Imidazo[1,2-α]pyridine and [1,2,4]triazolo[1,5-α]pyridine derivatives as inhibitors of TLR9 for the treatment of fibrosis

Abstract

Disclosed is a compound of formula (I): JPEG2023538393000229.jpg3250, or a salt or prodrug thereof, wherein X, G, Q1, Q2, R5, R 5a and R 5b is defined herein. Also disclosed are methods of using such compounds as inhibitors of TLR9 and pharmaceutical compositions containing such compounds. These compounds are useful in treating, preventing, or slowing fibrotic diseases.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 067,452, filed August 19, 2020, which is incorporated herein by reference in its entirety.

[0002] explanation The present invention relates generally to substituted bicyclic compounds useful as inhibitors of signal transduction via Toll-like receptor 9 (TLR9). Provided herein are substituted bicyclic compounds, compositions containing such compounds, and methods of use. The present invention further relates to pharmaceutical compositions containing at least one compound of the invention useful for treating conditions associated with TLR9 modulation, such as inflammatory and autoimmune diseases, and methods of inhibiting TLR9 activity in mammals. [Background technology]

[0003] Toll-like receptors (TLRs) are transmembrane proteins capable of initiating inflammatory responses through the recognition of pattern-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs). A total of 10 human TLRs have been identified, which can reside on the cell surface or, in the case of TLRs 7, 8, and 9, in endolysosomes. TLR9 recognizes unmethylated single-stranded DNA containing cytosine-phosphate-guanine (CpG) motifs, typically found in bacteria and mitochondrial DNA (mtDNA). TLR9 may contribute to fibrosis by promoting inflammation through a MyD88-dependent signaling pathway that ultimately mediates the activation of IL-6, IFN-α, IL-1β, and TNF-α, among other cytokines. (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535-42; Li X, Jiang S, Tapping RI (2010), Cytokine 49(1), 1-9).

[0004] TLR9 levels are higher in lung biopsy specimens from patients with rapidly progressing idiopathic pulmonary fibrosis (IPF) than in healthy controls or stable IPF patients (Sci. Transl. Med. 2010, 2(57):57ra82). Circulating mtDNA, a ligand for TLR9, was recently identified as a mechanism-based prognostic biomarker for IPF (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). Furthermore, TLR9 is upregulated in nonalcoholic steatohepatitis (NASH) in humans and mice (Clin. Sci. 2017, 131 (16), 2145), while hepatocyte mitochondrial DNA has been observed to cause NASH via TLR9 activation (J. Clin. Inv. 2016, 126 (3), 859). Therefore, inhibitors / antagonists of TLR9 are predicted to be effective as novel therapeutic agents for the treatment of fibrotic diseases.

[0005] TLR9 inhibition has been shown to be a promising therapeutic approach for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57):57ra82; Yoshizaki et al. Ann Rheum Dis. 2016 Oct;75(10):1858-65), nonalcoholic steatohepatitis (Garcia-Martinez et al. J Clin Invest 2016, 126: 859-864; Gabele et al. Biochem Biophys Res Commun. 2008;376:271-276), liver injury (Shaker et al. Biochem Pharmacol. 2016. 112:90-101; Hoeque et al. J. Immun. 2013, 190:4297-304), and scleroderma (systemic sclerosis or SSc) (Yoshizaki et al. Ann Rheum Dis. 2016 Oct;75(10):1858-65); and has been recognized as a potential route for the treatment of heart failure (Oka et al. Nature 485, pages 251-255(2012)) and hypertension (McCarthy et al. Cardiovascular Research, 2015, Pages 119-130). Summary of the Invention [Problem to be solved by the invention]

[0006] There is a continuing need for compounds useful as inhibitors of TLR9. Furthermore, there is a continuing need for compounds useful as inhibitors of TLR9 that have selectivity over TLR7 or TLR8.

[0007] In view of the conditions that may benefit from treatments involving modulation of Toll-like receptors, it is readily apparent that novel compounds capable of inhibiting TLR9 and methods of using these compounds would provide therapeutic benefit to a wide variety of patients.

[0008] Applicant has discovered potent compounds that are active as TLR9 inhibitors. Furthermore, Applicant has discovered compounds that are active as TLR9 inhibitors and selective over TLR7 or TLR8. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity profile, which are important for druggability. [Means for solving the problem]

[0009] Summary of the Invention The present invention relates to a novel class of substituted bicyclic compounds that have been found to be effective inhibitors of TLR9-mediated signaling. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity profile, which are important for druggability.

[0010] The present invention provides compounds of formula (I) or a stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, which are useful as inhibitors of signaling through Toll-like receptor 9 and are useful in the treatment of fibrotic diseases.

[0011] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0012] The present invention also provides a method of inhibiting Toll-like receptor 9, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0013] The present invention also provides a method for treating a fibrotic disease, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0014] The present invention also provides a method for treating a disease or disorder associated with Toll-like receptor 9 activity, comprising administering to a mammal in need thereof at least one of a compound of formula (I) or a salt, solvate, or prodrug thereof.

[0015] The present invention also provides processes and intermediates for preparing compounds of formula (I), including salts, solvates and prodrugs.

[0016] The present invention also provides at least one compound of formula (I) or a salt, solvate or prodrug thereof for use in therapy.

[0017] The present invention also provides the use of at least one compound of formula (I) or a salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of toll-like receptor 9 associated conditions, such as allergic diseases, autoimmune diseases, inflammatory diseases and proliferative diseases.

[0018] The compounds of formula (I) and compositions comprising the compounds of formula (I) can be used to treat, prevent or cure a variety of toll-like receptor 9-associated conditions. Pharmaceutical compositions comprising these compounds are useful for treating, preventing or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as allergic diseases, autoimmune diseases, inflammatory diseases and proliferative diseases.

[0019] These and other features of the invention will be set forth in expanded form as the disclosure continues.

[0020] Detailed Description A first aspect of the present invention is a compound comprising at least one compound of formula (I): [ka] [During the ceremony, The two dashed lines represent two single bonds or two double bonds; and R 5a and R 5bexists only if the dashed lines represent two single bonds; X is N or CR3; One of Q1 and Q2 is A, and the other of Q1 and Q2 is R5; G is: (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl-C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2NR x R x and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from: (ii) [ka] (iii) [ka] (iv) [ka] (v) [ka] [ka] [ka] a 9-membered heterocyclic ring selected from (vi) [ka] A 10-membered heterocyclic ring selected from and; A is cyclohexyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R4 and 0 to 1 R 4b is replaced by; L is a bond, -CR x R x - or -C(O)(CR x R x ) 0-2 - and; Each R2 is independently halo, -CN, -OH, -NO2, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 alkyl), C 1-3 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 alkyl), -O(CH2) 1-2 OC(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH2) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NRx C(O)(C 1-3 alkyl), -NR x CH2(C 3-6 cycloalkyl), -S(O)2(C 1-3 alkyl), -S(O)N(C 1-3 alkyl)2, -S(O)(NH)N(C 1-3 alkyl)2, -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or —C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl; Each R 2b are independently hydrogen, halo, -CN, or -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 alkyl), -(CH2) 0-3 C(O)NR x R x , -(CH2) 1-3 (C 3-6 cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3alkyl), -CR x =CR x R x or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b where R 2c and R 2d One of them is R 2a and R 2c and R 2d The other is R 2b and; R3 is hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; R4: (i)-N(CH3)2; (ii) 0 to 2 R 4a pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, pyridinyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl or diazabicyclo[3.2.1]octanyl substituted with; or (iii) [ka] and; Each R 4a is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, -(CH2) 0-2 O(C 1-2 alkyl), C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl), -C(O)O(C 1-4alkyl), oxetanyl, tetrahydrofuran or tetrahydropyranyl; R 4b is F, Cl or -CH3; Each R 4c is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-6 is cycloalkyl; Each R5 is independently hydrogen, F, Cl, or C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; R 5a and R 5b are independently hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; Each R x are independently hydrogen or -CH3; Each R y are independently hydrogen or C 1-6 is alkyl; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, or 4; and q is 1 or 2. or a stereoisomer, tautomer, solvate or salt thereof.

[0021] A second aspect of the present invention relates to a compound having at least one formula (I): [ka] [During the ceremony, The two dashed lines represent two single bonds or two double bonds; and R 5a and R 5b exists only if the dashed lines represent two single bonds; X is N or CR3; One of Q1 and Q2 is A, and the other of Q1 and Q2 is R5; G is: (i) F, Cl, Br, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy, C 3-4 Cycloalkyl-C(O)NR y R y , -S(O)2CH3, -S(O)2(phenyl), -S(O)2NR x R x and -S(O)(NH)NR x R x phenyl substituted with 1 to 3 substituents independently selected from: (ii) [ka] (iii) [ka] (iv) [ka] (v) [ka] [ka] [ka] a 9-membered heterocyclic ring selected from (vi) [ka] A 10-membered heterocyclic ring selected from and; A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R4 and 0 to 1 R 4bis replaced by; L is a bond, -CR x R x - or -C(O)(CR x R x ) 0-2 - and; Each R2 is independently halo, -CN, -OH, -NO2, C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-3 Aminoalkyl, -O(CH2) 1-2 OH, -(CH2) 0-4 O(C 1-4 alkyl), C 1-3 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 alkyl), -O(CH2) 1-2 OC(O)(C 1-3 alkyl), -O(CH2) 1-2 NR x R x , -C(O)O(C 1-3 alkyl), -(CH2) 0-2 C(O)NR y R y , -C(O)NR x (C 1-5 hydroxyalkyl), -C(O)NR x (C 2-6 Alkoxyalkyl), -C(O)NR x (C 3-6 cycloalkyl), -NR y R y , -NR y (C 1-3 Fluoroalkyl), -NR y (C 1-4 hydroxyalkyl), -NR x CH2(phenyl), -NR x S(O)2(C 3-6 cycloalkyl), -NR x C(O)(C 1-3 alkyl), -NR x CH2(C 3-6 cycloalkyl), -S(O)2(C 1-3alkyl), -S(O)N(C 1-3 alkyl)2, -S(O)(NH)N(C 1-3 alkyl)2, -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or —C(O)(thiazolyl); R 2a is C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-6 Hydroxyalkyl, C 1-3 Aminoalkyl, -(CH2) 0-4 O(C 1-3 alkyl), C 3-6 Cycloalkyl, -(CH2) 1-3 C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl or phenyl; Each R 2b are independently hydrogen, halo, -CN, or -NR x R x , C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-3 Fluoroalkoxy, -(CH2) 0-2 O(C 1-3 alkyl), -(CH2) 0-3 C(O)NR x R x , -(CH2) 1-3 (C 3-6 cycloalkyl), -C(O)O(C 1-3 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CR x R x or -CR x =CH(C 3-6 cycloalkyl); R 2c is R 2a or R 2b and; R 2d is R 2a or R 2b where R 2c and R 2d One of them is R 2a and R 2c and R 2d The other is R 2b and; R3 is hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; R4: (i)-N(CH3)2; (ii) 0 to 2 R 4a pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl or azabicyclo[3.2.1]octanyl substituted with; or (iii) [ka] and; Each R 4a is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl) or -C(O)O(C 1-4 alkyl); R 4b is F, Cl or -CH3; Each R 4c is independently C 1-6 Alkyl, C 1-3 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C1-4 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-6 is cycloalkyl; Each R5 is independently hydrogen, F, Cl, or C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; R 5a and R 5b are independently hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 Fluoroalkyl or C 3-4 is cycloalkyl; Each R x are independently hydrogen or -CH3; Each R y are independently hydrogen or C 1-6 is alkyl; m is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1, 2, 3, or 4; and q is 1 or 2. or a salt thereof.

[0022] In some embodiments, compounds of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof are provided, wherein the two dashed lines represent two double bonds. The compounds of this embodiment have formula (II): [ka] It has the following structure.

[0023] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two double bonds and X is CR3. The compounds of this embodiment have the formula (IIa): [ka] It has the following structure.

[0024] In certain embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof are provided, wherein the two dashed lines represent two double bonds and X is N. The compounds of this embodiment have the formula (IIb): [ka] It has the following structure.

[0025] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two double bonds; X is CR; Q is A; and Q is R. The compound of this embodiment has formula (IIa-1): [ka] It has the following structure.

[0026] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two double bonds; X is CR; Q is R; and Q is A. The compound of this embodiment has formula (IIa-2): [ka] It has the following structure.

[0027] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two double bonds; X is N; Q is A; and Q is R. The compound of this embodiment has formula (IIb-1): [ka] It has the following structure.

[0028] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two double bonds; X is N; Q is R; and Q is A. The compound of this embodiment has formula (IIb-2): [ka] It has the following structure.

[0029] In some embodiments, compounds of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof are provided, wherein the two dashed lines represent two single bonds. The compound of this embodiment has formula (III): [ka] It has the following structure.

[0030] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two single bonds and X is CR3. The compounds of this embodiment have the formula (IIIa): [ka] It has the following structure.

[0031] In certain embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof are provided, wherein the two dashed lines represent two double bonds and X is N. The compounds of this embodiment have the formula (IIIb): [ka] It has the following structure.

[0032] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two single bonds; X is CR; Q is A; and Q is R. The compound of this embodiment has formula (IIIa-1): [ka] (IIIa-1) It has the following structure.

[0033] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two single bonds; X is CR; Q is R; and Q is A. The compound of this embodiment has formula (IIIa-2): [ka] It has the following structure.

[0034] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two single bonds; X is N; Q is A; and Q is R. The compound of this embodiment has formula (IIIb-1): [ka] It has the following structure.

[0035] In some embodiments, compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein the two dashed lines represent two single bonds; X is N; Q is R; and Q is A. The compound of this embodiment has formula (IIIb-2): [ka] It has the following structure.

