanes a 0-10% EtOAc / DCM) to yield ethyl 2,7-dichloroquinoline-4-carboxylate (Int-Yl). 'HNMR (500 MHz, CDCI3) 88.77 (d, J= 9.2 Hz, 1H), 8.10 (d, J= 2.1 Hz, 1H), 7.93 (s, 1H), 7.64 (dd, J= 9.2, 2.2 Hz, 1H), 4.54 (q, J= 7.1 Hz, 2H), 1.50 (t, J= 7.2 Hz, 3H). MS: 270 (M+H)+.Intermediate Z2: (l-Isopropyl-3-methyl-lH-pyrazol-5-yl)methan-d2-ol (Int-Z2)LiAID4THF, 0 °C rt, 30 minStep BStep A: Methyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate (Int-Zl)

[0186] To a solution of methanol (1.00 mL, 24.7 mmol) and NEt3 (1.40 mL, 10.0 mmol) in DCM (12 mL), l-isopropyl-3-methyl-lH-pyrazole-5-carbonyl chloride (550 mg, 2.95 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, diluted with DCM, washed sequentially with saturated NH4CI, saturated NaHCCh, and brine, dried over MgSCh, filtered, and concentrated under reduced pressure to yield methyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate (Int-Zl). 'HNMR (500 MHz, CDCI3) 66.74 (s, 1H), 5.39 (dt, J= 13.3, 6.7 Hz, 1H), 3.96 (s, 3H), 2.29 (s, 3H), 1.49 (d, J= 6.6 Hz, 6H). MS: 183 (M+H)+.Step B: (l-Isopropyl-3-methyl-lH-pyrazol-5-yl)methan-d2-ol (Int-Z2)

[0187] A solution of methyl l-isopropyl-3-methyl-lH-pyrazole-5-carboxylate in THF (24 mL) was cooled to 0 °C. Then, LiAlD4 (342 mg, 8.15 mmol) was added portionwise. The resulting solution was stirred at 0 °C and then warmed to room temperature and stirred. The reaction mixture was cooled to 0 °C and carefully quenched with EtOAc, 342 pL water, 342 pL 15% w / v NaOH, 3 x 342 pL water, and MgSCU. The reaction mixture was warmed to room temperature, stirred, filtered through a plug of celite, and concentrated under reduced pressure to yield (1-isopropyl-3-methyl-lH-pyrazol-5-yl)methan-d2-ol (Int-Z2). 'HNMR (500 MHz, CDCI3) 66.12 (s, 1H), 4.76 (s, 1H), 4.63 (dt, J= 13.3, 6.7 Hz, 1H), 2.26 (s, 3H), 1.50 (d, J= 6.6 Hz, 6H). MS: 157 (M+H)+.26143Intermediate AF5a & AF5b: (R or )-6-ethyl-2-methyl-4,5,6,7-tetrahvdropyrazolo[L5- alpyrazine and (R or M-6-ethyl-2-methyl-4,5,6,7-tetrahydropyrazolo[L5-a1pyrazine HATU, DIPEA 1) HCI, rt LAH DMF, rt 2) TFA, 80 °C THF, 70 °C Step A Step B Step C lnt-AF1 AcOH PtO2, H2SFC MeOH, rt Step D Step Elnt-AF5b Step A: N-(l, l-diethoxybutan-2-yl)-3-methyl-lH-pyrazole-5-carboxamide (Int-AFl )

[0188] 3-methyl-lH-pyrazole-5-carboxylic acid (800 mg, 6.34 mmol), l,l-diethoxybutan-2-amine (1.02 g, 6.34 mmol) and HATU (2.89 g, 7.61 mmol) were dissolved in DMF (30 mL) and DIPEA (2.46 g, 3.31 mL, 19.0 mmol) was added dropwise. The mixture was stirred at room temperature. Saturated NH4CI (40 mL) was added, and the aqueous layer was extracted with CHCh:iPrOH 3:1 (3x10 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo to yield N-(l,l-diethoxybutan-2-yl)-3-methyl-lH-pyrazole-5-carboxamide (Int-AFl).Step B: 6-ethyl-2-methylpyrazolo [ 1,5-a]pyrazin-4(5H)-one (Int-AF2)

[0189] N-(l,l-diethoxybutan-2-yl)-3-methyl-lH-pyrazole-5-carboxamide (Int-AFl) (1.74 g, 6.46 mmol) was dissolved in 10M aqueous HCI (6.46 mL, 64.6 mmol) and stirred at room temperature. Water (20 mL) was added and the aqueous layer was neutralized with IM aqueous NaOH and then extracted with CHCh:iPrOH 3:1 (5x20 mL). The organic layers were combined, passed through a phase separator, and volatiles were removed in vacuo to yield 6-ethyl-7-hydroxy-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one. The residue was dissolved in TFA (9.94 mL, 129 mmol) and stirred at 80 °C. Volatiles were removed in vacuo. The mixture was purified via silica gel column chromatography (0 to 100% EtOAc: EtOH 3:l / hexanes) to yield 6-ethyl-2-methylpyrazolo[l,5-a]pyrazin-4(5H)-one (Int-AFl). MS: 178 (M+H)+.Step C: 6-ethyl-2-methyl-4,5-dihydropyrazolo [ 1,5-a]pyrazine (Int-AF3)

[0190] 6-ethyl-2-methylpyrazolo[l,5-a]pyrazin-4(5H)-one (Int-AF2) (1.26 g, 7.11 mmol) was dissolved in THF (30 mL), cooled to 0 °C, and LAH (2M in THF, 7.11 mL, 14.2 mmol) was added dropwise. The mixture was stirred at 70 °C and then cooled to room temperature. Next, a saturated aqueous solution of Rochelle's salt (300 mL) was cooled to 0 °C, the reaction mixture was added dropwise into the aqueous solution, and then DCM (150 mL) was added. The mixture26143was vigorously stirred at room temperature. The organic layers were combined, passed through a phase separator, and volatiles were removed in vacuo to yield 6-ethyl-2-methyl-4,5-dihydropyrazolo[l,5-a]pyrazine (Int-AF3) which was used without further purification. MS: 164 (M+H)+.Step D: rac-6-ethyl-2-methyl-4,5, 6, 7-tetrahydropyrazolo [ 1,5-a]pyrazine (Int-AF4)

[0191] 6-ethyl-2-methyl-4,5-dihydropyrazolo[l,5-a]pyrazine (Int-AF3)(655 mg, 4.01 mmol) and platinum dioxide (91.1 mg, 401 pmol) were placed in a 20 mL vial, MeOH (15 mL) was added, followed by acetic acid (2.41 g, 2.30 mL, 40.1 mmol), and the mixture was sparged with N2, followed by sparging the suspension with H2. The mixture was stirred at room temperature, filtered over celite, and volatiles were removed in vacuo. The mixture was purified via reverse phase HPLC (water / MeCN, NH4OH modifier) to yield rac-6-ethyl-2-methyl-4, 5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Int-AF4). ESLMS m / z 166 (M+H)+.Step E: (R or S)-6-ethyl-2-methyl-4,5,6, 7-tetrahydropyrazolo [ 1,5-a]pyrazine and (R or S)-6-ethyl-2-methyl-4,5,6, 7-tetrahydropyrazolo[l,5-a]pyrazine (Int-AF5a and Int-AF5b)

[0192] The mixture of the two stereoisomers (Int-AF4) was purified by chiral SFC (ID, 21x250mm, 5mm column, 10% IPA w / 0.1% NH4OH and 90% CO2) to afford Int-AF5 isomer A (faster eluting), ESLMS m / z 166 (M+H)+. and Int-AF5 isomer B (slower eluting), MS: 166 (M+H)+.Intermediate AG5: 2'-methyl-4',5'-dihvdro-7'H-spiro[cyclopropane-L6'- pyrazolo[L5a1pyrazine1o PPh3, DIAD 1) HCI / dioxane THF, 0 ° to rt 2) K2CO3EtOH, 50 °C Step A Step B lnt-AG2 BOC20 LAH TEA DMAP TFA THF, 50 °C DCM, rt DCM, rtStep C lnt-AG4 Step E lnt-AG5 Step A: Ethyl l-((l-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-lH- pyrazole-5-carboxylate (Int-AGl)

[0193] Ethyl 3-methyl-lH-pyrazole-5-carboxylate (100 mg, 649 pmol) was dissolved in THF (2.50 mL), triphenylphosphine (255 mg, 973 pmol) and 2-Methyl-2-propanyl [1-26143(hydroxymethyl)cyclopropyl]carbamate (146 mg, 778 pmol) were added, and the mixture was cooled to 0 °C. Next, DIAD (157 mg, 151 pL, 778 pmol) was added dropwise and the mixture was stirred at room temperature. Saturated NH4CI (10 mL) was added, and the aqueous layer was extracted with DCM (3x5 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo. The mixture was purified via reverse phase column chromatography (MeCN / ELO, TFA modifier) to yield ethyl l-((l-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-lH-pyrazole-5-carboxylate (Int-AGl). MS: 324 (M+H)+.Step B: 2'-methyl-7'H-spiro [cyclopropane- 1, 6'-pyrazolo[l,5-a]pyrazin]-4'(5'H)-one (Int- AG2)

[0194] Ethyl l-((l-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-methyl-lH-pyrazole-5-carboxylate (Int-AGl) (170 mg, 526 pmol) was dissolved in HC14M in dioxane (0.7 g, 5 mL, 0.02 mol) and stirred at room temperature. Volatiles were removed in vacuo. Potassium carbonate (291 mg, 2.10 mmol) was added, and the mixture was dissolved in EtOH (2.0 mL) and stirred at 50 °C. Saturated NH4CI (10 mL) was added and the aqueous layer was extracted with CHChdPrOH 3:1 (3x5 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo to yield 2'-methyl-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazin]-4'(5'H)-one (Int-AGl) which was used without further purification. ESIMS m / z 178 (M+H)+.Step C: 2'-methyl-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazin]-4'(5'H)-one (Int- AG3)

[0195] 2'-methyl-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazin]-4'(5'H)-one (Int-AGl) (135 mg, 762 pmol) was dissolved in THF (3.0 mL) and cooled to 0 °C. Next, LAH, 2M in THF (72.3 mg, 952 pL, 1.90 mmol) was added dropwise and the mixture was stirred at 50 °C. After cooling to room temperature, the mixture was then added to a vigorously stirring mixture of saturated aq. Rochelle's salt / DCM (100 mL, 1:1) at 0 °C and then stirred at room temperature. The organic layer was separated, and volatiles were removed in vacuo to yield 2'-methyl-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazin]-4'(5'H)-one (Int-AG3) which was used without further purification. MS: 164 (M+H)+.Step D: tert-butyl 2'-methyl-7'H-spiro [cyclopropane- 1, 6'-pyrazolo [1,5-a] pyrazine] - 5'(4'H)-carboxylate (Int-AG4)

[0196] 2'-methyl-4',5'-dihydro-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazine] (Int-AG3) (78 mg, 0.48 mmol) was dissolved in DCM (4.0 mL), DMAP (5.8 mg, 48 pmol), triethylamine (0.15 g, 0.20 mL, 1.4 mmol) and BOC2O (0.13 g, 0.13 mL, 0.57 mmol) were added, and the26143mixture was stirred at room temperature. Saturated NH4CI was added and the aqueous layer was extracted with DCM (3x5 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo. The mixture was purified via column chromatography (0 to 100% EtOAc: EtOH 3:l / hexanes) to yield tert-butyl 2'-methyl-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazine]-5'(4'H)-carboxylate (Int-AG4). MS: 264 (M+H)+.Step E: 2 '-methyl-4 ', 5 '-dihydro- 7 'H-spiro[ cyclopropane-1, 6 '-pyrazolo[ 1,5 -a ] pyrazine ] (Int-AG5)

[0197] Int-AG4 (98 mg, 0.37 mmol) was dissolved in DCM (1.0 mL) and TFA (1 g, 1 mL, 0.01 mol) was added. The mixture was stirred at room temperature. Volatiles were removed in vacuo and the mixture was desalted using a SCX column to yield 2'-methyl-4',5'-dihydro-7'H-spiro[cyclopropane-l,6'-pyrazolo[l,5-a]pyrazine] (Int-AG5). MS: 164 (M+H)+.

[0198] The example compounds in Table 7 below were prepared in a similar manner to Int-AG5 above with the appropriate alcohol in Step A.Table 7Compound Structure Compound Name [M+H]+[Found] Int-AG6 (R / S)-6-cyclopropyl-2- 178methyl-4, 5,6,7- tetrahydropyrazolo[ 1,5- a]pyrazineInt-AG7 (R / S)-6-isopropyl-2-methyl- 1804, 5,6,7- tetrahydropyrazolo[ 1,5- a]pyrazineInt-AG8 HNx^r^\ (R / S)-2,6-dimethyl-4, 5,6,7- 152tetrahydropyrazolo[ 1,5-a]pyrazineIntermediate AHI: 2-(6-ethyl-2-methyl-6,7-dihydropyrazolo[L5-a]pyrazin-5(4H)-yl)-7- methylquinoline-4-carboxylic acid (Int-AHl)CPhos PdG4 NaOtBu 50 °C 1,4 dioxane lnt-AG5blnt-AH126143

[0199] Methyl 2-chloro-7-methylquinoline-4-carboxylate (150 mg, 636 pmol), 6-ethyl-2-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Int-AG5b) (126 mg, 1.2 Eq, 764 pmol), and CPhos PdG4 (52.2 mg, 63.6 pmol) were placed in a 2 dram vial and evacuated and refilled with N2 (3x). Next, 1,4-Dioxane (3.0 mL) was added, followed by NaOtBu (153 mg, 1.59 mmol). The mixture was stirred at 50 °C. After cooling to room temperature, acetic acid (182 pL, 3.18 mmol) was added and volatiles were removed in vacuo. The mixture was purified via reverse phase column chromatography (MeCN / H2O, TFA modifier) to yield 2-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxylic acid. MS: 351 (M+H)+.Intermediate AJ5: 3-Fluoroquinuclidin-4-amine (Int. AJ5)LiAIH4, THF 30 min, 0 °C Step A Step B lnt-AJ2Step CStep A: tert-Butyl 4-amino-4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-l-carboxylate (Int-AJl)

[0200] To a 250 mL round-bottom flask, tert-Butyl 3 -fluoro-4-oxopiperidine-l -carboxylate (10 g, 46 mmol) was added and solubilized in EtOH (80 mL). 3 -Ethoxy-3 -oxo-propanoic acid (8.5 g, 64 mmol) and Ammonium acetate (3.5 g, 46 mmol) were added to the solution, and the mixture was stirred at 100 °C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with IN HC1 (50 mL) until pH 1 was reached. CH2CI2 (50 mL) was added, and the solution was transferred to a separatory funnel. The layers were separated, and the acidic layer was extracted with CH2CI2 (1 x 50 mL). The aqueous solution was basified26143with solid K2CO3 until pH 11 was reached. The aqueous layer was transferred back to the extraction funnel and extracted by CH2CI2 (70 mL x 2). The organic layers were combined, dried over Na2SC>4 and concentrated in vacuo to afford Zc / V-Butyl 4-amino-4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1 -carboxylate (Int-AJl) which was used without further purification. 'H NMR (400 MHz, CDCI3) 84.49 - 4.25 (m, 1H), 4.18 - 4.05 (m, 2H), 3.98 - 3.44 (m, 3H), 3.34 (ddd, J = 13.4, 10.6, 3.0 Hz, 1H), 2.66 -2.54 (m, 1H), 2.42 (dd, J=21.2, 7.7 Hz, 1H), 1.88 - 1.69 (m, 1H), 1.58 - 1.48 (m, 3H), 1.44 (s, 9H), 1.25 (t, J= 7.1 Hz, 3H).19F NMR (376 MHz, CDCI3) 6 -198.64 (s, IF). MS: 305 (M+H)+.Step B: tert-butyl 4-amino-3-fluoro-4-(2-hydroxyethyl)piperidine-l-carboxylate (Int-AJ2)

[0201] To a 500 mL round-bottom flask, tert-butyl 4-amino-4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1 -carboxylate (Int-AJl) (8.44 g, 1 Eq, 27.7 mmol) was added followed by dilution with THF (80 mL). This solution was cooled down to 0 °C over a water ice bath. Then, Aluminum lithium hydride, 2.4 M in THF (16.1 mL, 38.5 mmol), was added and the reaction was stirred at 0 °C. To the reaction mixture, cold water was added dropwise, then EtOAc (15 mL) was added with strong stirring. Then 2N NaOH was added until a solid formed. Once the solid and solvent separated, solid Na2SO4 was added, and the suspension was filtered over a Buchner. The solid was further washed with EtOAc (100 mL). The organic filtrate was concentrated in vacuo to provide tert-butyl 4-amino-3-fluoro-4-(2-hydroxyethyl)piperidine-l -carboxylate (Int-AJl) which was used without further purification. MS: 263 (M+H)+.Step C: 2-(3-Fluoro-4-(2-hydroxyethyl)piperidin-4-yl)isoindoline-l, 3-dione (Int-AJ3)

[0202] In a 250 mL pressure tube, Zc / V-butyl 4-amino-3-fluoro-4-(2 -hydroxy ethyl)piperi dine- 1-carboxylate (Int-AJl) (1.6 g, 6.1 mmol) was added along with phthalic anhydride (0.90 g, 1 Eq, 6.1 mmol) and zinc bromide (1.4 g, 6.1 mmol). The solids were diluted with toluene (40 mL) followed by addition of hexamethyldisiloxane (1.5 g, 1.9 mL, 9.1 mmol). The tube was sealed, and the mixture was stirred at 130 °C. The reaction mixture was cooled to room temperature and diluted with water (30 mL), EtOAc (30 mL), and transferred to a separating funnel, during which time a solid formed. Both layers were filtered over a Buchner funnel to separate them from the solids. The biphasic filtrate was transferred back to the separating funnel, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The aqueous layer was also evaporated to dryness via a stream of air which provided additional crude material. Both residues were combined to provide 2-(3-fluoro-4-(2 -hydroxy ethyl)piperidin-4-yl)isoindoline-l, 3-dione (Int-AJ3) which was used in the next step without further purification. MS: 293 (M+H)+.26143Step D: 2-(3-Fluoroquinuclidin-4-yl)isoindoline-l, 3-dione (Int-AJ4)

[0203] In a microwave vial, 2-(3-fluoro-4-(2 -hydroxy ethyl)piperidin-4-yl)isoindoline-l, 3-dione (Int-AJ3) (20 mg, 61 pmol) was solubilized in MeCN (5 mL). Then (cyanomethylene)tributylphosphorane (22 mg, 24 pL, 91 pmol) and diisopropylethylamine (39 mg, 52 pL, 0.30 mmol) were added dropwise to the solution. The vial was sealed and heated at 110 °C. Reaction mixture was cooled back to room temperature and concentrated in vacuo. The crude was purified over reverse phase chromatography using Buchi Pure C850 FlashPrep, Gemini 5pM NX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970, with a gradient of 0-100% MeCN / aq. 10 mM ammonium bicarbonate and a flow rate of 30 mL / min. Lyophilization of pure fractions provided 2-(3-fluoroquinuclidin-4-yl)isoindoline-l, 3-dione (Int-AJ4) as a solid which was used without further purification. MS: 275 (M+H)+.!H NMR (500 MHz, CDCh) 8 7.79 (s, 2H), 7.71 (s, 2H), 3.29 (m, 1H), 3.18 - 3.04 (m, 3H), 3.04 - 2.89 (m, 2H), 2.69 (s, 1H), 2.61 (s, 1H), 2.40 (s, 1H), 2.03 (d, J= 10.1 Hz, 1H), 1.82 - 1.39 (m, 1H).19F NMR (471 MHz, CDCh) 6 -182.62 - -183.28 (m, IF).Step E: 3-Fluoroquinuclidin-4-amine (Int-AJ5)

[0204] In a 50 mL round-bottom flask, 2-(3-fluoroquinuclidin-4-yl)isoindoline-l, 3-dione (Int-AJ4) (20 mg, 73 pmol) was solubilized in EtOH (5 mL) and hydrazine hydrate (22 mg, 22 pL, 50% Wt, 0.22 mmol) was added. The reaction mixture was heated at 85 °C. The reaction mixture was cooled back to room temperature and concentrated in vacuo to afford 3-fluoroquinuclidin-4-amine (Int-AJ5) as a solid which was used without further purification. MS: 145 (M+H)+.Intermediate AM4: 4-Fluoroquinuclidin-3 -amine (Int-AM4)Oj^F KO‘Bu, PhMe HCI (4N), DCM rt 110 °C, 12h Cs2CO3, THF then 70 °C HCI, 110 °C, 4h Step A Step B Int V' Step C. AM2NH3, MeOH F Pd / C, H2Step D Int. AM3 Int. AM426143Step A: Methyl 4-fluoropiperidine-4-carboxylate (Int-AMl)

[0205] In a 250 mL round-bottom flask, 1 -tert-butyl 4-methyl 4-fluoropiperi dine- 1,4-dicarboxylate (4.5 g, 17 mmol) was solubilized in CH2CI2 (80 mL) at 25 °C. Then, hydrogen chloride, 4 M in dioxane (3.1 g, 22 mL, 86 mmol) was added dropwise with stirring. The reaction was stirred. Next, the reaction mixture was concentrated to dryness in vacuo. Methyl 4-fluoropiperidine-4-carboxylate hydrochloride (Int-AMl) was obtained as a solid and used without further purification. MS: 162 (M+H)+.Step B: Methyl 4-fluoro-l-(2-methoxy-2-oxoethyl)piperidine-4-carboxylate (Int-AM2)

[0206] In a 250 mL round-bottom flask, methyl 4-fluoropiperidine-4-carboxylate hydrochloride (Int-AMl) (3.2 g, 16 mmol) was solubilized in THF (100 mL) at 25 °C. Cesium carbonate (16 g, 3.9 mL, 49 mmol) was added followed by dropwise addition of Methyl 2-bromoacetate (3.7 g, 2.3 mL, 24 mmol). The mixture was heated in a preheated oil bath at 70 °C. The reaction mixture was cooled back to room temperature and filtered over a sintered funnel under vacuum. The filtrate was concentrated to dryness. The crude product was purified by normal phase purification over silica gel using a Sepaflash 40 g cartridge with a gradient of 0-100% EtOAc in heptanes to afford methyl 4-fluoro-l-(2-methoxy-2-oxoethyl)piperidine-4-carboxylate (Int-AM2). MS: 234 (M+H)+.Step C: 4-Fluoroquinuclidin-3-one (Int-AM3)

[0207] In a 500 mL round-bottom flask, 4-fluoro-l-(2-methoxy-2-oxoethyl)piperidine-4-carboxylate (Int-AM2) (3.25 g, 13.9 mmol) was solubilized in toluene (100 mL) at 25 °C. Then, 2-methylpropan-2-olate potassium (3.91 g, 34.8 mmol) was added. The mixture was heated in a preheated oil bath at 110 °C. The reaction was cooled back to room temperature, and the reaction mixture was concentrated to dryness. The reaction was transferred to a 250 mL round-bottom flask and diluted with an aqueous hydrogen chloride 6M solution (8.8 g, 40 mL, 0.24 mol). The acidic mixture was further heated at 110 °C (reflux) and then cooled back to room temperature. The reaction mixture was filtered over a sintered funnel and concentrated in vacuo. 4-Fluoroquinuclidin-3-one hydrochloride (Int-AM3) was obtained as a solid and was used without further purification. MS: 144 (M+H)+.Step D: 4-Fluoroquinuclidin-3-amine (Int-AM4)

[0208] In a pressure tube, 4-fluoroquinuclidin-3-one hydrochloride (Int-AM3) (530 mg, 3.70 mmol) was solubilized in ammonia 7M in MeOH (1.9 g, 16 mL, 0.11 mol) and the solution was heated in preheated oil bath at 70 °C. Then, the mixture was cooled down to 25 °C, purged with nitrogen gas and palladium 10 wt % matrix carbon powder, wet support (0.39 g, 3.7 mmol) was added. The solution was again purged with nitrogen. The mixture was then purged with hydrogen26143(1 atm) and stirred under 1 atmosphere of H2 at 25 °C. The reaction mixture was purged with nitrogen and filtered over a sintered funnel and celite under vacuum. The filtrate was concentrated in vacuo. 4-Fluoroquinuclidin-3 -amine (Int. AM4) obtained as a solid.XH NMR (400 MHz, DMSO- e) 64.76 - 3.58 (m, 1H), 3.36 (d, J= 9.1 Hz, 1H, merging with water peak), 3.14 - 3.04 (m, 4H), 2.94 - 2.71 (m, 1H), 2.47 - 2.23 (m, 1H), 2.18 - 1.91 (m, 1H), 1.79 - 1.63 (m, 1H), 1.62 - 1.44 (m, 2H), 1.35 (m, 1H). MS: 145 (M+H)+.Intermediate AO9: 4-Aminoquinuclidin-3-ol dihydrochloride (Int. AO9)TBSOTf DIPEA NaBH42,6-lutidine MeCN, 80 C EtOH, -15 °C DCM, rt Step D Step E Step F lnt-AO4 i) DPPA.gpN, PhMe, N 2HCI C HCI (12M) ii) EtOH, 80 C 100 °C ' Step H Step Ilnt-AO8 lnt-AO9 Step A: l-(tert-Butyl) 4-ethyl 4-acetylpiperidine-l,4-dicarboxylate (Int-AOl)

[0209] To a stirred solution of ethyl l-Boc-piperidine-4-carboxylate (20.0 g, 19.1 mL, 77.7 mmol) in THF (180 mL), a Lithium diisopropylamide solution in THF (46.6 mL, 2.0 M, 93.3 mmol) was added dropwise at -78°C and stirred. Then, a solution of acetic anhydride (8.80 mL, 93.3 mmol) in THF (180 mL) was slowly added dropwise to the reaction mixture and the reaction was stirred for 1 hour at -78°C. The reaction mixture was allowed to warm up to room temperature and stirred. Saturated aqueous sodium bicarbonate was added (40 mL) and the mixture was transferred to an extraction funnel and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by normal phase chromatography (SiC>2, 100 g) with a gradient of 0-70% EtOAc in heptanes to afford 1 -(tert-butyl) 4-ethyl 4-acetylpiperidine-l,4-dicarboxylate (Int-AOl) as a liquid.1HNMR (400 MHz, CDCI3) 84.21 (q,26143J= 7.1 Hz, 2H), 3.66 (dt, J= 13.7, 4.7 Hz, 2H), 3.16 (ddd, J= 13.4, 9.7, 3.3 Hz, 2H), 2.24 - 2.07 (m, 5H), 1.91 - 1.78 (m, 2H), 1.43 (s, 9H), 1.28 - 1.23 (m, 3H).StepB: l-(tert-Butyl) 4-ethyl 4-(2-bromoacetyl)piperidine-l,4-dicarboxylate (Int-AO2)

[0210] To a stirred solution of lithium diisopropylamide solution (6.4 mL, 2.0 M, 13 mmol) in THF (30 mL) at -78°C, l-( / c77-butyl) 4-ethyl 4-acetylpiperidine-l,4-dicarboxylate (Int-AOl) (3.0 g, 85 Wt%, 8.6 mmol) was added in THF (10 mL) and the reaction mixture was stirred. Then, chlorotrimethylsilane (2.2 mL, 17 mmol) was added slowly at -78°C and the reaction mixture was stirred. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution (200 mL), transferred to an extraction funnel, and extracted twice with methyl / c / V-butyl ether (50 mL). The organic phases were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was dissolved in THF (40 mL), and solid sodium bicarbonate (1.3 g, 15 mmol) was added. The mixture was cooled to 0 °C in an ice / water bath and NBS (1.8 g, 10 mmol) was added in portions. The reaction mixture was warmed to room temperature and stirred. Ice cold water (200 mL) was added, and the mixture was transferred to a 500 mL extraction funnel and extracted with ethyl acetate (3 x 250 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by normal phase chromatography (SiC>2, 80 g) using a gradient of 1-100% EtOAc in heptanes to afford 1 -(tert-butyl) 4-ethyl 4-(2-bromoacetyl)piperidine-l,4-di carboxylate (Int-AOl) as a liquid. MS: 278, 280 (M+H-Boc)+. 'H NMR (400 MHz, CDC13) 64.27 - 4.18 (m, 2H), 4.07 (s, 2H), 3.65 - 3.54 (m, 2H), 3.32 - 3.20 (m, 2H), 2.21 - 2.10 (m, 2H), 2.00 - 1.88 (m, 2H), 1.42 (s, 9H), 1.26 (t, J= 7.1 Hz, 3H)Step C: Ethyl 4-(2-bromoacetyl)piperidine-4-carboxylate 2,2,2-trifhioroacetate (Int- AO3)

[0211] To a stirred solution of 1 -( / c / V-butyl) 4-ethyl 4-(2-bromoacetyl)piperi dine- 1,4-dicarboxylate (Int-AOl) (2.6 g, 6.87 mmol) in 2,2,2-trifluoroethanol (25 mL), TFA (2.7 mL, 34.4 mmol) was added at 0 °C and the reaction was allowed to stir at 25 °C. After that period, the reaction mixture was concentrated to dryness to afford ethyl 4-(2-bromoacetyl)piperidine-4-carboxylate 2,2,2-trifluoroacetate (Int-AO3) which was used in the next step without further purification. MS: 278, 280 (M+H)+.Step D: Ethyl 3-oxoquinuclidine-4-carboxylate (Int-AO4)