[0036] In certain embodiments, compounds of Formula (I), or stereoisomers, tautomers, solvates, or salts thereof, are provided wherein G is phenyl substituted with 1-2 substituents independently selected from F, -OCH, -S(O)CH, -S(O)N(CH), and -S(O)(NH)N(CH). Included in this embodiment are compounds wherein G is phenyl substituted with 1-2 substituents independently selected from F, -OCH, and -S(O)CH. Also included in this embodiment are compounds wherein G is: [ka] is a compound.

[0037] In some embodiments, G is [ka] or a stereoisomer, tautomer, solvate or salt thereof. Included in this embodiment are compounds wherein each R2 is independently F, Cl, Br, -CN, -OH, -CH3, -CH2CH3, -CF3, -CH2OH, -C(CH3)2OH, -CH2NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2OCH3, -OCH2CH2N(CH3)2, -OCHF2, -C(O)OCH3, -C(O)NH2, -C(O)NH(CH2CH3), -C(O)(thiazolyl), -NH2, -NH(CH3), -NH(CH2CH3), -N(CH3)2, -NHC(O)CH3, -NHC(O)C(CH3)3, -NH(CH2-cyclopropyl), cyclopropyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, or triazolyl. Also included in this embodiment are compounds where each R2 is independently F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl. Further included in this embodiment are compounds where p is 2; one R2 is -CH3; and the other R2 is F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl.

[0038] In some embodiments, G is [ka] [ka] [ka]

[0013] Provided are compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof, wherein G is a 9-membered heterocyclic ring selected from: [ka] is a compound.

[0039] In some embodiments, G is [ka]

[0013] Provided are compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof, wherein G is a 10-membered heterocyclic ring selected from: [ka] is a compound.

[0040] In some embodiments, G is: (i) phenyl substituted with 1 to 2 substituents independently selected from —OCH3, —S(O)2CH3, —S(O)2N(CH3)2, and —S(O)(NH)N(CH3)2; (ii) [ka] (iii) [ka] (iv) [ka] or a stereoisomer, tautomer, solvate, or salt thereof. Included in this embodiment are compounds where each R is independently Cl, —CH, —CHCH, —CHOH, —CHCHOH, —CHCN, —OCH, —CHOCH, or —CHCHS(O)CH.

[0041] In certain embodiments, compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided wherein p is 0, 1, 2, or 3. Included in this embodiment are compounds wherein p is 1 or 2.

[0042] In some embodiments, A is cyclohexyl, piperidinyl, phenyl, pyridinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R and 0-1 R 4b

[0023] Provided is a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein A is substituted with -L-R4. Included in this embodiment are compounds where A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octanyl, each substituted with -L-R4.

[0043] In some embodiments, A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is -L-R and 0-1 R 4b

[0013] Provided are compounds of formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein A is substituted with -L-R. Included in this embodiment are compounds where A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each substituted with -L-R. Also included in this embodiment are compounds where A is piperidinyl or 6-azabicyclo[3.2.1]octanyl, each substituted with -L-R.

[0044] In some embodiments, A is piperidinyl, phenyl, or pyridinyl, each of which is -L-R and 0-1 R 4b

[0023] The present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein A is piperidinyl or phenyl, and each of -L-R and 0-1 R is substituted. 4b Also included in this embodiment are compounds in which A is phenyl or pyridinyl, each of which is substituted with -L-R and 0-1 R 4b and is a compound.

[0045] In some embodiments, A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, each of which is -L-R and 0-1 R 4b and L is a bond. Included in this embodiment is a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein A is piperidinyl, phenyl, or pyridinyl, and each of -L-R and 0-1 R is substituted. 4b and L is a bond.

[0046] In certain embodiments, provided are compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein L is a bond.

[0047] In some embodiments, L is -CR x R x

[0013] Provided is a compound of formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein L is -. Included in this embodiment are compounds where L is -CH2-.

[0048] In some embodiments, L is —C(O)(CR x R x ) 0-2

[0020] Compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof are provided, wherein L is -. Included in this embodiment are compounds wherein L is -C(O)(CH)0-2 Also included within this embodiment are compounds where L is -C(O)(CH) 0-1 - Also included in this embodiment are compounds where L is -C(O)-.

[0049] In some embodiments, L is -CR x R x - or -C(O)(CR x R x ) 0-2 - or a stereoisomer, tautomer, solvate or salt thereof. Included in this embodiment is a compound of formula (I) wherein L is -CR x R x - or -C(O)(CR x R x ) 0-1 Also included in this embodiment are compounds where L is -CR x R x - or -C(O)-. Also included in this embodiment are compounds in which each R x is hydrogen.

[0050] In certain embodiments, L is a bond, —CH—, or —C(O)(CH) 0-2 or a stereoisomer, tautomer, solvate, or salt thereof. Included in this embodiment are compounds where L is a bond or —C(O)—.

[0051] In certain embodiments, compounds of Formula (I) or stereoisomers, tautomers, solvates or salts thereof are provided, wherein R4 is -N(CH3)2.

[0052] In some embodiments, R4 is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which has 0 to 2 R 4a

[0023] Included in this embodiment is a compound of formula (I) or a salt thereof, wherein R4 is piperidinyl, azaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with R 4a is a compound substituted with

[0053] In some embodiments, R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each of which has 0 to 2 R 4a or a stereoisomer, tautomer, solvate, or salt thereof. Included in this embodiment are compounds where R4 is piperidinyl, piperazinyl, or pyridinyl. Also included in this embodiment are compounds where R4 is piperidinyl or piperazinyl.

[0054] In some embodiments, R4 is [ka] or a stereoisomer, tautomer, solvate, or salt thereof. Included in this embodiment are compounds where n is 1 or 2. Also included in this embodiment are compounds where n is 1. Further included in this embodiment are compounds where n is 2.

[0055] In some embodiments, R4 is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each of which has 0 to 2 R 4a is replaced by; or [ka] or a stereoisomer, tautomer, solvate or salt thereof.

[0056] In certain embodiments, each R 4a independently C 1-5 Alkyl, C 1-2 Fluoroalkyl, -(CH2) 0-2 O(C1-2 alkyl), C 3-6 Cycloalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-4 alkyl), -C(O)(C 3-6 cycloalkyl), -C(O)(phenyl), -C(O)CH2(C 3-6 cycloalkyl), -C(O)CH2(phenyl), -C(O)O(C 1-3

[0023] Provided are compounds of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein each R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 4a is independently -CH(CH), -CHCH(CH), -CHCHOCH, -C(O)CH(CH), -C(O)(cyclopropyl), -CH(cyclopropyl), -CH(cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl. Also included in this embodiment are compounds where each R 4a are independently -CH(CH3)2, -CH2CH(CH3)2, -C(O)CH(CH3)2, -C(O)(cyclopropyl) or -CH2(cyclopropyl), cyclopropyl or cyclobutyl.

[0057] In some embodiments, R 4b is F or Cl. Included in this embodiment are compounds of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R 4b is a compound where F.

[0058] In certain embodiments, each R 4c independently C 1-4 Alkyl, C 1-2 Fluoroalkyl, -CH2(C 3-6 cycloalkyl), -C(O)(C 1-3 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-6

[0013] Provided are compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof, wherein each R is cycloalkyl. Included in this embodiment are 4c independently C 1-3 Alkyl, C 1-2 Fluoroalkyl, -CH2(C 3-4 cycloalkyl), -C(O)(C 1-2 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-4 A compound that is a cycloalkyl.

[0059] In some embodiments, each R2 is independently F, Cl, —CN, —OH, C 1-3 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Cyanoalkyl, C 1-3 Hydroxyalkyl, C 1-2 Aminoalkyl, -(CH2) 0-2 O(C 1-3 alkyl), C 3-6 Cycloalkyl, -NR x R x , -(CH2) 0-2 C(O)NR x R x , -CH2(C 3-6

[0023] Provided are compounds of Formula (I), or stereoisomers, tautomers, solvates, or salts thereof, wherein each R is independently Cl, -CH, -CHCH, -CHOH, -CHCHOH, -CHCN, -OCH, -CHOCH, or -CHCHS(O)CH. Also included in this embodiment are compounds wherein each R is independently Cl, -CH, -CHOH, or -OCH.

[0060] In some embodiments, R 2a C 1-4 Alkyl, C 1-2 Fluoroalkyl, C 1-4 Hydroxyalkyl, -(CH2) 1-3 OCH3, C3-6 Cycloalkyl, -CHC(O)NR x R x , -CH2(C 3-6 cycloalkyl), —CH (phenyl), tetrahydrofuranyl, or phenyl; and each R 2b are independently H, F, Cl, -CN, -NR x R x , C 1-6 Alkyl, C 1-2 Fluoroalkyl, C 1-3 Hydroxyalkyl, -(CH2) 0-2 O(C 1-2 alkyl), -(CH2) 0-2 C(O)NR x R x , -(CH2) 1-3 (cyclopropyl), -C(O)O(C 1-2 alkyl), -C(O)NR x (C 1-3 alkyl), -CR x =CH2 or -CH=CH(C 3-6

[0023] Also included in this embodiment are compounds of formula (I) or a stereoisomer, tautomer, solvate or salt thereof, wherein R is cycloalkyl. 2a is -CH3; and each R 2b are independently H, Cl, or -CH3.

[0061] In some embodiments, R3 is hydrogen, F, Cl, C 1-2 Alkyl or C 3-4

[0013] Compounds of formula (I) or stereoisomers, tautomers, solvates or salts thereof are provided, wherein R is hydrogen, C is cycloalkyl. Included in this embodiment are compounds where R is hydrogen, C is cycloalkyl ... 1-2

[0023] Also included in this embodiment are compounds where R3 is hydrogen or -CH3.

[0024] Further included in this embodiment are compounds where R3 is hydrogen.

[0062] In certain embodiments, compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof are provided, wherein each R5 is independently hydrogen, F, Cl, -CH3, or cyclopropyl. Included in this embodiment are compounds where each R5 is independently hydrogen, -CH3, or cyclopropyl. Also included are compounds where each R5 is hydrogen or -CH3.

[0063] In certain embodiments, G is phenyl substituted with 1 to 2 substituents independently selected from F, —OCH, and —S(O)CH; A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octanyl, each substituted with -L-R; L is a bond; R is hydrogen; and R is piperidinyl, piperazinyl, azepanyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with R 4a is substituted with;R 4a is —CH(CH3)2, —CH2CH(CH3)2, —CH2CHOCH3, —C(O)CH(CH3)2, —C(O)(cyclopropyl), —CH2(cyclopropyl), —CH2(cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl; and each R5 is hydrogen, F, or —CH3, or a stereoisomer, tautomer, solvate, or salt thereof.

[0064] In certain embodiments, G is phenyl substituted with 1 to 2 substituents independently selected from F, —OCH, and —S(O)CH; A is piperidinyl or 6-azabicyclo[3.2.1]octanyl, each substituted with -L-R; L is a bond; R is hydrogen; and R is piperidinyl, azaspiro[3.3]heptanyl, or azabicyclo[3.2.1]octanyl, each substituted with R 4a is substituted with;R 4ais —CH(CH3)2, —CH2CH(CH3)2, —C(O)CH(CH3)2, —C(O)(cyclopropyl) or —CH2(cyclopropyl), cyclopropyl or cyclobutyl; and each R5 is hydrogen or —CH3, or a stereoisomer, tautomer, solvate or salt thereof.

[0065]

[0010] Certain embodiments provide compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein the compounds are 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (1); 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine (2); 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1, 4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine(3); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3-fluoro-4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridine(4); 2-(3-fluoro-4-methoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine(5); 2-(3-fluoro-4-methoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin] 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine(6); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine(7); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine(8); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine (9); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine (10); 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (11); 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (12);2-(3,4-Dimethoxyphenyl)-6-(1-(2-isopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine (13); 6-(1-(2-cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (14); 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl) 6-(1-(2-(cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine(16); 6-(1-(2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine(17); 2-(3,4-dimethoxyphenyl)- 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (20-21); 2-(3,4-dimethoxyphenyl)-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine (22-23); 3-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine (22-23); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (24); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (25-26);2-(3,4-Dimethoxyphenyl)-6-(8-(1-isobutylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methylimidazo[1,2-a]pyridine (27-29); 2-(3,4-Dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methylimidazo[1,2-a]pyridine (30); 2-(3,4-Dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidine]-4 -yl)-[1,2,4]triazolo[1,5-a]pyridine (60); 2-(3,4-dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (61); 6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (62-63); 2-(3,4-dimethoxyphenyl)-8-methyl-6-( 4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (64); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (65); 8-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (67); 8-fluoro-6-(1-(8-isopropyl-8-azabicyclo[2-(2-methyl-4-phenyl-2-oxo-1,2- bipiperidin-4-yl)phenyl)imidazo[1,2-a]pyridine (68); 2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (68-69); 7-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (70); 8-fluoro-6-(1-(1-isopropylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (71-72);5-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (73); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (83-84); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4 -(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (85-86); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (87-88); 6-(1-(8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine 6-(1'-Cyclobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (91); 6-(1'-(Cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (92); 6-(1'-(Cyclobutylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo [1,2-a]pyridine (93); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isobutylpiperazin-1-yl)phenyl)-8-methylimidazo[1,2-a]pyridine (94); 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (95); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methylimidazo[1,2-a]pyridine (96);2-(3,4-dimethoxyphenyl)-8-methyl-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (97); 2-(3,4-dimethoxyphenyl)-6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-8-methylimidazo[1,2-a]pyridine (98); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (99); 6-(4 -(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (100); 6-(4-(4-(cyclobutylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (101); 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (102); 8-methyl- 2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (103); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (104); 6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (105); 7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (106); 8-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (107); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (108);6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (109); 6-(1'-cyclobutyl-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (110); 8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine phenyl)-6-(1'-(oxetan-3-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (111); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (112); 8-fluoro-6-(1-(8-isobutyl-8-azabicyclo[3.2 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (113-114); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (115-116); 6-(1-(8-cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (115-116); Butyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (117); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (118); 8-; Fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (119-120); 8-Fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (121-122); 7-Fluoro- 6-(1'-Isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (123); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-7-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (124); 8-Fluoro-6-(1-(1-isobutylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine ( 125-126; 6-(1-(1-(cyclopropylmethyl)azepan-4-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (127-128); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(1-(tetrahydro-2H-pyran-4-yl)azepan-4-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (129-130); 5-fluoro-6-(1'-isobutyl-[1,4'-bipiperidine 8-fluoro-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (131); 8-fluoro-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (132); or 8-fluoro-2-(4-(methylsulfonyl)phenyl)-7-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (133).

[0066]

[0010] Certain embodiments provide compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein the compounds are 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (31-33); 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (31-33). Pyridine (34-36); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (37-38); 1-(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)-2-methylpropan-1-one (39-41); cyclopropyl(4-(2-(3 ,4-Dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)methanone (42-44);-(3,4-Dimethoxyphenyl)-6-(1-(2-isopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (45-47);6-(1-(2-cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (45-47) 6-(1-(2-(cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (48-50); 6-(1-(2-(cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (51); 2-(3,4-dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (52-54); 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (55-57); (6R)-2-(3,4-dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridine (75-76); (6S)-2-(3,4-dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (77-78); (6R)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (79-80); (6S)-6-( 1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (81-82); (6R)-2-(3,4-dimethoxyphenyl)-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (134-135); (6S)-2-(3,4-dimethoxyphenyl)-6-(1-( 8-Isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (136-137); (6R)-6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (138-139); or (6S)-6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (140-141).

[0067]

[0013] Certain embodiments provide a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is 2-(3,4-dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (58); or 2-(3,4-dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (59).

[0068]

[0013] Certain embodiments provide a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is 7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (66); or 8-fluoro-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (74).

[0069]

[0013] Certain embodiments provide compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein the compounds are 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (142); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4 -dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (146); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (147); 2-(3,4-dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-[ 1,2,4]triazolo[1,5-a]pyridine (149); 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (151); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl) )phenyl)-[1,2,4]triazolo[1,5-a]pyridine (153); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (155); 2-(3,4-dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (156); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (157); 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (158); 6-(8-(1-cyclopropylpiperidine) -4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (159); 6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (160); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (161); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (162); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (163); 6-(1'-cyclopropyl-[1,4' 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (164); 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (166); or 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (167).

[0070]

[0013] Certain embodiments provide compounds of Formula (I) or stereoisomers, tautomers, solvates, or salts thereof, wherein the compounds are 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)cyclohexyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (143); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)- 8-Methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (144); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (145); 2-(3,4-dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl) -8-azabicyclo[3.2.1]octan-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (148); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (150); 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-3, 8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (152); or 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (154).

[0071]

[0013] Certain embodiments provide a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is 2-(3,4-dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (60); 2-(3,4-dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (61); or 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (165).

[0072] One embodiment is a TLR9 IC of ≦0.6 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0073] One embodiment is a TLR9 IC of ≦0.1 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0074] One embodiment is a TLR9 IC of ≦0.05 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0075] One embodiment is a TLR9 IC of ≦0.025 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0076] One embodiment is a TLR9 IC of ≦0.015 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0077] One embodiment is a TLR9 IC of ≦0.01 μM 50

[0023] The present invention provides a compound of formula (I) having the value:

[0078] In other embodiments, the present invention provides compositions comprising at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0079] In other embodiments, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0080] In other embodiments, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0081] In another embodiment, the present invention provides a method for preparing a compound of the present invention.

[0082] In other embodiments, the present invention provides intermediates for the preparation of compounds of the present invention.

[0083] In another embodiment, the present invention provides a pharmaceutical composition as defined above, further comprising one or more additional therapeutic agents.

[0084] definition The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It will be recognized that, for reasons of clarity, certain features of the invention that are described above and below in separate embodiments may be combined to form a single embodiment. Conversely, for reasons of brevity, various features of the invention that are described in a single embodiment may also be combined to form subcombinations thereof. Embodiments identified herein as examples or preferred are intended to be illustrative, not limiting.

[0085] Unless otherwise specified herein, the singular terms "a," "an," "the," "there" and "them" may refer to one or more.

[0086] As used herein, the term "compound" refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) and two or more compounds of formula (I).

[0087] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have a hydrogen atom to submit the valences.

[0088] The definitions provided herein take precedence over definitions set forth in any patents, patent applications and / or patent application publications incorporated herein by reference.

[0089] Listed below are definitions of various terms used to describe this invention. These definitions apply wherever the terms are used herein, either individually or as part of a larger group (unless otherwise defined in a specific instance).

[0090] Throughout the specification, groups and substituents thereof can be chosen by one skilled in the art to provide stable moieties and compounds.

[0091] According to the conventions used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

[0092] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0093] The term "cyano" refers to the group --CN.

[0094] The term "amino" refers to the group -NH2.

[0095] The term "oxo" refers to the group =O.

[0096] The term "alkyl," as used herein, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When the symbol "C" is followed by a subscript number, the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" refers to straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0097] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C, C, C, and C alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF and -CHCF.

[0098] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and C 1-4 Contains hydroxyalkyl.

[0099] The term "aminoalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more amine groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2 and C 1-4 Contains aminoalkyl.

[0100] The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "aminoalkyl" includes -CHCN, -CHCHCN, and C 1-4 Includes cyanoalkyl.

[0101] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, such as a methoxy group (-OCH). 1-3 "Alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms.

[0102] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3 and C4 fluoroalkoxy groups.

[0103] The term "alkoxyalkyl," as used herein, refers to an alkoxy group attached through its oxygen atom to an alkyl group, which in turn is attached to the parent molecular moiety through a carbon atom, e.g., a methoxymethyl group (-CH2OCH3). 2-4 "Alkoxyalkyl" refers to an alkoxyalkyl group having 2 to 4 carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3 and -CH2CH2OCH2CH3.

[0104] The term "cycloalkyl," as used herein, refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When the symbol "C" is followed by a number as a subscript, the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms.

[0105] The term "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0106] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. To provide the compound of formula (I) as an amorphous solid, lyophilization may be used.

[0107] It should further be understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules, either organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate is capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0108] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0109] Additionally, following their preparation, compounds of formula (I) can be isolated and purified to obtain compositions each containing 99% or more by weight of a compound of formula (I) ("substantially pure"), which can then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also contemplated herein as part of the invention.

[0110] "Stable compound" and "stable structure" refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent. The present invention contemplates stable compounds.

[0111] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone or in combination with other active ingredients that is effective to act as an inhibitor of TLR9 or that is effective in treating or preventing a fibrotic disease or disorder, such as pathological fibrosis, or a disorder associated with bile acid dysregulation.

[0112] As used herein, "treating" or "treatment" encompasses the treatment of a disease state in a mammal, particularly a human, and includes (a) preventing the onset of the disease state in a mammal, particularly when such a mammal is predisposed to, but has not yet been diagnosed with, the disease state; (b) arresting the disease state, i.e., halting its progression; and / or (c) alleviating the disease state, i.e., causing the disease state to regress.

[0113] The compounds of the present invention are intended to include all isotopes of atoms present in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon are 13 C and 14 C. Isotopically labeled compounds of the invention may be prepared by conventional techniques generally known to those skilled in the art or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for an otherwise unlabeled reagent. For example, methyl (-CH3) also includes deuterated methyl groups such as -CD3.

[0114] usefulness The compounds of the present invention are useful in inhibiting the TLR9 receptor.

[0115] Certain embodiments provide a method of treating a disease, disorder, or condition associated with bile acid dysregulation in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0116] One embodiment provides a method of treating a disease, disorder, or condition associated with activity of the TLR9 receptor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0117] Certain embodiments provide methods for treating a disease, disorder, or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention, alone or, optionally, in combination with other compounds of the present invention and / or at least one other type of therapeutic agent.

[0118] One embodiment provides a method of eliciting a TLR9 receptor antagonizing effect in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0119] In certain embodiments, the disease, disorder, or condition is associated with TLR9 dysfunction and includes pathological fibrosis, cancer, inflammatory disorders, metabolic, or cholestatic disorders.

[0120] In certain embodiments, the disease, disorder, or condition is associated with fibrosis, including liver, bile duct, kidney, heart, skin, eye, and pancreatic fibrosis.

[0121] In other embodiments, the disease, disorder, or condition is associated with a cell proliferation disorder, such as cancer. In some embodiments, the cancer comprises solid tumor growth or tumor. In other embodiments, the cancer comprises tumor metastasis. In some embodiments, the cancer is of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, reproductive organs, genitourinary tract, head, larynx, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testicle, or thyroid. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0122] Examples of diseases, disorders, or conditions associated with FXR activity that can be prevented, modulated, or treated by the present invention include, but are not limited to, transplantation, fibrotic disorders (e.g., liver fibrosis, kidney fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and cell proliferation disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0123] Fibrotic, inflammatory and cell proliferation disorders suitable for prevention or treatment with the compounds of the invention include non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, liver cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, liver hypofunction, liver blood flow disorders, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory disorders, benign prostatic hyperplasia, neurogenic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, viral-induced fibrosis, idiopathic pulmonary fibrosis (IDF). PF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal tumors, herniated disc, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot and mouth disease, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, The present invention provides a method for treating fibrotic disorders, inflammatory disorders or cell proliferation disorders, including but not limited to solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scars, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scars, Crohn's disease or systemic lupus erythematosus; keloid formation due to abnormal wound healing; fibrosis occurring after organ transplantation, myelofibrosis and uterine fibroids.In some embodiments, the present invention provides a method for treating fibrotic disorders, inflammatory disorders or cell proliferation disorders, comprising administering to the patient in need of such treatment at least one of the compounds of the present invention in a therapeutically effective amount, alone or optionally in combination with other compounds of the present invention and / or at least one other type of therapeutic agent.

[0124] In another embodiment, the present invention provides a compound of the present invention for use in therapy.

[0125] In other embodiments, the present invention provides a compound of the present invention for use in treating a fibrotic, inflammatory, or cell proliferation disorder.

[0126] In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a fibrotic, inflammatory, or cell proliferative disorder.

[0127] In other embodiments, the present invention provides a method of treating a fibrotic, inflammatory, or cell proliferative disorder, comprising administering to a patient in need thereof therapeutically effective amounts of first and second therapeutic agents, wherein the first therapeutic agent is a compound of the present invention.

[0128] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in therapy.

[0129] In other embodiments, the present invention provides a combined preparation of a compound of the present invention and an additional therapeutic agent for simultaneous, separate or sequential use in the treatment of a fibrotic, inflammatory or cell proliferative disorder.

[0130] The compounds of the present invention may be used in combination with one or more additional therapeutic agents, such as anti-fibrotic and / or anti-inflammatory therapeutic agents.

[0131] In certain embodiments, the additional therapeutic agent used in the combined pharmaceutical composition or combination method or combined use is selected from one or more, preferably one to three, of the following therapeutic agents: TGFβ receptor inhibitors (e.g., galunisertib), TGFβ synthesis inhibitors (e.g., pirfenidone), vascular endothelial growth factor (VEGF) inhibitors, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase inhibitors (e.g., nintedanib), humanized anti-α Vβ6 integrin monoclonal antibodies (e.g., 3G9), human recombinant pentraxin-2, recombinant human serum amyloid P, recombinant human antibodies against TGFβ-1, -2, and -3, endothelin receptor antagonists (e.g., macitentan), interferon gamma, c-Jun amino-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purine-2 -yl]amino]-trans-cyclohexanol, 3-pentylbenzeneacetic acid (PBI-4050), manganese(III)-containing tetrasubstituted porphyrin derivatives, eotaxin-2 targeting monoclonal antibodies, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar 9 , Met(O2) 11-Substance P), Syntredekin Besdotox, human recombinant DNA-derived, IgG1 kappa monoclonal antibody and fully human IgG1 kappa antibody against binding growth factors, CC-chemokine ligand 2 selective (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents for treating obstructive airway diseases, such as muscarinic antagonists (e.g., tiotropium, iprazolam), tropium), adrenergic beta-2 agonists (e.g., salbutamol, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus) and therapeutic agents useful in the treatment of fibrotic conditions, such as hepatic, biliary and renal fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF) and systemic sclerosis. Therapeutic agents useful for treating such fibrotic conditions include FXR agonists (e.g., OCA, GS-9674, and LJN452), LOXL2 inhibitors (e.g., simtuzumab), LPA1 antagonists (e.g., BMS-986020 and SAR100842), PPAR modulators (e.g., elafibranor, pioglitazone, and saroglitazar, IVA337), SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997 or These include, but are not limited to, ACC inhibitors (e.g., selonsertib), ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976), FGF21 mimetics (e.g., LY2405319 and BMS-986036), caspase inhibitors (e.g., emricasan), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors (e.g., BMS-963272), αV integrin inhibitors (e.g., abituzumab), and bile acid / fatty acid conjugates (e.g., aramchol).In various embodiments of the present invention, the FXR agonist may be administered in combination with one or more therapeutic agents, such as a CCR2 / 5 inhibitor (e.g., cenicriviroc), a Galectin-3 inhibitor (e.g., TD-139, GR-MD-02), a leukotriene receptor antagonist (e.g., tipelukast, montelukast), an SGLT2 inhibitor (e.g., dapagliflozin, remogliflozin), a GLP-1 receptor agonist (e.g., liraglutide and semaglutide), a F It may also be used in combination with AK inhibitors (e.g., GSK-2256098), CB1 inverse agonists (e.g., JD-5037), CB2 agonists (e.g., APD-371 and JBT-101), autotaxin inhibitors (e.g., GLPG1690), prolyl t-RNA synthetase inhibitors (e.g., halofuginone), FPR2 agonists (e.g., ZK-994), and THR agonists (e.g., MGL:3196). In other embodiments, the additional therapeutic agent used in the combined pharmaceutical composition, combination method, or combined use is selected from one or more, preferably 1 to 3, of tumor immunotherapeutic agents, such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab, and rituximab.