[0212] To a stirred solution of DIPEA (12.0 mL, 68.7 mmol) in acetonitrile (50 mL) at 80 °C, a solution of ethyl 4-(2-bromoacetyl)piperidine-4-carboxylate (Int-AO3) (1.9 g, 6.9 mmol) in acetonitrile (50 mL) was slowly added. The mixture was further stirred at 80 °C. The mixture26143was cooled back to room temperature and quenched with an aqueous saturated NaHCCh solution (30 mL). The mixture was transferred to an extraction funnel and extracted with ethyl acetate (2 x 60 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (SiCh, 80 g) using a gradient of 1-20% methanol in DCM to afford ethyl 3-oxoquinuclidine-4-carboxylate (Int-AO4) as a solid. MS: 198 (M+H)+.Step E: Ethyl 3-hydroxyquinuclidine-4-carboxylate (Int-AO5)

[0213] To a stirred solution of ethyl 3-oxoquinuclidine-4-carboxylate (Int-AO4) (200 mg, 1.01 mmol) in EtOH (1 mL) in a 2-5 mL microwave vial, sodium tetrahydroborate (40.3 mg, 1.06 mmol) was added at -15°C. The reaction mixture was stirred at -15°C. Ice cold water (2 mL) was added. The solution was transferred to an extraction funnel, and the aqueous layer was extracted with 10% MeOH in CH2CI2 (2 x 20 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide ethyl 3-hydroxyquinuclidine-4-carboxylate (Int-AO5) as a solid. MS: 200 (M+H)+.Step F: Ethyl 3-((tert-butyldimethylsilyl)oxy)quinuclidine-4-carboxylate (Int-AO6)

[0214] To a solution of ethyl 3-hydroxyquinuclidine-4-carboxylate (Int-AO5) (700 mg, 3.51 mmol) in CH2CI2 (30 mL) in a 100 mL round-bottom flask, 2,6-lutidine (1.43 mL, 12.3 mmol) and trifluoromethanesulfonic acid terLbutyldimethylsilyl ester (2.32 g, 2.02 mL, 8.78 mmol) were added at 0 °C (ice / water bath). The reaction was stirred. The resulting solution was then gradually warmed to 25 °C. The reaction mixture was poured into saturated aqueous NaHCCh solution (20 mL). The biphasic mixture was transferred to an extraction funnel and extracted with CH2CI2 (3 x 50 mL). The organic layers were combined, washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude was purified by a reverse phase chromatography (C18, 25 g) using a gradient of 5-100% acetonitrile in aqueous 10 mM ammonium bicarbonate to afford ethyl 3-(( / c / 7-butyldimethylsilyl)oxy)quinuclidine-4-carboxylate (Int-AO6). MS: 314 (M+H)+.Step G: 3-((tert-Butyldimethylsilyl)oxy)quinuclidine-4-carboxylic acid (Int-AO7)

[0215] A mixture of ethyl 3-(( / c77-butyldimethylsilyl)oxy)quinuclidine-4-carboxylate (Int-AO6) (250 mg, 1 797 pmol) and an aqueous sodium hydroxide solution (128 mg, 3.2 mL, 1 M, 3.19 mmol) were added to MeOH (9 mL). The reaction was stirred at 50 °C. The reaction was cooled back to room temperature and an aqueous IM hydrogen chloride solution (3.4 mL, 1 M, 3.43 mmol) was added and the mixture was concentrated under reduced pressure. The crude was redissolved in MeCN (10 mL) and was concentrated under reduced pressure. This dilution / evaporation step was repeated 3 times. The crude was dissolved again in C LCh / MeOH26143(1:1) and sodium sulfate was added. Next, the suspension was filtered through a sintered funnel, and the filtrate was concentrated under reduced pressure to afford 3- (tert-butyldimethylsilyl)oxy)quinuclidine-4-carboxylic acid (Int-AO7) as a solid. MS: 286 (M+H)+.Step H: Ethyl (3-((tert-butyldimethylsilyl)oxy)quinuclidin-4-yl)carbamate (Int-AO8)

[0216] A 20 mL vial was charged with 3-(( / c / 7-butyldimethylsilyl)oxy)c|uinuclidine-4-carboxylic acid (Int-AO7) (228 mg, 799 pmol), toluene (2 mL), triethylamine (306 pL, 2.20 mmol) and diphenylphosphoryl azide (484 mg, 379 pL, 1.76 mmol). The mixture was stirred at 25 °C and then heated to 80 °C. The mixture was concentrated under reduced pressure to afford 3 -(( / <? / ■ / -butyldimethylsilyl)oxy)-4-isocyanatoquinuclidine (226 mg, 800 pmol). MS: 283 (M+H)+. A mixture of 3-((terLbutyldimethylsilyl)oxy)-4-isocyanatoquinuclidine (226 mg, 800 pmol) in EtOH (6 mL) was stirred at 90 °C. After that period, the mixture was concentrated under reduced pressure. The crude was purified by reverse phase chromatography (Cl 8, 10 g) using a gradient of 5-100% acetonitrile in aqueous 10 mM ammonium bicarbonate to afford ethyl (3-(( / c77-butyldimethylsilyl)oxy)quinuclidin-4-yl)carbamate (Int-AO8). MS: 329 (M+H)+.Step I: 4-Aminoquinuclidin-3-ol dihydrochloride (Int-AO9)

[0217] A mixture of ethyl (3-((tert-butyldimethylsilyl)oxy)quinuclidin-4-yl)carbamate (Int-AO8) (150 mg, 457 pmol) in concentrated hydrogen chloride (11.4 mL, 12 M, 137 mmol) was heated at 100 °C in a 20 mL microwave vial and the reaction was stirred. The reaction mixture was cooled back to room temperature and concentrated under reduced pressure. The crude was redissolved in a mixture of acetonitrile / water and lyophilized to afford 4-aminoquinuclidin-3-ol dihydrochloride (Int-AO9) as a solid. MS: 143 (M+H)+.Intermediate AQ5: trans-2-Methyl-6-(2-methylpyridin-4-yl)morpholine (Int-AQ5)(BOC)2O, NaHCOs, THF / H2O DMA, rt, 2 h Step A Sfep C lnt-AQ1 lnt-AQ3 lnt-AQ44 M HCI in dioxane Sfep Dlnt-AQ526143Step A: 4-(tert-Butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (Int-AQl)

[0218] To a 100 mL round-bottom flask, 6-methylmorpholine-2-carboxylic acid (1.5 g, 10.33 mmol) in THF (10.5 mL) and Water (10.5 mL) were added at room temperature. Next, sodium hydrogen carbonate (1.302 g, 15.50 mmol) and di-tert-butyl dicarbonate (3.383 g, 15.50 mmol) were added. The reaction mixture was stirred at room temperature. The reaction mixture was then diluted with H2O (40 mL) and EtOAc (40 mL). The aqueous layer was acidified with IM HC1 to pH 2.0 and the biphasic mixture was transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 40 mL). The organic phases were combined, washed with brine (1 x 40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. It provided 4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (Int-AQl) as a solid. 1HNMR (400 MHz, DMSO-d6) 8 12.95 (s, 1H), 4.10 -3.93 (m, 2H), 3.78 (d, J = 12.0 Hz, 1H), 3.55 - 3.41 (m, 1H), 2.80 - 2.63 (m, 1H), 2.46 - 2.35 (m, 1H), 1.41 (s, 9H), 1.11 (d, J = 6.2 Hz, 3H).Step B: 4-( tert-Butyl)-2-( 1, 3-dioxoisoindolin-2-yl)-6-methylmorpholine-2, 4-dicarboxylate (Int-AQ2)

[0219] A 100 mL round-bottom flask was charged with 4-(tert-butoxycarbonyl)-6-methylmorpholine-2-carboxylic acid (Int-AQl), (3.0 g, 12 mmol), N-hydroxyphthalimide (2.1 g, 13 mmol), and DMAP (0.15 g, 1.2 mmol). The solids were diluted with DCM (36 mL) and the reaction was stirred at room temperature. EDC (2.8 g, 15 mmol) was added to the reaction which was stirred. The reaction was diluted with DCM (30 mL) and aqueous IM HC1 (30 mL). The biphasic mixture was transferred to an extraction funnel, and the layers were separated. The organic layer was washed with brine (1 x 40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-(tert-butyl)-2-(l,3-dioxoisoindolin-2-yl)-6-methylmorpholine-2, 4-dicarboxylate (Int-AQ2) as a solid.1H NMR (400 MHz, CDCI3) 67.95 -7.86 (m, 2H), 7.85 - 7.75 (m, 2H), 4.52 (dd, J = 11.0, 2.7 Hz, 1H), 4.46 - 4.13 (m, 1H), 4.08 -3.75 (m, 1H), 3.72 - 3.62 (m, 1H), 3.17 - 2.96 (m, 1H), 2.70 - 2.49 (m, 1H), 1.49 (s, 9H), 1.29 (d, J = 6.2 Hz, 3H).Step C: rac-tert-Butyl-trans-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate and rac-tert-Butyl-cis-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate (Int- AQ3)

[0220] To a microwave vial, zinc (837 mg, 12.8 mmol), (2,2'-bipyridine)nickel dichloride (68.6 mg, 240 pmol), 4-iodo-2-methylpyridine (351 mg, 1.60 mmol), and a stirring bar were added. The vial was evacuated and backfilled with nitrogen (x3). 4-( / c / 7-butyl) 2-(l,3-dioxoisoindolin-2-yl)-6-methylmorpholine-2, 4-dicarboxylate (Int-AQ2) (1.25 g, 3.20 mmol) was dissolved in26143DMA (8 mL) in a separate flame-dried, nitrogen-flushed microwave vial. This solution was added to the reaction mixture at 0 °C. TMSC1 (446 mg, 522 pL, 4.11 mmol) was then quickly added. The reaction mixture was stirred at 0 °C. The reaction was opened to air and EtOAc (20 mL) was added. The mixture was filtered over a short pad of celite over a sintered funnel and the cake was washed with EtOAc (20 mL). The filtrate was evaporated to dryness under reduced pressure. The crude residue was dissolved in DMSO and purified by reverse phase chromatography (Cl 8, 10 g) using a gradient of 10% MeCN in aqueous 10 mM ammonium formate to 100% MeCN. Pure fractions were combined and lyophilized to afford rac-tert-butyl-trans-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate (Int-AQ3) as a solid: MS m / z 293 (M+H)+. 'H NMR (400 MHz, CDC13) 88.55 (d, J = 6.4 Hz, 1H), 7.71 - 7.43 (m, 2H), 4.92 (s, 1H), 3.99 - 3.64 (m, 3H), 3.59 - 3.45 (m, 1H), 3.29 - 3.15 (m, 1H), 2.84 (s, 3H), 1.46 (s, 9H), 1.26 (d, J = 6.4 Hz, 3H); and rac-tert-butyl-cis-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate (Int-AQ4) as a solid: MS: 293 (M+H)+. 'H NMR (400 MHz, CDCI3) 68.52 (d, J = 5.6 Hz, 1H), 7.45 - 7.34 (m, 2H), 4.54 (d, J = 9.7 Hz, 1H), 4.42 - 3.80 (m, 4H), 3.78 - 3.65 (m, 1H), 2.77 (s, 3H), 1.49 (s, 9H), 1.29 (d, J = 6.2 Hz, 3H).Step D: (2S,6S and 2R,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholine (Int-AQ5)

[0221] To a 20 mL vial, rac-terLbutyl trans-2-methyl-6-(2-methylpyridin-4-yl)morpholine-4-carboxylate (Int-AQ3) (180 mg, 616 pmol) was added. Aqueous 4 M HC1 in dioxane (224 mg, 1.54 mL, 4 molar, 6.16 mmol) was added at room temperature and the reaction was stirred. After that period, the reaction was concentrated to dryness in vacuo. DCM (5 mL, three times) was added, and the solution was concentrated in vacuo. This dilution / evaporation cycle was repeated 3 times. This resulted in (25,65 and 27?,67? J-2-methyl-6-(2-methylpyridin-4-yl)morpholine as a solid. MS: 193 (M+H)+.

[0222] The example compounds in Table 8 below were prepared in a similar manner to Int-AQ5 above with the appropriate aryl halide in Step C.Table 8Compound Structure Compound Name [M+H]+[Found] Int-AQ6 trans-2-methyl-6-(thiazol-2- 185yl)morpholineN^S26143Intermediate AT3: 4-Aminobicyclo[2.2.21octane-l -sulfonamide 2,2,2-trifluoroacetate (Int. AT3)( io mor / ojFe(OTf)3 C< NHTr TrNSO (1.5 equiv) Et3N (20 mol%) TCCA, then H2O TFA, DCM DMSO, 25 °C 405 nm NHBoc Step A Step B Step Clnt-AT2 Step A: Tert-Butyl (4-((tritylamino)sulfmyl)bicyclo[2.2.2]octan-l-yl)carbamate (Int-ATl)

[0223] A 1-dram vial was charged with 4-tert-butoxycarbonylamino-bicyclo[2.2.2]octane-l-carboxylic acid (54 mg, 0.20 mmol), DMSO (2.0 mL) and Triethylamine (4.0 mg, 5.6 pL, 40 pmol). Iron tris(trifluoromethanesulfonate) (15 mg, 30 pmol) was then added, followed by N-sulfmyltritylamine (92 mg, 0.30 mmol). The headspace was flushed with nitrogen, and the vial sealed with electrical tape. The reaction was then stirred under 400 nm LED irradiation (Kessil lamp, 100% intensity, fan cooling) at 25 °C. The reaction mixture was diluted with ethyl acetate (20 mL) and transferred to an extraction funnel. The organic layer was washed with saturated aqueous NaHCOs (3 x 10 mL), and brine (1 x 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (SiCh, 25 g) using a gradient of 0-20% EtOAc / heptanes then 1: 1 EtOAc / heptanes isocratic with a flow rate of 25 mL / min. Pure fractions were combined and evaporated to dryness to afford tert-butyl (4-((tritylamino)sulfmyl)bicyclo[2.2.2]octan-l-yl)carbamate. MS: 531 (M+H)+.StepB: tert-Butyl (4-(N-tritylsulfamoyl)bicyclo[2.2.2]octan-l-yl)carbamate (Int-AT2)

[0224] To a solution of tert-butyl (4-((tritylamino)sulfmyl)bicyclo[2.2.2]octan-l-yl)carbamate (197 mg, 371 pmol) in MeCN (3.71 mL), trichloroisocyanuric acid (43.1 mg, 186 pmol) was added and the resulting mixture was stirred at 25 °C. Then, water (0.10 g, 0.10 mL, 5.5 mmol) was added and the resulting mixture was stirred at 25 °C. The reaction was transferred to an extraction funnel. The reaction mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with aqueous saturated NH4CI (3 x 20 mL). The organic layer was dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford tert-butyl (4-(N-tritylsulfamoyl)bicyclo[2.2.2]octan-l-yl)carbamate as a solid. MS: 547 (M+H)+.Step C: 4-Aminobicyclo[2.2.2]octane-l-sulfonamide 2,2,2-trifluoroacetate (Int-AT3)

[0225] To a solution of tert-butyl (4-(N-tritylsulfamoyl)bicyclo[2.2.2]octan-l-yl)carbamate (175 mg, 320 pmol) in CH2CI2 (3.52 mL), Trifluoroacetic acid (365 mg, 244 pL, 3.20 mmol) was added and the mixture was stirred at 25 °C. The reaction mixture was concentrated under reduced26143pressure, and co-evaporated with DCM (3 x 5 mL) to dryness. The crude solid was triturated with Et2O, and the precipitated solid was filtered to afford the desired product 4-aminobicyclo[2.2.2]octane-l-sulfonamide 2,2,2-trifluoroacetate as a solid. MS: 205 (M+H)+.1H-NMR (400 MHz, DMSO-t / 6) 67.93 (br s, 3H), 6.75 (s, 2H), 1.96 - 1.86 (m, 6H), 1.79 - 1.71 (m, 6H).19F-NMR (376 MHz, DMSO-t / r,) 6 -73.81 (s, 3F).Compound ExamplesExample 1: 7-Chloro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 1)

[0226] To a solution of 7-chloro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxylic acid (Int-B2) (200 mg, 500 pmol) and quinuclidin-4-amine (94.7 mg, 751 pmol) in DMF (5 mL), DIPEA (436 pL, 2.50 mmol) and HATU (476 mg, 1.25 mmol) were added at room temperature. The reaction mixture was stirred at 23 °C. Next, the reaction mixture was quenched with ice cold water and extracted with EtOAc (2 x 30 mL). The organic layers were combined, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (elution: acetonitrile / water, 0.1% formic acid) to give the title compound (Compound 1) as a solid. 1H-NMR (400 MHz, DMSO-D6) 68.38 (s, 1H), 8.25-8.31 (m, 2H), 8.20 (br d, J = 8.8 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 9.0 Hz, 2.2 Hz, 1H), 7.50 (t, J = 8.6 Hz, 1H), 4.99 (q, J = 8.8 Hz, 2H), 2.91 (t, J = 7.6 Hz, 6H), 1.98 (t, J = 7.6 Hz, 6H). MS: 508 (M+H)+.

[0227] The example compounds in Table 9 below were prepared in a similar manner to Compound 1 above with the corresponding carboxylic acid intermediate and amine.26143Table 9Compound Structure Compound Name [M+H]+SFC [Found] Conditions 2 7-chloro-2-(4- 438o ethoxyphenyl)-N- (quinuclidin-4- yl)quinoline-4- Q o carboxamide / \ I / _ _o3 7-chloro-N- 492o (quinuclidin-4-yl)-2- w (4-(2,2,2- trifluoroethoxy)phenylO )quinoline-4- carboxamide\ / / 14 H \z— ' — N 7-chloro-2-(3-chloro- 472Q / 4-ethoxyphenyl) -N - (quinuclidin-4- o NH yl)quinoline-4- 6 carboxamide5 N 7 -chloro-2-(4-ethoxy- 4563 -fluorophenyl) -N - (quinuclidin-4- Vo NH yl)quinoline-4- carboxamidec | N6 N 2-(4-ethoxyphenyl)-N- 472(quinuclidin-4-yl) -7- (trifluoromethyl)quino9o NH line-4-carboxamidejfY jF3c-^^26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 7 2-(4-ethoxyphenyl)-7- 416methyl-N- (quinuclidin-4- yl)quinoline-4- carboxamide° / \^ M^Tzz- / \ I / _ _8 7-methyl-N- 472(quinuclidin-4-yl)-2- O(4-(2,2,2- trifluoroethoxy)phenylCO )quinoline-4- O carboxamide<o9 N 6-methyl-N- 470\ / I )(quinuclidin-4-yl)-2- h e z — ' - ' (4-(2,2,2- V0 NH trifluoroethoxy)phenyl°z)quinoline-4- carboxamideNI ^O^^LO^CF310 N 6,7-dimethyl-N- 484(quinuclidin-4-yl)-2- (4-(2,2,2- V0 NH trifluoroethoxy)phenyl)quinoline-4- carboxamide^^^O^CF331, N.. 7-chloro-2-(6- 437ethoxypyridin-3 -yl) - N-(quinuclidin-4- Vyl)quinoline-4- carboxamide^^ '■'O^'XCFS26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 68 y — N (1,4- 488°NS? diazabicyclo [3.2.2]nonan-4-yl)(2-(3-fluoro-4- (2,2,2- trifluoroethoxy)phenyl)-7-methylquinolin-4-Fyl)methanone32 \1 x / =\ 2-(3-fluoro-4-(2,2,2- 516trifluoroethoxy)phenylO -n )-7-methyl-N-(9- methyl-9- azabicyclo[3.3. l]nonan-3 -yl)quinoline-4- LL LL carboxamidero33 N (R)-7-methyl-2-(7- 431methyl-6,7- OOzdihydropyrazolo [1,5- ozVo NH a] pyrazin-5 (4H)-yl) - N-(quinuclidin-4- yl)quinoline-4- carboxamide0734 N,7-dimethyl-N- 484(quinuclidin-4-yl)-2- (4-(2,2,2- trifluoroethoxy)phenyl)quinoline-4- carboxamide35 N (S)-7-methyl-2-(7- 431methyl-6,7- dihydropyrazolo [1,5- Vo NH a] pyrazin-5 (4H)-yl) - N-(quinuclidin-4- yl)quinoline-4- carboxamidefXo26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 36 N-(l- 486isopropylpiperidin-4- yl)-7-methyl-2-(4- (2,2,2- 9HN O trifluoroethoxy)phenyl)quinoline-4- carboxamideX XX F37 (7-methyl-2-(2- 445methyl-6,7- CL N J \ dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinolin-4-yl)( 1 - methyl- 1,7- diazaspiro[3,5]nonan- A 7-yl)methanone38 (1,4- 431diazabicyclo [3.2.2]nonC \ z —an-4-yl)(7-methyl-2- C \ / >=(2-methyl-6,7- dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinolin-4- yl)methanone39 7 -methyl-2-(2-methyl- 459xNx 6,7- dihydropyrazolo [1,5- a] pyrazin-5 (4H)-yl) - 0 NH N-(9-methyl-9- azabicyclo[3.3. l]nonan-3 -yl)quinoline-4- XXA carboxamideGCG40F FN-(4- 480(difluoromethyl)bicyclo [2.2.2] octan- 1 -yl) -7 - methyl -2-(2-methyl- 6,7- 0 NH dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- carboxamidek / N-N^26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 41 N N-(4- 455I I cyanobicyclo [2.2.2] octan- 1 -yl)-7 -methyl -2- (2-methyl-6,7- dihydropyrazolo [1,5- a]pyrazin-5(4H)- 0 NHyl)quinoline-4- carboxamide42 H2N 0 N-(4- 473carbamoylbicyclo [2.2.2]octan-l-yl)-7- methyl-2-(2-methyl- 6,7- 0 NH dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- carboxamide43 '''0 N-(4- 460methoxybicyclo [2.2.2]octan- 1 -yl) -7 -methyl - 2-(2-methyl-6,7- O / ^H dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- X00>carboxamide44 F N-(4- 448fluorobicyclo [2.2.2] octan- 1 -yl)-7 -m ethyl -2- (2-methyl-6,7- dihydropyrazolo [1,5- °v^ a]pyrazin-5(4H)- yl)quinoline-4- JTOL carboxamide26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 45 N-(4- 460(hydroxymethyl)bicyclo [2.2.2] octan- 1 -yl) -7 - methyl -2-(2-methyl- 6,7- 0 NH dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- carboxamide46 OH 2-(3-oxa-8- 422azabicyclo[3.2. l]octan-8-yl)-N-(4- hydroxybicyclo [2.2.2]octan-l-yl)-7- Omethylquinoline-4- carboxamiderYj AA / i47 ^ VA 2-(3-oxa-8- 436Oazabicyclo[3.2. l]octan-8-yl)-N-(4- methoxybicyclo [2.2.2]octan-l-yl)-7- methylquinoline-4- carboxamide48 "" O (Ror S)-N-(4- 500 Chiral SFC methoxybicyclo [2.2.2] column octan- 1 -yl) -7 -methyl - (ChiralPak 2-(2-(o- AS-H, tolyl)morpholino)quin 30%:70%, oline-4-carboxamide MeOH: CO 2) to afford isomer A JOL! (faster eluting)Single enantiomer (R or S),configuration unknown (SFCisomer A)Compound Structure Compound Name [M+H]+SFC [Found] Conditions 49 (Ror S)-N-(4- 500 Chiral SFC methoxybicyclo [2.2.2] column octan- 1 -yl) -7 -methyl- (ChiralPak 2-(2-(o- AS-H, tolyl)morpholino)quin 30%:70%, O. ^H oline-4-carboxamide MeOH: CO 2) to afford isomer B (slower eluting)Single enantiomer (R or S),configuration unknown (SFCisomer B)50 N 2-(8-oxa-3- 407azabicyclo[3.2. l]octan-3-yl)-7-methyl-N- V (quinuclidin-4- 0 NHyl)quinoline-4- carboxamide51 N (Ror S)-N-(4- 495 Chiral SFC I I cyanobicyclo [2.2.2] oct column an- 1 -yl)-7 -methyl -2- (ChiralPak (2-(o- AS-H, tolyl)morpholino)quin 30%:70%, oline-4-carboxamide MeOH: CO O NH2) to afford isomer B (slower eluting)^0Single enantiomer (R or S),configuration unknown (SFCisomer B)Compound Structure Compound Name [M+H]+SFC [Found] Conditions 52 (R)-N-(4- 486methoxybicyclo [2.2.2]octan- 1 -yl) -7 -methyl - 2-(2- phenylmorpholino)quinoline-4-carboxamide053 OH N-(4- 446hydroxybicyclo [2.2.2]octan- 1 -yl) -7 -methyl - 2-(2-methyl-6,7- dihydropyrazolo [1,5- °v^ a]pyrazin-5(4H)- yl)quinoline-4- carboxamideO-rf54 H N-8- 431Nazabicyclo[3.2. l]octan-3-yl)-7-methyl-2-(2- methyl-6,7- 0 NH dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- f n carboxamide120 ^" N N-((l- 470azabicyclo[2.2. l]heptan-4-yl)methyl)-7- HN O methyl-2-(4-(2,2,2- trifluoroethoxy)phenylJTXJL )quinoline-4- carboxamideu.Compound Structure Compound Name [M+H]+SFC [Found] Conditions 168 N< P N-(4- 495(difluoromethyl)quinuclidin-3-yl)-2-(l,3- O NH F dimethyl-1, 4,5,7- tetrahydro-6H- pyrazolo[3,4- c]pyridin-6-yl)-7- methylquinoline-4- I carboxamideRacemic172 2-(l,3-dimethyl- 499N^1LAL / F 1,4,5,7-tetrahydro-6H- J PF pyrazolo[3,4- O NH F c]pyridin-6-yl)-7- methyl-N- ((lR,3R,4R)-4- (trifluoromethyl) -1- azabicyclo[2.2. l]heptan-3 -yl)quinoline-4- carboxamide220 N- l-azaadamantan-4- 457 / L / _N yl)-7-methyl-2-(2- methyl-6,7- 0 NH dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- carboxamidePP^N^N'P^LAN^221 H 7 -methyl-2-(2-methyl- 4336,7- dihydropyrazolo [1,5- p - a] pyrazin-5 (4H)-yl) - 0 NH N-(3- (methylamino)cyclohexyl)quinoline-4- JTL! carboxamidePP^N^N^T^Xk^^'NMix of cis and trans isomers26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 222 N-(4- 473(dimethylamino)bicyclo [2.2.2] octan- 1 -yl) -7 - methyl -2-(2-methyl- 6,7- O. ^H dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- carboxamide223 N (Ror S)-N-(3- 446 Chiral SFC fluoroquinuclidin-4- column yl)-7-methyl-2-(6- (Phenomen O NH methyl- 1,3 -dihydro- ex AS-H,2H-pyrrolo[3,4- 40%:60%, c]pyridin-2- (MeOH+ JTTJ yl)quinoline-4- 0.1%carboxamide NH4OH: C 02) to afford isomer A Single isomer, configuration (faster unknown eluting) 224 N (Ror S)-N-(3- 446 Chiral SFC fluoroquinuclidin-4- column yl)-7-methyl-2-(6- (Phenomen O NH methyl- 1,3 -dihydro- ex AS-H,2H-pyrrolo[3,4- 40%:60%, c]pyridin-2- (MeOH+ JTTJ yl)quinoline-4- 0.1%carboxamide NH40H: C 02) to afford isomer B Single isomer, configuration (slower unknown eluting) 225 0 7 -methyl-2-(2-methyl- 5090=&-NH26,7- dihydropyrazolo [1,5- a] pyrazin-5 (4H)-yl) - N-(4- sulfamoylbicyclo [2.2.O^^H2]octan-l- yl)quinoline-4- carboxamide26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 254 N N-((R- orS)-3- 490 Chiral SFC fluoroquinuclidin-4- column yl)-7-methyl-2-((7?)-2- (ChiralPak O NH methyl-2- IA,phenylmorpholino)qui 40%:60%, noline-4-carboxamide (1:1MeCN: EtO H+0.1% NH4OH / C O2) to afford isomer A (faster Single isomer, configurationeluting) unknown at F-carbon255 N N-((2? or S)-3- 490 Chiral SFC fluoroquinuclidin-4- column yl)-7-methyl-2-((7?)-2- (ChiralPak O NH methyl-2- IA,phenylmorpholino)qui 40%:60%, noline-4-carboxamide (1:1MeCN: EtO H+ 0.1% NH4OH / C O2) to afford isomer B (slower Single isomer, configurationeluting) unknown at F-carbon256 (R or S)-N-(4- 449 Chiral SFC I * I Fluoroquinuclidin-3 - column I ^Fyl)-7-methyl-2-(2- (Phenomen 0 NH methyl-6,7- ex Lux i- dihydropyrazolo [1,5- Amylose-1, a\ pyrazin-5 (477)- 40%:60%, JOOL yl)quinoline-4- (IPA+ carboxamide 0.1%NH4OH / C O2) to Single isomer, configuration afford unknown isomer A (faster eluting) 257 N<% (R or S)-N-^- 449 Chiral SFC I * 1 Fluoroquinuclidin-3 - column yl)-7-methyl-2-(2- (Phenomen 0 NH methyl-6,7- ex Lux i- dihydropyrazolo [1,5- Amylose-1, a\ pyrazin-5 (477)- 35%:65%, yl)quinoline-4- (IPA+ carboxamide 0.1%NH4OH / CO2) to26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions Single isomer, configuration afford unknown isomer B (slower eluting) 258 N (R or S)-N-(3- 449 Chiral SFC Fluoroquinuclidin-4- column a yl)-7-methyl-2-(2- (Phenomen 0 NH methyl-6,7- ex Lux i- dihydropyrazolo [1,5- Amylose-1, a\ pyrazin-5 (477)- 40%:60%, yl)quinoline-4- (IPA+ carboxamide 0.1%NH4OH / C O2) to Single isomer, configuration afford unknown isomer A (faster eluting) 259 N (R or S)-N-(3- 449 Chiral SFC Fluoroquinuclidin-4- column a yl)-7-methyl-2-(2- (Phenomen 0 NH methyl-6,7- ex Lux i- dihydropyrazolo [1,5- Amylose-1, a\ pyrazin-5 (477)- 35%:65%, yl)quinoline-4- (IPA+ carboxamide 0.1%NH4OH / C O2) to Single isomer, configuration afford unknown isomer B (slower eluting) 262 N A-((R / S)-3- 487hydroxyquinuclidin-4- yl)-7-methyl-2-((7?)-2- O NH methyl-2- phenylmorpholino)quinoline-4-carboxamideMix of 2 diastereomers (R and Sat the -OH carbon)26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 263 N 2V-((R / S)-3- 447hydroxyquinuclidin-4- yl)-7-methyl-2-(2- 0 NH methyl-6,7- dihydropyrazolo [1,5- a]pyrazin-5(4H)- yl)quinoline-4- N N carboxamideRacemic264 o NH23-Oxa-8- 449azabicyclo[3.2. l]octan-8-yl)-JV-(4- carbamoylbicyclo [2.2.2]octan-l-yl)-7- O NH methylquinoline-4- carboxamide^^^N^N^^282 N-(2- 475(methoxymethyl)quinufr°' clidin-4-yl)-7-methyl- 0 NH 2-(2-methyl-6,7- dihydropyrazolo [1,5- a]pyrazin-5(4H)- JTYJL yl)quinoline-4- carboxamideM-rfRacemic284 N (S or R)-2-(3-fluoro-4- 504 Chiral SFC (2,2,2- column ^ OH trifluoroethoxy)phenyl (CHIRALC 0 NH )-N-(3- EL OX-H, hydroxyquinuclidin-4- 20% / 80%, yl) -7 -methylquinoline- (MeOH+ 4-carboxamide 0.5% XXIQ NH4OH / C O2) to \^0^CF3afford isomer A Single isomer, configuration (faster unknow eluting)n26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 285 N (S or 7?)-2-(3-fluoro-4- 504 Chiral SFC (2,2,2- column ^ OH trifluoroethoxy)phenyl (CHIRALC 0 NH )-N-(3- EL OX-H, hydroxyquinuclidin-4- 20% / 80%, yl) -7 -methylquinoline- (MeOH+ 4-carboxamide 0.5% X CXQ NH4OH / C O2) to \^O^CF3afford isomer B Single isomer, configuration (slower unknown eluting) 286 2-(l,3-dimethyl- 288° flm 1,4,5,7-tetrahydro-6H- pyrazolo[3,4- c]pyridin-6-yl)-7- methyl-N-(4- (methylcarbamoyl)bicO NH yclo [2.2.1 ]heptan- 1 - yl)quinoline-4- carboxamideI Ji / / 287 2-(l,3-dimethyl- 4591,4,5,7-tetrahydro-6H- pyrazolo[3,4- O NH c]pyridin-6-yl)-7- methyl-N- (quinuclidin-4- ylmethyl)quinoline-4- carboxamide288 O NH2N-(4- 541carbamoylbicyclo [2.2.2]octan-l-yl)-7- methyl-2-( 1 -methyl-3 - (trifluoromethyl) - 0 NH 1,4,5,7-tetrahydro-6H- pyrazolo[3,4- c]pyridin-6- yl)quinoline-4- carboxamideCF326143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 289 0 NH2N-(4- 527carbamoylbicyclo [2.2.l]heptan-l-yl)-7- methyl-2-( 1 -methyl-3 - (trifluoromethyl) - O NH 1,4,5,7-tetrahydro-6H- pyrazolo[3,4- c]pyridin-6- yl)quinoline-4- carboxamideL dCA'CF3283 N 6-methyl-3-(2-methyl- 4316,7- dihydropyrazolo [1,5- V O NH a] pyrazin-5 (4H)-yl) - N-(quinuclidin-4- yl)isoquinoline-l- carboxamideExample 11: 7-chloro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 11)Compound 1 Compound 11 Step A: 2-( 3-fluoro-4-( 2, 2, 2 -trifluor oethoxy)pheny I)- 7-methyl-N-( quinuclidin-4- yl)quinoline-4-carboxamide (Compound 11)

[0228] To a stirred solution of Compound 1 (70 mg, 0.14 mmol) in 1,4-dioxane (5 mL), potassium carbonate (57 mg, 0.41 mmol) was added at room temperature. Reaction mixture was degassed and purged with nitrogen gas. Then to this reaction mixture, 1, l'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (4.5 mg, 6.9 pmol) and 2,4,6-Trimethyl- 1,3,5,2,4,6-trioxatriborinane (0.12 mL, 0.83 mmol) were added in a sealed vial. The reaction mixture was stirred at 100 °C. Reaction mixture was cooled to room temperature, filtered through26143a celite pad and washed with EtOAc (2 xl5 mL). The organic layers were combined, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (elution: ACN / water, 0.1% formic acid modifier) to give the title compound (Compound 11) as a solid. 1H-NMR (400 MHz, DMSO-D6) 68.35 (s, 1H), 8.20-8.26 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.45-7.51 (m, 2H), 4.98 (q, J = 8.8 Hz, 2H), 2.96 (t, J = 7.6 Hz, 6H), 2.54 (s, 3H), 2.01 (t, J = 8.0 Hz, 6H). MS: 488 (M+l). (Compound 11).Example 12: 7-chloro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 12)N NVHO> V O NHcataCXium A Pd G3, NaOTMS Jl ' l 1 THF, 90 °C, 16h Jl JL jLlnt-A5 Compound 12

[0229] To a stirred solution of Int-5A (190 mg, 565 pmol) and 2-methyl-4, 5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (116 mg, 847 pmol) in THF (7 mL) in a 40 mL vial, IM sodium trimethylsilanoate in THF (1.69 mL, 1.69 mmol) and Mesylate[(di(l-adamantyl)-n-butylphosphine)-2-(2'-amino-l,l'-biphenyl)]palladium(II) (41.1 mg, 56.5 pmol) were added at room temperature in a glove box. The mixture was stirred at 90 °C. The reaction mixture was cooled to room temperature, residue was quenched with water (80 mL) and extracted with EtOAc (2 x 70 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase prep-HPLC (ACN / water, 5 mM ammonium bicarbonate modifier) to give the title compound (Compound 12) as a solid. 'HNMR (400 MHz, DMSO-tfc): 6 (ppm) 8.14 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.11-7.19 (m, 2H), 5.96 (s, 1H), 4.90 (s, 2H), 4.17-4.24 (m, 2H), 4.09-4.17 (m, 2H), 2.85 (t, J= 7.6 H, 6H), 2.43 (s, 3H), 2.13 (s, 3H), 1.92 (t, J= 7.6 Hz, 6H). MS: 431 (M+l).(Compound 12).

[0230] The example compounds in Table 10 below were prepared in a similar manner to Compound 12 above.26143Table 10Compound Structure Compound Name [M+H]+[Found] 13 N 2-(2-ethyl-6,7- 445 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-7-methyl-N- Vo NH (quinuclidin-4-yl)quinoline-4- carboxamide\14 N 7-methyl-N-(quinuclidin-4-yl)-2- 481 (5-(trifluoromethyl)isoindolin-2- yl)quinoline-4-carboxamideVo NHfnCF315 N 7-methyl-2-(5-methylisoindolin-2- 427 yl)-N-(quinuclidin-4-yl)quinoline- 4-carboxamidelVJo NH£n16 N 7-methyl-2-(2-methyl-4, 5,7,8- 445 tetrahydro-6H-pyrazolo[ 1,5- d][l,4]diazepin-6-yl)-N- Vo NH (quinuclidin-4-yl)quinoline-4- carboxamideifY j26143Compound Structure Compound Name [M+H]+[Found] 17 N 7-methyl-2-(3-methyl-6,7- 431 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-N-(quinuclidin-4- Vo NH yl)quinoline-4-carboxamide JTXJL / 28 N 2-(5 -methoxyisoindolin-2-yl)-7 - 443 methyl -N-(quinuclidin-4- yl)quinoline-4-carboxamideV0 NHfY jA- / ^OCH329 N 2-(5-(2-fluoroethoxy)isoindolin-2- 475 yl)-7-methyl-N-(quinuclidin-4- yl)quinoline-4-carboxamideV O NH^ vv-30 N 2-(4-(2-fluoroethoxy)isoindolin-2- 475 yl)-7-methyl-N-(quinuclidin-4- yl)quinoline-4-carboxamideV0 NHJCCA °-^F55 N 7-methyl-N-(quinuclidin-4-yl)-2- 407 (4-oxa-7 -azaspiro [2.5] octan-7 - yl)quinoline-4-carboxamideo NHjTY j A26143Compound Structure Compound Name [M+H]+[Found] 56 N 2-(3,4-dihydroisoquinolin-2(lH)- 427 yl)-7-methyl-N-(quinuclidin-4- yl)quinoline-4-carboxamideo NH57 N 2-(l,3-dihydro-2H-pyrrolo[3,4- 414 c]pyridin-2-yl)-7-methyl-N- (quinuclidin-4-yl)quinoline-4- 910 NH carboxamide58 N 2-(3,4-dihydro-2,7-naphthyridin- 4282(lH)-yl)-7-methyl-N- (quinuclidin-4-yl)quinoline-4- 0 NH carboxamideNN^J^59 N (7?)-7-methyl-2-(3- 441 phenylpyrrolidin- 1 -yl) -N - (quinuclidin-4-yl)quinoline-4- carboxamide0 NH60 N (7?)-7-methyl-2-(2- 457 phenylmorpholino)-N- (quinuclidin-4-yl)quinoline-4- o Q NH1carboxamideXXI026143Compound Structure Compound Name [M+H]+[Found] 61 N 2-(4,7-dihydrothieno[2,3- 433 c]pyridin-6(5H)-yl)-7-methyl-N- (quinuclidin-4-yl)quinoline-4- o NH carboxamide° / \) Z \ - / \62 N 7-methyl-N-(quinuclidin-4-yl)-2- 497 (5-(trifluoromethoxy)isoindolin-2- yl)quinoline-4-carboxamideV so NHJTX J.F\ F63 (S)-7-methyl-2-(6-methyl-6,7- 431 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide64 N ( / ?)-7-mcthyl-2-(6-mcthyl-6.7- 431 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-N-(quinuclidin-4- Q / ^H yl)quinoline-4-carboxamide65 N 7-methyl-2-(4-methyl-6,7- 431 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-N-(quinuclidin-4- O / ^H yl)quinoline-4-carboxamide JCOL IRacemic26143Compound Structure Compound Name [M+H]+[Found] 66 N 7 -methyl-2-( 1 -methyl-3 - 499 (trifluoromethyl) - 1,4, 5,7- tetrahydro-6H-pyrazolo [3,4- V0 NH c]pyridin-6-yl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide67 N 7 -methyl-2-( 1 -methyl-3 - 499 (trifluoromethyl)- 1,4,6,7- tetrahydro-5H-pyrazolo[4,3- 9o NH c]pyridin-5-yl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide FT jFVFF69 N (. S)-7-mcthyl-2-(2- 457 phenylmorpholino)-N- (quinuclidin-4-yl)quinoline-4- 9o NH carboxamide[*J]71 N 7 -methyl-2-(2-(prop- 1 -yn- 1 -yl)- 4556,7 -dihydropyrazolo [1,5- a] pyrazin-5 (4H)-yl) -N - 90 NH (quinuclidin-4-yl)quinoline-4- carboxamidefV j9^N-r? ~26143Compound Structure Compound Name [M+H]+[Found] 72 N 7-methyl-N-(quinuclidin-4-yl)-2- 407 (4-oxa-7 -azaspiro [2.5] octan-7 - yl)quinoline-4-carboxamideo NHjOCl A74 N 2-(2-chloro-6,7- 451 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-7-methyl-N- 90 NH (quinuclidin-4-yl)quinoline-4- carboxamide293 N 2-(7,7-dimethyl-6,7- 445 dihydropyrazolo [ 1,5 -a] pyrazin- 5(4H)-yl)-7-methyl-N- Vo NH (quinuclidin-4-yl)quinoline-4- carboxamideJCI JLExample 18: N-(l-azabicyclo[2.2.11heptan-4-yl)-7-methyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)quinoline-4-carboxamide (Compound 18)lnt-B1 Compound 1826143Step A: N-(l -azabicyclo [ 2.2.1 ]heptan-4-yl)-7-methyl-2-(4-( 2, 2, 2- trijluoroethoxy)phenyl)quinoline-4-carboxamide (Compound 18)

[0231] To a stirred solution of Int-Bl (50 mg, 0.14 mmol), l-azabicyclo[2.2.1]heptan-4-amine dihydrochloride (26 mg, 0.14 mmol), and PyAOP (72 mg, 0.14 mmol) in DMF (0.46 mL), DIPEA (72 pL, 0.42 mmol) was added. The reaction was stirred at room temperature. The reaction was diluted wit0h / \ H z z p X — <2O and extracted with EtOAc (3 x 5 mL). The organic layers were / / \ \ \\combined, washed with brine / V / \ ( I3 x 5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude mixture was purified by column chromatography using amino fucntionalized silica gel (0 to 40% (8:2 DCM: MeOH 0 O w / 1% Et3N) / hexanes) to give the title compound (Compound 18) as a solid. ' H NMR (500 MHz, DMSO) 89.12 (s, 1H), 8.31 (d, J= 8.8 Hz, 2H),0 O8.00 (d, J= 10.0 Hz, 2H), 7.89 (s, 1H), 7.47 (d w w, J= 8.4 Hz, 1H), 7.25 (d, J= 8.8 Hz, 2H), 4.88 (q, J= 8.8 Hz, 2H), 2.95 (td, J= 10.6, 4.9 Hz, 2H), 2.69 (s, 2H), 2.64 (s, 2H), 2.54 (s, 3H), 2.01 (td, J= 10.0, 4.3 Hz, 2H), 1.71 (t, J= 11.4 Hz, 2H). MS: 455 (M+l). (Compound 18).

[0232] The example compounds in Table 11 below were prepared in a similar manner to Compound 18 above with the corresponding carboxylic acid intermediate and amine.Table 11Compound Structure Compound Name [M+H]+[Found] 19 (5)-7-methyl-N-(quinuclidin-3-yl)- 4702-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- 4-carboxamide20 (A)-7-methyl-N-(quinuclidin-3- 470yl)-2-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- 4-carboxamide26143Compound Structure Compound Name [M+H]+[Found] 21 rac-N-(l-azabicyclo[3.2.1]octan-6- 470 yl)-7-methyl-2-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- O NH4-carboxamideJCX JLNT ^Q^L O^CF3Peak 1 - Racemic,Diastereomer 122 rac-N-(l-azabicyclo[3.2.1]octan-6- 470 yl)-7-methyl-2-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- O NH4-carboxamideJTX JNT ^O^LO^CF3Peak 2 - Racemic,Diastereomer 223 rac- N-(l-azabicyclo[2.2.1]heptan- 4563-yl)-7-methyl-2-(4-(2,2,2- "3tri fluoroethoxy )phenyl)quinoline- O NH4-carboxamiderY jN" L ^X^O^CFgPeak 1 - Racemic,Diastereomer 124 rac- N-(l-azabicyclo[2.2.1]heptan- 456NO 3-yl)-7-methyl-2-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- O NH4-carboxamideJTY JnlY\^O^CF3Peak 2 - Racemic,Diastereomer 226143Compound Structure Compound Name [M+H]+[Found] 25 NH2N-(4-aminobicyclo[2.1.1]hexan-l- 456 yl)-7-methyl-2-(4-(2,2,2- tri fluoroethoxy )phenyl)quinoline- 4-carboxamide° / =\ / \ / I I _ _^^O^CF327 O -n N,7-dimethyl-N-(quinuclidin-3- 484 o yl)-2-(4-(2,2,2- O tri fluoroethoxy )phenyl)quinoline- 4-carboxamideJCOLN^Q^^O^CF3Racemic75 2-(3-fluoro-4-(2,2,2- 502 trifluoroethoxy)phenyl)-N-(4- hydroxybicyclo[2.2.2]octan-l-yl)- 7-methylquinoline-4-carboxamide76 o NH2N-(4- 487 carbamoylbicyclo[2.2.2]octan-l- yl)-2-(l,3-dimethyl-l,4,5,7- tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-7-methylquinoline- O NH4-carboxamideAXXN^T^I dL Z / 26143Example 77: 2-(2-cyano-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methyl-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 77)Pd-PEPPSI-IHept-CICS2CO3 dioxane, 90 °Clnt-A5

[0233] Int -5A (60 mg, 0.18 mmol) was stirred in 1,4-di oxane (1.8 mL) and degassed with N2. Next, (SP-4-l)-[l,3-Bis[2,6-bis(l-propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-kappaN)-Palladium (18 mg, 18 pmol), 4, 5,6,7-tetrahydropyrazolo[l,5-a]pyrazine-2-carbonitrile (30 mg, 0.20 mmol) and CS2CO3 (210 mg, 0.64 mmol) were added and the mixture was further degassed with N2. The reaction mixture was heated at 90 °C. The reaction mixture was filtered through celite, washed with DCM / MeOH, and evaporated in vacuo. The residue was dissolved in DMSO and purified by reverse phase column chromatography (ACN / water,0.1% TFA modifier) to afford the title compound (Compound 77) as a solid. 'HNMR (400 MHz, t / 6-DMSO) 8 = 9.37 (s, 1H, ), 8.61 (s, 1H), 7.68 (d, J=8.4, 1H), 7.50 (s, 1H), 7.29 (s, 1H), 7.17 (dd, J=8.5, 1H), 6.95 (s, 1H), 5.04 (s, 2H), 4.41 - 4.33 (m, 2H), 4.32 - 4.23 (m, 2H), 3.49 - 3.34 (m, 6H), 2.45 (s, 3H), 2.35 - 2.24 (m, 6H). MS: 442 (M+l).

[0234] The example compounds in Table 12 below were prepared in a similar manner to Compound 77 above using the appropriate amine.Table 12Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 78 N 2-(l,3-dimethyl- 444 RuPhos Pd 1,4,5,7-tetrahydro- G4 (0.1 6H-pyrazolo[3,4- V equiv), 0 NH c]pyridin-6-yl)-7- NaOtBu (3 methyl-N- equiv), 100 (quinuclidin-4- °C yl)quinoline-4- carb oxami de26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 79 N 2-(2- 466(difluoromethyl)- V 6,7- o NH dihydropyrazolof 1,5-a]pyrazin-5(4H)- ° / =\ yl)-7-methyl-N- O Uw (quinuclidin-4- yl)quinoline-4- UiT\ carb oxami de80 N0 07 7-methyl-N- 459 P(tBu)3Pd (quinuclidin-4-yl)- G4 (0.1 2-(l,3,5-trimethyl- equiv), Vo NH 1,4,5,7-tetrahydro- NaOtBu (36H-pyrazolo[3,4- equiv), 100 c]pyridin-6- °C yl)quinoline-4- carb oxami deRacemic81 (R)-N-(4- 500methoxybicyclo[2.2,2]octan-l-yl)-7- methyl-2-(2- methyl-2- phenylmorpholino)quinoline-4- carb oxami de82 N (R or 5)-7-methyl- 471 Chiral SFC 2-(2-methyl-2- column 9 phenylmorpholino)- (ChiralPak o NH N-(quinuclidin-4- IB,yl)quinoline-4- 50% / 50%, carb oxami de heptane +0.1% TEA / CO2) to afford isomer A (faster s eluting) Single enantiomer (R or S),configuration unknown26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 83 N (R or 5)-7-methyl- 471 Chiral SFC 2-(2-methyl-2- column 9 phenylmorpholino)- (ChiralPak o NH N-(quinuclidin-4- IB,yl)quinoline-4- 50% / 50%, HP / carb oxami de heptane + z y v — / — < 0.1% / ) 7 r0= z—— TEA / CO2) ^ W \1zrto afford isomer B (slower JU eluting) Single enantiomer (R or S),configuration unknown84 N-(4- 457methoxybicyclo[2.2,2]octan-l-yl)-7- methyl-2-(6- methyl-1,3- dihydro-2H- pyrrolo[3,4- c]pyridin-2- yl)quinoline-4- carb oxami de85 N (R or 5)-7-methyl- 471 Chiral 2-(2-phenyl-l,4- column V oxazepan-4-yl)-N- (Daicel 0 NH (quinuclidin-4- ChiralPak yl)quinoline-4- IB, carb oxami de 40% / 60%, UL I (Heptane+O.1 * / 1%TEA) / CO2) r0to afford isomer A o (faster Single isomer, configuration eluting) unknownSFC isomer A26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 86 N (R or 5)-7-methyl- 471 Chiral 2-(2-phenyl-l,4- column V oxazepan-4-yl)-N- (Daicel 0 NH (quinuclidin-4- ChiralPak yl)quinoline-4- IB, carb oxami de 40% / 60%,(Heptane+0. N N / ~''A1 * / 1% TEA):CO2) to afford isomer B o (slower Single isomer, configuration eluting) unknownSFC isomer B87 N 7-methyl-2-(2- 432methyl-6,7- V dihydrooxazolo[4,50 NH -c]pyridin-5(4H)- yl)-N-(quinuclidin- 4-yl)quinoline-4- carb oxami de88 N 2-(2-(2- 487methoxyphenyl)mop rpholino)-7-methyl- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami de°, / LX)Racemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 89 N 2-(2-(2- 475fluorophenyl)morp'V1holino)-7-methyl- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami deRacemic90 N 7-methyl-N- 471(quinuclidin-4-yl)- V 2-(2-(p- o NH tolyl)morpholino)quinoline-4- carb oxami de1Racemic91 N 2-(2-(3- 475fluorophenyl)morpV holino)-7-methyl- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami de / ^^N^N^^JL J]Racemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 92 N 2-(2-(4- 491chlorophenyl)morpV holino)-7-methyl- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami deJOOLRacemic93 N 2-(2-(3- 482cyanophenyl)morpholino)-7-methyl-N- V O NH (quinuclidin-4- yl)quinoline-4- carb oxami deHARacemic94 N 7-methyl-N- 525(quinuclidin-4-yl)- 2-(2-(3- V O NH (trifluoromethyl)phenyl)morpholino)quinoline-4- jfn carb oxami de^ ^ ^ ^uuFdTRacemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 95 N 7-methyl-N- 541(quinuclidin-4-yl)- 2-(2-(3- Vo NH (trifluoromethoxy)p henyl)morpholino)quinoline-4- carb oxami de. iRacemic96 N 7-methyl-N- 525(quinuclidin-4-yl)- 9 2-(2-(2- o NH (trifluoromethyl)phenyl)morpholino)quinoline-4- carb oxami deF / STFURacemic97 N 7-methyl-N- 471(quinuclidin-4-yl)- 9 2-(2-(m- o NH tolyl)morpholino)quinoline-4- carb oxami dej^j]Racemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 98 N 2-(2-(3- 523(difluoromethoxy)phenyl)morpholino)- o NH 7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami deRacemic99 N 2-(2-(4- 487methoxyphenyl)mo9 rpholino)-7-methyl- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami deJTX IIARacemic100 N 2-(3-oxa-8- 407azabicyclo[3.2.1]octan-8-yl)-7-methyl- N-(quinuclidin-4- yl)quinoline-4- carb oxami de^^^N^N^^26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 101 N 2-(2-(4- 523(difluoromethoxy)p9 henyl)morpholino)- o NH 7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami de0F'x°Racemic102 N 2-(2-(4- 482cyanophenyl)morpholino)-7-methyl-N- 9o NH (quinuclidin-4- yl)quinoline-4- carb oxami detSuRacemic226 N 2-(((l-isopropyl-3- 461methy 1 - 1 H-py razol - V 5- o NH yl)methyl)(methyl)amino)-7-methyl- N-(quinuclidin-4- rVl yl)quinoline-4- carb oxami deL _ NT?26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 227 N 2-(((l-isopropyl-3- 447methy 1 - 1 H-py razol - V 5- o NH yl)methyl)amino)- 7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami deL _ N228 N 7-methyl-2-(5- 471methyl-2- V phenylmorpholino)- o NH N-(quinuclidin-4- yl)quinoline-4- carb oxami deRacemic229 N 7-methyl-2-(2- 431methyl-2, 4,6,7- V tetrahydro-5H- 0 NH pyrazolo[4,3- c]pyridin-5-yl)-N- (quinuclidin-4- yl)quinoline-4- carb oxami de230 N 7-methyl-2-(2- 471methyl-6- V phenylmorpholino)- o NH N-(quinuclidin-4- yl)quinoline-4- JOTI carb oxami deRacemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 231 N 2-(2-cyclopropyl- 4576,7- V dihydropyrazolof 1,0 NH 5-a]pyrazin-5(4H)- yl)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami de232 N (R or S)-7-methyl- 458 Chiral SFC 2-(2-(pyridin-2- column 9 yl)morpholino)-N- (Phenomene o NH (quinuclidin-4- x Lux yl)quinoline-4- Cellulose-2, carb oxami de 40%:60%,CO2: (1:1 MeCN: EtO Hw / 0.1% NH40H)) to r^NL n afford isomer B Single isomer, configuration (slower unknown eluting) 233 N 2-(2- 461(methoxymethyl)- V 6,7- 0 NH dihydropyrazolof 1,5-a]pyrazin-5(4H)- yl)-7-methyl-N- jfTl(quinuclidin-4- ^X / N'N OMe yl)quinoline-4- carb oxami de234 N (R or S)-7-methyl- 449 Chiral SFC N-(quinuclidin-4- column yl)-2-(2- (Daicel o NH (trifluoromethyl)mo Chiralpak rpholino)quinoline- IC,4-carboxamide 55%:45%, JTL I CO2: (1:1MeCN: EtO Hw / 0.1% X NH40H)) to afford Single isomer, configurationisomer A unknown(fastereluting)26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 235 N (R or S)-2-(2- 421 Chiral SFC cyclopropylmorpho column lino)-7-methyl-N- (Phenomene o NH (quinuclidin-4- x Lux yl)quinoline-4- Cellulose-2, carb oxami de 55%:45%,CO2: (1:1 MeCN: EtO Hw / 0.1% NH4OH)) to afford Single isomer, configuration isomer B unknown (slower eluting) 236 N (R)-2-(2- 423isopropylmorpholinQ o)-7-methyl-N- o NH (quinuclidin-4- yl)quinoline-4- ^£ 1 carb oxami de237 N (R or S)-7-methyl- 470 Chiral SFC 2-(4-methyl-3- column Q phenylpiperazin- 1 - (Daicel o NH yl)-N-(quinuclidin- Chiralpak 4-yl)quinoline-4- IC, carb oxami de 40%: 60%, XTL I CO2: (1:1MeCN: EtO Hw / 0.1% NH4OH)) to afford ■ ■ isomer B Single isomer, configuration (slowerunknown eluting)26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 238 N 2-(2-cyclopropyl- 4555,7-dihydro-6H- V pyrrolo[3,4- o NH d]pyrimidin-6-yl)- 7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami deA239 N 2-(l-ethyl-3- 445methyl-4,6- V dihydropyrrolo[3,4- 0 NH c]pyrazol-5(lH)- yl)-7-methyl-N- (quinuclidin-4- JCOL yl)quinoline-4- Z^M^N^NA - - i / / " N carb oxami de240 N 2-(2-ethyl-3- 445methyl-2,6- dihydropyrrolo[3,4- Vo NH c]pyrazol-5(4H)- yl)-7-methyl-N- (quinuclidin-4- jCrt yl)quinoline-4- 1 >=: N carb oxami de241 N 2-(l-isopropyl-3- 459methyl-4,6- dihydropyrrolo[3,4- 0 NH c]pyrazol-5(lH)- yl)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- i >-N carb oxami de26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 242 N 2-(2-isopropyl-3- 459methyl-2,6- V dihydropyrrolo[3,4- o NH c]pyrazol-5(4H)- yl)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- 1 AsN carb oxami de243 N 2-(l-isopropyl-4,6- 432dihydropyrrolo[3,4- c]pyrazol-5(lH)- V0 NH yl)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- JuOL \ carb oxami dei y~N244 N 2-(2-isopropyl-2,6- 432dihydropyrrolo[3,4- V c]pyrazol-5(4H)- o NH yl)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- PA carb oxami de1 AN272 N 7-methyl-2-((2S,6S 486 Chiral SFC or 2R,6R)-2- column methyl-6-(2- (Phenomene 0 NH methylpyri din-4- x Lux yl)morpholino)-N- Cellulose-2, (quinuclidin-4- 45%:55%, XXI.. yl)quinoline-4- CO2: (1:1carboxamide MeCN: EtO Hw / 0.1% NH40H)) to afford isomer A (faster Single diastereomer andeluting)racemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 273 N 7-methyl-2-((2S,6S 486 Chiral SFC or 2R,6R)-2- column methyl-6-(2- (Phenomene 910 NH methylpyri din-4- x Lux yl)morpholino)-N- Cellulose-2, (quinuclidin-4- 45%:55%, yl)quinoline-4- CO2: (1:1 carboxamide MeCN: EtO Hw / 0.1% NH4OH)) to afford nj isomer B x^N^(slower Single diastereomer andeluting) racemic274 N / ra / 7.s-7-methyl-2-2- 477methyl-6-(thiazol- 9- 2-yl)morpholino)- 0 NH N-(quinuclidin-4- yl)quinoline-4- carb oxami deN^SSingle diastereomer andracemicExample 103 and 104: N-((3S,4R)-3-fluoropiperidin-4-yl)-7-methyl-2-(2-methyl-6,7- dihydropyrazolori,5-a1pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 103) andN-26143((3S,4R)-3-fluoro-l-isopropylpiperidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihvdropyrazolo[L5-a1pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 104)HATU, DIPEA TFA DMF, 23 °C DCM, 23 °C Step A Step Bacetone Na(OAc)3BH DCE, 23 °C Step CCompound 104 Compound 103 Step A: tert-butyl (3S,4R)-3-fluoro-4-(7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5- a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)piperidine-l-carboxylate (Int-Gl)

[0235] To a mixture of 7 -methyl -2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylic acid (Int-E2) (131 mg, 406 pmol) and DIPEA (0.21mL, 1.22 mmol) in DMF (0.5 mL), HATU (155 mg, 406 pmol) was added and the reaction stirred at 23 °C. The reaction mixture was pipetted into 4 mL water upon which a solid crashed out of solution. The mixture was suction filtered to afford tert-butyl (3S,4R)-3-fluoro-4-(7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)piperidine-l-carboxylate (Int-Gl). MS: 523 (M+l).Step B: N-((3S,4R)-3-fluoropiperidin-4-yl)-7-methyl-2-(2-methyl-6, 7- dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 103)

[0236] To a solution of tert-butyl (3S,4R)-3-fluoro-4-(7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)piperidine-l-carboxylate (Int-Gl) (100 mg, 191 pmol) in DCM (1.9 mL), Trifluoroacetic acid (0.15 mL, 1.91 mmol) was added and stirred at 23 °C. The reaction was concentrated and purified by reverse-phase flash column chromatography over C-18 silica gel (first isocratic solution of 20% ACN / 0.1% aq TFA26143solution followed by isocratic solution of 20% ACN / 10 mM ammonium formate). The relevant fractions were combined and lyophilized to afford N-((3S,4R)-3-fluoropiperidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 103). MS: 423 (M+l) 'H NMR (400 MHz, CD3OD) 87.86 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.08 (s, 1H), 5.34 (s, 1H), 5.22 (s, 1H), 5.08 (s, 2H), 4.53 (d, J = 31.0 Hz, 1H), 4.33 (dd, J = 13.6, 4.9 Hz, 4H), 3.78 (t, J = 11.6 Hz, 1H), 3.65 - 3.39 (m, 2H), 2.54 (s, 3H), 2.24 (s, 3H), 2.18 (dd, J = 10.0, 3.5 Hz, 2H).Step C: N-((3S,4R)-3-fluoro-l-isopropylpiperidin-4-yl)-7-methyl-2-(2-methyl-6, 7- dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 104)

[0237] To a solution of N-((3S,4R)-3-fluoropiperidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 103) (100 mg, 237 pmol) in DCM (1.0 mL), acetone (0.03mL, 427 pmol) was added followed by addition of sodium triacetoxyborohydride (83 mg, 394 pmol) and stirring at 23 °C. The reaction was concentrated and purified by reverse-phase flash column chromatography (ISCO 20% MeCN / H2O + 0.1% TFA). The relevant fractions were combined and lyophilized to afford N-((3S,4R)-3-fluoro-l-isopropylpiperidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 104). MS: 465 (M+l) 'HNMR (400 MHz, CD3OD) 67.78 (d, J= 8.4 Hz, 1H), 7.53 (d, J= 4.1 Hz, 1H), 7.23 (s, 1H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 6.00 (s, 1H), 5.04 (s, 1H), 5.00 - 4.87 (m, 3H), 4.22 (tt, J= 21.8, 10.8 Hz, 3H), 2.98 (d, J= 10.7 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.71 - 2.55 (m, 1H), 2.48 (s, 3H), 2.21 (d, J = 11.2 Hz, 2H), 2.04 (dt, J= 12.2, 8.5 Hz, 1H), 1.89 (d, J= 10.5 Hz, 1H), 1.10 (t, J= 6.8 Hz, 6H).