[0132] The terms "TLR9-associated condition" or "TLR9-associated disease or disorder," as used herein, are each intended to encompass, to the same extent as, all of the above-identified conditions, as well as any other conditions affected by TLR9 inhibition.

[0133] The above-mentioned other therapeutic agents, when used in combination with the compounds of the present invention, can be used in amounts, for example, as described in the Physicians' Desk Reference (PDR) or determined by one skilled in the art. In the methods of the present invention, such other therapeutic agents can be administered before, simultaneously with, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating TLR9-related conditions.

[0134] The compositions of the present invention may include other therapeutic agents, as described above, and may be formulated by techniques such as those well known in the art of pharmaceutical formulation, using, for example, conventional solid or liquid vehicles or diluents and pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavoring agents, and the like) of a type appropriate to the desired method of administration.

[0135] Accordingly, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

[0136] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers depend on several factors well within the purview of those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the drug-containing composition will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may contain several different components and additives in addition to the active agent; such additional components are included in the formulation for a variety of reasons well known to those skilled in the art, e.g., active agent stabilization, binders, etc. A discussion of suitable pharmaceutically acceptable carriers and the implications for their selection can be found, for example, in Remington: The Science and Practice of Pharmacy, 22 nd It can be found in a variety of readily available sources, such as Edition (2013).

[0137] The compounds of formula (I) may be administered by any means appropriate to the condition to be treated, which may depend on the need for site-specific treatment or the amount of formula (I) compound to be delivered.

[0138] The compound of formula (I) can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the intended treatment.The compounds and compositions of the present invention can be administered, for example, orally, mucosally, or parenterally, including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.For example, the pharmaceutical carrier can include a mixture of mannitol or lactose and microcrystalline cellulose.The mixture can include additional ingredients such as lubricants, disintegrants such as magnesium stearate and crospovidone.The carrier mixture can be filled into gelatin capsules or compressed into tablets.The pharmaceutical composition can be administered, for example, as an oral dosage form or infusion.

[0139] For oral administration, pharmaceutical compositions may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of the active ingredient. For example, pharmaceutical compositions may be provided as tablets or capsules containing about 0.1 to 1000 mg of active ingredient, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. A suitable daily dose for a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0140] Any pharmaceutical composition contemplated herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared by any method known in the art for the manufacture of pharmaceutical compositions intended for oral administration. To provide a pharmaceutically acceptable formulation, the pharmaceutical composition of the present invention may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0141] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharmaceutically acceptable additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, sodium croscarmellose, corn starch, and alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Furthermore, tablets may be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant-tasting drugs or delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the effect of the active ingredient for a long time. Examples of water-soluble taste-masking substances include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Examples of time-delay materials include, but are not limited to, ethylcellulose and cellulose acetate butyrate.

[0142] Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent, such as calcium carbonate; calcium phosphate; and kaolin.

[0143] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier, such as polyethylene glycol; and at least one oil medium, such as peanut oil, liquid paraffin, and olive oil.

[0144] Aqueous suspensions can be prepared, for example, by mixing at least one compound of formula (I) with at least one additive suitable for preparing aqueous suspensions. Examples of additives suitable for preparing aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides, for example, lecithin; condensation products of alkylene oxides and fatty acids, for example, polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol; condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain at least one preservative, for example, ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, for example, but not limited to, sucrose, saccharin, and aspartame.

[0145] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in vegetable oil, such as peanut oil; olive oil; sesame oil; and coconut oil; or mineral oil, such as liquid paraffin.Oily suspensions can also contain at least one thickening agent, such as beeswax; hard paraffin; and cetyl alcohol.To make oily suspensions easy to swallow, at least one of the sweeteners and / or at least one flavoring agent described above can be added to the oily suspension.Oily suspensions can further contain at least one preservative, including, but not limited to, antioxidants, such as butylated hydroxyanisole and alpha-tocopherol.

[0146] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing and / or wetting agent; at least one suspending agent; and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants, such as ascorbic acid. In addition, dispersible powders and granules can also contain at least one additive, including, but not limited to, sweeteners; flavoring agents; and coloring agents.

[0147] Emulsions of at least one compound of Formula (I) can be prepared, for example, as oil-in-water emulsions. The oil phase of emulsions containing a compound of Formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but is not limited to, vegetable oils, such as olive oil and peanut oil; mineral oils, such as liquid paraffin; and mixtures thereof. The phase can contain only an emulsifier, or a mixture of at least one emulsifier with a fat, an oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. In summary, the emulsifiers, with or without stabilizers, form what is called an emulsifying wax, and the wax, together with the oil and fat, forms what is called an emulsifying ointment base, which forms the oily dispersed phase of a cream formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with waxes or other materials known in the art.

[0148] The compound of formula (I) can be delivered, for example, intravenously, subcutaneously and / or intramuscularly, through any pharmaceutically acceptable and suitable injection form.Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents, such as water, Ringer's solution and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0149] Parenteral formulations may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents described for use in oral formulations, or other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection in a composition with a suitable carrier, including saline, dextrose, or water, or using cyclodextrins (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol), or micelle solubilization (i.e., Tween 80).

[0150] Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution, among others. In addition, sterile, fixed oils can be commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables.

[0151] Sterile injectable oil-in-water microemulsions can be prepared, for example, by 1) dissolving at least one compound of formula (I) in an oil phase, such as a mixture of soybean oil and lecithin; 2) combining the formula (I)-containing oil phase with a water and glycerol mixture; and 3) treating the combination to form the microemulsion.

[0152] Sterile aqueous or oily suspensions can be prepared by methods already known in the art. For example, sterile aqueous solutions or suspensions can be prepared using non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol; and sterile oily suspensions can be prepared using sterile non-toxic acceptable solvents or suspending media, such as sterile fixed oils, for example, synthetic mono- or diglycerides; and fatty acids, such as oleic acid.

[0153] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, polyethoxylated castor oil, e.g., Cremophor surfactants (BASF) or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins, such as alpha-, beta-, and gamma-cyclodextrin or chemically modified derivatives, such as hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl-cyclodextrin or other solubilizing derivatives, may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0154] The pharmaceutically active compounds of the present invention can be processed by conventional methods of pharmacy to produce medicaments for administration to patients, including humans and other mammals.The pharmaceutical compositions can be subjected to conventional pharmaceutical practices such as sterilization and / or can contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.Tablets and pills can further be enteric coated.Such compositions can also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and fragrances.

[0155] The amount of compound administered and the dosage regimen for treating a disease state with the compounds and / or compositions of the present invention depend on a variety of factors, including the subject's age, weight, sex, medical condition, type of disease, disease severity, route and frequency of administration, and the particular compound used. Thus, dosage regimens can vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosing schedules include weekly and once-every-two-day cycles.

[0156] For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants suitable for the indicated administration route.If administered orally, the compound is mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can contain controlled-release formulations, such as can be provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0157] Pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention comprises a compound of formula (I) described herein or a prodrug thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0158] The present invention also includes articles of manufacture. As used herein, article of manufacture is intended to include, but is not limited to, kits and packages. Articles of manufacture of the present invention include (a) a first container; (b) a pharmaceutical composition disposed within the first container, wherein the composition comprises a first therapeutic agent, the first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert describing that the pharmaceutical composition can be used to treat cardiovascular disorders, diuresis, and / or natriuresis. In other embodiments, the package insert describes that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat cardiovascular disorders, diuresis, and / or natriuresis. The article of manufacture may further include (d) a second container, wherein elements (a) and (b) are disposed within the second container and element (c) is disposed within or outside the second container. Disposed within the first and second containers means that each container contains the item within its boundaries.

[0159] A primary container is a receptacle used to hold a pharmaceutical composition. This container may be for manufacturing, storage, shipping, and / or individual / bulk sale. Primary containers are intended to include bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used in manufacturing, holding, storing, or dispensing pharmaceutical products.

[0160] The second container is used to contain the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and drawstring bags. The package insert may be physically attached to the outside of the first container by tape, glue, staples, or other attachment methods, or may be placed in the second container without any attachment means to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert be physically attached by tape, glue, staples, or other attachment methods. Alternatively, the package insert may be adjacent to or in contact with the outside of the second container without being physically attached.

[0161] The package insert is a label, tag, marker, or other written material that provides information about the pharmaceutical composition disposed in the first container. The information provided is typically determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) governing the region in which the product is sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition has been approved. The package insert can be manufactured from any material from which the information contained therein can be read. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper, or plastic) onto which the desired information is recorded (e.g., printed or applied).

[0162] Manufacturing method The compounds of the present invention can be prepared by several methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, or variations thereon recognized by those skilled in the art, in combination with synthetic methods known in the art of synthetic organic chemistry. Preferred methods include, but are not limited to, those described below.

[0163] The reactions and techniques described in this section are carried out in solvents appropriate to the reactants and materials used and suitable for the transformations being effected. It is also understood that in the following description of synthetic methods, all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and workup method, are selected to be standard conditions for the reactions readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will recognize that the functional groups present on each portion of the molecule must be compatible with the proposed reactants and reactions. Such limitations on the substituents that are compatible with the reaction conditions will be readily apparent to those skilled in the art, and if so, alternative methods will be used. This may necessitate judgment in altering the order of synthetic steps or selecting a particular process scheme over another to obtain the desired compound of the invention. Another major concern in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the compounds described herein. An authoritative reference describing many options to the skilled practitioner is Greene et al. (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0164] Scheme 1 [ka] Scheme 1 describes the synthesis of compounds of Formulae II-A and II-B, which are subsets of Formula II. The term "halo." in this scheme refers to any halogen that one skilled in the art would deem appropriate for achieving the intended transformation. The term "PG" refers to any suitable amino-protecting group, such as alkyl carbamate, alkyl amide, or alkyl. Although Ring A shown in Formulae II-A and II-B is substituted at the 6-position of the imidazo[1,2-a]pyridine ring, one skilled in the art can easily modify this synthetic scheme to introduce Ring A at the 7-position by using an appropriate starting material.

[0165] Compound 1a can be reacted with alpha-halo-ketone 1b in any typical reaction solvent (e.g., EtOH, DMF, DMSO) with or without heating. The reaction can be carried out in the presence of a base such as potassium carbonate or sodium bicarbonate, but this is not required. Compound 1c can be coupled with boronic ester 1d under standard Suzuki coupling conditions. The resulting alkene can be reduced by catalytic hydrogenation using a catalyst such as Pd or Pt. One skilled in the art can remove the protecting group PG using appropriate reagents and conditions. Reductive amination of amine 1f with ketone 1g or 1h can be achieved with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, with or without an acid catalyst (i.e., AcOH), to give compounds of Formula II-A and II-B.

[0166] Scheme 2 [ka] Scheme 2 describes the synthesis of compounds of formula III-A and III-B, which are subgroups of formula III. The term "PG" refers to any suitable amino-protecting group, such as alkyl carbamate, alkyl amide, or alkyl. Although ring A shown in formula III-A and III-B is substituted at the 6-position of the 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine ring, those skilled in the art can easily modify this synthetic scheme to introduce ring A at the 7-position by using appropriate starting materials.

[0167] Compound 1e (see Scheme 1) can be reduced by catalytic hydrogenation using a catalyst such as Pd or Pt at 1 atmosphere or greater. Reaction times can vary but are typically greater than 24 hours. Reductive amination of amine 2a with ketone 2b or 2c can be achieved with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, with or without an acid catalyst (i.e., AcOH), to give compounds of formula III-A and III-B. [Example]

[0168] The compounds of this invention and intermediates used in preparing the compounds of this invention can be prepared using the methods illustrated in the following examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not intended to be limiting, but rather to illustrate how to prepare the compounds of this invention. The starting materials and reactants used in these examples, when not prepared by the methods described herein, are generally commercially available or are described in the chemical literature or can be prepared using methods described in the chemical literature. The invention is further defined in the following examples. It should be understood that the examples are given by way of illustration only. From the above description and examples, one skilled in the art will be able to ascertain the essential features of this invention and can make various changes and modifications to adapt this invention to various uses and conditions without departing from its spirit and scope. Consequently, the present invention is not limited by the following illustrative examples, but rather by the appended claims.

[0169] In the examples given, the term "concentration to dryness" refers to drying a solution in an organic solvent, typically with sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (typically under reduced pressure and at a temperature appropriate for the stability of the material being concentrated to dryness).

[0170] Chemical names were determined using ChemDraw Ultra, version 9.0.5 (CambridgeSoft). The following abbreviations were used: aq. water-based Salt water saturated aqueous sodium chloride DCM dichloromethane DMAP dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol g grams h time HPLC High-Performance Liquid Chromatography LCMS Liquid Chromatography-Mass Spectrometry MeCN acetonitrile MeOH Methanol pet ether petroleum ether TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran

[0171] manufacturing All reagents purchased from commercial suppliers were used without further purification unless otherwise noted. All reactions involving air- or moisture-sensitive reagents were performed under an inert atmosphere. Proton magnetic resonance spectra were recorded on a Bruker Avance 400 or a JEOL Eclipse 500 spectrometer. LCMS analysis was performed on a Waters Acquity UPLC system coupled with a Waters TUV and SQ mass detector (column: BEH C18 2.1 x 50 mm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; gradient: 2 to 98% B over 1.6 min; flow rate: 0.8 mL / min); HPLC analysis was recorded on a Shimadzu LC10-AT HPLC system coupled with an SPD-10AV UV detector (column YMC S5 Combiscreen ODS 4.6 x 50 mm; mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; gradient: 0 to 100% B over 40 min, followed by a 1 min hold at 100% B; flow rate: 1 mL / min); preparative HPLC purification was performed on a Shimadzu LC10-AT HPLC system coupled with an SPD-10AV UV detector (column YMC S5 Combiscreen ODS 4.6 x 50 mm; mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; gradient: 0 to 100% B over 40 min, followed by a 1 min hold at 100% B; flow rate: 1 mL / min); The analysis was carried out on a Shimadzu LC-8 preparative HPLC system coupled with a UV detector. The detailed conditions are described in the experimental procedures.