[0238] The example compounds in Table 13 below were prepared in a similar manner to Compound 103 & 104 above with the corresponding carboxylic acid.Table 13Compound Structure Compound Name [M+H]+SFC [Found] Conditions 105 N-((3R,4R)-3- 465fluoro-1- isopropylpiperidin- 4-yl)-7-methyl-2- -A0 NH (2-methyl-6,7- dihydropyrazolo[ 1,5-a]pyrazin-5(4H)- JOOL yl)quinoline-4- carb oxami deLA26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 106 HN N-((3R,4R)-3- 423fluoropiperidin-4- yl)-7-methyl-2-(2- -V methyl-6,7- dihydropyrazolof 1,5-a]pyrazin-5(4H)- jfT Nii yl)quinoline-4- N carb oxami dek / N-N^107 HN N-((3S,4R)-3- 463 Chiral SFC fluoropiperidin-4- column yl)-7-methyl-2-((R (ChiralPak or S)-2-(o- AS-H, O NHtolyl)morpholino)q 60%:40% uinoline-4- CO2: IPAw / JOTI carb oxami de 0.1%NH4OH) to afford isomer B (slower eluting) Single isomer, configurationunknown108 HN N-((3S,4R)-3- 463fluoropiperidin-4- yl)-7-methyl-2- ((R)-2-methyl-2- O NHphenylmorpholino)quinoline-4- carb oxami de0109 N-((3S,4R)-3- 522fluoro-1- isopropylpiperidin- 4-yl)-2-(3 -fluoro-4-F* i^O NH (2,2,2- tri fluoroethoxy )phenyl)-7- methylquinoline-4- carb oxami de26143Compound Structure Compound Name [M+H]+SFC [Found] Conditions 110 N-((3R,4R)-3- 522fluoro-1- isopropylpiperidin- 4-yl)-2-(3 -fluoro-4- (2,2,2- trifluoroethoxy)phenyl)-7- methylquinoline-4- carb oxami de245 N-((3S,4R)-3- 463fluoro-1- methylpiperidin-4- r yl)-7-methyl-2- O NH O u. ((R)-2- phenylmorpholino)quinoline-4- \ \ / X / carb oxami de / \ / / = zZ- \ (\■ z ' — \ — 'a LL V-246 N-(l-isopropyl-4- 461methylpiperidin-4- yl)-7-methyl-2-(2- methyl-6,7- 0 NH dihydropyrazolof 1,5-a]pyrazin-5(4H)- yl)quinoline-4- JOT NI carb oxami deNExample 111: 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-((3S,4R)-3-fluoropiperi din-4- yl)-7-methylquinoline-4-carboxamide (Compound 111)26143Step A: tert-butyl (3S,4R)-3-fluoro-4-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7- methylquinoline-4-carboxamido)piperidine-l -carboxylate (Int-Hl)

[0239] 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxylic acid (50 mg, 0.13 mmol) was stirred in DMF (1.3 mL), tert-butyl (3 S,4R)-4-amino-3 -fluoropiperidine- 1-carboxylate (35 mg, 0.16 mmol) and DIPEA (85 mg, 0.11 mL, 0.66 mmol) were added, and the mixture was stirred at room temperature. Next, HATU (0.10 g, 0.26 mmol) was added, and the reaction stirred at room temperature. It was purified directly by reverse phase chromatography (ISCO 10-100% MeCN / H2O + 0.1% Ammonium Formate). The relevant fractions were combined and lyophilized to afford tert-butyl (3S,4R)-3-fluoro-4-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxamido)piperidine-l-carboxylate (Int-Hl). MS 580 (M+l).Step B: 2-(3-fluoro-4-(2, 2, 2-trifluoroethoxy)phenyl)-N-((3S, 4R)-3-fluoropiperidin-4-yl)- 7-methylquinoline-4-carboxamide (Compound 111)

[0240] Tert-butyl (3 S,4R)-3-fluoro-4-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxamido)piperidine-l -carboxylate (60 mg, 0.10 mmol) was stirred in DCM (2 mL), TFA (0.16 mL, 2.1 mmol) was added, and the mixture was stirred at room temperature. The reaction mixture was evaporated in vacuo with DCM (2x15 mL). The residue was dissolved in DMSO and purified by reverse phase chromatography (ISCO 0-100% MeCN / H2O + 0.1% Ammonium Formate). Pure fractions were lyophilized to afford 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-((3S,4R)-3-fluoropiperidin-4-yl)-7-methylquinoline-4-carboxamide (Compound 111). MS: 480 (M+l). 'HNMR (400 MHz, dmso) 8 = 8.90 (d, J=7.7, 1H), 8.22 (dd, J=12.8, 2.1, 1H), 8.14 (d, J=8.6, 1H), 8.06 - 8.00 (m, 2H), 7.91 (s, 1H), 7.52 -7.44 (m, 2H), 4.97 (q, J=8.8, 2H), 4.81 (d, J=50.5, 1H), 4.34 - 4.07 (m, 1H), 3.20 - 3.07 (m, 1H), 3.04 - 2.93 (m, 1H), 2.88 - 2.69 (m, 1H), 2.69 - 2.56 (m, 1H), 2.55 (s, 3H), 1.81 - 1.70 (m, 1H), 1.70 - 1.59 (m, 1H). 1H exchangeable proton not visible.

[0241] The example compounds in Table 14 below were prepared in a similar manner to Compound 111 above with the corresponding carboxylic acid intermediate.26143Table 14Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 112 2-(3-fluoro-4- 479(2,2,2- trifluoroethoxy)phenyl)-N- ((3R,4R)-3- fluoropiperidin-4- yl)-7- methylquinoline- 4-carboxamide113 NH2N-3- 483aminobicyclo[3.2.O o u- l]octan-8-yl)-7- methyl-2-(4- O. ^H \ CN (2,2,2- \ / >\ / / I X1 / / ( iz y^z= trifluoroethoxy)p\ X e z — \zhenyl)quinoline- O U- 4-carboxamide°ZUL114 N-8- 483aminobicyclo[3.2.l]octan-3-yl)-7- methyl-2-(4- (2,2,2- trifluoroethoxy)phenyl)quinoline- 4-carboxamide115 H N-((3R,4R)-3- 460Nhydroxypiperidin- 4-yl)-7-methyl-2- „ u(4-(2,2,2- O NHtrifluoroethoxy)phenyl)quinoline- 4-carboxamide / Y jUL26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 116 NH2N-(4- 470aminobicyclo[2.2.l]heptan-l-yl)-7- methyl-2-(4- o NH (2,2,2- trifluoroethoxy)phenyl)quinoline- 4-carboxamide117 N-(4- 484aminobicyclo[2.2.2]octan-l-yl)-7- o methyl-2-(4- (2,2,2- trifluoroethoxy)p / / A / i x henyl)quinoline- VL / z4-carboxamideQ / 118 H_N N-(6- 470azabicyclo[3.2.1]octan-2-yl)-7- methyl-2-(4- HN O (2,2,2- trifluoroethoxy)phenyl)quinoline- 4-carboxamideRacemic119 H 7-methyl-N- 444N(piperidin-4-yl)- 2-(4-(2,2,2- 9 trifluoroethoxy)pHN ohenyl)quinoline- 4-carboxamideX^r i26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 121 N-(2-(4- 487H2N^ aminotetrahydro- 2H-pyran-4- yl)ethyl)-7- HN 0 methyl-2-(4- (2,2,2- trifluoroethoxy)pjfhenyl)quinoline- 4-carboxamide^ o-^F122H2N Y N-(3- 432aminobutyl)-7- methyl-2-(4- HN 0 (2,2,2- trifluoroethoxy)phenyl)quinoline- 4-carboxamide^ o^:FRacemic123 N-(2-(l- 486H2NXaminocyclohexyl)ethyl)-7-methyl- 2-(4-(2,2,2- HN 0 trifluoroethoxy)phenyl)quinoline- 4-carboxamide ^\ > ^F124 F N-(3-amino-4- 450H2N J fluorobutyl)-7- methyl-2-(4- (2,2,2- HN 0 trifluoroethoxy)phenyl)quinoline- 4-carboxamideu ^FRacemic26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 125 H N-((lR,4R)-2- 470Nazabicyclo[2.2.2]9 octan-5-yl)-7- methyl-2-(4- HN o(2,2,2- trifluoroethoxy)phenyl)quinoline- jfY j 4-carboxamide126 H N-((lS,4S)-2- 470Nazabicyclo[2.2.2]octan-5-yl)-7- methyl-2-(4- HN o(2,2,2- trifluoroethoxy)pJQ I henyl)quinoline- 4-carboxamide127 H 7-methyl-2-(2- 417Nmethyl-6,7- dihydropyrazolofH" V;Hl,5-a]pyrazin- 0 NH 5(4H)-yl)-N- ((lR,5S,6r)-6- methyl-3- azabicyclo[3.1.0]hexan-6- yl)quinoline-4- carb oxami de128 H N-((3R,4R)-3- 447Nhydroxypiperidin- 4-yl)-7-methyl-2- HO.- U((R)-2- O NHphenylmorpholino)quinoline-4- carb oxami de26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 129 HN N-((3S,4R)-3- 447hydroxypiperidin- 4-yl)-7-methyl-2- O NH ((R)-2- phenylmorpholino)quinoline-4- jTY x carb oxami de130 HN N-((3S,4R)-3- 449fluoropiperidin-4- yl)-7-methyl-2- O NH ((R)-2- phenylmorpholino)quinoline-4- carb oxami de0161 NH2N-(4- 448aminobicyclo[2.2.l]heptan-l-yl)-2- ((l-isopropyl-3- methyl-lH- pyrazol-5- XXX Xx yl)methoxy)-7- methylquinoline-N° XN4-carboxamide162 N-(2- 448azabicyclo[2.2.2]octan-4-yl)-2-((l- O NH isopropyl-3- methyl-lH- pyrazol-5- xxx xx yl)methoxy)-7- u z / methylquinoline- 4-carboxamide26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 163 N-(3- 462azabicyclo[3.2.2]nonan-l-yl)-2- 0 NH ((l-isopropyl-3- methyl-lH- pyrazol-5- yl)methoxy)-7- methylquinoline- ° XN4-carboxamide164 CL H 2-((l-isopropyl-3- 422 SFC column Nmethyl-lH- (Lux-2, pyrazol-5- 40%: 60%, yl)methoxy)-7- (MeOH+ methyl-N- 0.1% (piperi din-3 - NH4OH NXyl)quinoline-4- modifier): C carb oxami de C>2)affordin Single isomer, configuration g isomer A unknown (faster eluting) 165 CL H 2-((l-isopropyl-3- 422 SFC column Nmethyl-lH- (Lux-2, pyrazol-5- 40%: 60%, JTYJL yl)methoxy)-7- (MeOH+ methyl-N- 0.1% NX (piperi din-3 - NH4OH yl)quinoline-4- modifier): C carb oxami de O2) Single isomer, configuration affording unknown isomer B (slower eluting) 215 N-((lR,3R)-3- 419aminocyclohexyl)-7-methyl-2-(2- 0 NH methyl-6,7- dihydropyrazolofl,5-a]pyrazin- CX x 5(4H)- yl)quinoline-4- U-r carb oxami de26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 216 XX>*NH2 N-((lS,3R)-3- 419aminocyclohexyl)-7-methyl-2-(2- 0 NH methyl-6,7- dihydropyrazolofl,5-a]pyrazin- 5(4H)- yl)quinoline-4- carb oxami de,Trifluoroaceticacid217. NH2N-((lR,3S)-3- 419aminocyclohexyl)-7-methyl-2-(2- 0 NH methyl-6,7- dihydropyrazolofl,5-a]pyrazin- JUOL 5(4H)- ^^^N^N^^Xyl)quinoline-4- M-rf carb oxami de,Trifluoroaceticacid218 / \. NH2N-((lS,3S)-3- 419aminocyclohexyl)-7-methyl-2-(2- 0 NH methyl-6,7- dihydropyrazolofl,5-a]pyrazin- fY l 5(4H)- N Nyl)quinoline-4- k / N-N^ carb oxami de,Trifluoroaceticacid219 NH2(R or 5)-N-(4- 459aminobicyclo[2.2.l]heptan-l-yl)-2- (6-ethyl-2- °v^ methyl-6,7- dihydropyrazolofl,5-a]pyrazin- 5(4H)-yl)-7- i *?> — methylquinoline- 4-carboxamide,TrifluoroaceticSingle isomer, configuration acidunknown26143Compound Structure Compound [M+H]+SFC Name [Found] separation conditions 294 N-(4- 484aminobicyclo[2.2.l]heptan-l-yl)- N,7-dimethyl-2- (4-(2,2,2- trifluoroethoxy)phenyl)quinoline- 4-carboxamideCOExample 131: 2-((L3-dimethyl-lH-pyraz Ool-5-yl)methoxy)-7-methyl-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compou <nd 131)o / / IC\ £ / \ / \ZHATU, DIP fl \Ez— ' —A DMF, #423 °” °zC Step Alnt-A4 lnt-K1 Compound 131 Step A: 2-((3H-[ 1, 2, 3 ]triazolo[ 4, 5-b ]pyridin-3-yl)oxy)~ 7-methyl-N-(quinuclidm-4- yl)quinoline-4-carboxamide (Int-Kl ).

[0242] To a vial, 2-chloro-7-methylquinoline-4-carboxylic acid (6.19 g, 27.9 mmol), 1-Azabicyclo[2.2.2]octan-4-amine, dihydrochloride (6.12 g, 30.7 mmol) and DIPEA (24.3 mL, 140 mmol) in DMF (619 mL) were added. The vial was sealed, and the reaction was heated at 80 °C. The reaction was cooled to room temperature and HATU (11.7 g, 30.7 mmol) was added. The reaction mixture was stirred at room temperature. The reaction was concentrated under reduced pressure. The residue was diluted with water and the solid was filtered off. The solid was diluted in DMSO and purified by reverse phase chromatography (25% Water (0.1% ammonium formateacetonitrile)) to give 2-((3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Int-Kl). MS: 430 (M+l).Step B: 2-((l, 3-dimethyl-lH-pyrazol-5-yl)methoxy)-7-methyl-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 131).

[0243] In a microwave vial 2-((3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)-7-methyl-N- (quinuclidin-4-yl)quinoline-4-carboxamide (50 mg, 0.12 mmol), l,3-Dimethyl-5-hydroxymethyl-26143IH-pyrazole (44 mg, 0.35 mmol), and DMSO (1 mL) were added. Then cesium carbonate (0.11 g, 0.35 mmol) was added, and the vial was sealed and stirred at 120 °C. The reaction was cooled down and directly purified by reverse phase chromatography (ISCO 0-100% MeCN / H2O + 0.1% Ammonium Formate). Pure fractions were lyophilized to afford 2-((l,3-dimethyl-lH-pyrazol-5-yl)methoxy)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide as a solid (Compound 131). MS: 420 (M+l) 'HNMR (400 MHz, DMSO) 88.37 (s, 1H), 8.30 (s, 1H, formic acid), 7.82 (d, J= 8.4 Hz, 1H), 7.66 (s, 1H), 7.34 (dd, J= 8.5, 1.6 Hz, 1H), 6.90 (s, 1H), 6.18 (s, 1H), 5.49 (s, 2H), 3.82 (s, 3H), 3.04 - 2.93 (m, 6H), 2.50 (s, 3H, merging with DMSO-d6), 2.11 (d, J= 4.8 Hz, 3H), 2.03 - 1.95 (m, 6H).

[0244] The example compounds in Table 15 below were prepared in a similar manner to Compound 131 above with the corresponding nucleophile in step B.Table 15Compound Structure Compound Name [M+H]+Alternative [Found] Step B Conditions 132 N quinuclidin-4-yl 7- 429 DBU,methyl-2-(6-methyl- MeCN l,3-dihydro-2H- V0 NH pyrrolo[3,4- c]pyridin-2- yl)quinoline-4- carb oxy late133 N (R or S )-7-methyl-N- 471 DBU,(quinuclidin-4-yl)-2- MeCN V (2-(o- o NH tolyl)morpholino)qui SFC column noline-4-carboxamide (ChiralPak AS-H, 30%: 70%, ^^^N^N^^(MeOH+ 0.1% NH4OH modifier): C C>2)affordin Single isomer, configuration g isomer A unknown, SFC isomer B (fastereluting)26143Compound Structure Compound Name [M+H]+Alternative [Found] Step B Conditions 134 N (R or S)-7-methyl-N- 471 DBU, (quinuclidin-4-yl)-2- MeCN 9 (2-(o- o NH tolyl)morpholino)qui SFC column noline-4-carboxamide (ChiralPak AS-H, 30%: 70%, (MeOH+ 0.1% NH4OH modifier): C C>2)affordin Single isomer, configuration g isomer A unknown, SFC isomer A (faster eluting) 135 N 2-(2-methoxy-5,7- 445 DBU, dihydro-6H- MeCN pyrrolo[3,4- 0 NH d]pyrimidin-6-yl)-7- methyl-N- (quinuclidin-4- yl)quinoline-4- X^^N^N^ carb oxami de136 N 2-(6-chloro-l,3- 448 DBU, dihydro-2H- MeCN pyrrolo[3,4- O. ^H c]pyridin-2-yl)-7- methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami deCl26143Compound Structure Compound Name [M+H]+Alternative [Found] Step B Conditions 137 N 2-(2-(2- 492 DBU,chlorophenyl)morpho MeCN lino)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- carb oxami deXRacemic138 N 2-((l-isopropyl-3- 448 Tri ethylene methyl-lH-pyrazol-5- diamine, a yl)methoxy)-7- Cs2CO3, 0 NH methyl-N- DMF (quinuclidin-4- yl)quinoline-4- xxx carb oxami deExample 1392-((l,3-dimethyl-lH-pyrazol-5-yl)methoxy)-N-(4-methoxybicvclo[2.2.21octan- l-yl)-7-methylquinoline-4-carboxamide (Compound 139)HATU, DIPEA DMF, 23 °C Step Blnt-A4 Step A: 2-((l -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4- carboxylic acid, Trifluoroacetic acid (Int-Nl).

[0245] To a vial, cesium carbonate (691 mg, 2.12 mmol) and l,4-diazabicyclo[2.2.2]octane (11.9 mg, 106 pmol) were added. Next, DMSO (3.54 mL) was added followed by (l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (130 mg, 843 pmol) and methyl 2-chloro-7-methylquinoline-4-carboxylate (125 mg, \ 530 pmol). The vial was sealed and stirred at 130 °C. The reaction26143solution was filtered and directly purified by reverse phase chromatography (ISCO 0-100% MeCN / H2O + 0.1% TFA) resulting in 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxylic acid, Trifluoroacetic acid (Int- Nl). MS: 340 (M+l).Step B: 2-( ( 1 -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-( 4- methoxybicyclo [ 2.2.1 ]heptan-l-yl)~ 7-methylquinoline-4-carboxamide ( Compound 139).

[0246] To a vial, 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxylic acid, Trifluoroacetic acid (10 mg, 22 pmol) dissolved in DMF (0.44 mL), 4-methoxybicyclo[2.2.2]octan-l -amine, HC1 (4.7 mg, 24 pmol), HATU (17 mg, 44 pmol), and DIPEA (15 pL, 88 pmol) were added. The vial was sealed, and the resulting mixture was allowed to stir at 23 °C. The reaction mixture was diluted with DCM (3x 2mL) and washed with saturated. NEUCl (3 mL), and the biphasic mixture was passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (eluting acetonitrile / water gradient with 0.1% Ammonium hydroxide modifier, linear gradient) and lyophilized to afford 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(4-methoxybicyclo[2.2.1]heptan-l-yl)-7-methylquinoline-4-carboxamide (Compound 139). MS:463 (M+l). 1HNMR (500 MHz, DMSO) 88.79 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 6.15 (s, 1H), 5.52 (s, 2H), 4.65 (p, J = 6.5 Hz, 1H), 3.22 (s, 3H), 2.14 (s, 3H), 2.08 (t, J = 11.0 Hz, 2H), 1.93 (d, J = 11.3 Hz, 4H), 1.83 (t, J = 11.2 Hz, 2H), 1.59 (s, 2H), 1.40 (d, J = 6.5 Hz, 6H). Missing 3H potentially under DMSO peak.

[0247] The example compounds in Table 16 below were prepared in a similar manner to Compound 139 above with the corresponding nucleophile in step B.Table 16Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 140 O NH2N-(4- 476carbamoylbicyclo[2.2.1 ]heptan-l-yl)-2-((l- isopropyl-3-methyl-lH- pyrazol-5 -yl)methoxy) -7 - O NH methylquinoline-4- carboxamide26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 141 OH N-(4- 449hydroxybicyclo[2.2. l]heptan- 1 -yl)-2-(( 1 -isopropyl - 3 -methyl- lH-pyrazol-5 - O^^^ yl)methoxy)-7- methylquinoline-4- carboxamide°^L?142XO 2-(( 1 -isopropyl-3 -methyl - 463lH-pyrazol-5- yl)methoxy)-N-(4- methoxybicyclo[2.2.1 ]heptan-l-yl)-7- o / ^Hmethylquinoline-4- carboxamidexxiN°^GN143 OH N-(4- 463hydroxybicyclo [2.2.2] octan- 1 -yl)-2-(( 1 -isopropyl - 3 -methyl- lH-pyrazol-5 - 0^^ yl)methoxy)-7- methylquinoline-4- carboxamideXxx ^, 'r° £^,N144 2-(( 1 -isopropyl-3 -methyl - 462 Chiral SFC lH-pyrazol-5- column (CCO yl)methoxy)-7-methyl-N- F4, 20%: 80%, CJ ((7R or S,8aRor S)- (MeOH+ 0.1% o IIH octahydroindolizin-7 - NH4OH in IPA yl)quinoline-4- modifier): CO2) carboxamide (Isomer A - faster eluting)) XXX ^ ^TN°^L?Single isomer,configuration unknown26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 145 2-(( 1 -isopropyl-3 -methyl - 462 Chiral SFC 0 lH-pyrazol-5- column (CCO yl)methoxy)-7-methyl-N- F4, 20%: 80%, CJ ((7R or S,8aRor S)- (MeOH+ 0.1% o FIH octahydroindolizin-7 - NH4OH in IPA yl)quinoline-4- modifier): CO2) carboxamide (Isomer D - slowest eluting) XXXN°X?Single isomer,configuration unknown146 2-(( 1 -isopropyl-3 -methyl - 462 Chiral SFC 0 lH-pyrazol-5- column (CCO yl)methoxy)-7-methyl-N- F4, 20%: 80%, CJ ((7R or S,8aRor S)- (MeOH+ 0.1% o FIH octahydroindolizin-7 - NH4OH in IPA yl)quinoline-4- modifier): CO2) carboxamide (Isomers B& C - two isomers XXX ^ Y co-eluting as middleN°X?eluting).Isomers B& C Single isomer,were separated configuration unknownwith a second purification: chiral SFC column Chiral SFC column (CCO F4, 20%: 80%, (MeOH+ 0.1% NH4OH in IPA modifier): CO2) to afford Isomer B - faster eluting 147 2-(( 1 -isopropyl-3 -methyl - 462 Chiral SFC lH-pyrazol-5- column (CCO F4, 20%: 80%, u yl)methoxy)-7-methyl-N- ((7R or S,8aRor S)- (MeOH+ 0.1% o FIH octahydroindolizin-7 - NH4OH in IPA yl)quinoline-4- modifier): CO2) carboxamide (Isomers B& C - two isomers XXX ^ Y co-eluting as middleN°XL?eluting).26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions Single isomer, Isomers B& C configuration unknown were separated with a second purification: chiral SFC column Chiral SFC column (CCO F4, 20%: 80%, (MeOH+ 0.1% NH4OH in IPA modifier): CO2) to afford Isomer C - slower eluting 148 HCL N / (R& S)-2-(( 1 -isopropyl-3 - 436methyl - 1 H-pyrazol-5 - yl)methoxy)-7-methyl-N- ( 1 -methylpiperidin-3 - yl)quinoline-4- carboxamideRacemic149 HO. N., (R& S)-2-((l-isopropyl- 4223 -methyl- lH-pyrazol-5 - 1 ""’jyl)methoxy)-7-methyl-N- ( 1 -methylpyrrolidin-3 - yl)quinoline-4-N~N carboxamideRacemic150 2-(( 1 -isopropyl-3 -methyl - 5021 Fi Xi / lH-pyrazol-5- yl)methoxy)-7-methyl-N- O NH F ((lR,3R,4R)-4- (trifluoromethyl)- 1 - azabicyclo[2.2. l]heptan- 3-yl)quinoline-4- carboxamide151K\lH (R or S)-(2-((l -isopropyl - 450 Chiral \*z 3 -methyl- lH-pyrazol-5 - resolution of yl)methoxy)-7- the two isomers yO methylquinolin-4-yl)(3 - was achieved methyl -3 - by chiral (methylamino)piperidin- preparative l-yl)methanone SFC separation, chiral SFCcolumn26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions Single isomer, (Lux-2, configuration unknown 70%:30%, (MeOH+ 0.1% NH4OH modifier): CO2) affording Isomer A - faster eluting.152. \lH (R or S)-(2-((l -isopropyl - 450 Chiral \*z 3 -methyl- lH-pyrazol-5 - resolution of yl)methoxy)-7- the two isomers o O methylquinolin-4-yl)(3 - was achieved methyl -3 - by chiral (methylamino)piperidin- preparative l-yl)methanone SFC separation, chiral SFC column (Lux-2, Single isomer, 70%:30%, configuration unknown (MeOH+ 0.1%NH4OH modifier): CO2) affording isomer B - faster eluting 153 N 7 -methyl-2-((3-methyl- 1 - 476(pentan-3 -yl)-lH- pyrazol-5 -yl)methoxy) - N-(quinuclidin-4- yl)quinoline-4- carboxamide154 N 7 -methyl-2-((3-methyl- 1 - 448propyl- lH-pyrazol-5 - yl)methoxy)-N- (quinuclidin-4- yl)quinoline-4- carboxamide26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 155 N 2-(( 1 -cyclopropyl-3 - 446methyl - 1 H-pyrazol-5 - yl)methoxy)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- carboxamidexn J\\ A156 N 2-((3 -cyclopropyl- 1 - 446methyl - 1 H-pyrazol-5 - yl)methoxy)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- carboxamideN^O^V- 4157 N 2-(( l-ethyl-3 -methyl- 1H- 434pyrazol-5 -yl)methoxy) -7 - tu methyl -N-(quinuclidin-4- o NH yl)quinoline-4- carboxamide158 N 2-((l-isopropyl-3- 463(methylamino) - 1 H- pyrazol-5 -yl)methoxy) -7 - methyl -N-(quinuclidin-4- °v^ yl)quinoline-4- carboxamidexx Nx O^ y 'NU z<NF26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 159 N 2-((3 -(difluoromethyl)- 1 - 484isopropyl-lH-pyrazol-5- yl)methoxy)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- carboxamideFF160 N 2-((3 -cyclopropyl- 1 - 474isopropyl-lH-pyrazol-5- yl)methoxy)-7-methyl-N- (quinuclidin-4- yl)quinoline-4- JOCX carboxamide166 N-((3Ror S)-4- 498 Chiral SFC (difluoromethyl)quinuclid column (OD-H, vr in-3 -yl)-2-(( 1 -isopropyl - 25%:75%, 0 NH F 3 -methyl- lH-pyrazol-5 - (MeOH+ 0.1% yl)methoxy)-7- NH4OH methylquinoline-4- modifier): CO2) carboxamide affording isomer A - faster eluting. Single isomer,configuration unknown167 N-((3Ror S)-4- 498 Chiral SFC (difluoromethyl)quinuclid column (OD-H, 9y in-3 -yl)-2-(( 1 -isopropyl - 25%:75%, O NH F 3 -methyl- lH-pyrazol-5 - (MeOH+ 0.1% yl)methoxy)-7- NH4OH JCXX methylquinoline-4- modifier): CO2)Y carboxamide affordingNisomer B - Qslower eluting. Single isomer,configuration unknown26143Compound Structure Compound Name [M+H]+SFC [Found] separation conditions 253 0 NH2N-(4- 490carbamoylbicyclo [2.2.2] 0ctan-l-yl)-2-((l- isopropyl-3-methyl-lH- pyrazol-5 -yl)methoxy) -7 - O NHmethylquinoline-4- carboxamideExample 169: (R / S)-N-(2-(hvdroxymethyl)quinuclidin-4-yl)-2-((l-isopropyl-3-methyl-lH- Pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamide (Compound 169)Step A: methyl 4-(2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline- 4-carboxamido)quinuclidine-2-carboxylate, Trifluoroacetic acid (Int-Ql)

[0248] To a vial 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxylic acid, Trifluoroacetic acid (53 mg, 0.12 mmol) dissolved in DMF (2.3 mL), methyl 4-aminoquinuclidine-2-carboxylate, 2HC1 (33 mg, 0.13 mmol), HATU (89 mg, 0.23 mmol), and DIPEA (60 mg, 81 pL, 0.47 mmol) were added. The vial was sealed, and the resulting mixture was allowed to stir at 23 °C. The reaction mixture was diluted with DCM (5 mL), washed with saturated NH4CI (6 mL), and the biphasic mixture was passed through a phase separator cartridge and concentrated under reduced pressure. The reaction was concentrated under reduced pressure,26143and the crude was dissolved in DMF and purified by reverse phase chromatography (ISCO 0-100% MeCN / H₂O + 0.1% TFA) resulting in methyl 4-(2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylate, Trifluoroacetic acid (Int-Ql). MS: 506 (M+l).Step B: N-(2-formylquinuclidin-4-yl)-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)- 7-methylquinoline-4-carboxamide (Int-Q2).