[0172] Analytical LC / MS method Method 1: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0173] Method 2: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220 nm).

[0174] Method 3: Column: Waters Acquity BEH C18, 2.1 x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 MeOH:water with 10 mM ammonium acetate; Mobile phase B: 95:5 MeOH:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220, 254 nm).

[0175] Method 4: Column: Waters Acquity BEH C18, 2.1 x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Temperature: 50 °C; Gradient: 0% B to 100% B over 3 min, then hold at 100% B for 0.50 min; Flow rate: 1 mL / min; Detection: MS and UV (220, 254 nm).

[0176] Method 5: Column: Waters Acquity BEH C18, 2.1 x 50 mm, 1.7 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Temperature: 60 °C; Gradient: 2% B to 98% B over 1 min, then hold at 98% B for 0.50 min; Flow rate: 0.8 mL / min; Detection: MS and UV (220 nm).

[0177] Chiral Analysis Methods SFC Method 1: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 2 mL / min; Detection wavelength: 220 nm.

[0178] SFC Method 2: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 60% CO2 / 40% MeOH w / 0.1% DEA; Flow conditions: 2 mL / min. Detector wavelength: 220 nm.

[0179] SFC Method 3: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 75% CO2 / 25% IPA-acetonitrile 50-50 w / 0.1% DEA; Flow conditions: 2 mL / min; Detection wavelength: 220 nm.

[0180] SFC Method 4: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 55% CO2 / 45% IPA w / 0.1% DEA; Flow conditions: 2 mL / min; Detection wavelength: 220 nm.

[0181] SFC Method 5: Apparatus: Berger SFC; Column: Chiral OD 4.6 x 250 mm, 5 micron; Mobile phase: 70 / 30 CO2 / EtOH-0.1% DEA; Flow conditions: 4 mL / min; Detection wavelength: 220 nm.

[0182] SFC Method 6: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 65% CO2 / 35% IPA w / 0.6% DEA / 0.1% TFA; Flow conditions: 2 mL / min; Detection wavelength: 220 nm.

[0183] SFC Method 7: Apparatus: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 micron; Mobile phase: 80% CO2 / 20% MeOH w / 0.1% DEA; Flow conditions: 2 mL / min; Detection wavelength: 220 nm.

[0184] SFC Method 8: Apparatus: Agilent SFC; Column: Chiralcel OD-H, 4.6 x 250 mm, 5 micron; Mobile phase: 55% CO2 / 40% MeOH-0.1% DEA; Flow conditions: 2.0 mL / min, 120 bar, RT; Detection wavelength: 220 nm

[0185] SFC Method 9: Apparatus: Agilent SFC; Column: Chiralcel OD-H, 4.6 x 250 mm, 5 micron; Mobile Phase: 65% CO2 / 45% EtOH-0.1% DEA; Flow Conditions: 2.0 mL / min; Detection Wavelength: 220 nm

[0186] Preparative HPLC method Preparative Method 1: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: % B over 20 min (variable; depending on substrate), then hold at 100% B for 0 min; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was initiated by MS and UV signals.

[0187] Preparative Method 2: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; Gradient: % B over 20 min (variable; depending on substrate), then hold at 100% B for 0 min; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was initiated by the MS signal.

[0188] Example 1 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo [1,2-a]pyridine [ka] Step A. Intermediate 1A. Preparation of 6-bromo-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] To a 250 mL round-bottom flask was added 5-bromo-3-methylpyridin-2-amine (2.5 g, 13 mmol), 2-bromo-1-(3,4-dimethoxyphenyl)ethan-1-one (4.5 g, 17 mmol), and EtOH (50 mL). The reaction mixture was stirred at reflux. After 18 h, a precipitate formed. The reaction mixture was cooled and stored at -20 °C for 1 h, and the precipitate was collected by vacuum filtration. The filter cake was washed with a minimal amount of ether, and the product was dried under reduced pressure to give the title compound (4.6 g, 13 mmol, 99% yield) as a tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.93-8.88 (m, 1H), 8.41 (s, 1H), 7.92-7.86 (m, 1H), 7.55 (s, 2H), 7.20-7.16 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 2.76-2.72 (m, 3H). Analytical LC / MS (Method 5): Observed mass: 349.1; Retention time: 0.66 min

[0189] Step B. Intermediate 1B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] A 200 mL recovery flask was charged with Intermediate 1A (2.8 g, 8.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 9.7 mmol), 1,4-dioxane (30 mL), followed by potassium phosphate (5.1 g, 24 mmol) dissolved in water (7 mL). The vessel was evacuated and purged with N (2×), followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.30 g, 0.37 mmol). The vessel was again evacuated and purged and stirred at 75 °C. After 18 h, the reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2 × 100 mL). The organic phases were combined, washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 80 mL / min). The pure fractions were combined, concentrated, and dried under reduced pressure to give the title compound (3.5 g, 7.8 mmol, 98% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.31-8.27 (m, 1H), 8.06 (s, 1H), 7.62-7.58 (m, 1H), 7.51-7.47 (m, 1H), 7.33-7.30 (m, 1H), 7.07-7.02 (m, 1H), 6.30-6.19 (m, 1H), 4.16-4.09 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.71-3.67 (m, 2H), 2.66-2.61 (m, 3H), 2.59-2.53 (m, 2H), 1.22 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 450.4; retention time: 0.81 min

[0190] Step C. Intermediate 1C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate [ka] To a 1 L round-bottom flask was added Intermediate 1B (3.5 g, 7.8 mmol) and MeOH (150 mL). The vessel was evacuated and purged with N, then Pd—C (5% on carbon) (1.7 g, 0.78 mmol) was added and the reaction mixture was again evacuated and purged. The reaction mixture was stirred under 1 atmosphere of hydrogen. After 1 hour, 1 H NMR showed conversion of the starting material. The reaction mixture was filtered, the filtrate was concentrated, and the product was dried under reduced pressure to give the title compound (3.1 g, 6.9 mmol, 88% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.19-8.16 (m, 1H), 8.08 (s, 1H), 7.62-7.58 (m, 1H), 7.51-7.47 (m, 1H), 7.18-7.14 (m, 1H), 7.07-7.03 (m, 1H), 4.31-4.22 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 2.98-2.86 (m, 2H), 2.84-2.72 (m, 1H), 2.62 (s, 3H), 1.97-1.88 (m, 2H), 1.70-1.59 (m, 2H), 1.51 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 452.4; Retention time: 1.18 min

[0191] Step D. Intermediate 1D. Preparation of 2-(3,4-dimethoxyphenyl)-8-methyl-6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride [ka] To a 1 L round-bottom flask was added Intermediate 1C (3.1 g, 6.9 mmol), a minimal amount of MeOH to solubilize, followed by 4 M HCl in dioxane (150 mL). The reaction mixture was stirred. After 1 h, the solvent was concentrated, and the residue was co-evaporated with toluene. The product was dried under reduced pressure to give the title compound (2.1 g, 5.4 mmol, 78% yield) as an off-white solid. 1H NMR (500 MHz, methanol-d4) δ 8.60-8.55 (m, 1H), 8.45-8.40 (m, 1H), 7.75-7.70 (m, 1H), 7.58-7.53 (m, 2H), 7.20-7.15 (m, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.62-3.57 (m, 2H), 3.28-3.20 (m, 2H), 3.17-3.11 (m, 1H), 2.74 (s, 3H), 2.28-2.20 (m, 2H), 2.10-1.98 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 352.2; Retention time: 0.68 minutes

[0192] Step E. Preparation of the compound of Example 1 To a 40 mL vial was added Intermediate 1D (70 mg, 0.18 mmol), 1-cyclopropylpiperidin-4-one (130 mg, 0.90 mmol), AcOH (0.011 mL, 0.20 mmol), DMF (2 mL), and MgSO (220 mg, 1.8 mmol). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the reaction mixture was stirred. After 24 hours, the reaction mixture was filtered, and the filter cake was washed with 10% IPA / chloroform (20 mL). The filtrate was washed with 10% aqueous NaOH (10 mL), brine, dried over MgSO, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (51 mg, 0.11 mmol, 60% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.21 (m, 1H), 8.19-8.13 (m, 1H), 7.57-7.52 (m, 1H), 7.51-7.46 (m, 1H), 7.05-6.99 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.53-3.34 (m, 1H), 3.09-2.93 (m, 4H), 2.45-2.32 (m, 3H), 2.20-2.12 (m, 2H), 1.89-1.81 (m, 2H), 1.80-1.74 (m, 2H), 1.73-1.62 (m, 2H), 1.62-1.54 (m, 1H), 1.48-1.36 (m, 2H), 0.45-0.38 (m, 2H), 0.33-0.27 (m, 2H) (3 protons unclear). Analytical LC / MS (Method 1): Purity: 99.2 %; Observed mass: 474.91; Retention time: 1.38 min. (Method 2): Purity: 98.9 %; Observed mass: 475.36; Retention time: 0.99 min

[0193] Example 2 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Example 2 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 1D (70 mg, 0.18 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (130 mg, 0.90 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (52 mg, 0.11 mmol, 61% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.20 (m, 1H), 8.20-8.13 (m, 1H), 7.57-7.52 (m, 1H), 7.52-7.47 (m, 1H), 7.06-6.99 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.51-3.44 (m, 1H), 3.06-2.96 (m, 3H), 2.93-2.85 (m, 1H), 2.41-2.27 (m, 5H), 1.92 (s, 3H), 1.87-1.80 (m, 4H), 1.73-1.61 (m, 2H), 1.60-1.49 (m, 2H), 1.04 (br d, J=6.4 Hz, 6H) (1 proton obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 477.29; Retention time: 1.42 min. (Method 2): Purity: 100 %; Observed mass: 477.03; Retention time: 0.97 minutes

[0194] Example 3 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Example 3 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 1D (70 mg, 0.18 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (140 mg, 0.90 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (52 mg, 0.11 mmol, 61% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.46 (br s, 1H), 7.57 (br s, 2H), 7.52-7.47 (m, 1H), 7.17-7.13 (m, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.74-3.60 (m, 1H), 3.25-3.15 (m, 1H), 3.09-2.91 (m, 4H), 2.64 (s, 3H), 2.36-2.27 (m, 2H), 2.23-1.96 (m, 8H), 1.01-0.95 (m, 6H) (5 protons ambiguous). Analytical LC / MS (Method 1): Purity: 97%; Observed Mass: 491.18; Retention Time: 1.51 min. (Method 2): Purity: 100%; Observed Mass: 491.27; Retention Time: 0.94 min.

[0195] Example 4 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3-fluoro-4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] Step A. Intermediate 4A. Preparation of 6-bromo-2-(3-fluoro-4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] Intermediate 4A was prepared according to the general method described for the synthesis of Intermediate 1A, starting from 5-bromo-3-methylpyridin-2-amine (0.76 g, 4.1 mmol), substituting 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethan-1-one (1.0 g, 4.1 mmol) as needed, to afford the title compound (1.0 g, 3.0 mmol, 73% yield) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 9.08-9.02 (m, 1H), 8.59 (s, 1H), 7.96-7.90 (m, 1H), 7.89-7.80 (m, 2H), 7.44-7.37 (m, 1H), 2.64 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 337.0; Retention time: 0.75 min

[0196] Step B. Intermediate 4B. Preparation of tert-butyl 4-(2-(3-fluoro-4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Intermediate 4B was prepared following the general method described for the synthesis of Intermediate 1B, starting from Intermediate 4A (500 mg, 1.5 mmol) to afford the title compound (480 mg, 1.1 mmol, 73% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.32-8.27 (m, 1H), 8.09-8.05 (m, 1H), 7.72-7.66 (m, 2H), 7.36-7.30 (m, 1H), 7.21-7.14 (m, 1H), 6.27-6.20 (m, 1H), 4.19-4.08 (m, 2H), 3.94 (s, 3H), 3.73-3.65 (m, 2H), 2.64-2.60 (m, 3H), 2.59-2.53 (m, 2H), 1.52 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 438.4; Retention time: 0.88 min

[0197] Step C. Intermediate 4C. 2-(3-fluoro-4-methoxyphenyl)-8-methyl-6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride [ka] Intermediate 4C was prepared following the general method described for the synthesis of Intermediate 1D (Steps C-D), starting from Intermediate 4B (480 mg, 1.1 mmol) to afford the title compound (410 mg, 1.1 mmol, 100% yield) as a tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.64-8.60 (m, 1H), 8.49-8.45 (m, 1H), 7.83-7.80 (m, 1H), 7.80-7.74 (m, 2H), 7.39-7.33 (m, 1H), 4.00 (s, Analytical LC / MS (Method 5): Observed mass: 340.2; Retention time: 0.58 min

[0198] Step D. Preparation of the compound of Example 4 Example 4 was synthesized using Intermediate 4C (60 mg, 0.15 mmol) as the starting material according to the general method described for the preparation of Example 1 (Step E). The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (40 mg, 0.086 mmol, 57% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.92 (s, 1H), 7.49 (br d, J=2.7 Hz, 2H), 7.01-6.95 (m, 1H), 6.81-6.75 (m, 1H), 3.63 (s, 3H), 2.80-2.65 (m, 2H), 2.30 (s, 3H), 1.95-1.83 (m, 2H), 1.65-1.54 (m, 2H), 1.54-1.36 (m, 4H), 1.36-1.29 (m, 1H), 1.26-1.09 (m, 2H), 0.20-0.11 (m, 2H), 0.08--0.01 (m, 2H) (6 protons obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 463.14; Retention time: 1.53 min. (Method 2): Purity: 100 %; Observed mass: 463.16; Retention time: 0.99 min