[0249] To a vial, methyl 4-(2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylate, Tri fluoroacetic acid (70 mg, 0.11 mmol), and THF (1.5 mL) were added. The vial was sealed, and its contents were placed under an inert atmosphere by performing 3 vacuum / nitrogen cycles and was cooled to -78 °C.Diisobutylaluminum hydride (0.14 mL, 1 molar, 0.14 mmol) was added and the solution was stirred at -78 °C. Then Diisobutylaluminum hydride (0.17 mL, 1 molar, 0.17 mmol) was added. The reaction was stirred at 23 °C. The reaction was quenched with aqueous Na2SO4 (2 ml) and the resulting slurry was stirred and filtered. The solvents were removed in vacuo to give N-(2-formylquinuclidin-4-yl)-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamide (Int-Q2). MS: 494 (M+I+H₂O).Step C: N-(2-(hydroxymethyl)quinuclidin-4-yl)-2-( ( 1 -isopropyl-3-methyl-lH-pyrazol-5- yl)methoxy)-7-methylquinoline-4-carboxamide (Compound 169).

[0250] N-(2-formylquinuclidin-4-yl)-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamide (0.14 mmol) was dissolved in MeOH (1.5 mL) and SodiumTetrahydroborate (26 mg, 24 pL, 0.69 mmol) was added. The reaction mixture was stirred. The solvents were removed in vacuo. The residue was purified via reverse phase HPLC (acetonitrile / water gradient with 0.1% Ammonium hydroxide modifier) and lyophilized to afford N-(2-(hydroxymethyl)quinuclidin-4-yl)-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methylquinoline-4-carboxamide (Compound 169; Racemic). MS: 478 (M+l). 1HNMR (500 MHz, DMSO) 88.24 (s, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.66 (s, 1H), 7.34 (d, J= 8.5 Hz, 1H), 6.83 (s, 1H), 6.15 (s, 1H), 5.51 (s, 2H), 4.65 (p, J= 6.5 Hz, 1H), 4.36 (s, 1H), 3.53 - 3.42 (m, 1H), 3.05 - 2.86 (m, 4H), 2.75 - 2.63 (m, 1H), 2.14 (s, 3H), 2.07 - 1.91 (m, 2H), 1.80 (s, 3H), 1.58 - 1.47 (m, 1H), 1.40 (d, J= 6.5 Hz, 6H). Missing 3H possibly under DMSO peak.26143Example 170: 2-(((3-(difluorom ethyl)- 1 -methyl- lH-pyrazol-5-yl)methyl)amino)-7-methyl- N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 170)CPhos PdG4 NaOtBu HATU, DI PEA 1,4-dioxane, 90 °C DMF, 23 °C Step A Step Blnt-A5 Step A: 7-methyl-2-(methyl( ( 1 -methyl-3-(trifluoromethyl)-lH-pyrazol-5- yl)methyl)amino)quinoline-4-carboxylic (Int- U2)

[0251] Methyl 2-chloro-7-methylquinoline-4-carboxylate, Trifluoroacetic acid (50 mg, 0.14 mmol), CPhos PdG4 (12 mg, 14 pmol), and N-methyl-l-(l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)methanamine (33 mg, 0.17 mmol) were taken up in 1,4-Dioxane (1.4 mL). Next, NaOtBu (2.0 M, 0.21 mL, 0.43 mmol) was added. The mixture was purged with nitrogen gas and stirred at 90 °C. The reaction was quenched with water, acidified with 2 N HC1, and the mixture was extracted with CHCh:iPrOH 3:1 (3x15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and volatiles were removed in vacuo. The residue was purified via reverse phase HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) affording 7-methyl-2-(methyl((l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)methyl)amino)quinoline-4-carboxylic acid as the TFA salt (Int-U2). MS: 347 (M+l).Step B: 2-( ((3-(difluoromethyl)-l-methyl-lH-pyrazol-5-yl)methyl)amino)-7-methyl-N- (auinuclidin-4-yl)auinoline-4-carboxamide (Compound 170)

[0252] Quinuclidin-4-amine, 2HC1 (7.47 mg, 37.5 pmol), Int-U2, Trifluoroacetic acid (14.4 mg, 31.3 pmol), and HATU (23.8 mg, 62.6 pmol) were dissolved in DMF (0.313 mL), and DIPEA (21.8 pL, 125 pmol) was added. The mixture was stirred at room temperature. The reaction mixture was diluted with CHCh:iPrOH 3: 1 (3x 2ml) and washed with saturated NH4CI (3 mL), and the biphasic mixture was passed through a phase separator cartridge and concentrated under reduced pressure. The residue was purified via reverse phase HPLC (acetonitrile / water gradient with 0.1% Ammonium hydroxide modifier) affording 2-(((3-(difluoromethyl)-l-methyl-lH-pyrazol-5-yl)methyl)amino)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 170). MS: 455 (M+l), 'NMR (500 MHz, DMSO) 88.14 (s, 1H), 7.61 (d, J= 8.3 Hz, 1H), 7.58 (t, J= 5.6 Hz, 1H), 7.39 (s, 1H), 7.05 (d, J= 8.2 Hz, 1H), 6.67 (s, 1H), 6.45 (s,261431H), 4.68 (d, J= 5.6 Hz, 2H), 3.95 (s, 3H), 2.93 - 2.76 (m, 6H), 2.41 (s, 3H), 1.92 - 1.83 (m, 6H).

[0253] The example compounds in Table 17 below were prepared in a similar manner to Compound 170 above with the corresponding nucleophile in step B.Table 17Compound Structure Compound Name [M+H]+[Found] 171 N 7-methyl-2-(methyl((l -methyl- 4873 -(trifluoromethyl)- 1 H- ep pyrazol-5-yl)methyl)amino)- 0 NH N-(quinuclidin-4-yl)quinoline- 4-carboxamideJCCL)—FFExample 173: 6-Fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 173)NStep A: 6-Fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)qumolme-4-carboxylic acid (Int-Vl)

[0254] To ethyl 2-chloro-6-fluoroquinoline-4-carboxylate (12.7 mg, 0.050 mmol) and SiliaCat DPP-Pd (16.6 mg, 0.005 mmol, 10 mol%, 0.3 mmol / g), a solution of (3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)boronic acid (11.9 mg, 0.050 mmol) in EtOH (0.50 mL) was added under an atmosphere of nitrogen gas. To the reaction mixture, aqueous K2CO3 (75 pL, 2 M in water, 0.15 mmol) was added. The sealed vial was heated to 125 °C in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with DCM, dried over anhydrous MgSC, filtered, and concentrated under reduced pressure to yield 6-fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxylic acid (Int-Vl). MS: 384 (M+l).26143Step B: 6-Fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(qumuclidm-4- yl)quinoline-4-carboxamide (Compound 173)

[0255] To 6-fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxylic acid (Int-VI), a tepid solution of quinuclidin-4-amine dihydrochloride (10.0 mg, 0.050 mmol), PyAOP (26.1 mg, 0.050 mmol), and DIPEA (26 pL, 0.15 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (elution: acetonitrile / water, 0.1% TFA) to yield 6-fluoro-2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 173).XH NMR (600 MHz, DMSO-d6) 88.83 (s, 1H), 8.26 (dd, J = 12.8, 2.0 Hz, 1H), 8.24 (d, J = 1.6 Hz, 1H), 8.23 - 8.20 (m, 1H), 8.19 (d, J = 10.0 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.51 (t, J = 8.7 Hz, 1H), 4.99 (q, J = 8.7 Hz, 2H), 3.49 - 3.42 (m, 6H), 2.44 - 2.30 (m, 6H). MS: 492 (M+l).Example 174: 6-Fluoro-2-(2-methyl-6,7-dihydropyrazolo[L5-a1pyrazin-5(4H)-yl)-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 174)Pd-PEPPSI-IPentCI, Cs2CO3dioxane, 90 °C, overnight then LiOH, H2O, rt, 1 hStep A lnt-W1 Step A: 6-Fluoro-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinolme-4- carboxylic acid (Int-Wl)

[0256] To ethyl 2-chloro-6-fluoroquinoline-4-carboxylate (19.0 mg, 0.075 mmol) and CS2CO3 (73.3 mg, 0.225 mmol), a solution of 2-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (10.3 mg, 0.075 mmol) and Pd-PEPP SI-IP ent (5.9 mg, 0.0075 mmol) in dioxane (1 mL) was added under an atmosphere of nitrogen gas. The sealed vial was heated to 90 °C. The reaction mixture was cooled to room temperature. To the reaction mixture, LiOH (0.25 mL, 1 N in water, 0.25 mmol) was added. The sealed vial was stirred at room temperature and then concentrated under reduced pressure to yield 6-fluoro-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylic acid (Int-Wl). MS: 327 (M+l).Step B: 6-Fluoro-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 174)

[0257] To 6-fluoro-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylic acid (Int-Wl), a tepid solution of quinuclidin-4-amine dihydrochloride (14.9 mg,261430.075 mmol), PyAOP (39.1 mg, 0.075 mmol), and DIPEA (39 pL, 0.225 mmol) in DMF (1 mL) were added. The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (elution: acetonitrile / water, 0.1% TFA) to yield 6-fluoro-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 174). 'HNMR (600 MHz, DMSO-d6) 69.69 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 7.73 (dd, J = 9.2, 5.5 Hz, 1H), 7.53 (td, J = 8.7, 3.0 Hz, 1H), 7.49 (dd, J = 9.9, 2.9 Hz, 1H), 7.45 (s, 1H), 5.98 (s, 1H), 4.92 (s, 1H), 4.19 (dt, J = 43.3, 5.2 Hz, 2H), 3.62 (ddd, J = 13.2, 8.5, 5.3 Hz, 2H), 3.14 (qd, J = 7.4, 4.3 Hz, 2H), 2.55 (s, 3H), 2.36 - 2.28 (m, 6H). Of note, 6H quinuclidine peaks are buried underneath the residual water in the spectra. MS: 435 (M+l).Example 175: 2-((l -Isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-m ethoxy -N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 175)Step A: 2-( ( 1 -Isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy) - 7-methoxyquinolme-4- carboxylic acid (Int-AAl)

[0258] To ethyl 7-methoxy-2-oxo-l,2-dihydroquinoline-4-carboxylate (Int-Xl, 12.0 mg, 0.050 mmol), (l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (Int-M2, 8.5 mg, 0.055 mmol) and PPhs (16 mg, 0.060 mmol) in dioxane (1 mL), DIAD (12 pL, 0.060 mmol) was added. The sealed vial was heated to 50 °C. The reaction mixture was cooled to room temperature. To the reaction mixture, LiOH (0.25 mL, 1 N in water, 0.25 mmol) was added. The sealed vial was stirred at room temperature and then concentrated under reduced pressure to yield 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methoxyquinoline-4-carboxylic acid (Int-AAl). MS: 356 (M+l).Step B: 2-((l-Isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methoxy-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 175)

[0259] To 2-(( 1 -i sopropyl-3 -methyl- 1 H-pyrazol-5 -yl)m ethoxy)-7-m ethoxy quinoline-4-carboxylic acid (Int-AAl), quinuclidine-4-amine dihydrochloride (11.0 mg, 0.055 mmol), PyAOP (26.0 mg, 0.050 mmol), and DMF (1 mL) were added, followed by DIPEA (26 pL, 0.15 mmol). The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and26143purified via reverse phase HPLC (acetonitrile / water, 0.1% NH4OH) to yield 2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-7-methoxy-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 175). 'HNMR (500 MHz, DMSO) 68.21 (s, 1H), 7.82 (d, J= 9.1 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.14 (dd, J= 9.1, 2.5 Hz, 1H), 6.74 (s, 1H), 6.15 (s, 1H), 5.50 (s, 2H), 4.64 (p, J = 6.5 Hz, 1H), 3.91 (s, 3H), 2.88 - 2.80 (m, 6H), 2.14 (s, 3H), 1.93 - 1.84 (m, 6H), 1.40 (d, J = 6.5 Hz, 6H). MS: 464 (M+l).

[0260] The example compounds in Table 18 below were prepared in a similar manner to Compound 175 above with the corresponding starting intermediate.Table 18Compound Structure Compound Name [M+H]+[Found] 176 N 6-Fluoro-2-((l-isopropyl-3-methyl- 452lH-pyrazol-5-yl)methoxy)-N- (quinuclidin-4-yl)quinoline-4- V0 NH carb oxami deT Y JL J177 N 8-Fluoro-2-((l-isopropyl-3-methyl- 452lH-pyrazol-5-yl)methoxy)-N- (quinuclidin-4-yl)quinoline-4- V0 NH carb oxami deCOLF °O 'N178 N 8-Chloro-2-((l-isopropyl-3-methyl- 468lH-pyrazol-5-yl)methoxy)-N- V (quinuclidin-4-yl)quinoline-4- 0 NH carb oxami deCo CCl ll z'26143Compound Structure Compound Name [M+H]+[Found] 179 N 7-Bromo-2-((l-isopropyl-3-methyl- 512 lH-pyrazol-5-yl)methoxy)-N- V (quinuclidin-4-yl)quinoline-4- o NH carb oxami deJTYJL yLi z,180 N 6-Chloro-2-((l-isopropyl-3-methyl- 468 lH-pyrazol-5-yl)methoxy)-N- V (quinuclidin-4-yl)quinoline-4- O NH carb oxami dezT Y JL J / T°181 7-Fluoro-2-((l-isopropyl-3-methyl- 452 / \YZlH-pyrazol-5-yl)methoxy)-N- ° \z=z(quinuclidin-4-yl)quinoline-4- carb oxami de182 N 2-((l-Isopropyl-3-methyl-lH- 448 py razol - 5 -y 1 )m ethoxy )-6 -methyl -N - (quinuclidin-4-yl)quinoline-4- Vo NH carb oxami deyyy y26143Example 183: 7-Ethyl-2- l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N- quinuclidin- 4-yl)guinoline-4-carboxamide (Compound 183)Step A Step BStep A: Ethyl 7-bromo-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4- carboxylate (Int-ABl).

[0261] To 7-bromo-2-oxo-l,2-dihydroquinoline-4-carboxylic acid ethyl ester (500 mg, 1.69 mmol), (l-isopropyl-3-methyl-lH-pyrazol-5-yl)methanol (Int-M2, 286 mg, 1.86 mmol) and PPhs (531 mg, 2.03 mmol) in dioxane (12 mL), DIAD (394 pL, 2.03 mmol) was added. The sealed vial was heated to 50 °C. The reaction mixture was concentrated under reduced pressure. The crude product was purified via silica gel chromatography (elution: 0-15% EtOAc in DCM) to yield ethyl 7-bromo-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylate (Int-ABl). 'H NMR (500 MHz, CDC13) 88.53 (d, J= 9.0 Hz, 1H), 8.11 (d, J= 2.0 Hz, 1H), 7.58 (dd, J= 9.0, 2.0 Hz, 1H), 7.44 (s, 1H), 6.14 (s, 1H), 5.49 (s, 2H), 4.57 (dt, J= 13.3, 6.7 Hz, 1H), 4.47 (q, J= 7.1 Hz, 2H), 1.52 (d, J= 6.6 Hz, 6H), 1.44 (t, J= 7.1 Hz, 3H). MS: 432 (M+l).Step B: 7-Ethyl-2-( I -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4- carboxylic acid (Int-AB2).

[0262] To ethyl 7-bromo-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylate (10.3 mg, 0.024 mmol) and XPhos Pd G4 (2.1 mg, 0.0024 mmol) in THF (0.5 mL) under an atmosphere of nitrogen gas, ethylzinc bromide (0.15 mL, 0.5 M in THF, 0.075 mmol) was added. The sealed vial was heated at 50 °C. The reaction mixture was cooled to room temperature. To the reaction mixture LiOH (0.25 mL, 1 N in water, 0.25 mmol) was added. The sealed vial was stirred at room temperature and then concentrated under reduced pressure to yield261437-ethyl-2-(( 1 -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-AB2). MS: 354 (M+l).Step C: 7-Ethyl-2-( ( 1 -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 183).

[0263] To 7-ethyl-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-AB2), quinuclidine-4-amine dihydrochloride (5.2 mg, 0.026 mmol), PyAOP (12.4 mg, 0.024 mmol), and DMF (1 mL) were added followed by addition of DIPEA (13 pL, 0.071 mmol). The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (acetonitrile / water, 0.1% NEUOH) to yield 7-ethyl-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 183). 'H NMR (500 MHz, DMSO) 88.21 (s, 1H), 7.83 (d, J= 8.4 Hz, 1H), 7.65 (s, 1H), 7.37 (dd, J= 8.5, 1.6 Hz, 1H), 6.84 (s, 1H), 6.14 (s, 1H), 5.50 (s, 2H), 4.64 (p, J= 6.5 Hz, 1H), 2.87 - 2.81 (m, 6H), 2.82 - 2.76 (m, 2H), 2.13 (s, 3H), 1.92 - 1.86 (m, 6H), 1.39 (d, J= 6.5 Hz, 6H), 1.27 (t, J= 7.6 Hz, 3H). MS: 462 (M+H)+.

[0264] The example compounds in Table 19 below were prepared in a similar manner to Compound 183 above with the corresponding starting intermediate.Table 19Compound Structure Compound Name [M+H]+[Found] 184 N 7 -Cyclobutyl -2-(( 1 -isopropyl-3 - 488methyl - 1 H-pyrazol-5 -yl)methoxy) -N - (quinuclidin-4-yl)quinoline-4- V O NH carboxamide185 N 7 -Cyclopropyl-2-(( 1 -isopropyl-3 - 474methyl - 1 H-pyrazol-5 -yl)methoxy) -N - CO (quinuclidin-4-yl)quinoline-4- 0 NH carboxamideJTTJ26143Example 186: 7-Chloro-2- l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N- quinuclidin-4- yl)quinoline-4-carboxamide (Compound 186)then LiOH, H2O, rt, 3 hlnt-Y2 Step A Step A: 7-Chloro-2-( ( 1 -ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinolme-4-carboxylic acid (Int-ACl)

[0265] A suspension of ethyl 2,7-dichloroquinoline-4-carboxylate (Int-Y2, 14 mg, 0.050 mmol), CS2CO3 (65 mg, 0.20 mmol) and DABCO (3.0 mg, 0.027 mmol) in NMP (0.5 mL) was heated to 150 °C in a microwave reactor. The reaction mixture was cooled to room temperature. To the reaction mixture LiOH (0.25 mL, 1 N in water, 0.25 mmol) was added. The sealed vial was stirred at room temperature and then concentrated under reduced pressure to yield 7-chloro-2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-ACl). MS: 346 (M+l).Step B: 7-Chloro-2-( ( 1 -ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 186)

[0266] To 7-chloro-2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-ACl) quinuclidine-4-amine dihydrochloride (11 mg, 0.055 mmol), PyAOP (26 mg, 0.050 mmol) and DMF (1 mL), followed by DIPEA (26 pL, 0.15 mmol) were added. The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (elution: acetonitrile / water, 0.1% NH4OH) to yield 7-chloro-2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 186).XH NMR (500 MHz, DMSO) 88.29 (s, 1H), 7.94 (d, J= 8.8 Hz, 1H), 7.90 (s, 1H), 7.55 (d, J= 8.9 Hz, 1H), 6.99 (s, 1H), 6.19 (s, 1H), 5.52 (s, 2H), 4.14 (q, J= 7.1 Hz, 3H), 2.90 -2.80 (m, 6H), 2.12 (s, 3H), 1.96 - 1.83 (m, 6H), 1.34 (t, J= 7.2 Hz, 3H). MS: 454 (M+l).26143Example 187: 2-((l-Ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoro-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 187)Step A: 2-((l-Ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoroqumolme-4-carboxylic acid (Int-ADl)

[0267] A suspension of ethyl 2-chloro-6-fluoroquinoline-4-carboxylate (13 mg, 0.050 mmol), CS2CO3 (65 mg, 0.20 mmol), and DABCO (3.0 mg, 0.027 mmol) in NMP (0.5 mL) was heated to 150 °C in a microwave reactor. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to yield 2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoroquinoline-4-carboxylic acid (Int-ADl). MS: 330 (M+l).Step B: 2-((l-Ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoro-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 187)

[0268] To 2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoroquinoline-4-carboxylic acid (Int-ADl), quinuclidine-4-amine dihydrochloride (11 mg, 0.055 mmol), PyAOP (26 mg, 0.050 mmol), and DMF (1 mL) were added, followed by DIPEA (26 pL, 0.15 mmol). The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (elution: acetonitrile / water, 0.1% NH4OH) to yield 2-((l-ethyl-3-methyl-lH-pyrazol-5-yl)methoxy)-6-fluoro-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 187).'HNMR (500 MHz, DMSO) 88.29 (s, 1H), 7.93 (dd, J= 9.0, 5.5 Hz, 1H), 7.65 (ddd, J= 17.6, 8.9, 2.8 Hz, 2H), 7.05 (s, 1H), 6.18 (s, 1H), 5.52 (s, 2H), 4.15 (q, J= 7.2 Hz, 2H), 2.89 - 2.81 (m, 6H), 2.13 (s, 3H), 1.95 - 1.85 (m, 6H), 1.35 (t, J = 7.2 Hz, 3H), 0.95 (d, J = 6.5 Hz, 6H). MS: 438 (M+l).

[0269] The example compounds in Table 20 below were prepared in a similar manner to Compound 187 above with the corresponding starting intermediate and amine.26143Table 20Compound Structure Compound Name [M+H]+[Found] 188 N 2-((l-ethyl-3-(trifluoromethyl)-lH- 488 pyrazol-5 -yl)methoxy) -7 -methyl -N - (quinuclidin-4-yl)quinoline-4- V O NH carboxamideCF189 N37 -chloro-2-(( 1 -isopropyl-3 -methyl - 469 1 H-pyrazol-5 -yl)methoxy) -N - (quinuclidin-4-yl)quinoline-4- O NH carboxamideci^ JO^ON^Lo^qN190 N N-( 1 -azabicyclo [2.2.1 ]heptan-4-yl)-2- 420 (( 1 -ethyl-3 -methyl- lH-pyrazol-5 - yl)methoxy)-7-methylquinoline-4- O’O NH carboxamideXXXo^X191 2-(( 1 -ethyl-3 -methyl- lH-pyrazol-5 - 463 yl)methoxy)-N-(4- methoxybicyclo [2.2.2] octan- 1 -yl) -7- methylquinoline-4-carboxamideXXX^ f26143Compound Structure Compound Name [M+H]+[Found] 192 (S)-2-(( 1 -ethyl-3 -methyl- IH-pyrazol- 4345 -yl)methoxy) -7 -methyl -N- (quinuclidin-3 -yl)quinoline-4- O KIH carboxamideXX°= / / \ / / ) ZZNx - / / — / / X / X\ \ \-Z!-T° v6193 2-(( 1 -ethyl-3 -methyl- lH-pyrazol-5 - 440 yl)methoxy)-N-((3 S,4R)-4-fluoro- 1 - L z~.^ methylpiperidin-3 -yl) -7- O NH \zmethylquinoline-4-carboxamide XlXo^X194 2-(( 1 -ethyl-3 -methyl- lH-pyrazol-5 - 440 yl)methoxy)-N-((3R,4S)-4-fluoro-l- \X'Tmethylpiperidin-3 -yl) -7- O NH methylquinoline-4-carboxamidexxx^x195 2-(( 1 -ethyl-3 -methyl- lH-pyrazol-5 - 440 yl)methoxy)-N-((3S,4S)-4-fluoro-l- methylpiperidin-3 -yl) -7- methylquinoline-4-carboxamide196xN / \ 2-(( 1 -ethyl-3 -methyl- lH-pyrazol-5 - 440 yl)methoxy)-N-((3R,4R)-4-fhioro- 1 - XX> F methylpiperidin-3 -yl) -7- O NH methylquinoline-4-carboxamideXlXo^X26143Compound Structure Compound Name [M+H]+[Found] 198 N 2-((l-isopropyl-3-methyl-lH-pyrazol- 4505 -yl)methoxy-d2)-7 -methyl-N - (quinuclidin-4-yl)quinoline-4- V O NH carboxamide< o / =) Z X - / D DZ / ~ / / X / \ ) \\-Z!212 (R)-2-(( 1 -ethyl-3 -methyl- IH-pyrazol- 4345 -yl)methoxy) -7 -methyl -N- \z(quinuclidin-3 -yl)quinoline-4- carboxamide213XNA (R)-2-(( 1 -ethyl-3 -methyl- IH-pyrazol- 4225 -yl)methoxy) -7 -methyl -N-( 1 - methylpiperidin-3-yl)quinoline-4- O NH carboxamideXQo^X214 (S)-2-(( 1 -ethyl-3 -methyl- IH-pyrazol- 4225 -yl)methoxy) -7 -methyl -N-( 1 - methylpiperidin-3-yl)quinoline-4- O NH carboxamideXQo^X26143Example 199: 7-Cvano-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin- 4-yl)quinoline-4-carboxamide (Compound 199)K4Fe(CN)6’3H2O, XPhos Pd G4, KOAc dioxane, H2O, 100 °C, 3 h then LiOH, H2O, rt, 3 h Sfep AStep A: 7-Cyano-2-( ( 1 -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4- car boxy lie acid (Int-AEl)

[0270] To ethyl 7-bromo-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylate (10 mg, 0.023 mmol), XPhos Pd G4 (2.0 mg, 0.0023 mmol), KOAc (1.0 mg, 0.0010 mmol), and K4Fe(CN)6'3H2O (9.8 mg, 0.023 mmol) in dioxane (0.5 mL), water (0.25 mL) was added under an atmosphere of nitrogen gas. The sealed vial was heated at 100 °C. The reaction mixture was cooled to room temperature. To the reaction mixture, LiOH (0.25 mL, 1 N in water, 0.25 mmol) was added. The sealed vial was stirred at room temperature and then concentrated under reduced pressure to yield 7-cyano-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-AEl). MS: 351 (M+l).Step B: 7-Cyano-2-( ( I -isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4- yl)quinoline-4-carboxamide (Compound 199).

[0271] To 7-cyano-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)quinoline-4-carboxylic acid (Int-AEl), quinuclidine-4-amine dihydrochloride (5.0 mg, 0.025 mmol), PyAOP (12 mg, 0.023 mmol), and DMF (1 mL) were added, followed by addition of DIPEA (12 pL, 0.069 mmol). The reaction mixture was stirred at room temperature, diluted with DMSO, filtered, and purified via reverse phase HPLC (acetonitrile / water, 0.1% NH4OH) to yield 7-cyano-2-((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methoxy)-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 199). 'HNMR (500 MHz, DMSO) 88.37 (s, 1H), 8.34 (s, 1H), 8.06 (d, J= 8.5 Hz, 1H), 7.83 (d, J= 8.5 Hz, 1H), 7.14 (s, 1H), 6.19 (s, 1H), 5.56 (s, 2H), 4.65 (p, J= 6.4 Hz, 1H), 2.90 - 2.77 (m, 6H), 2.13 (s, 3H), 1.94 - 1.82 (m, 6H), 1.39 (d, J= 6.5 Hz, 6H). MS: 459 (M+l).Example 200 and 201: (R or )-2-(6-ethyl-2-methyl-6,7-dihvdropyrazolo[L5-a1pyrazin- 5(4H)-yl)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 200) and (R26143or )-2-(6-ethyl-2-methyl-6,7-dihvdropyrazolo[l,5-a1pyrazin-5(4H)-yl)-7-methyl-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 201)CPhos PdG4 NaOtBu 90 °C 1,4 dioxanelnt-A5 lnt-AF5a (Peak 1) orlnt-AF5b (Peak 2) Compound 200 Compound 201

[0272] 2 -chloro-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Int-A5) (80 mg, 0.18 mmol), CPhos PdG4 (15 mg, 18 pmol), and 6-ethyl-2-methyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrazine (Int-AF5a, Peak 1) (36 mg, 0.22 mmol) or (Int-AF5b, Peak 2) (36 mg, 0.22 mmol) were placed in a 1 dram vial and evacuated and backfilled with N2 (3x). The mixture was dissolved in 1,4-dioxane (1.8 mL) and NaOtBu (52 mg, 0.54 mmol) was added. The mixture was stirred at 90 °C. After cooling to room temperature, saturated NH4CI (5 mL) was added, and the mixture was extracted with CHCh:iPrOH 3:1 (3x5 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo. The residue was purified via reverse phase HPLC (water / MeCN, NH4OH modifier) to yield (R or 5)-2-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 200; Single isomer, configuration unknown):XH NMR (500 MHz, DMSO) 88.14 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.12 (d, J = 6.1 Hz, 2H), 5.98 (s, 1H), 5.29 (d, J = 16.9 Hz, 1H), 5.17 (s, 1H), 4.37 (d, J = 17.0 Hz, 1H), 4.21 -4.11 (m, 2H), 2.88 -2.83 (m, 6H), 2.43 (s, 3H), 2.15 (s, 3H), 1.95 - 1.89 (m, 6H), 1.58 - 1.47 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). MS: 459 (M+H)+; or to yield (R or 5)-2-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (Compound 201; Single isomer, configuration unknown):1H NMR (500 MHz, DMSO) 69.50 (s, 1H), 8.64 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.22 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 5.99 (s, 1H), 5.30 (d, J = 16.7 Hz, 1H), 5.18 (s, 1H), 4.41 (d, J = 17.0 Hz, 1H), 3.42 (d, J = 7.6 Hz, 6H), 2.44 (s, 3H), 2.35 - 2.27 (m, 6H), 2.16 (s, 3H), 1.58 - 1.49 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). MS:459 (M+l).

[0273] The example compounds in Table 21 below were prepared in a similar manner to Compound 200 above with the corresponding starting intermediate and amine and using the following modifications where applicable.26143Table 21Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 202 N 7-methyl-2-(2'- 457 Reaction was methyl-7'H- stirred at 50 °C spiro [cyclopropane - for 3h.0 NH l,6'-pyrazolo[l,5- a]pyrazin]-5'(4'H)- yl)-N-(quinuclidin-4- yl)quinoline-4- carboxamide203 N (R or 5)-2-(6- 471 Reaction was cyclopropyl-2- stirred at 50 °C methyl-6,7- for 3h. Chiral J dihydropyrazolo [1,5- SFC column a]pyrazin-5(4H)-yl)- (Lux-2, 7-methyl-N- 50% / 50% (quinuclidin-4- MeOH+ 0.1% yl)quinoline-4- NH4OH in carboxamide IPA / CO2) affording isomer A - Single isomer, configuration faster eluting unknown (Compound 203).204 N (R or 5)-2-(6- 471 Reaction was cyclopropyl-2- stirred at 50 °C methyl-6,7- for 3h. Chiral J dihydropyrazolo [1,5- SFC column a]pyrazin-5(4H)-yl)- (Lux-2, 7-methyl-N- 50% / 50% (quinuclidin-4- MeOH+ 0.1% yl)quinoline-4- NH4OH in carboxamide IPA / CO2) affording isomer B - Single isomer, configuration slower eluting unknown (Compound 204).205 N (2-(6-isopropyl-2- 473 Reaction was methyl-6,7- stirred at 50 °C dihydropyrazolo [1,5- for 3h 0 NH a]pyrazin-5(4H)-yl)- 7-methyl-N- (quinuclidin-4- yl)quinoline-4- ^^N^N^^ carboxamideRacemic26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 291 N (R or S)-2-(2,6- 445 Chiral SFC dimethyl-6,7- column (OD-H, dihydropyrazolo [1,5- 45% / 55% V0 NH a]pyrazin-5(4H)-yl)- MeOH+ O.1%7-methyl-N- NH4OH / CO2) (quinuclidin-4- affording yl)quinoline-4- isomer A - carboxamide faster eluting. I * / )Single isomer, configurationunknown292 N (R or S)-2-(2,6- 445 Chiral SFC dimethyl-6,7- column (OD-H, dihydropyrazolo [1,5- 45% / 55% V0 NH a]pyrazin-5(4H)-yl)- MeOH+ O.1%7-methyl-N- NH4OH / CO2) (quinuclidin-4- affording yl)quinoline-4- isomer B - carboxamide slower eluting. i * ASingle isomer, configurationunknownExample 206 & Example 207: (R or S)-4-(2-(R or N)-(6-ethyl-2-methyl-6,7- dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2- carboxamide (Compound 206) and (R or S)-4-(2-(R or N)-(6-ethyl-2-methyl-6,7-26143dihvdropyrazolo[L5-a1pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2- carboxamide (Compound 207)Compound 206 Compound 207(Peak 1) (Peak 2)Step A: methyl 4-(2-(6-ethyl-2-methyl-6, 7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7- methylquinoline-4-carboxamido)quinuclidine-2-carboxylate (Int-AIl)

[0274] 2-(R or 5)-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxylic acid (Int-AHl) (80 mg, 0.23 mmol), methyl 4-aminoquinuclidine-2-carboxylate dihydrochloride (88 mg, 0.34 mmol), and HATU (0.17 g, 0.46 mmol) were dissolved in DMF (3.0 mL), and DIPEA (0.16 mL, 0.91 mmol) was added. The mixture was stirred at room temperature. Next, saturated NFUCl (10 mL) was added, and the aqueous layer was extracted with CHCh:iPrOH 3:1 (3x10 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo to yield methyl 4-(2-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylate (Int-AIl) which was used without further purification. MS: 517 (M+l).Step B: 4-(2-(R or S)-(6-ethyl-2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)-7- methylquinoline-4-carboxamido)quinuclidine-2-carboxylic acid (Int-AI2).

[0275] Methyl 4-(2-( / or 5)-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylate (Int-AIl) (120 mg, 232 pmol) and lithium hydroxide monohydrate (48.7 mg, 1.16 mmol) were dissolved in THF (2.0 mL) / Water (1.0 mL) and stirred at 40 °C. After cooling to room temperature, the mixture was acidified to a pH of 3-4 using IM aq. HC1 and extracted with CHCh:iPrOH 3:1 (3x5 mL). The organic layers26143were combined, passed through a phase separator and volatiles were removed in vacuo. The mixture was purified via reverse phase column chromatography (5 to 100% MeCN / H2O + 0.1% TFA) to yield 4-(2-(7? or 5)-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylic acid (Int-AI2). MS: 503 (M+l).Step C: (R / S)-4-(2-(R or S)-(6-ethyl-2-methyl-6,7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)~ yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxamide (Int-AI3).

[0276] 4-(2-(7? or 5)-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxylic acid (Int-AI2) (60 mg, 0.12 mmol), ammonium chloride (26 mg, 0.48 mmol), and HATU (68 mg, 0.18 mmol) were dissolved in DMF (1.0 mL) and DIPEA (62 mg, 83 pL, 0.48 mmol) was added. The mixture was stirred at room temperature. Next, NFUCl (5 mL) was added and the aqueous layer was extracted with CHCh:iPrOH 3:1 (3x5 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo. The residue was purified via HPLC (MeCN / FLO, NH4OH modifier) to yield (R or S)-4- 2-(R or 5)-(6-ethyl-2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxamide (Int-AI3).MS: 502 (M+l).Step D: SFC separation of (R or S)-4-(2-(R or S)-(6-ethyl-2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)-7-methylquinoline-4-carboxamido)quinuclidine-2-carboxamide (Compound 206 / Compound 207)

[0277] Step C yielded diastereomeric mixture which was purified via chiral SFC to separate single diasteromers using the following conditions: Column - SJ, 15%: 85% MeOH w / 0.1% NH4OH: CO2 to afford isomer A (Compound 206; Single isomer, configuration unknown) (faster eluting): 1HNMR (500 MHz, DMSO) 88.22 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.13 (d, J = 8.6 Hz, 4H), 5.99 (s, 1H), 5.40 - 5.11 (m, 2H), 4.37 (d, J = 16.9 Hz, 1H), 4.24 -4.10 (m, 2H), 3.49 - 3.41 (m, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.97 - 2.86 (m, 1H), 2.80 (t, J = 7.7 Hz, 2H), 2.43 (s, 3H), 2.27 -2.20 (m, 1H), 2.15 (s, 3H), 2.05 (t, J = 11.6 Hz, 1H), 1.93 (d, J = 31.1 Hz, 4H), 1.79 (s, 1H), 1.55 - 1.50 (m, 2H), 0.84 (t, J = 7.4 Hz, 4H). MS: 502 (M+l) and isomer B (Compound 207; Single isomer, configuration unknown) (slower eluting): 1HNMR (500 MHz, DMSO) 68.22 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.13 (d, J = 8.8 Hz, 4H), 5.99 (s, 1H), 5.30 (d, J = 17.2 Hz, lH), 5.18 (s, 1H), 4.37 (d, J = 17.1 Hz, 1H), 4.21 -4.11 (m, 2H), 3.48 - 3.42 (m, 1H), 2.98 (dt, J = 49.6, 9.1 Hz, 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H), 2.15 (s, 3H), 2.05 (t, J = 11.7 Hz, 1H), 1.94 (d, J = 16.3 Hz, 1H), 1.93 - 1.85 (m, 2H), 1.79 (s, 1H), 1.52 (d, J = 3.7 Hz, 3H), 0.84 (t, J = 7.4 Hz, 3H). MS: 502 (M+l).26143

[0278] The example compounds in Table 22 below were prepared in a similar manner to Compound 206 and 207 above using the appropriate amine for Step C.Table 22Compound Structure Compound Name [M+H]+SFC Conditions [Found]208 O (R or S)-4-(2-((R or 516 Chiral SFC. S')-6-cthyl-2- column (OJ-H, methyl-6,7- 15% / 85% dihydropyrazolo [ 1, MeOH+ 0.1% O NH 5 -a]pyrazin-5 (4H)- NH4OH / CO2) yi)-7- affording isomer methylquinoline-4- A - faster eluting JTXJL carboxamido) -N- (Compound 208).methylquinuclidinei* / > — -2-carboxamideSingle isomer, configurationunknown209 O (R or S)-4-(2-((R or 516 Chiral SFC. S')-6-cthyl-2- column (OJ-H, AV methyl-6,7- 15% / 85%dihydropyrazolo [ 1, MeOH+ 0.1% O NH 5 -a]pyrazin-5 (4H)- NH4OH / CO2) yi)-7- affording isomer methylquinoline-4- B - slower JCOL carboxamido) -N- eluting methylquinuclidine (Compound 209).1* / > - -2-carboxamideSingle isomer, configurationunknown210 O (R or S)-4-(2-((R or 530 Chiral SFC. S')-6-cthyl-2- column (Lux-2, methyl-6,7- 50% / 50% (1:1 dihydropyrazolo [ 1, MeOH / CH3CN O NH 5 -a]pyrazin-5 (4H)- w / 0.1%yl)-7- NH4OH) / CO2) methylquinoline-4- affording isomer carboxamido) -N, N - A - faster eluting I* / > — dimethylquinuclidi (Compound 210).ne-2 -carboxamideSingle isomer, configurationunknown26143Compound Structure Compound Name [M+H]+SFC Conditions [Found]211 0 (R or S)-4-(2-((R or 530 Chiral SFC. S')-6-cthyl-2- column (Lux-2, methyl-6,7- 50% / 50% (1:1 c / "' dihydropyrazolo [ 1, MeOH / CH3CN 0 NH 5 -a]pyrazin-5 (4H)- w / 0.1%yl)-7- NH4OH) / CO2) methylquinoline-4- affording isomer carboxamido) -N, N - B - slower N N / x^\ dimethylquinuclidi elutingi* / > — ne-2 -carboxamide (Compound 211). Single isomer, configurationunknown247 0 (R orS)-N, N- 503 Chiral SFC dimethyl-4-(7- column methyl-2-(2- (Phenomenex ny - methyl-6,7- Lux i-Amylose-1, 0 NH dihydropyrazolo [ 1, 50%:50%5 -a]pyrazin-5 (4H)- (MeOH w / 0.1% yl)quinoline-4- NH4OH): CO2) carboxamido)quinu affording isomer jf l l clidine-2- A - faster eluting carboxamideSingle isomer, configurationunknown248 0 (R orS)-N, N- 503 Chiral SFCCldimethyl-4-(7- column y..methyl-2-(2- (Phenomenex methyl-6,7- Lux i-Amylose-1, 0 NH dihydropyrazolo [ 1, 50%:50%5 -a]pyrazin-5 (4H)- (MeOH w / 0.1% yl)quinoline-4- NH4OH): CO2) carboxamido)quinu affording isomer f ri clidine-2- B - slower carboxamide eluting Single isomer, configurationunknown249 0 (Ror S)-4-(7- 474 Chiral SFC methyl-2-(2- column < / Ny^NH2methyl-6,7- (Phenomenex dihydropyrazolo [ 1, Lux i-Amylose-1, 0 NH 5 -a]pyrazin-5 (4H)- 15%:85%yl)quinoline-4- (MeOH w / 0.1% carboxamido)quinu NH4OH): CO2) clidine-2- affording isomer carboxamide A - faster elutingSingle isomer, configurationunknown26143Compound Structure Compound Name [M+H]+SFC Conditions [Found]250 0 (Ror S)-4-(7- 474 Chiral SFC methyl-2-(2- column < / Ny^NH2methyl-6,7- (Phenomenex dihydropyrazolo [ 1, Lux i-Amylose-1, 0 NH 5 -a]pyrazin-5 (4H)- 15%:85%yl)quinoline-4- (MeOH w / 0.1% carboxamido)quinu NH4OH): CO2) clidine-2- affording isomer carboxamide B - slower eluting M-YSingle isomer, configurationunknown278 0 (R or 5)-4-(2-((l- 491 Chiral SFC isopropyl-3- column (ChiralPak AS-H, methyl- IH-pyrazol- 5 -yl)methoxy) -7- 35%:65%, (1:1 0 NH methylquinoline-4- MeCN: EtOH carboxamido)quinu w / 0.1% clidine-2- NH4OH): CO2) xxi xXr carboxamide affording isomer A - faster eluting ° |QSingle diastereomer andracemic279 0 (R or 5)-4-(2-((l- 491 Chiral SFC isopropyl-3- column(l / - methyl- IH-pyrazol- (ChiralPak AS-H,5 -yl)methoxy) -7- 35%:65%, (1:1 methylquinoline-4- MeCN: EtOH 0 NHcarboxamido)quinu w / 0.1% clidine-2- NH4OH): CO2) XXI X carboxamide affording isomer ° X2NB - slower elutingSingle diastereomer andracemic0 280 519 (R orS)-N, N- Chiral SFC dimethyl-4-(7- column methyl-2-(2- (ChiralPak IC, [jYr methyl-6,7- 45%:55%, (1:1MeCN: EtOH dihydropyrazolo [ 1, 0 NH5 -a]pyrazin-5 (4H)- w / 0.1% yl)quinoline-4- NH4OH): CO2) affording isomer carboxamido)quinu XXI xx X clidine-2- A - faster eluting carboxamideN° i / Single diastereomer andracemic26143Compound Structure Compound Name [M+H]+SFC Conditions [Found]281 0 (J? orS)-N, N- 519 Chiral SFC dimethyl-4-(7- column methyl-2-(2- (ChiralPak IC, [jYrmethyl-6,7- 45%:55%, (1:1 0 NH dihydropyrazolo [ 1, MeCN: EtOH 5 -a]pyrazin-5 (4H)- w / 0.1% yl)quinoline-4- NH4OH): CO2) carboxamido)quinu affording isomer clidine-2- B - slowerN° v carboxamide elutingSingle diastereomer andracemic290 0 7-methyl-2-(2- 487methyl-6,7- dihydropyrazolo [ 1,5 -a]pyrazin-5 (4H)- 0 NH yl)-N-(3- (methylcarbamoyl)bicyclo[2.2.2]octan-l-yl)quinoline-4- jCocarboxamideUxRacemicExample 251: 7-Methyl-2-(2-methyl-6,7-dihydropyrazolori,5-a]pyrazin-5(4H)-yl)-N-(l- (methylcarbamoyl)-2-oxabicyclor2.2.21octan-4-yl)quinoline-4-carboxamide (Compound 251)Compound 25126143Step A: methyl 4-(7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)- yl)quinoline-4-carboxamido)-2-oxabicyclo[ 2.2.2 ] octane- 1 -carboxylate (Int-AKl )

[0279] A vial was charged with 7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylic acid (Int-E2) (20 mg, 1 Eq, 62 pmol), methyl 4-amino-2-oxabicyclo[2.2.2]octane-l -carboxylate hydrochloride (17 mg, 1.2 Eq, 74 pmol), and DMSO (0.31 mL). Next, N-Ethyl-N-isopropylpropan-2-amine (40 mg, 54 pL, 5 Eq, 0.31 mmol) was added followed by 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (35 mg, 1.5 Eq, 93 pmol), and the resulting reaction mixture was stirred at 25 °C. The reaction mixture was directly subjected to reverse-phase purification (Cl 8, 12 g) using a gradient of 10-100% MeCN in aqueous 10 mM ammonium bicarbonate gradient with a flow rate of 12 mL / min. Pure fractions were combined and lyophilized to afford Int-AKl. MS: 490.3 (M+H)+.Step B: 4-(7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinoline- 4-carboxamido)-2-oxabicyclo [2.2.2] octane-1 -carboxylic acid (Int-AK2)

[0280] Methyl 4-(7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)-2-oxabicyclo[2.2.2]octane-l -carboxylate (Int-AKl) (28 mg, 1 Eq, 57 pmol) was dissolved in THF (0.9 mL) and MeOH (0.3 mL). Then, a 2M aqueous solution of Lithium Hydroxide (5.5 mg, 0.11 mL, 4 Eq, 0.23 mmol) was added and the resulting mixture was stirred at 25 °C. The ongoing reaction was quenched with a IM aqueous solution of hydrogen chloride (10 mg, 0.29 mL, 5 Eq, 0.29 mmol). The solution and concentrated under reduced pressure. Next, MeCN (5 mL) was added to the crude residue, and the solution was evaporated to dryness. The dilution / evaporation was repeated over 3 cycles. The residue was dissolved in DCM / MeOH (1:1) (5 mL), and sodium sulfate was added. Solids were filtered and the filtrate was concentrated under reduced pressure to afford Int-AK2. MS: 476.3 (M+H)+.Step C: 7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)-N-( 1- (methylcarbamoyl) -2 -oxabicyclo [2.2.2] octan-4-yl)quinoline-4-carboxamide (Compound 251)

[0281] A vial was charged with 4-(7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)-2-oxabicyclo[2.2.2]octane-l-carboxylic acid (Int-AK2) (27 mg, 1 Eq, 57 pmol), methylamine hydrochloride (12 mg, 3 Eq, 0.17 mmol), and DMSO (500 pL). Next, N-ethyl-N-isopropylpropan-2-amine (37 mg, 50 pL, 5 Eq, 0.28 mmol) was added followed by 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (33 mg, 1.5 Eq, 86 pmol), and the resulting reaction mixture was stirred at 25 °C. The reaction mixture was directly subjected to reverse-phase purification (Cl 8, 12 g)26143using a gradient of 10% MeCN in aqueous 10 mM ammonium bicarbonate to 100% MeCN (flow rate: 12 mL / min) to afford Compound 251 as a solid. MS: 489.4 (M+H)+. 'H NMR (400 MHz, DMSO-ifc) 68.38 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61 (q, J = 4.7 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.14 (dd, J = 8.5, 1.5 Hz, 1H), 5.96 (s, 1H), 4.90 (s, 2H), 4.23 -4.16 (m, 4H), 4.13 (t, J = 5.2 Hz, 2H), 2.58 (d, J = 4.7 Hz, 3H), 2.43 (s, 3H), 2.25 - 2.16 (m, 2H), 2.14 (d, J = 5.4 Hz, 3H), 2.11 - 1.98 (m, 4H), 1.92 - 1.79 (m, 2H).Example 252: N-(l-carbamoyl-2-oxabicvclor2.2.2]octan-4-yl)-7-methyl-2-(2-methyl-6,7- dihydropyrazolori,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 252)Step A: tert-butyl (1 -carbamoyl-2 -oxabicyclo [2.2.2]octan-4-yl)carbamate (Int-ALl)

[0282] To a solution of 4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-l -carboxylic acid (90 mg, 1 Eq, 0.33 mmol) in THF (1.1 mL), N, N'-Carbonyldiimidazole (81 mg, 1.5 Eq, 0.50 mmol) was added at 0 °C. The mixture was stirred at 0 °C and Ammonia (7N in MeOH) (28 mg, 0.24 mL, 5 Eq, 1.7 mmol) was added dropwise. The resulting mixture was stirred at 25 °C. The reaction mixture was diluted with CH2CI2 (10 mL), transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine (2 x 10 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford Int-ALl as a solid. 'H-NMR. (400 MHz, DMSO-t / e) 67.04 (br s, 1H), 6.96 (br s, 1H), 6.69 (br s, 1H), 3.86 (s, 2H), 2.00 - 1.85 (m, 4H), 1.84 - 1.70 (m, 4H), 1.36 (s, 9H). MS: 271 (M+H)+.Step B: 4-amino-2-oxabicyclo[2.2.2]octane-l-carboxamide hydrochloride (Int-AL2)

[0283] To a solution of tert-butyl (l-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate (Int-ALl) (60 mg, 1 Eq, 0.22 mmol) in 1,4-Dioxane (0.5 mL), Hydrogen chloride (4M in dioxane) (40 mg, 0.28 mL, 4 molar, 5 Eq, 1.1 mmol) was added and the resulting mixture was stirred at 25 °C. The reaction mixture was concentrated under reduced pressure. Additional Hydrogen chloride (4M in dioxane) (81 mg, 0.55 mL, 4 molar, 10 Eq, 2.2 mmol) was added to the crude residue and stirred at 25 °C. The reaction mixture was concentrated under reduced pressure to26143afford Int-AL2 as a solid. ’H-NMR (400 MHz, DMSO ) 68.39 (br s, 2H), 7.16 (br s, 1H), 7.05 (br s, 1H), 3.85 (s, 2H), 2.07 - 1.94 (m, 2H), 1.94 - 1.80 (m, 6H). MS: 171 (M+H)+.Step C: N-(l-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl)-7-methyl-2-(2-methyl-6, 7- dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 252)

[0284] A vial was charged with 7-Methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxylic acid (Int-E2) (20 mg, 1 Eq, 62 pmol), 4-Amino-2-oxabicyclo[2.2.2]octane-l -carboxamide hydrochloride (Int-AL2) (15 mg, 1.2 Eq, 74 pmol), and DMSO (0.31 mL). N-Ethyl-N-isopropylpropan-2-amine (40 mg, 54 pL, 5 Eq, 0.31 mmol) was added to the vial followed by addition of 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (35 mg, 1.5 Eq, 93 pmol) and the resulting reaction mixture was stirred at 25 °C. The reaction mixture was directly subjected to reversephase purification (Cl 8, 12 g) using a gradient of 10% MeCN in aqueous 10 mM ammonium bicarbonate to 100% MeCN (flow rate: 12 mL / min). Pure fractions were combined and lyophilized to Compound 252 as a solid. MS: 475.4 (M+H)+. 'H NMR (400 MHz, DMSO-t / r,) 6 8.37 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.14 (dd, J= 8.5, 1.6 Hz, 1H), 7.11 (br s, 1H), 7.05 (br s, 1H), 5.96 (s, 1H), 4.90 (s, 2H), 4.21 (t, J= 5.4 Hz, 2H), 4.16 (s, 2H), 4.13 (t, J = 5.4 Hz, 2H), 2.43 (s, 3H), 2.25 - 2.16 (m, 2H), 2.13 (s, 3H), 2.10 - 1.98 (m, 4H), 1.95 - 1.84 (m, 2H).26143Example 260: 7,8-Dimethyl-2-(6-methyl-L3-dihvdro-2J / -pyrrolo[3,4-c1pyridin-2-yl)-A- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 260)Step A: Methyl 7,8-dimethylquinoline-4-carboxylate (Int-ANl)

[0285] 7,8-Dimethylquinoline-4-carboxylic acid (800 mg, 1 equiv., 3.98 mmol) was stirred in anhydrous MeOH (9.94 mL). Then, H2SO4 (780 mg, 424 qL, 2 equiv., 7.95 mmol) was added and the mixture was stirred at 80°C. The reaction was cooled to room temperature, and the mixture was slowly added to a mixture of ice and aqueous saturated K2CO3 solution (10 mL). The biphasic layers were transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with CHCI3 / IPA (3: 1) (2 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness to yield Int-ANl as a solid, which was used for the next step without further purification. MS: 216.1 (M+H)+.StepB: 4-(Methoxycarbonyl)-7,8-dimethylquinoline 1 -oxide (Int-AN2)

[0286] In a 100 mL round-bottom flask, Methyl 7,8-dimethylquinoline-4-carboxylate (Int-ANl) (856 mg, 1 equiv., 3.98 mmol) was dissolved in CH2CI2 (39.8 mL) at 0 °C (water / ice). To this26143solution, 3 -Chloroperoxybenzoic acid (2.74 g, 4 equiv., 15.9 mmol) was added and the mixture was allowed to warm to 25 °C. The reaction mixture was diluted with an aqueous saturated NaHCCh solution (50 mL), transferred to an extraction funnel and extracted with CH2CI2 (2 x 75 mL). The organic layers were combined, dried over sodium sulphate, filtered, and the filtrate was concentrated to dryness in vacuo. The crude was dissolved in DMSO (2 mL) and purified by reverse phase chromatography (Cl 8, 24 g) using a gradient of 10% MeCN in aqueous 10 mM Ammonium Formate to 100% MeCN. The pure fractions were combined and lyophilized to provide Int-AN2 as a solid. MS: 232.2 (M+H)+.Step C: Methyl 2-chloro-7,8-dimethylquinoline-4-carboxylate (Int-AN3)

[0287] In a 10 mL round-bottom flask neat phosphorus oxychloride (Int-AN2) (5.13 g, 3.08 mL, 18 equiv., 33.5 mmol) was added and cooled to 0-5 °C. Then, it was slowly added to 4-(Methoxycarbonyl)-7,8-dimethylquinoline 1-oxide (430 mg, 1 equiv., 1.86 mmol) in another 10 mL round-bottom flask. The reaction was then allowed to warm up to 25 °C and stirred. The mixture was slowly poured onto ice and aqueous saturated K2CO3 solution (30 mL, gas evolution noted). The biphasic mixture was transferred to an extraction funnel and the layers were separated. The aqueous layer was extracted in CH2CI2 (100 mL x 2). The organic layers were combined, washed with brine (1 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide Int-AN3. MS: 250.8 (M+H)+.XH NMR (400 MHz, CDCI3) 8 8.43 (d, J= 8.7 Hz, 1H), 7.80 (s, 1H), 7.46 (d, J= 8.7 Hz, 1H), 4.03 (s, 3H), 2.72 (s, 3H), 2.51 (s, 3H).Step D: 2-Chloro-7,8-dimethylquinoline-4-carboxylic acid (Int-AN4)

[0288] Methyl 2-chloro-7,8-dimethylquinoline-4-carboxylate (Int-AN3) (200 mg, 1 equiv., 801 pmol) was stirred in THF (6 mL) and H2O (2 mL) at 25 °C in a 20 mL scintillation vial. Then, Lithium hydroxide monohydrate (33.6 mg, 1 equiv., 801 pmol) was added and the mixture was stirred at 25 °C. The reaction was quenched with aqueous 2M HC1 (32.1 mg, 441 pL, 1.1 equiv., 881 pmol). The biphasic mixture was transferred to an extraction funnel and extracted with CH2CI2 / IPA (3:1) (100 ml x 2). The organic layers were combined, dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness to provide Int-AN4 as a solid. MS: 234.2 (M+H)+.Step E: 2-Chloro-7,8-dimethyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide-2,2,2- trifhioroacetic acid (Int-AN5)

[0289] To a 25 round-bottom flask, Quinuclidin-4-amine dihydrochloride (Int-AN4) (176 mg, 1.10 equiv., 882 pmol) and A-Ethyl-A-isopropylpropan-2-amine (518 mg, 698 pL, 5 equiv., 4.01 mmol) were added. The reagents were dissolved in DMSO (4.0 mL) by sonicating, 2-Chloro-7,8-26143dimethylquinoline-4-carboxylic acid (189 mg, 1 equiv., 802 pmol) was added, and the reaction was stirred. Then, HATU (457 mg, 1.5 equiv., 1.20 mmol) was added in one portion. The reaction was stirred at room temperature. The reaction was directly purified by reverse-phase chromatography by using a gradient of 5% MeCN in H2O (with 0.05% TFA) to 100% MeCN. The pure fractions were combined and lyophilized to provide (Int-AN5) as a solid. MS: 344.2 (M+H)+.Step F: 7, 8-Dimethyl-2-( 6-methyl-l, 3-dihydro-2H-pyrrolo[ 3, 4-c ]pyridin-2-yl)-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 260)

[0290] To a 2-5 mL microwave vial, a solution of 2-Chloro-7,8-dimethyl-A-(quinuclidin-4-yl)quinoline-4-carboxamide-2,2,2-trifluoroacetic acid (Int-AN5) (75 mg, 1.0 equiv., 0.17 mmol) in anhydrous dioxane (1.7 mL) was added. The solution was sparged by nitrogen (1 atm). Then, 6-Methyl-2,3-dihydro-17 / -pyrrolo[3,4-c]pyridine dihydrochloride (53 mg, 1.5 equiv., 0.25 mmol), Cesium carbonate (0.28 g, 5 equiv., 0.85 mmol), and Pd-PEPPSI™ MIPent catalyst (13 mg, 10% mol, 17 pmol) were added. The mixture was purged with nitrogen (1 atm). Then, the suspension was stirred at 95 °C. It was cooled back to room temperature and filtered through a PTFE membrane filter, then purified by reverse-phase chromatography using Buchi Pure C850 FlashPrep, Gemini 5pMNX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970, with a gradient of 10 to 100% MeCN in aqueous 10 mM Ammonium Bicarbonate with a flow rate of 30 mL / min. The pure fractions were combined and lyophilized to provide Compound 260 as a solid. MS: 442.3 (M+H)+. 'H NMR (400 MHz, DMSO-t / r,) 68.56 (s, 1H), 8.15 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J= 8.3 Hz, 1H), 6.83 (s, 1H), 4.93 (s, 2H), 4.92 (s, 2H), 2.86 (s, 6H), 2.59 (s, 3H), 2.40 (s, 3H), 1.97 - 1.87 (m, 6H). 3H methyl proton overlapped with solvent peak.