[0199] Example 5 2-(3-fluoro-4-methoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Example 5 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 4C (60 mg, 0.15 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (49 mg, 0.11 mmol, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.18-8.15 (m, 1H), 7.77-7.70 (m, 2H), 7.26-7.19 (m, 1H), 7.06-7.01 (m, 1H), 3.88 (s, 3H), 3.03-2.97 (m, 2H), 2.97-2.90 (m, 1H), 2.56-2.53 (m, 1H), 2.51 (s, 3H), 2.49-2.44 (m, 1H), 2.38-2.21 (m, 4H), 1.86-1.76 (m, 4H), 1.71-1.60 (m, 2H), 1.56-1.43 (m, 2H), 1.07-0.97 (m, 6H) (2 protons obscured). Analytical LC / MS: (Method 1): Purity: 100 %; Observed mass: 465.01; Retention time: 1.54 min. (Method 2): Purity: 100 %; Observed mass: 465.29; Retention time: 1.04 minutes

[0200] Example 6 2-(3-fluoro-4-methoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Example 6 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 4C (60 mg, 0.15 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (40 mg, 0.084 mmol, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.19 (s, 1H), 7.79-7.72 (m, 2H), 7.28-7.22 (m, 1H), 7.07-7.03 (m, 1H), 3.90 (s, 3H), 3.42-3.35 (m, 1H), 3.21-3.17 (m, 1H), 3.14-3.02 (m, 2H), 3.00-2.88 (m, 2H), 2.44-2.35 (m, 2H), 2.12-2.04 (m, 2H), 1.91-1.85 (m, 2H), 1.83-1.75 (m, 3H), 1.74-1.61 (m, 3H), 1.60-1.45 (m, 3H), 0.87 (br d, J=6.4 Hz, 6H) (3 protons unclear). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 479.13; Retention time: 1.77 min. (Method 2): Purity: 98.8%; Observed mass: 479.05; Retention time: 1.04 min

[0201] Example 7 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 7A. Preparation of 6-bromo-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Intermediate 7A was prepared according to the general method described for the synthesis of Intermediate 1A, starting from 5-bromo-3-methylpyridin-2-amine (0.60 g, 3.2 mmol), substituting 2-bromo-1-(4-(methylsulfonyl)phenyl)ethan-1-one (0.89 g, 3.2 mmol) as needed, to afford the title compound (1.0 g, 2.7 mmol, 84% yield) as a tan solid. 1H NMR (500 MHz, methanol-d4) δ 9.01-8.95 (m, 1H), 8.66 (s, 1H), 8.24-8.17 (m, 4H), 7.98-7.92 (m, 1H), 3.25-3.22 (m, 3H), 2.78-2.74 (m, 3H). Analytical LC / MS (Method 5): Observed mass: 367.1; Retention time: 0.72 min

[0202] Step B. Intermediate 7B. Preparation of tert-butyl 4-(8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Intermediate 7B was prepared following the general method described for the synthesis of Intermediate 1B, starting from Intermediate 7A (1.0 g, 2.7 mmol) to afford the title compound (1.2 g, 2.6 mmol, 96% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.37-8.32 (m, 2H), 8.24-8.19 (m, 2H), 8.07-8.01 (m, 2H), 7.42-7.36 (m, 1H), 6.32-6.24 (m, 1H), 4.19-4.09 (m, 2H), 3.72-3.65 (m, 2H), 3.19 (s, 3H), 2.64 (s, 3H), 2.61-2.53 (m, 2H), 1.53 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 468.4; Retention time: 0.81 minutes

[0203] Step C. Intermediate 7C. Preparation of 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride [ka] Intermediate 7C was prepared following the general method described for the synthesis of Intermediate 1D (Steps C-D), starting from Intermediate 7B (1.2 g, 2.5 mmol) to afford the title compound (1.0 g, 2.5 mmol, 100% yield) as a tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.74 (s, 1H), 8.72-8.69 (m, 1H), 8.22 (d, J=10.2 Hz, 4H), 7.91-7.87 (m, 1H), 3.71-3.67 (m, 1H), 3.63-3.61 (m, 1H), 3.61-3.58 (m, 1H), 3.28-3.24 (m, 2H), 3.23 (s, 3H), 2.78 (s, 3H), 2.29-2.22 (m, 2H), 2.12-2.02 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 370.4; Retention time: 0.51 min

[0204] Step D. Preparation of the compound of Example 7 Example 7 was synthesized using Intermediate 7C (70 mg, 0.16 mmol) as the starting material according to the general method described for the preparation of Example 1 (Step E). The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (61 mg, 0.12 mmol, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.21 (br d, J=8.6 Hz, 3H), 8.01-7.94 (m, 2H), 7.11-7.07 (m, 1H), 3.25-3.22 (m, 1H), 3.02-2.94 (m, 2H), 2.53 (s, 3H), 2.40-2.25 (m, 2H), 2.18-2.09 (m, 2H), 1.88-1.81 (m, 2H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H), 1.60-1.54 (m, 1H), 1.46-1.35 (m, 2H), 0.42-0.37 (m, 2H), 0.30-0.25 (m, 2H) (6 protons obscured). Analytical LC / MS (Method 1): Purity: 96.8 %; Observed mass: 493.14; Retention time: 1.45 min. (Method 2): Purity: 94.9 %; Observed mass: 493.15; Retention time: 0.90 min

[0205] Example 8 6-(1'-Isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Example 8 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 7C (70 mg, 0.16 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to afford the title compound (49 mg, 0.10 mmol, 63% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.22 (br d, J=8.9 Hz, 3H), 7.98 (br d, J=8.5 Hz, 2H), 7.13-7.08 (m, 1H), 3.26-3.22 (m, 2H), 3.02-2.95 (m, 2H), 2.87-2.81 (m, 2H), 2.72-2.64 (m, 1H), 2.53 (s, 3H), 2.49-2.44 (m, 1H), 2.29-2.17 (m, 3H), 2.16-2.05 (m, 2H), 1.94-1.89 (m, 1H), 1.86-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.70-1.57 (m, 2H), 1.49-1.38 (m, 2H), 1.00-0.93 (m, 6H). Analytical LC / MS (Method 1): Purity: 94.4 %; Observed mass: 494.90; Retention time: 1.19 min. (Method 2): Purity: 95 %; Observed mass: 495.17; Retention time: 0.90.

[0206] Example 9 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Example 9 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 7C (70 mg, 0.16 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (62 mg, 0.12 mmol, 75% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.23 ​​(br d, J=8.9 Hz, 3H), 8.00 (s, 2H), 7.15-7.08 (m, 1H), 3.28-3.23 (m, 1H), 3.05-2.97 (m, 2H), 2.92-2.83 (m, 2H), 2.54 (br s, 4H), 2.34-2.23 (m, 3H), 2.06-1.99 (m, 2H), 1.90-1.81 (m, 4H), 1.79-1.71 (m, 3H), 1.71-1.59 (m, 3H), 1.55-1.43 (m, 2H), 0.86 (br d, J=6.4 Hz, 6H) (1 proton obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 509.17; Retention time: 1.38 min. (Method 2): Purity: 99.3 %; Observed mass: 509.18; Retention time: 0.94 minutes

[0207] Example 10 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 10A. Preparation of 6-bromo-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine [ka] Intermediate 10A was prepared according to the general method described for the synthesis of Intermediate 1A, substituting 5-bromopyridin-2-amine (5.0 g, 29 mmol) as needed to afford the title compound (9.5 g, 29 mmol, 100% yield) as a tan solid. 1H NMR (500 MHz, methanol-d4) δ 9.10-9.08 (m, 1H), 8.48 (s, 1H), 8.09-8.05 (m, 1H), 7.87-7.83 (m, 1H), 7.52-7.47 (m, 2H), 7.20-7.16 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 335.2; Retention time: 0.62 min

[0208] Step B. Intermediate 10B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Intermediate 10B was prepared following the general method described for the synthesis of Intermediate 1B, starting from Intermediate 10A (2.5 g, 7.5 mmol) to afford the title compound (3.2 g, 7.4 mmol, 99% yield) as a yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.40-8.36 (m, 1H), 8.05 (s, 1H), 7.55-7.53 (m, 1H), 7.51-7.48 (m, 2H), 7.47-7.43 (m, 1H), 7.05-7.00 (m, 1H), 6.26-6.18 (m, 1H), 4.14-4.09 (m, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.70-3.66 (m, 2H), 2.59-2.53 (m, 2H), 1.54-1.51 (m, 9H). Analytical LC / MS (Method 5): Observed mass: 436.4; Retention time: 0.78 minutes

[0209] Step C. Intermediate 10C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate [ka] To a 100 mL recovery flask was added Intermediate 10B (3.2 g, 7.4 mmol) and MeOH (40 mL). The vessel was evacuated and purged with N (2x), then platinum(IV) oxide (0.68 g, 3.0 mmol) was added, and the reaction mixture was stirred under 1 atmosphere of hydrogen. After 1 h, the catalyst was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min). Pure fractions were combined, concentrated, and dried under reduced pressure to give the title compound (1.0 g, 2.3 mmol, 31% yield) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ 8.31-8.28 (m, 1H), 8.10-8.07 (m, 1H), 7.58-7.55 (m, 1H), 7.52-7.46 (m, 2H), 7.31-7.27 (m, 1H), 7.06-7.02 (m, 1H), 4.30-4.24 (m, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 2.99-2.87 (m, 2H), 2.84-2.77 (m, 1H), 1.97-1.90 (m, 2H), 1.71-1.61 (m, 2H), 1.51 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 438.4; Retention time: 0.78 min

[0210] Step D. Intermediate 10D. Preparation of 2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine 2,2,2-trifluoroacetate [ka] To a 100 mL recovery flask was added Intermediate 10C (1.0 g, 2.3 mmol), DCM (5 mL), and TFA (5 mL). After stirring for 1 h, the solvent was concentrated, the residue was co-evaporated with toluene, and the product was dried under reduced pressure to give the title compound (1.0 g, 2.2 mmol, 96% yield) as a tan solid. 1H NMR (500 MHz, methanol-d4) δ 8.74-8.70 (m, 1H), 8.49-8.46 (m, 1H), 7.99-7.94 (m, 1H), 7.93-7.89 (m, 1H), 7.52-7.46 (m, 2H), 7.20-7.16 (m, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.63-3.58 (m, 2H), 3.27-3.23 (m, 2H), 2.30-2.22 (m, 2H), 2.08-1.98 (m, 2H) (1 proton obscured). Analytical LC / MS (Method 5): Observed mass: 338.3; Retention time: 0.50 minutes

[0211] Step E. Preparation of the compound of Example 10 Example 10 was synthesized using Intermediate 10D (70 mg, 0.16 mmol) as the starting material according to the general method described for the preparation of Example 1 (Step E). The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (25 mg, 0.054 mmol, 34% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.53-7.46 (m, 2H), 7.23-7.18 (m, 1H), 7.05-7.01 (m, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.14-3.05 (m, 1H), 3.04-2.97 (m, 2H), 2.61-2.55 (m, 1H), 2.49-2.35 (m, 2H), 2.21-2.13 (m, 2H), 1.92-1.84 (m, 2H), 1.82-1.75 (m, Analytical LC / MS (Method 1): Purity: 95.9 %; Observed mass: 461.27; Retention time: 1.35 min. (Method 2): Purity: 96.7 %; Observed mass: 460.99; Retention time: 1.02 min

[0212] Example 11 2-(3,4-dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine [ka] Example 11 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 10D (70 mg, 0.16 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (43 mg, 0.093 mmol, 58% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.33-8.29 (m, 1H), 8.22 (s, 1H), 7.55-7.51 (m, 1H), 7.47 (s, 2H), 7.23-7.18 (m, 1H), 7.03-6.97 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.01-2.94 (m, 2H), 2.90-2.81 (m, 2H), 2.76-2.65 (m, 1H), 2.29-2.19 (m, 3H), 2.18-2.07 (m, 2H), 1.85-1.72 (m, 4H), 1.69-1.59 (m, 2H), 1.50-1.37 (m, 2H), 0.97 (d, J=6.6 Hz, 6H) (1 proton obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 463.29; Retention time: 1.33 min. (Method 2): Purity: 100%; Observed mass: 463.16; Retention time: 0.96 min

[0213] Example 12 2-(3,4-dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine [ka] Example 12 was synthesized according to the general method described for the preparation of Example 1 (Step E), using Intermediate 10D (70 mg, 0.16 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (23 mg, 0.050 mmol, 31% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.25 (s, 1H), 7.56-7.53 (m, 1H), 7.53-7.46 (m, 2H), 7.25-7.19 (m, 1H), 7.05-7.00 (m, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.60-3.49 (m, 1H), 3.20-3.17 (m, 1H), 3.13-3.05 (m, 2H), 2.99-2.89 (m, 2H), 2.46-2.36 (m, 3H), 2.14-2.06 (m, 2H), 2.00-1.94 (m, 1H), 1.91-1.85 (m, 2H), 1.84-1.75 (m, 3H), 1.75-1.64 (m, 2H), 1.59-1.49 (m, 2H), 0.86 (s, 6H) (1 proton unclear). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 477.03; Retention time: 1.39 min. (Method 2): Purity: 100 %; Observed mass: 477.02; Retention time: 1.04 min