[0291] The example compounds in Table 23 below were prepared in a similar manner to Compound 260 above using the appropriate amine for Step F.Table 23Compound Structure Compound Name [M+H]+[Found] 261 N 7,8-Dimethyl-2-(2-methyl-6,7- 445dihydropyrazolo[l,5-a]pyrazin- 5(4J7)-yl)-A-(quinuclidin-4- 0 NH yl)quinoline-4-carboxamide126143Example 265 & 266: (R or S)-7V-(2-Cvanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7- dihvdropyrazolorL5-a1pyrazin-5(4J7)-yl)quinoline-4-carboxamide (Compound 265) & (R orS)-7V-(2-Cyanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolori,5-a1pyrazin- 5(4J7)-yl)quinoline-4-carboxamide (Compound 266)lnt-AI3 (Ex. 249) lnt-AP1 Compound 265 Compound 266 Step A: rac-N-(2-Cyanoquinuclidm-4-yl)-7-methyl-2-(2-methyl-6, 7-dihydropyrazolo[l,5- a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Int-APl )

[0292] To a4-dram vial, 4-(7-Methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4J7)-yl)quinoline-4-carboxamido)quinuclidine-2-carboxamide (Int-AI3) (17 mg, 1 equiv., 36 pmol) was added and dissolved in anhydrous DCM (200 pL). Then, Burgess Reagent (21 mg, 2.5 equiv., 90 pmol) was added and the reaction was stirred at 25 °C. The reaction was quenched by slow addition of water (1 mL) to the mixture. The reaction mixture was then transferred to an extraction funnel and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by reverse phase chromatography over Buchi Pure C850 FlashPrep, Gemini 5pM NX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970 using a gradient of 5% CH3CN in aqueous 10 mM Ammonium Bicarbonate to 100% CH3CN. The pure fractions were combined and lyophilized to afford Int-APl as a solid. MS: 456.5 (M+H)+.!H NMR (400 MHz, DMSO-ifc) 68.35 (s, 1H), 7.67 (d, J= 8.4 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.14 (dd, J= 8.3, 1.1 Hz, 1H), 5.96 (s, 1H), 4.90 (s, 2H), 4.36 - 4.28 (m, 1H), 4.21 (t, J= 4.9 Hz, 2H), 4.13 (t, J = 4.9 Hz, 2H), 3.17 - 3.05 (m, 1H), 3.01 - 2.82 (m, 3H), 2.45 - 2.39 (m, 4H), 2.17 - 2.09 (m, 4H), 2.08 - 1.94 (m, 2H), 1.92 - 1.76 (m, 2H).Step B: (R or S)-N-(2-cyanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6, 7- dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 265) and (R or S)-N-(2-cyanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6, 7-dihydropyrazolo [ 1,5- a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 266)

[0293] Int-APl (34 mg, 75 pmol) was separated by ChiralPak IA 5pm, 21x 250 mm; 40%:60%, (IPA + lOmM ammonium formate): CC>2 to afford Compound 265 fastest eluting peak (Single26143isomer, configuration unknown) and Compound 266 as the slowest eluting peak (Single isomer, configuration unknown).

[0294] Compound 265 was repurified by dissolving in DMSO, loading onto a reverse phase column overBuchi Pure C850 FlashPrep, Gemini 5pMNX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970 and eluting using a gradient of 5% CH3CN in aqueous 10 mM Ammonium Bicarbonate to 100% CH3CN. The pure fractions were combined and lyophilized to afford (R or 5)-N-(2-cyanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide Compound 265 as a solid (Single isomer, configuration unknown). MS: 456.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 88.35 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.14 (dd, J = 8.4, 1.5 Hz, 1H), 5.96 (s, 1H), 4.90 (s, 2H), 4.33 (dd, J = 9.2, 7.5 Hz, 1H), 4.21 (t, J = 5.1 Hz, 2H), 4.13 (t, J = 4.9 Hz, 2H), 3.17 - 3.06 (m, 1H), 3.00 - 2.85 (m, 3H), 2.47 - 2.40 (m, 4H), 2.18 - 2.09 (m, 4H), 2.09 - 1.94 (m, 2H), 1.94 - 1.76 (m, 2H).

[0295] Compound 266 was repurified by dissolving in DMSO, loading onto a reverse phase column Buchi Pure C850 FlashPrep, Gemini 5pM NX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970 and eluting using a gradient of 5% CH3CN in aqueous 10 mM Ammonium Bicarbonate to 100% CH3CN. The pure fractions were combined and lyophilized to afford (R or 5)-N-(2-cyanoquinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide Compound 266 as a solid (Single isomer, configuration unknown). MS: 456.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 68.35 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.22 (s, 1H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 5.96 (s, 1H), 4.90 (s, 2H), 4.33 (dd, J = 9.0, 7.2 Hz, 1H), 4.21 (t, J = 5.1 Hz, 2H), 4.13 (t, J = 5.0 Hz, 2H), 3.16 - 3.06 (m, 1H), 3.02 - 2.84 (m, 3H), 2.48 - 2.39 (m, 4H), 2.17 - 2.10 (m, 4H), 2.09 - 1.76 (m, 4H).

[0296] The example compounds in Table 24 below were prepared in a similar manner to Compound 265 & 266 above using the appropriate starting material in step A.Table 24Compound Structure Compound Name [M+H]+Alternative [Found] Conditions 267 N CN N-((Ror S)-2- 484 Started from cyanoquinuclidin- Compound 0 4-yl)-2-((R or S)-6- 206. No SFC O NH ethyl-2-methyl-6,7- conditions dihydropyrazolo [ 1, used.5 -a]pyrazin-5 (4H)- yl)-7- methylquinoline-4- 1 * ✓> carboxamide26143Compound Structure Compound Name [M+H]+Alternative [Found] Conditions Single isomer, configurationunknown268 N CN N-((Ror S)-2- 484 Started from cyanoquinuclidin- Compound 4-yl)-2-((R or S)-6- 207. No SFC V0 NH ethyl-2-methyl-6,7- conditions dihydropyrazolo [ 1, used.5 -a]pyrazin-5 (4H)- yl)-7- methylquinoline-4- 1 * / > carboxamideSingle isomer, configurationunknownExample 269: 2-(3-oxa-8-azabicyclo[3.2.11octan-8-yl)-N-(2-(hvdroxymethyl)quinuclidin-4- yl)-7-methylquinoline-4-carboxamide (Compound 269)

[0297] Methyl 4-(7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamido)quinuclidine-2-carboxylate (50.0 mg, 83.9 pmol) was dissolved in THF (0.8 mL). This solution was cooled to -78 °C and Diisobutyl aluminum hydride IM in THF (17.9 mg, 126 pL, 1 molar, 126 pmol)) was added. The reaction was stirred 1 h -78 °C. A second portion of Diisobutylaluminum hydride IM in toluene (17.9 mg, 126 pL, 1 molar, 126 pmol) was added and stirred at -78 °C. Then the reaction mixture was allowed to gradually warm up to room temperature. The reaction was quenched with solid Na2SO4 IOH2O then the slurry was stirred and filtered over a sintered funnel. The filtrate was evaporated to dryness. The crude residue was loaded onto a reverse phase column and purified over Buchi Pure C850 FlashPrep, Gemini 5pM NX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970, using a gradient of 5-100% MeCN in aqueous 10 mM Ammonium Bicarbonate gradient with a flow rate of 30 mL / min. Pure fractions were combined and lyophilized to afford Compound 269 as a solid (Racemic). MS: 461.5 (M+H)+. 'H NMR (400 MHz, CD3CN) 87.76 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.14 (dd, J26143= 8.4, 1.6 Hz, 1H), 7.09 (s, 1H), 6.61 (s, 1H), 5.93 (s, 1H), 4.89 (s, 2H), 4.19 (d, J = 5.3 Hz, 2H), 4.15 (d, J = 5.1 Hz, 2H), 3.51 (dd, J= 11.0, 9.7 Hz, 1H), 3.41 (dd, J= 11.1, 5.5 Hz, 1H), 3.13 -3.03 (m, 2H), 3.03 - 2.93 (m, 2H), 2.78 (ddd, J = 13.8, 10.5, 3.4 Hz, 1H), 2.46 (s, 3H), 2.12 -2.02 (m, 3H), 1.91 - 1.81 (m, 2H), 1.46 (ddd, J = 12.2, 7.7, 2.9 Hz, 1H). 3H are under water peak and 1H (OH) is not visible.

[0298] The example compounds in Table 25 below were prepared in a similar manner to Compound 269 above using the appropriate starting material in step A.Table 25Compound Structure Compound Name [M+H]+[Found] 270 N 2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N- 437(2-(hydroxymethyl)quinuclidin-4-yl)-7- methylquinoline-4-carboxamideO NHRacemicExample 271: N-(2-(fluoromethyl)quinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7- dihydropyrazolo|T,5-a]pyrazin-5(4H)-yl)quinoline-4-carboxamide (Compound 271)Compound 269 Compound 271

[0299] To a stirred solution of A-(2-(Hydroxymethyl)quinuclidin-4-yl)-7-methyl-2-(2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-5(4J7)-yl)quinoline-4-carboxamide (Compound 269) (30 mg, 65 pmol) in CH2CI2 (200 pL), l,8-Diazabicyclo[5.4.0]undec-7-ene (30 mg, 29 pL, 0.20 mmol) and Nonafluorobutanesulfonyl Fluoride (59 mg, 35 pL, 3.0 equiv., 0.20 mmol) were added at 0 °C. The reaction mixture was stirred from 0 °C to 25 °C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL). The organic phases were combined, washed with brine (1 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated26143under reduced pressure. The crude was purified by reverse phase chromatography over Buchi Pure C850 FlashPrep, Gemini 5pMNX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970, with a gradient of 5-100% MeCN in aqueous 10 mM Ammonium Bicarbonate gradient over a flow rate of 30 mL / min. Pure fractions were combined and lyophilized to dryness to afford Compound 271 as a solid (Racemic). MS: 463.4 (M+H)+. 'H NMR (400 MHz, CD3CN) 87.76 (d, J= 8.4 Hz, 1H), 7.47 (s, 1H), 7.15 (dd, J= 8.4, 1.6 Hz, 1H), 7.10 (s, 1H), 6.62 (s, 1H), 5.93 (s, 1H), 4.89 (s, 2H), 4.23 - 4.13 (m, 4H), 3.60 - 3.56 (m, 1H), 3.54 - 3.49 (m, 1H), 3.11 - 3.04 (m, 2H), 3.03 -2.97 (m, 2H), 2.87 -2.77 (m, 1H), 2.46 (s, 3H), 1.91 - 1.84 (m, 3H), 1.75 - 1.70 (m, 2H), 1.63 (dd, J= 7.9, 5.0 Hz, 1H). 3H under water peak.Example 275: N-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4- yl)quinuclidine-4-carboxamide (Compound 275)Step A: tert-butyl (2-chloro-7-methylquinolin-4-yl)carbamate (Int-ARl)

[0300] To a microwave vial, 2-chloro-7-methylquinoline-4-carboxylic acid (450 mg, 2.03 mmol) and triethylamine (566 pL, 4.06 mmol) were added. The reagents were dissolved in a mixture of toluene (4 mL) and tert-butyl alcohol (6 mL) at room temperature. Then, Diphenylphosphoryl azide (525 pL, 1.2 Eq, 2.44 mmol) was added and the mixture was heated at 70 °C, followed by heating at 100 °C. The reaction mixture was cooled back to room temperature and evaporated in vacuo. The crude residue was purified on silica gel (40 g) using a gradient of 0-100% EtOAc in heptanes. The pure fractions were combined and concentrated to dryness to provide Int-ARl as a solid. MS: 293 (M+H)+.Step B: tert-butyl (2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4- yl)carbamate (Int-AR )

[0301] To a microwave vial, a mixture of tert-butyl (2-chloro-7-methylquinolin-4-yl)carbamate (550 mg, 1.88 mmol), Potassium phosphate tribasic (1.20 g, 5.64 mmol), and 3-Fluoro-4-(2,2,2-26143trifluoroethoxy)phenylboronic acid (671 mg, 2.82 mmol) was added in a mixture of 1,4-Dioxane (10 mL) and H2O (1.1 mL). The solution was purged under nitrogen. 1, l'-Bis(di-t-butylphosphino)ferrocene palladium dichloride (122 mg, 0.10 Eq, 188 pmol) was then added and the reaction mixture tube heated at 80 °C. The reaction mixture was then cooled back to room temperature and diluted with EtOAc (20 mL) and water (5 mL). The biphasic mixture was transferred to an extraction funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified on silica gel (SiO2, 40 g) using a gradient of 0-100% EtOAc in heptanes. The pure fractions were combined and concentrated in vacuo to afford Int-AR2 as a solid. MS: 451.3 (M+H)+.Step C: 2-(3 luoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-amine Trifluoroacetic acid salt (581 mg, 1.1 mmol) (Int-AR3)

[0302] A 250 mL round-bottom flask was charged with tert-butyl (2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-yl)carbamate (585 mg, 1.30 mmol) and DCM (10 mL). Then, Trifluoroacetic acid (5 mL, 0.07 mol) was added, and this homogenous solution was stirred at 25 °C. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in DCM (20 mL) and evaporated to dryness. This dilution / evaporation cycle was done 3 times to afford Int. AR3 as a solid. MS: 351.2 (M+H)+.Step D: N-(2-(3 luoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4- yl)quinuclidine-4-carboxamide (Compound 275)

[0303] To a 50 mL round-bottom flask was added a mixture of 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-amine and Trifluoroacetic acid salt (100 mg, 215 pmol) in DMF (5 mL). Then, l-azabicyclo[2.2.2]octane-4-carboxylic acid hydrochloride (82.6 mg, 2.0 Eq, 431 pmol) was added followed by Diisopropylethylamine (185 pL, 5 Eq, 1.08 mmol). The reaction was stirred at room temperature. To this solution, HATU (205 mg, 2.5 Eq, 538 pmol) was added and the reaction mixture was heated at 80 °C. The reaction mixture was cooled back to room temperature and diluted with a mixture of water (3 mL) and EtOAc (8 mL). The biphasic mixture was transferred to an extraction funnel, and the layers were separated. The aqueous layer was extracted with EtOAc (8 mL x 2). The organic layers were combined and dried over Na2SO4, filtered, and evaporated in vacuo. The crude was purified via reverse phase chromatography (10 g, Cl 8) using a gradient of 0% to 100% MeCN in aqueous 10 mM Ammonium formate. The pure fractions were combined and lyophilized to afford Compound 275 as a solid. MS: 488.2 (M+H)+. 'H NMR (400 MHz, CD3CN) 88.39 (d, J= 5.3 Hz, 2H), 8.28 (d, J= 5.3 Hz, 1H, formate), 8.07 (dd, J= 12.9, 2.0 Hz, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.86 (d, J26143= 8.4 Hz, 2H), 7.45 (d, J= 9.1 Hz, 1H), 7.28 (t, J= 8.6 Hz, 1H), 4.68 (q, J= 8.4 Hz, 2H), 3.14 -3.07 (m, 6H), 2.57 (s, 3H), 2.11 - 2.05 (m, 6H). Isolated as a formate salt.19F NMR (376 MHz, CD3CN) 6 -74.88 (t, J= 8.4 Hz, 3F), -134.94 - -135.14 (m, IF).Example 276: 2-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-yl)- 4,5,6,7-tetrahydrooxazolor4,5-c1pyridine (Compound 276)Cbz OH(10 mol%), Pd(dppf)Cl2 K3PO4(COCI)2, DIPEA, DCM, rt Dioxane / H2O (9.1)80 °Clnt'A4Step Alnt-AS1Step Blnt-AS2Step Clnt-AS3 Compound 276Step A: benzyl 3-(2-chloro-7-methylquinolme-4-carboxamido)-4-oxopiperidme-l- carboxylate (Int-ASl)

[0304] To a solution of 2-chloro-7-methylquinoline-4-carboxylic acid (150 mg, 677 pmol) in anhydrous DCM (3 mL) in a 4-dram vial, oxalyl chloride (129 mg, 88.9 pL, 1.02 mmol) was added. The reaction was stirred at 25 °C. After that period, the solvent was evaporated to dryness under vacuum. To a separate 4 dram-vial, benzyl 3 -amino-4-oxopiperidine-l -carboxylate hydrochloride (289 mg, 1.02 mmol) was added and diluted with DCM (3 mL). Next, DIPEA (437 mg, 589 pL, 3.38 mmol) was added and the mixture was transferred to the residue from the first vial. The reaction was stirred and diluted with DCM (5 mL). The organic layer was transferred to an extraction funnel, washed with water (1 x 5 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude residue was dissolved in DMSO and purified using a gradient of 10% MeCN in aqueous 10 mM Ammonium bicarbonate to 100% MeCN. Pure fractions were combined and lyophilized to afford Int-ASl. MS: 452.2 (M+H)+.26143Step B: benzyl 2-(2-chloro-7-methylquinolin-4-yl)-6, 7-dihydrooxazolo [4,5-c]pyridine- 5 (4H) -carboxylate (Int-AS2)

[0305] Benzyl 3-(2-chloro-7-methylquinoline-4-carboxamido)-4-oxopiperidine-l -carboxylate (85 mg, 0.19 mmol) was charged in a vial. Then, pyridine (0.15 g, 0.15 mL, 1.9 mmol) and Phosphorus oxychloride (0.58 g, 0.35 mL, 3.8 mmol) were added and the mixture was stirred at 70 °C. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and poured slowly in cold water. The mixture was basified with aqueous saturated K2CO3 until pH was found to be 11-12. The biphasic mixture was extracted in EtOAc (2 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude residue was purified by silica gel column using a gradient of 5% to 50% EtOAc in Heptanes. Pure fractions were combined and evaporated under reduced pressure to provide Int-AS2. MS: 434.2 (M+H)+.Step C: benzyl 2-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-yl)-6, 7- dihydrooxazolo[ 4, 5-c ]pyridine-5( 4H)-carboxylate (Int-AS3)

[0306] Benzyl 2-(2-chloro-7-methylquinolin-4-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (27 mg, 1 Eq, 62 pmol) was stirred in anhydrous dioxane (1.1 mL) and water (0.12 mL) in a flame-dried, nitrogen-flushed 0.5-2.0 mL microwave vial. Nitrogen gas was bubbled through the reaction mixture. Then, Benzyl 2-(2-chloro-7-methylquinolin-4-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (27 mg, 1 equiv, 62 pmol), 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (4.6 mg, 0.1 equiv, 6.2 pmol) and Potassium phosphate, tribasic (40 mg, 3 Eq, 0.19 mmol) were added to the vial. The solution was sparged with nitrogen and stirred at 80 °C in an oil bath. The reaction was cooled back to room temperature and quenched with water (10 mL). The biphasic mixture was transferred to an extraction funnel and extracted with DCM (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to afford Int-AS3. MS: 592.2 (M+H)+.Step D: 2-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-yl)-4,5, 6, 7- tetrahydrooxazolo [4, 5-c] pyridine (Compound 276)

[0307] Benzyl 2-(2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-7-methylquinolin-4-yl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)-carboxylate (37 mg, 1 Eq, 63 pmol) was stirred in MeOH (1.6 mL). The solution was sparged with nitrogen. Palladium on carbon (6.7 mg, 5% Wt, 0.05 Eq, 3.1 pmol) was added and the suspension sparged with nitrogen. Then, the solution was sparged with hydrogen (1 atm) for and stirred under a hydrogen (1 atm). The reaction was sparged again by nitrogen and filtered through celite. The cake was washed with DCM / MeOH (1:1, 10 mL) and then washed with 1% v / v Formic acid in MeOH (10 mL). The filtrate was26143concentrated in vacuo. The residue was dissolved in DMSO and purified by reverse phase column using a gradient of 10% MeCN in aqueous 10 mM Ammonium bicarbonate to 100% MeCN. Pure fractions were combined and lyophilized to provide Compound 276 as a solid. MS: 458.2 (M+H)+. 'HNMR (400 MHz, DMSO-d6) 89.14 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H), 8.23 (dd, J = 12.8, 2.1 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.56 (dd, J = 8.7, 1.7 Hz, 1H), 7.47 (t, J = 8.7 Hz, 1H), 4.97 (q, J = 8.8 Hz, 2H), 3.78 (s, 2H), 3.06 (t, J = 5.5 Hz, 2H), 2.84 - 2.76 (m, 2H), 2.55 (s, 3H). 1H exchangeable proton not visible.Example 277: 2-(((l-isopropyl-3-methyl-lH-pyrazol-5-yl)methyl)thio)-7-methyl-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 277)Step A: 2-mer capto-7-methyl-N-(quinuclidm-4-yl)qumolme-4-carboxamide (Int-A U1 )

[0308] To a 20 mL vial, 2-chloro-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide— 2,2,2-trifluoroacetic acid (1 / 1) (75 mg, 1 Eq, 0.18 mmol) was added and the mixture diluted with EtOH (5 mL). Then, thiourea (80 mg, 6 Eq, 1.1 mmol) was added and the mixture was stirred at 100 °C. The reaction was cooled back to room temperature and quenched by addition of IN NaOH (5 mL). The biphasic mixture was stirred at 50°C, acidified with acetic acid until the pH reached 4, and concentrated to dryness. Next, the mixture was dissolved in DMSO (2 mL) and the crude residue was purified by reverse-phase chromatography using a gradient of 10% MeCN in aqueous ammonium bicarbonate to 100% MeCN. Pure fractions were combined and lyophilized to dryness to provide Int-AUl as a solid. MS: 328.1 (M+H)+.Step B: 2-( ((1 -isopropyl-3-methyl-lH-pyrazol-5-yl)methyl) thio)- 7-methyl-N-(quinuclidin- 4-yl)quinoline-4-carboxamide (Compound 277)

[0309] To avial, (3,5-dimethyl-lH-pyrazol-l-yl)methanol (23 mg, 1.1 Eq, 0.18 mmol), triphenylphosphine (0.11 g, 2.5 Eq, 0.42 mmol), DEAD (0.18 g, 0.16 mL, 40% Wt, 2.5 Eq, 0.42 mmol), and 2-mercapto-7-methyl-N-(quinuclidin-4-yl)quinoline-4-carboxamide (55 mg, 1 Eq, 0.17 mmol) were added. The reactants were dissolved in THF (4 mL) and stirred at 60 °C. LC-MS showed the product. The reaction was cooled back to room temperature, and the solvent was evaporated to dryness. The crude residue was loaded onto a reverse-phase column and purified26143using a gradient of 10% MeCN in aqueous 0.05% TFA to 100% MeCN. Pure fractions were combined and air-dried to a solid. The solid was dissolved in DMSO, filtered through a membrane, then loaded onto a reverse-phase column Buchi Pure C850 FlashPrep, Gemini 5pM NX-C18 110A, LC column, 150 x21.2 mm, AX, H25-084970, using a gradient of 10% to 100% MeCN in aqueous 10 mM Ammonium Bicarbonate gradient and a flow rate of 30 mL / min. Pure fractions were combined and lyophilized to dryness to provide Compound 277 as a solid. MS:464.4 (M+H)+. 'H NMR (400 MHz, DMSO-d6) 88.26 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.40 (dd, J = 8.6, 1.6 Hz, 1H), 7.21 (s, 1H), 6.00 (s, 1H), 4.74 - 4.57 (m, 3H), 2.91 - 2.77 (m, 6H), 2.52 (s, 3H), 2.06 (s, 3H), 1.93 - 1.82 (m, 6H), 1.36 (d, J = 6.5 Hz, 6H).Example 295: l-methyl-4-(7-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4- carboxamido)quinuclidin-l-ium trifluoroacetic acid (Compound 295)OH3C-I, K2CO3DMF, 80 °CCompound 8 Compound 295

[0310] 7-methyl-N-(quinuclidin-4-yl)-2-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxamide (Compound 8) (196 mg, 417 pmol), potassium carbonate (173 mg, 1.25 mmol), methyl iodide (71.1 mg, 31.3 pL, 501 pmol) and DMF (4.17 mL) were added to a vial. The reaction was stirred at 80 °C. The reaction was diluted in water (5 mL) and extracted with EtOAc (3 x 10 mL). The organics were combined and washed with brine (3 x 15 mL). The organic layers were combined, dried over Na2SC>4, and concentrated under reduced pressure. The mixture was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to Compound 295 as a solid. MS: 485 (M+H)+. 'H NMR (500 MHz, DMSO) 68.82 (s, 1H), 8.30 (d, J= 8.7 Hz, 2H), 8.02 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J= 8.6 Hz, 1H), 7.25 (d, J= 8.7 Hz, 2H), 4.89 (q, J= 8.7 Hz, 2H), 3.66 - 3.60 (m, 6H), 2.98 (s, 3H), 2.54 (s, 3H), 2.45 -2.38 (m, 6H).26143Example 296: N-(l-azabicvclo[2.2.21oct-2-en-4-yl)-2-(3-fluoro-4-(2,2,2- trifluoroethoxy)phenyl)-7-methylquinoline-4-carboxamide (Compound 296)Compound 285 Compound 296

[0311] 2-(3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-N-(3-hydroxyquinuclidin-4-yl)-7-methylquinoline-4-carboxamide (8.0 mg, 16 pmol) was dissolved in DCM (500 pL), cooled to -78 °C, and Diethylaminosulfur trifluoride (8.2 pL, 64 pmol) was added. The mixture was warmed to room temperature and stirred. The mixture was cooled to 0 °C, saturated NaHCCh (2 mL) was added, and the aqueous layer was extracted with CHCh:iPrOH 3:1 (3x2 mL). The organic layers were combined, passed through a phase separator and volatiles were removed in vacuo. The mixture was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to afford Compound 296 as a solid. MS: 486 (M+H)+.!H NMR (500 MHz, DMSO) 8 10.41 (s, 1H), 10.25 (s, 1H), 8.28 - 8.14 (m, 3H), 7.99 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.50 (t, J = 9.4 Hz, 2H), 6.23 (s, 1H), 4.98 (q, J = 8.7 Hz, 2H), 4.23 (d, J = 16.4 Hz, 1H), 3.81 (d, J = 13.7 Hz, 1H), 3.67 (s, 1H), 3.54 (d, J = 10.0 Hz, 1H), 3.15 (s, 1H), 2.56 (s, 3H), 2.41 (s, 1H), 2.26 (s, 1H).Example 297: 4-(7-methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4- carboxamido)quinuclidine 1 -oxide (Compound 297)Ct-mCPBA DCM, -78 °CCompound 8 Compound 29726143

[0312] To a stirred solution of 7-methyl-N-(quinuclidin-4-yl)-2-(4-(2,2,2- trifluoroethoxy)phenyl)quinoline-4-carboxamide (Compound 8) (10 mg, 21 pmol) in DCM (53 pL), mCPBA (3.3 mg, 19 pmol) was added at -78 °C. The reaction was stirred. The reaction mixture was diluted with water (10 mL) and saturated NaHCCh (10 mL) and then it was extracted with EtOAc (3 x 5mL). The organic layers were combined and concentrated under reduced pressure. The mixture was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to afford Compound 297 as the trifluoroacetic acid salt (1:1). MS: 486 (M+H)+. 'H NMR (500 MHz, DMSO) 88.68 (s, 1H), 8.29 (d, J= 8.9 Hz, 2H), 7.97 (s, 1H), 7.94 - 7.86 (m, 2H), 7.46 (dd, J= 8.5, 1.5 Hz, 1H), 7.24 (d, J= 8.9 Hz, 2H), 4.88 (q, J= 8.8 Hz, 2H), 3.36 (s, 6H), 2.54 (s, 3H), 2.47 - 2.33 (m, 6H).Example 298: 7-methyl-2-(2-methyl-4-oxo-6,7-dihvdropyrazolo[L5-a1pyrazin-5(4H)-yl)-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 298)o2HCIHATU, DIPEA DMF, 23 °CStep A: methyl 7-methyl-2-(2-methyl-4-oxo-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)- yl)quinoline-4-carboxylate (Int-A VI )

[0313] To a stirred suspension of 2-methyl-6,7-dihydropyrazolo[l,5-a]pyrazin-4(5H)-one, 2HC1 (20 mg, 89 pmol), methyl 2-chloro-7-methylquinoline-4-carboxylate (Int-A3) (32 mg, 0.13 mmol), xantphos (10 mg, 18 pmol), cesium carbonate (58 mg, 0.18 mmol) in 1,4-Dioxane (0.4526143mL), tetrakis(triphenylphosphine)palladium(0) (10 mg, 8.9 pmol) was added. The reaction was stirred at 100 °C. The mixture was cooled down to room temperature, diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organics were combined, dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford Int-AVl. MS: 351 (M+H)+.Step B: 7-methyl-2-(2-methyl-4-oxo-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)- yl)quinoline-4-carboxylic acid (Int-A V2)

[0314] Int-AVl (66 mg, 0.19 mmol) and LiOH (14 mg, 3 Eq, 0.57 mmol) were added to a vial followed by THF (0.78 mL) and Water (0.16 mL). The reaction was stirred at 23 °C. The reaction was acidified to a pH < 1 using 4M HC1 (aq) and extracted with EtOAc (3 x 10 mL). The organic layers were combined and concentrated under reduced pressure to afford Int-AVl as a solid. MS: 337 (M+H)+.Step C: 7-methyl-2-(2-methyl-4-oxo-6, 7-dihydropyrazolo [ 1,5-a]pyrazin-5(4H)-yl)-N- (quinuclidin-4-yl)quinoline-4-carboxamide (Compound 298)

[0315] Quinuclidin-4-amine, 2HC1 (23 mg, 0.12 mmol), Int-AVl (33 mg, 98 pmol), and HATU (75 mg, 0.20 mmol) were added to a vial. Then DMF (0.98 mL), followed by DIPEA (51 mg, 68 pL, 4 Eq, 0.39 mmol) were added. The reaction was stirred at room temperature. The reaction was diluted in water (5 mL) and extracted with EtOAc (3 x 5 mL). The organics were combined, dried over Na? SO4, filtered, and concentrated under reduced pressure. The mixture was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to afford Compound 198 as the trifluoroacetic acid salt (1:1). MS: 445 (M+H)+. 'HNMR (500 MHz, DMSO) 89.50 (s, 1H), 8.80 (s, 1H), 7.97 (s, 1H), 7.87 (d, J= 8.5 Hz, 1H), 7.77 (s, 1H), 7.47 (dd, J= 8.5, 1.4 Hz, 1H), 6.75 (s, 1H), 4.64 - 4.57 (m, 2H), 4.50 - 4.43 (m, 2H), 3.44 (s, 7H), 2.53 (s, 3H), 2.34 - 2.28 (m, 6H), 2.26 (s, 3H).