[0214] Example 13 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Step A. Intermediate 13A. Preparation of 6-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine dihydrochloride [ka] To a 40 mL vial was added Intermediate 1D (0.50 g, 1.3 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (0.82 g, 3.9 mmol), AcOH (0.081 mL, 1.4 mmol), magnesium sulfate (2.3 g, 19 mmol), and DMF (10 mL). The reaction mixture was stirred for 20 min, then sodium triacetoxyborohydride (0.82 g, 3.9 mmol) was added and the reaction mixture was stirred. After 20 h, the reaction mixture was adsorbed onto Celite, and the product was purified by flash column chromatography (100 g reverse-phase C18 GOLD silica gel cartridge; A = water:MeCN:TFA 90:10:0.05%, B = water:MeCN:TFA 10:90:0.05%; 20 min gradient; 0% B to 50% B; flow rate = 80 mL / min). Pure fractions were combined and concentrated, and the intermediate was dissolved in a minimal amount of MeOH and diluted with 4 M HCl in dioxane (10 mL). After stirring for 1.5 h, the solvent was concentrated. The resulting solid was triturated with MeOH, and the product was collected by vacuum filtration and dried under reduced pressure to give the title compound (0.40 g, 0.77 mmol, 59% yield) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ 8.58-8.51 (m, 1H), 8.43-8.36 (m, 1H), 7.77-7.66 (m, 1H), 7.58-7.52 (m, 2H), 7.19-7.14 (m, 1H), 4.25-4.21 (m, 2H), 4.19-4.15 (m, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.74-3.70 (m, 1H), 3.68-3.62 (m, 2H), 3.18-3.10 (m, 1H), 3.08-2.98 (m, 2H), 2.85-2.80 (m, 3H), 2.73 (s, 3H), 2.28-2.20 (m, 4H) (1 proton obscured). Analytical LC / MS (Method 5): Observed mass: 447.4; Retention time: 0.50 min

[0215] Step B. Preparation of the compound of Example 13 To a 40 mL vial was added Intermediate 13A (70 mg, 0.14 mmol), propan-2-one (80 mg, 1.4 mmol), AcOH (8.4 mg, 0.14 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (87 mg, 0.41 mmol) was added and the reaction mixture was stirred. After stirring for 24 hours, the reaction mixture was filtered, and the filter cake was washed with 10% IPA / chloroform (20 mL). The filtrate was washed with 10% aqueous NaOH (10 mL), brine, dried over MgSO, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (36 mg, 0.074 mmol, 53% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.17-8.13 (m, 1H), 7.54-7.51 (m, 1H), 7.50-7.46 (m, 1H), 7.03-6.98 (m, 2H), 3.85-3.82 (m, 3H), 3.79-3.77 (m, 3H), 3.70-3.64 (m, 2H), 3.18-3.15 (m, 1H), 2.92-2.85 (m, 2H), 2.65-2.59 (m, 1H), 2.56-2.53 (m, 2H), 2.49-2.44 (m, 2H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.86-1.77 (m, 4H), 1.67-1.57 (m, 2H), 0.97-0.92 (m, 6H) (2 protons obscured). Analytical LC / MS (method 1): Purity: 100 %; Observed mass: 489.07; Retention time: 1.2 min. (Method 2): Purity: 95.2 %; Observed mass: 489.29; Retention time: 0.98 min

[0216] Example 14 6-(1-(2-cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] Example 14 was synthesized according to the general method described for the preparation of Example 13 (Step B), using Intermediate 13A (70 mg, 0.14 mmol) as the starting material, substituting cyclobutanone (98 mg, 1.4 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to afford the title compound (48 mg, 0.096 mmol, 69% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.32-8.22 (m, 1H), 8.18-8.14 (m, 1H), 7.57-7.47 (m, 2H), 7.04-6.98 (m, 2H), 4.00-3.95 (m, 1H), 3.90-3.87 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.69-3.61 (m, 1H), 3.58-3.48 (m, 1H), 3.09-2.98 (m, 1H), 2.57-2.54 (m, 3H), 2.49-2.39 (m, 2H), 2.24-2.09 (m, (Method 2): Purity: 95.2 %; Observed mass: 501.21; Retention time: 0.95 minutes

[0217] Example 15 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Example 15 was synthesized according to the general method described for the preparation of Example 13 (Step B), using Intermediate 13A (90 mg, 0.17 mmol) as the starting material, substituting isobutyraldehyde (63 mg, 0.87 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to afford the title compound (32 mg, 0.064 mmol, 38% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.17-8.13 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.51-7.45 (m, 1H), 7.00 (br d, J=1.2 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 2.93-2.85 (m, 2H), 2.62-2.57 (m, 1H), 2.55 (s, 4H), 2.48-2.43 (m, 1H), 2.41-2.33 (m, 2H), 2.27-2.20 (m, 2H), 2.16-2.02 (m, 1H), 1.94 (br s, 2H), 1.80 (br d, J=11.4 Hz, 4H), 1.67-1.54 (m, 3H), 0.90-0.87 (m, 1H), 0.84 (d, J=6.7 Hz, 6H) (1 proton ambiguous). Analytical LC / MS (Method 1): Purity: 99.2 %; Observed mass: 502.96; Retention time: 1.46 min. (Method 2): Purity: 100 %; Observed mass: 502.96; Retention time: 1.03 min

[0218] Example 16 6-(1-(2-(cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] Example 16 was synthesized according to the general method described for the preparation of Example 13 (Step B), using Intermediate 13A (90 mg, 0.17 mmol) as the starting material, substituting cyclopropanecarbaldehyde (61 mg, 0.87 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to afford the title compound (49 mg, 0.098 mmol, 58% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.21 (br s, 1H), 7.30 (br s, 2H), 7.28-7.24 (m, 1H), 6.91-6.86 (m, 1H), 4.04-3.95 (m, 1H), 3.92-3.80 (m, 3H), 3.63 (s, 3H), 3.58 (s, 3H), 3.39-3.20 (m, 1H), 2.80-2.73 (m, 3H), 2.70-2.59 (m, 2H), 2.52-2.44 (m, 1H), 2.37 (s, 3H), 2.35-2.29 (m, Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 501.25; Retention time: 1.01 min. (Method 2): Purity: 100 %; Observed mass: 501.28; Retention time: 1.52 min

[0219] Example 17 6-(1-(2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] To a 40 mL vial was added Intermediate 13A (100 mg, 0.19 mmol), (1-ethoxycyclopropoxy)trimethylsilane (100 mg, 0.58 mmol), activated 3 Å molecular sieves (500 mg), and MeOH (5 mL). The reaction mixture was flushed with N2 and stirred at 80 °C for 1 h. Cooled to room temperature, sodium cyanoborohydride (36 mg, 0.58 mmol) was then added. The vessel was flushed with N2, and the reaction mixture was stirred at 40 °C. After 18 h, the vessel was cooled and (1-ethoxycyclopropoxy)trimethylsilane (100 mg, 0.58 mmol), AcOH (0.066 mL, 1.2 mmol), sodium cyanoborohydride (36 mg, 0.58 mmol), and additional 3 Å molecular sieves were added. The vessel was flushed with N2 and heated to 50 °C and stirred. After 18 h, the reaction mixture was cooled, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (10 mg, 0.021, 11% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.08-8.04 (m, 1H), 7.96-7.93 (m, 1H), 7.32 (br d, J=1.7 Hz, 2H), 7.30-7.26 (m, 1H), 6.82-6.80 (m, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 3.08-3.04 (m, 1H), 2.97-2.94 (m, 1H), 2.76-2.68 (m, 2H), 2.35-2.34 (m, 3H), 2.09-2.06 (m, 1H), 2.02-1.95 (m, 3H), 1.90-1.85 (m, 2H), 1.72-1.65 (m, 4H), 1.63-1.58 (m, 2H), 1.47-1.40 (m, 2H), 0.27-0.20 (m, 1H), 0.12-0.09 (m, 2H), 0.03--0.02 (m, 2H). Analytical LC / MS (Method 1): Purity: 84.9 %; Observed mass: 487.23; Retention time: 1.5 min. (Method 2): Purity: 100 %; Observed mass: 487.22; Retention time: 1.0 min

[0220] Examples 18 and 19 2-(3,4-Dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] Step A. Intermediate 18A. Preparation of 6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine bis(2,2,2-trifluoroacetate) [ka] To a 40 mL vial was added Intermediate 1D (400 mg, 1.0 mmol), tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (700 mg, 3.1 mmol), AcOH (0.065 mL, 1.1 mmol), magnesium sulfate (1900 mg, 16 mmol), and DMF (10 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (660 mg, 3.1 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with DCM / MeOH and filtered. Water (0.5 mL) was added to the filtrate and then concentrated. The remaining DMF solution was filtered, and the crude product was purified by flash column chromatography (100 g reverse-phase C18 GOLD silica gel cartridge; A = water:MeCN:TFA 90:10:0.05%, B = water:MeCN:TFA 10:90:0.05%; 20 min gradient; 0% B to 40% B; flow rate = 60 mL / min). Fractions corresponding to this intermediate were combined and concentrated. The resulting residue was dissolved in THF (20 mL) and TFA (20 mL) and stirred. After 3 h, the solvent was concentrated, and the residue was purified by flash column chromatography (100 g reverse-phase C18 GOLD silica gel cartridge; A = water:MeCN:TFA 90:10:0.05%, B = water:MeCN:TFA 10:90:0.05%; 20 min gradient; 0% B to 40% B; flow rate = 60 mL / min). The desired fractions were combined and concentrated, and the product was dried under vacuum to give the title compound (120 mg, 0.26 mmol, 26% yield) as a colorless residue. 1H NMR (500 MHz, methanol-d4) δ 8.55-8.50 (m, 1H), 8.41 (s, 1H), 7.75-7.69 (m, 1H), 7.48 (br s, 2H), 7.10-7.04 (m, 1H), 4.31-4.19 (m, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.83-3.77 (m, 2H), 3.35-3.32 (m, 1H), 3.31-3.22 (m, 2H), 3.18-3.08 (m, 1H), 2.70 (s, 3H), 2.44-2.36 (m, 2H), 2.31-2.18 (m, 8H), 2.15-2.09 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 461.3; Retention time: 0.50 min

[0221] Step B. Preparation of the compounds of Examples 18 and 19 To a 40 mL vial was added Intermediate 18A (40 mg, 0.058 mmol), isobutyraldehyde (21 mg, 0.29 mmol), AcOH (3.8 mg, 0.064 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 15% B at 0 min hold, 15 to 70% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was initiated by MS signal. Fractions containing each desired product were combined and dried by centrifugal evaporation. Example 18 (12 mg, 0.023 mmol, 40% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.16 (s, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.52-7.48 (m, 1H), 7.05-6.99 (m, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.07-3.01 (m, 1H), 2.69-2.60 (m, 1H), 2.50-2.44 (m, 1H), 2.31-2.12 (m, 4H), 1.94-1.91 (m, 1H), 1.91-1.80 (m, 4H), 1.75-1.50 (m, 9H), 0.91 (d, J=6.4 Hz, 6H) (5 protons unknown). LC / MS analysis (Method 1): Purity: 97.7%; Observational quality: 516.90; Holding time: 1.59 min. (Method 2): Purity: 96.1%; Observational quality: 517.24; Holding time: 1.09 min. The compound of Example 19 (3.6 mg, 0.0070 mmol, 12% yield) was dissolved in the second phase and the opposite body was separated. 1 H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.20-8.16 (m, 1H), 7.56-7.53 (m, 1H), 7.52-7.47 (m, 1H), 7.02 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.27-3.20 (m, 1H), 3.11-3.05 (m, 2H), 2.57 (s, 3H), 2.49-2.43 (m, 1H), 2.42-2.36 (m, 1H), 2.04-1.98 (m, 2H), 1.97-1.92 (m, 2H), 1.88-1.80 (m, 6H), 1.78–1.72 (m, 2H), 1.70–1.57 (m, 5H), 0.89 (d, J=6.4 Hz, 6H) (1 proton unknown). Analytical LC / MS (Method 1): Purity: 98.9%; Observational quality: 517.01; Holding time: 1.69 min. (Method 2): Purity: 100%; Observational quality: 517.33; Holding time: 1.1 min.

[0222] Example 20および21 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] The compounds of Examples 20 and 21 were synthesized according to the general method described for the synthesis of Examples 18 and 19, using Intermediate 18A (40 mg, 0.058 mmol) as the starting material, substituting cyclopropanecarbaldehyde (20 mg, 0.29 mmol) as needed. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 13% B at 0 min hold, 13–53% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was initiated by MS signal. Fractions containing each desired product were combined and dried by centrifugal evaporation. Example 20 (7.5 mg, 0.015 mmol, 26% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 8.01-7.97 (m, 1H), 7.36 (s, 1H), 7.35-7.30 (m, 1H), 6.85 (s, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 2.88-2.78 (m, 2H), 2.58-2.46 (m, 1H), 2.31-2.19 (m, 3H), 2.09-2.00 (m, 2H), 1.75 (s, 3H), 1.70-1.62 (m, 2H), 1.45 (br d, J=8.9 Hz, 8H), 1.21-1.03 (m, 1H), 0.79–0.68 (m, 1H), 0.33 (br d, J=7.0 Hz, 2H), 0.01 (br d, J=4.3 Hz, 2H) (3 protons unknown). LC / MS analysis (Method 1): Purity: 95.9%; Observational quality: 514.94; Holding time: 1.52 min. (Method 2): Purity: 96.2%; Observational quality: 514.33; Holding time: 1.08 min. The compound of Example 21 (4.1 mg, 0.0080 mmol, 14% yield) was dissolved in 2 times and the opposite body was separated. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 8.02-7.97 (m, 1H), 7.36 (s, 1H), 7.35-7.31 (m, 1H), 6.85 (s, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 2.87-2.79 (m, 2H), 2.57-2.46 (m, 1H), 2.33-2.20 (m, 3H), 2.09-2.00 (m, 2H), 1.75 (s, 3H), 1.69-1.61 (m, 2H), 1.45 (br d, J=8.9 Hz, 8H), 0.79-0.69 (m, 1H), 0.37-0.28 (m, 2H), 0.05-0.03 (m, 2H) (4 protons unknown). Analytical LC / MS (Method 1): Purity: 100%; Observational quality: 515.25; Holding time: 1.74 min. (Method 2): Purity: 96.1%; Observational quality: 515.41; Holding time: 1.08 min.