[0316] The example compounds in Table 26 below were prepared in a similar manner to Compound 198 above using the appropriate amine in step A.Table 16Compound Structure Compound Name [M+H]+[Found] 299 N 2-(2,6-dimethyl-4-oxo-6,7- 459dihydropyrazolo[ 1,5 -a]pyrazin- 5(4H)-yl)-7-methyl-N- A (quinuclidin-4-yl)quinoline-4- carb oxami de26143Compound Structure Compound Name [M+H]+[Found] Single isomer, configurationunknownExample 300: l-(30-(5,5-difh >ro-7,9-dirnethyl-5H-514,614-dipyrrolo[l,2-c:2',l'- firi,3,21diazaborinin-3-yl)-28-oxo-3,6,9,12,15,18,21,24-octaoxa-27-azatriacontyl)-4-(7- methyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)quinoline-4-carboxamido)quinuclidin-l-ium 2,2,2-Step A: l-(26-amino-3,6,9,12,15,18,21,24-octaoxahexacosyl)-4-(7-methyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)quinoline-4-carboxamido)quinuclidin-l-ium 2, 2, 2-trifluoroacetate (Int-AXl)

[0317] Compound 8 (30 mg, 51 pmol), potassium carbonate (21 mg, 0.15 mmol), 26-bromo-3,6,9,12,15,18,21,24-octaoxahexacosan-l-amine, Trifluoroacetic acid (30 mg, 51 pmol) and DMF (0.51 mL) were added to a vial and stirred at 80 °C. The reaction was taken up in DMF (1 mL) and columned by reverse phase chromatography (C18, 0-100% MeCN / H2O + 0.1% TFA) to afford Int-AXl. MS: 866 (M+H)+.Step B: l-(30-(5, 5-difluoro- 7, 9-dimethyl-5H-5l4, 6l4-dipyrrolo[ 1, 2-c:2 ', 1 '- f][ 1, 3, 2 ]diazaborinin-3-yl)-28-oxo-3, 6, 9, 12, 15, 18, 21, 24-octaoxa-27 -azatriacontyl) -4-(7- methyl-2-(4-(2,2,2-trijluoroethoxy)phenyl)quinoline-4-carboxamido)quinuclidin-l-ium 2, 2, 2 -trifluoroacetate (Compound 300)

[0318] A vial was charged with Int-AXl (20.4 mg, 23.6 pmol), 3-(5,5-difluoro-7,9-dimethyl-5H-514,614-dipyrrolo[l,2-c:2',l'-f][l,3,2]diazaborinin-3-yl)propanoic acid (6.88 mg, 23.6 pmol), EDC (9.03 mg, 47.1 pmol), and 1 -Hydroxybenzotriazole - hydrate (7.21 mg, 5.02 pL, 47.1 pmol) in DMF (236 pL). To this solution, DIPEA (10.3 pL, 58.9 pmol) was added dropwise under inert atmosphere. The reaction was stirred at 23 °C. The reaction was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organics were combined, dried over MgSCL, filtered, and concentrated under reduced pressure. The residue was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to afford Compound 300. 'H NMR (500 MHz,26143DMSO) 68.83 (s, 1H), 8.30 (d, J= 8.8 Hz, 2H), 8.03 (s, 1H), 8.00 (d, J= 5.4 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.48 (d, J= 8.6 Hz, 1H), 7.26 (d, J= 8.8 Hz, 2H), 7.09 (d, J= 4.0 Hz, 1H), 6.36 (d, J= 4.0 Hz, 1H), 6.30 (s, 1H), 4.89 (q, J= 8.8 Hz, 2H), 3.86 (s, 3H), 3.74 - 3.66 (m, 12H), 3.56 (s, 11H), 3.57 - 3.52 (m, 13H), 3.50 (d, J= 4.3 Hz, 17H), 3.42 (dd, J = 12.9, 6.8 Hz, 5H), 3.22 (q, J= 5.7 Hz, 2H), 3.08 (t, J= 7.7 Hz, 2H), 2.55 (s, 3H), 2.47 (s, 3H), 2.46 - 2.39 (m, 6H), 2.26 (s, 3H). MS: 1140 (M+H)+.Biological Assays

[0319] Compounds 1-25, 27-69, 71, 74-138, 168, 172-174, 184-186, 200-202, 208, 220-221, 223-225, 228-231, 246-248,253-264, 269-279, 283-288, 293-298, 300 were tested using R848 stimulation assay which is described below. Compounds 1-31, 34, 36-39, 57-58, 63-67, 71, 74, 77, 79, 82, 103-104, 106, 111-112, 115-119, 121-127,173-174, 231, 237, 275-276, 284-285, 294-296 were additionally tested using LPS stimulation assay which is described below.R848 stimulation assay: Evaluation of inhibitory activity of compounds on IRF activity in THP1 Dual cell line with R848 stimulation

[0320] THPl-Dual cells (from InvivoGen) were derived from the human THP-1 monocyte cell line by stable integration of two inducible reporter constructs, Lucia reporter gene under the control of an ISG54 minimal promoter to measure IRF activity, and a SEAP reporter gene fused to five copies of NF-KB consensus transcriptional response element and three copies of the c-Rel binding site. As a result, THPl-Dual cells allow the simultaneous study of the NF- KB pathway by monitoring the activity of SEAP and the IRF pathway, by assessing the activity of Lucia in cultured supernatants. Lucia reporter was used herein to assess IRF actively only. Assay ready THPl-Dual cells were thawed and cultured in complete medium (RPMI1640 + 10% HI FBS + 1% Pen Strep + 1 mL Normocin) for 7 days and then in selective medium (RPMH640 + 10% HI FBS + 1% Pen Strep + 1 mL Normocin lOpg / ml Blasticidin, lOOpg / ml Zeocin) for 3 days. Then THPl-Dual cells were suspended at 2 x 106cells / mL in complete RPMH640 media. The compounds obtained in the Examples section were used as test compounds and were dissolved in DMSO. The test compounds were plated into a 384-well plate with a 30 pM top dose and 3-fold dilution for each test compound. Next, 25 pl of the THP1-DUAL cell suspension was added into each well of the compound plate and cultured in an incubator containing 5% CO2 gas at 37°C for 24 h. 5 pl R848 solution (final concentration 5pg / ml) was added to each well with final 3 Opl total volume, the plate was mixed, then spun down at 1500 rpm for 5. The plate was then cultured in an incubator containing 5% CO2 gas at 37°C. The plate was spun down at 1500 rpm for 526143minutes and the cell supernatant from each well was transferred to a new 384-well plate, and QUANTI-Luc™ 4 Lucia / Gaussia was added to each well to assess IRF activity. The plate was spun down at 1500 rpm for 2 minutes, then luminescence was measured immediately by a Envision plate reader. The data were normalized to % effect, where 100% effect is defined as no R848 stimulation and 0% effect is DMSO control. Dose response data were analyzed using the 4-parameter logistic nonlinear regression model using Spotfire. The concentration of the test compound at which 50% inhibition was achieved (IC50 (nM)) was determined.LPS stimulation assay: Evaluation of inhibitory activity of compounds on IRF activity in THP1 Dual cell line with LPS stimulation.

[0321] THPl-Dual cells (from InvivoGen) were derived from the human THP-1 monocyte cell line by stable integration of two inducible reporter constructs, Lucia reporter gene under the control of an ISG54 minimal promoter to measure IRF activity, and a SEAP reporter gene fused to five copies of NF-KB consensus transcriptional response element and three copies of the c-Rel binding site. As a result, THPl-Dual cells allow the simultaneous study of the NF- KB pathway by monitoring the activity of SEAP and the IRF pathway, by assessing the activity of Lucia in cultured supernatants. Here we utilized Lucia reporter to assess IRF actively only. Assay ready THPl-Dual cells were thawed and cultured in complete medium (RPMI 1640 + 10% HI FBS + 1% Pen Strep + 1 mL Normocin) for 7 days and then in selective medium (RPMH640 + 10% HI FBS + 1% Pen Strep + 1 mL Normocin 10 pg / ml Blasticidin, 100 pg / ml Zeocin) for 3 days. Then THPl-Dual cells were suspended at 2 x 106cells / mL in complete RPMI 1640 media. The compounds obtained in the Examples section were used as test compounds and were dissolved in DMSO. The test compounds were plated into a 384-well plate with a 30 pM top dose and 3-fold dilution for each test compound. 25 pl of The THPl-Daul cell suspension was added into each well of the compound plate and cultured in an incubator containing 5% CO2 gas at 37°C for 24 h.5 pl LPS solution (final concentration 40 ng / ml) was added to each well with final 30 pl total volume, the plate was mixed, then spun down at 1500 rpm for 5 minutes. The plate was then cultured in an incubator containing 5% CO2 gas at 37°C. The plate was spun down at 1500 rpm for 5 minutes and the cell supernatant from each well was transferred to a new 384-well plate, and QUANTI-Luc™ 4 Lucia / Gaussia was added to each well to assess IRF activity. The plate was spun down at 1500 rpm for 2 minutes, then luminescence was measured immediately by a Envision plate reader. The data were normalized to % effect, where 100% effect is defined as no LPS stimulation and 0% effect is DMSO control. Dose response data were analyzed using the 4-parameter logistic nonlinear regression model using Spotfire. The concentration of the test compound at which 50% inhibition was achieved (IC50 (nM)) was determined.26143

[0322] Table 27 below shows the results of testing the compounds using the R848 and LPS stimulation assays.Table 27: Results of R848 and LPS stimulation assaysExample R848 LPS StimulationCompound Stimulation IC50IC501 7.788 89592 10.61 103303 9.246 121604 372.7 116105 7.782 113706 105.9 69077 5.197 >299108 2.848 205109 582.8 1654010 73.38 1779011 1.934 1307012 16.40 >2991013 45.09 >2991014 14.05 400315 30.96 503016 47.45 >2991017 8370 >2991018 20.76 297919 1710 1975020 120.9 656321 152.6 1372022 150.3 1603023 379.8 2419024 172.8 1599025 263.2 497627 944.6 2057028 9.612 630629 247.9 847930 417.2 400831 23.55 411632 171.233 229.734 91.64 1871035 154236 61.08 1850037 621.6 >2991038 555.1 >2991039 608.7 >2991040 55.9141 43.9426143Example R848 LPS Stimulation Compound Stimulation IC50IC5042 15.3543 14.1644 135.945 874.146 217147 92.1848 899.649 10.150 40.6851 35.252 71.8353 354.655 731.856 705.657 540.7 996258 879.8 2982059 106760 21.661 192.662 21.1363 16.86 >2991064 453.6 2363065 122.1 2641066 40.36 1061067 906.5 291868 242.369 142071 1048 >999072 731.874 50.84 231175 79.276 7.4277 225.4 >2991078 5.5979 73.04 2264080 2.6781 16.882 3.29 1446083 404.784 25.2885 4.4186 602.626143Example R848 LPS Stimulation Compound Stimulation IC50IC5087 106.588 15.3589 41.2890 45.2191 54.7592 183.293 276.594 364.195 39696 20.5597 51.5698 15899 336.1100 26.69101 860.2102 584.8103 451.6 >29910104 825.1 >29910105 300.6106 412.2 >29910107 657.4108 288.6109 133.6110 275.8111 27.66 21870112 109 23860113 462.2114 496115 353.2 22180116 39.3 12740117 336.4 14340118 31.72 15400119 69.51 18830120 93.81121 497.1 20620122 118.8 19170123 235.3 13210124 362 18580125 134.9 13470126 344.5 12670127 456.3 >29910128 859.626143Example R848 LPS Stimulation Compound Stimulation IC50IC50129 967.5130 602.9131 39.07132 10.22133 5.89134 96.59135 4.60136 24.02137 11.93138 <0.5168 75.73172 3567.18173 30.09 11892174 729.68 >29910184 17.2185 14.55186 9.25200 61.98201 0.5202 38.58208 56.4220 430.96221 357.03223 28.04224 42.48225 556.59228 621.68229 1398.29230 301.9231 60.39 >29910232 632.88233 852.58234 475.05235 733.62236 868.01237 512.57 7976.85246 703.53247 27.44248 318.71253 949.68254 12.75255 8.4726143Example R848 LPS StimulationCompound Stimulation IC50IC50256 2310.15257 438.53258 30.7259 23.63260 27.4261 125.36262 15.74263 98.57264 274.13269 112.41270 235.3271 34.94272 252.99273 365.64274 776.05275 367.76 12940276 394.02 13763277 69.24278 2.24279 19.15283 8.99284 2.22 13578285 6.07 13388286 144.6287 208.68288 3.36293 424.58294 659.91 10904295 95.04 11176296 51.84 8827.52297 63.19298 6055.57300 1054

[0323] Compounds 1, 7-8, 11, 33, 35, 40-51, 60, 64, 66, 76, 78, 80-82, 84, 100, 107-108, 110, 112, 131-219, 222-229, 238-271, 277-293, 295, 298, 299 were tested using one HTRF assay, as described below.HTRF assay: Measure displacement of a fluorescent probe from human SLC15A4,

[0324] A time-resolved fluorescence resonance energy transfer (TR-FRET) assay was developed to measure displacement of a fluorescent probe from human SLC15A4. Assay buffer was26143prepared comprising 25 mM sodium phosphate (pH 8.2), 150 mM sodium chloride, 0.1% bovine serum albumin (BSA), 0.003% lauryl maltose neopentyl glycol (LMNG), and 0.0003% cholesteryl hemisuccinate (CHS). Recombinant biotinylated human SLC15A4-Avi-FLAG protein (PC24902) was diluted in this buffer to a final concentration of 0.9 nM in the assay.

[0325] Test compounds (10 mM in DMSO) were dispensed acoustically into 384-well white, non-binding plates (Coming 3824) to produce a 20-point, two-fold serial dilution series. DMSO served as the low-effect control, and a 1 pM reference ligand was used as the high-effect control. Five microliters of the biotinylated SLC15A4 protein solution were added to each well, followed by centrifugation and a 30-minute incubation at ambient temperature.

[0326] A detection mixture was prepared containing the fluorescent ligand (Compound 300) (25 nM final) and terbium-streptavidin (0.225 nM final) in assay buffer, and 5 pL of this mixture was added to each well. Plates were centrifuged and incubated for 120 minutes before TR-FRET measurement on a PHERAstar FSX instrument equipped with a LanthaScreen module.

[0327] Data analysis employed a four-parameter logistic model. Percent effect values were calculated using high- and low-control signals, and ICso values were determined from the fitted concentration-response curves. Assay quality acceptance criteria for each plate included a control window greater than 3 and a Z'-factor of at least 0.5.SLC15A4 Protein Purification: procedure for protein purification of human SLC15A4,

[0328] Full length SLC15A4 containing a C-terminal GGGS2-Avi-FLAG sequence was inserted into pcDNA3.1 vector for transient transfection of Expi293 cells (Thermo Fisher). Cells were harvested 48 hours post transfection and lysed by homogenization in 50 mM HEPES, pH 7.4; 150 mM NaCl. Membranes were isolated by centrifugation at 48000 x g for 2 hours and resuspended in 50 mM HEPES, pH 7.4; 150 mM NaCl; 0.25 mM TCEP. Protein was solubilized by addition of lauryl maltose neopentyl glycol (LMNG) and cholesterol hemisuccinate (CHS) to final concentration of 2% and 0.4% respectively. Insoluble material was then pelleted by another centrifugation cycle at 48000 x g for 2 hours.

[0329] Solubilized protein was captured on 3x Flag G1 Affinity Resin (Genscript) and washed with 50 mM HEPES, pH 7.4; IM NaCl; 0.01% LMNG; 0.001% CHS; 0.25mM TCEP; 2 mM MgCh; 1 mM ATP. Beads were subjected to a second wash in 50 mM HEPES, pH 7.4; 150 mM NaCl; 0.01% LMNG; 0.001% CHS; 0.25 mM TCEP and eluted with the same buffer supplemented with 0.3 mg / mL FLAG peptide. SLC15A4 was biotinylated via incubation with BirA (Avidity, LLC) in the presence of 10 mM ATP, 10 mM magnesium acetate, and 0.05 mM d-biotin. Biotinylated protein was loaded on a HiLoad 16 / 60 Superose 6 (Cytiva) column equilibrated with 25 mM HEPES, pH 7.4; 150 mMNaCl; 0.01% LMNG; 0.001% CHS; 0.25 mM26143TCEP. Fractions corresponding to monomeric and dimeric SLC15A4 in LMNG micelles were pooled and concentrated prior to flash freezing in liquid N2 and storage at -80C.

[0330] Table 28 below shows the results of testing the compounds using the HTRF assay. Table 28: Results of SLC15A4 HTRF assayExample Compound HTRF IC501 6.357 4.88 21.1911 7.633 143.7835 27.6240 44.3441 39.2542 19.6343 12.3144 15.1845 118.2246 256.647 77.548 19.949 178.6350 9.8751 49.5660 9.164 1266 8.976 24.3178 39.8480 28.2481 35.7182 6.584 163.06100 14.55107 37.08108 39.15110 354.4112 13.9131 6.04132 50.78133 5.8134 9.1135 56.74136 32.9138 3.61139 9.86140 11.37141 24.6926143Example Compound HTRF IC50 142 11.02143 18.1144 53.95145 7.49146 15147 49.9148 35.6149 41150 33.39151 556.3152 894.9153 6.4154 5.8155 8.6156 4.8157 5.6158 7.3159 2.6160 6.8161 2.86162 14163 42.1164 6.7165 14.8166 9.33167 1054.31 168 134.93 169 4.9170 3.2171 3.5172 3060.41 175 8.76176 2.7177 2.5178 7.6179 6.9180 7.6181 11182 14.3183 5.7184 2.61185 2.48186 1.48187 15.3188 207.8189 3.6190 4.626143Example Compound HTRF IC50 191 7.4192 705.9193 27.2194 14.3195 40.2196 384.4198 10.2199 9.9200 24.32201 12202 28.92203 79204 49.8205 49.8206 27.4207 30.9208 50209 34.3210 47.8211 46.6212 3.8213 29214 35.3215 68.6216 700217 36.4218 205.6219 2.1222 28.8223 54.84224 70.55225 86.05226 9.1227 21229 93.77238 61.2239 200.7240 24.3241 323.3242 39.1243 57.6244 40.3247 17.41248 67.57249 84250 12.7251 840.626143Example C...

Claims

CLAIMSWhat is claimed is:

1. A compound having the structural Formula (I) or Formula (II):or a pharmaceutically acceptable salt thereof, wherein:Wi and W2, each is C or N, provided that one and only one of Wi and W2 is N;Ri at each occurrence is independently selected from the group consisting of H, F, Cl, Br, (Ci-C6)alkyl, (Ci-C6)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, CN, OH, and NR4R5;A is selected from the group consisting of:(i) an aryl, a heteroaryl having 1-3 ring nitrogen atoms and 0-1 other hetero atoms independently selected from S and O, a pyrazol-O(Ci-C4)alkyl, a pyrazol-S(Ci-C4)alkyl, or an N(pyrazol-(Ci-C4)alkyl)R4, wherein each of aryl and heteroaryl is optionally substituted with 1 to 4 R7; pyrazol ring is optionally substituted with 1 to 3 R7; and one or more H atoms in the (Ci-C4)alkyl is optionally substituted with deuterium;(ii) a monocyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally fused to an aryl or a heteroaryl having 1-2 hetero atoms independently selected from N, O, and S, or optionally in a spiro linkage with a (C3- C6)cycloalkyl; wherein the monocyclic heterocyclyl and the fused aryl or heteroaryl, each is optionally substituted with 1 to 4 R7; and wherein the (C3-C6)cycloalkyl is optionally substituted with 1 to 2 groups selected independently from F, Cl, Br, (Ci-Ce)alkyl, (Ci- C6)haloalkyl, CN, OH, and NR4Rs; and(iii) a bicyclic heterocyclyl having 1-4 hetero atoms independently selected from N and O, optionally substituted with 1 to 4 R7;- (CH2)m0, - S(CH2)m, and -N(R3)(CH2)m, wherein the (CH2)mgroups are optionally independently substituted with 1-4 halogen, deuterium, (Ci-C4)alkyl or (Ci-C4)haloalkyl;B is selected from the group consisting of:R2A(B-c)(B-k)R.2 is absent or present; when present, when Y is C, R2 is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, R2 is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;R3, R4, and Rs, at each occurrence is independently selected from H, (Ci-C4)alkyl and (Ci-C4)haloalkyl;Re is absent or present; when present, when Y is C, Re is selected from the group consisting of H, F, Cl, Br, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, CN, -CONR4R5, -(CH2)nOH, NR4R5, -SO2NR4R5, -SO(NR4)(Ci-C4)alkyl, -SO(NR4)(CI-C4)haloalkyl, and-(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)n0H, and NR4R5; and when present, when Y is N, Re is selected from the group consisting of H, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O, and -(CH2)n0H, and -(CH2)nphenyl, wherein the phenyl is optionally substituted with F, Cl, Br, Ci-C4)alkyl, (Ci-C4)haloalkyl, -(CH2)nOH, and NR4R5;R.7, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, OH, SH, NR4R5, phenyl, pyridyl, thiazolyl, -COOH,(Ci-Ce)alkyl, (Ci-C6)haloalkyl, (C2-C4)alkenyl, (C2-C4)haloalkenyl, (C2-Ce)alkynyl, (C2-C6)haloalkynyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, O(C3-C6)cycloalkyl, and O(C3-C6)halocycloalkyl; the phenyl, pyridyl and thiazolyl being optionally substituted with 1-3 groups independently selected from F, Cl, Br, CN, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, and O(Ci-C4)haloalkyl;Rs, at each occurrence, is independently selected from the group consisting of H, F, Cl, Br, CN, -(CH2)nOH, NR4R5, CONR4R5, (Ci-C4)alkyl, (Ci-C4)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, and (Ci-C4)alkyl-O-(Ci-C4)alkyl optionally substituted independently with 1-4 halogen;Y is C or N;m at each occurrence is independently 1, 2, or 3; andn and p, at each occurrence is independently 0, 1, 2, or 3;with the proviso that the compound is notN-((lR,4R,5R)-2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carb oxami de,2-(4-ethoxyphenyl)-N-((lR, 4R)-2-(2 -hydroxy ethyl)-2-azabicyclo[2.

2. l]heptan-5-yl)quinoline-4-carboxamide,N-((lR,4R)-2-benzyl-2-azabicyclo[2.2.1]heptan-5-yl)-2-(4-ethoxyphenyl)quinoline-4-carb oxami de,2-(4-ethoxyphenyl)-N-((lR,5S,6s)-3-(2-hydroxy-2-methylpropyl)-3-azabicyclo[3.1.0]hexan-6-yl)quinoline-4-carboxamide,N-(3-azabicyclo[3.1.0]hexan-6-yl)-2-(4-ethoxyphenyl)quinazoline-4-carboxamide.

2. The compound of claim 1 having the structural Formula (I), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 having Formula (II), or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2, wherein W2 is C, or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1, 2, and 4, wherein B is selected from the group consisting of:26143optionally substituted with (Rs)p.

6. The compound of any one of claims 1, 2, and 4, wherein B is selected from the group consisting of:2614326143261437. The compound of any one of claims 1, 2, 4, and 5, wherein A is selected from the group consisting of:26143acceptable salt thereof.

8. The compound of any one of claims 1, 2, 4, and 5, wherein A is selected from the group consisting of:2614326143R69. The compound of claim 1 having the Formula (I), wherein Bis, or a pharmaceutically acceptable salt thereof.2614310. The compound of claim 9, wherein A is,, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9, wherein Ais, optionally substituted independently with 1 to 4 R7, and wherein one or both H atoms in -OCH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.

12. The compound of claim 9, wherein A is,, optionally substituted independently with 1 to 4 R7, and wherein one or both H atoms in -N(R4)CH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.

13. The compound of claim 9, wherein Bis, optionally substituted with (Rs)p, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 9 or claim 13, wherein A is selected from the group consisting of2614315. The compound of any one of claims 1, 2, and 4, wherein Bis optionally substituted with (Rs)P, or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1, 2, and 4, wherein Bis, optionally substituted with (Rs)P, or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1, 2, and 4-6, wherein A is phenyl or pyridyl, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1, 2, and 4-6, wherein A isoptionally substituted independently with 1 to 5 R7, or a pharmaceutically acceptable salt thereof.

19. The compound of any one of claims 1, 2, and 4-6, wherein Ais optionally substituted independently with 1 to 6 R7, or a pharmaceutically acceptable salt thereof.

20. The compound of any one of claims 1, 2, and 4-6, wherein Ais optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.2614321. The compound of any one of claims 1, 2, and 4-6, whereinA is, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1, 2, and 4-6, wherein Ais ', wherein the pyrazole ring is optionally substituted independently with 1 to 3 R7, and one or more H atoms in -OCH2- linker is optionally substituted with deuterium; or a pharmaceutically acceptable salt thereof.R23. The compound of any one of claims 1, 2, and 4, wherein Bis optionally substituted with (Rs)Pand A is phenyl optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.R24. The compound of any one of claims 1, 2, and 4, wherein Bis Noptionally substituted with (Rs)P, and A is, optionally substituted independently with 1 to 4 R7, or a pharmaceutically acceptable salt thereof.2614325. The compound of any one of claims 1, 2, and 4, wherein Bisoptionally substituted with (Rs)P, and A is optionally substituted with up to two groups independently selected from (Ci-Ce)alkyl, (Ci- Ce)haloalkyl, 0(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocycloalkyl, and one or more H atoms in the -OCH2- linker is optionally substituted with deuterium, or a pharmaceutically acceptable salt thereof.

26. The compound of any one of claims 1, 2, and 4, wherein Bisoptionally substituted with (Rs)Pand A is, optionally substituted with up to two groups independently selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, O(Ci-C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, and (C3-C6)halocycloalkyl, or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 1, 2, and 4, wherein Bisoptionally substituted with (Rs)P, and A is, optionally substituted with up to three groups independently selected from (Ci-Ce)alkyl, (Ci-C6)haloalkyl, F, Cl, Br, CN, O(Ci- C4)alkyl, O(Ci-C4)haloalkyl, (C3-C6)cycloalkyl, (C3-C6)halocycloalkyl, and (C2-Ce)alkynyl, (C2-C6)haloalkynyl, or a pharmaceutically acceptable salt thereof.2614328. The compound of claim 1 having the structural Formula (II), wherein C isor a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 having the structural Formula (II), wherein C isR6, or a pharmaceutically acceptable salt thereof.2614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143261432614326143or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 30, and a pharmaceutically acceptable carrier.

32. A compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30, or the pharmaceutical composition of claim 31, for use in treating an inflammatory condition.2614333. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30, or the pharmaceutical composition of claim 31, in treating an inflammatory condition.

34. Use of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30, or the pharmaceutical composition of claim 31 in the manufacture of a medicament for treating an inflammatory condition.

35. The use in treating according to any one of claims 32-34, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

36. A method of treating an inflammatory condition, the method comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 to a person in need thereof.

37. The method of claim 36, wherein the inflammatory condition is systemic lupus erythematosus, ulcerative colitis, Crohn’s disease (CD), or colitis-associated cancer (CAC).

38. The method of claim 36 or claim 37, or the use in treating of claims 32-35, wherein said compound or pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

39. The method of claim 38, wherein said additional therapeutic agent is selected from the group consisting of upadacitinib, deucravacitinib, litifilimab, and dapirolizumab.

Images