[0223] Example 22 2-(3,4-Dimethoxyphenyl)-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methylimidazo[1,2-a]pyridine [ka] The compounds of Examples 22 and 23 were synthesized according to the general method described for the synthesis of Examples 18 and 19, using Intermediate 18A (40 mg, 0.058 mmol) as the starting material, substituting propan-2-one (17 mg, 0.29 mmol) as needed. The crude isomeric mixture was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 15% B at 0 min hold, 15–60% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was initiated by the MS signal. Fractions containing each desired product were combined and dried by centrifugal evaporation. Example 22 (5.3 mg, 0.011 mmol, 19% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 8.18-8.14 (m, 1H), 7.56-7.53 (m, 1H), 7.52-7.48 (m, 1H), 7.02 (br d, J=1.2 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.05-2.97 (m, 2H), 2.86-2.77 (m, 1H), 2.70-2.61 (m, 1H), 2.58-2.56 (m, 1H), 2.50-2.41 (m, 1H), 2.24-2.13 (m, 2H), 1.95-1.90 (m, 1H), 1.87-1.78 (m, 4H), 1.73-1.53 ​​(m, 6H), 1.52-1.45 (m, 2H), 1.05 (br d, J=5.8 Hz, 6H) (3 protons unknown). LC / MS analysis (Method 1): Purity: 100%; Observational quality: 503.18; Holding time: 1.39 min. (Method 2): Purity: 100%; Observational quality: 503.21; Holding time: 1.00 min. The compound of Example 23 (2.6 mg, 0.0052 mmol, 9.0% yield) was dissolved in 2 times and the opposite body was separated. 1 H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.20-8.17 (m, 1H), 7.57-7.52 (m, 1H), 7.52-7.47 (m, 1H), 7.05-7.00 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.35-3.24 (m, 1H), 2.72-2.62 (m, 1H), 2.49-2.43 (m, 1H), 2.40-2.32 (m, 1H), 1.92 (br s, 13H), 1.70-1.60 (m, 2H), 1.04 (br d, J=5.8 Hz, 6H) (Proton 5 unknown). LC / MS analysis (Method 1): Purity: 97%; Observational quality: 502.90; Holding time: 1.65 min. (Method 2): Purity: 98.6%; Observational quality: 503.16; Holding time: 1.07 min.

[0224] Example 24 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine (mixture of isomers) [ka] Step A. Intermediate 24A. Preparation of tert-butyl 3-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridin-6-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate [ka] To a 40 mL vial was added Intermediate 1A (260 mg, 0.75 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (250 mg, 0.75 mmol), XPhos Pd G3, 95% (63 mg, 0.075 mmol), 1,4-dioxane (15 mL), followed by potassium phosphate tribasic (550 mg, 2.6 mmol) dissolved in water (3 mL). The vessel was flushed with N2, capped, and the reaction mixture was stirred at 85 °C. After 18 h, the reaction mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (2 × 50 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 80 mL / min). Pure fractions were combined, concentrated, and dried under reduced pressure to give the title compound (270 mg, 0.56 mmol, 75% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 8.27 (s, 1H), 8.06 (s, 1H), 7.60 (s, 1H), 7.52-7.45 (m, 1H), 7.30 (s, 1H), 7.08-7.01 (m, 1H), 6.65-6.57 (m, 1H), 4.57-4.53 (m, 1H), 4.53-4.48 (m, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.16-3.03 (m, 1H), 2.62 (s, 3H), 2.38-2.22 (m, 2H), 2.10-2.00 (m, 2H), 1.86-1.75 (m, 1H), 1.49 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 476.4; Retention time: 0.88 min

[0225] Step B. Intermediate 24B. Preparation of 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine Hydrochloride [ka] To a 100 mL recovery flask was added Intermediate 24A (270 mg, 0.57 mmol) and MeOH (30 mL). The vessel was evacuated and purged with N2, then Pd-C (10% on carbon) (60 mg, 0.057 mmol) was added, and the reaction mixture was stirred under 1 atmosphere of hydrogen. After 18 h, the catalyst was filtered, and to the filtrate was added 4 M HCl in dioxane (30 mL). After stirring for 30 min, the solvent was concentrated, the residue was coevaporated with toluene (2x), and the product was dried under reduced pressure to give the title compound (230 mg, 0.56 mmol, 98% yield) as a tan solid. 1H NMR (500 MHz, methanol-d4) δ 8.83-8.59 (m, 1H), 8.46 (s, 1H), 7.80 (s, 1H), 7.56 (s, 2H), 7.21-7.15 (m, 1H), 4.25-4.14 (m, 2H), 3.98 Analytical LC / MS (Method 5): Observed mass: 378.3; Retention time: 0.58 min

[0226] Step C. Preparation of the compound of Example 24 To a 40 mL vial was added Intermediate 24B (70 mg, 0.16 mmol), 1-cyclopropylpiperidin-4-one (110 mg, 0.79 mmol), AcOH (10 mg, 0.17 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, partitioned into 10% NaOH (20 mL), and extracted with 10% IPA / chloroform (3 × 10 mL). The organic phases were combined, dried over NaSO, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (57 mg, 0.11 mmol, 69% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.01-7.94 (m, 2H), 7.32-7.22 (m, 2H), 6.83-6.75 (m, 2H), 3.62 (s, 3H), 3.56 (s, 3H), 2.82-2.66 (m, 3H), 2.66-2.58 (m, 1H), 2.24-2.15 (m, 1H), 2.11-2.02 (m, 1H), 2.02-1.90 (m, 2H), 1.58 (br s, 9H), 1.50-1.30 (m, 4H), 1.29-1.20 (m, 1H), 1.15-1.01 (m, 2H), 0.23-0.14 (m, 2H), 0.10-0.02 (m, 2H). Analytical LC / MS (Method 1): Purity: 98.9 %; Observed mass: 501.17; Retention time: 1.52 min. (Method 2): Purity: 100 %; Observed mass: 500.96; Retention time: 1.16 minutes

[0227] Examples 25 and 26 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine [ka] The individual isomers, Example 25 and Example 26, were obtained by separation of the isomeric mixture, Example 24 (21 mg, 0.041 mmol), under the following conditions: Apparatus: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% IPA w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 600 μL 21 mg dissolved in 3 mL MeOH. Example 25 (5.6 mg, 0.011, 27% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.94-7.90 (m, 1H), 7.30-7.26 (m, 1H), 7.25-7.19 (m, 1H), 6.76 (br s, 2H), 3.60 (s, 3H), 3.54 (s, 3H), 3.36-3.19 (m, 1H), 2.76-2.62 (m, 3H), 1.98-1.89 (m, 2H), 1.67-1.52 (m, 6H), 1.51-1.42 (m, 2H), 1.35-1.25 (m, 3H), 1.07-0.95 (m, 2H), 0.17-0.11 (m, 2H), 0.07-0.00 (m, 2H) (5 protons obscured). Analytical LC / MS (Method 1): Purity: 99.3 %; Observed mass: 501.21; Retention time: 1.46 min. (Method 2): Purity: 100 %; Observed mass: 500.98; Retention time: 1.01 min. Chiral analysis (SFC method 4): Chiral purity > 95 %. Retention time: 2.2 min Example 26 (4.1 mg, 0.0082 mmol, 20% yield) was isolated as the second eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.42-8.35 (m, 1H), 8.21 (s, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.48 (dd, J=8.2, 1.8 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J=8.5 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.13-3.01 (m, 1H), 3.00-2.89 (m, 2H), 2.51 (dd, J=3.8, 1.9 Hz, 6H), 2.43-2.30 (m, 2H), 2.24-2.13 (m, 2H), 1.93-1.82 (m, 5H), 1.62-1.49 (m, 4H), 1.46-1.33 (m, 2H), 0.43-0.38 (m, 2H), 0.32-0.28 (m, 2H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 500.93; Retention time: 1.46 min. (Method 2): Purity: 98.6 %; Observed mass: 500.96; Retention time: 0.99 min. Chiral analysis (SFC method 4): Chiral purity > 95 %. Retention time: 4.2 min

[0228] Example 27 2-(3,4-Dimethoxyphenyl)-6-(8-(1-isobutylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methylimidazo[1,2-a]pyridine (mixture of isomers) [ka] Example 27 was prepared according to the general method described in the synthesis of Example 24 (Step C), using Intermediate 24C (70 mg, 0.16 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (76 mg, 0.15 mmol, 94% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(s, 2H), 7.55-7.52 (m, 1H), 7.51-7.46 (m, 1H), 7.07-6.99 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.69-3.62 (m, 1H), 3.05-2.94 (m, 1H), 2.88-2.79 (m, 2H), 2.56 (s, 4H), 2.33-2.23 (m, 1H), 2.06-2.01 (m, 2H), 1.89-1.72 (m, 6H), 1.66-1.55 (m, 2H), 1.49-1.30 (m, 3H), 0.88-0.85 (m, 6H) (4 protons obscured). Analytical LC / MS (Method 1): Purity: 97.9 %; Observed mass: 516.97; Retention time: 1.59 min. (Method 2): Purity: 100 %; Observed mass: 516.96; Holding time: 1.1 minutes

[0229] Examples 28 and 29 2-(3,4-Dimethoxyphenyl)-6-(8-(1-isobutylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methylimidazo[1,2-a]pyridine [ka] The individual isomers, Example 28 and Example 29, were obtained by separation of the isomeric mixture, Example 27 (50 mg, 0.097 mmol), under the following conditions: Apparatus: Berger SFC; Column: OD 30 x 250 mm ID, 5 μm; Temperature: 40°C; Flow rate: 85.0 mL / min; Mobile phase: 75 / 25 CO2 / EtOH-0.1% DEA; Detection wavelength: 220 nm; Injection volume: 500 μL; Sample preparation: Dissolve 50 mg of sample in 3 mL MeOH. Example 28 (22 mg, 0.043 mmol, 44% yield) was isolated as the first eluting isomer. 1H NMR (400 MHz, methanol-d4) δ 8.12-8.07 (m, 1H), 8.01 (s, 1H), 7.61-7.58 (m, 1H), 7.49-7.44 (m, 1H), 7.09-7.05 (m, 1H), 7.04-6.98 (m, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.69-3.61 (m, 2H), 3.35-3.32 (m, 1H), 3.05-2.89 (m, 3H), 2.59 (s, 3H), 2.56-2.49 (m, 1H), 2.11 (s, 2H), 2.05-1.89 (m, Analytical LC / MS (Method 3): Purity: 96.9 %; Observed mass: 517.55; Retention time: 2.27 min. (Method 4): Purity: 98.0 %; Observed mass: 517.20; Retention time: 1.25 min. Chiral analysis (SFC method 5): Chiral purity > 99 %. Retention time: 11.58 min Example 29 (12 mg, 0.010 mmol, 23% yield) was isolated as the second eluting isomer. 1H NMR (400 MHz, methanol-d4) δ 8.42-8.37 (m, 1H), 8.08-8.05 (m, 1H), 7.62-7.59 (m, 1H), 7.52-7.46 (m, 1H), 7.19-7.15 (m, 1H), 7.07-7.02 (m, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.68-3.64 (m, 1H), 3.52-3.48 (m, 1H), 3.40-3.36 (m, 1H), 3.17-3.05 (m, 4H), 2.63 (s, 3H), 2.54-2.44 (m, 4H), 2.39-2.35 (m, 1H), 2.12-2.01 (m, 6H), 1.78-1.64 (m, 5H), 0.98-0.97 (m, 3H), 0.97-0.95 (m, 3H). Analytical LC / MS (method 3): Purity: 98.5 %; Observed mass: 517.50; Retention time: 2.28 min. (Method 4): Purity: 96.1 %; Observed mass: 517.20; Retention time: 1.18 min. Chiral analysis (SFC method 5): Chiral purity > 99 %. Retention time: 19.81 min

[0230] Example 30 2-(3,4-Dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methylimidazo[1,2-a]pyridine (mixture of isomers) [ka] Example 30 was prepared according to the general method described in the synthesis of Example 24 (Step C), using Intermediate 24C (70 mg, 0.16 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (44 mg, 0.088 mmol, 55% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.23-8.18 (m, 2H), 7.56-7.52 (m, 1H), 7.51-7.47 (m, 1H), 7.05-6.99 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.62-3.40 (m, 1H), 3.02-2.91 (m, 1H), 2.88-2.80 (m, 2H), 2.76-2.67 (m, 1H), 2.56 (s, 3H), 2.49-2.40 (m, 1H), 2.24-2.16 (m, 2H), 1.91-1.70 (m, 8H), 1.59-1.51 (m, 2H), 1.38-1.29 (m, 2H), 0.99 (s, 6H) (1 proton obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 502.90; Retention time: 1.41 min. (Method 2): Purity: 100 %; Observed mass: 502.96; Retention time: 1.08 minutes

[0231] Example 31 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Step A. Intermediate 31A. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate [ka] To a 100 mL recovery flask was added Intermediate 10B (2.5 g, 5.7 mmol) and MeOH (350 mL). The vessel was evacuated and purged with N2, then Pd-C (10% on carbon) (1.2 g, 0.57 mmol) was added, and the reaction mixture was stirred under 1 atmosphere of hydrogen. After stirring for 96 h, the catalyst was filtered, and the filtrate was concentrated. The crude residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 10% B; flow rate = 80 mL / min). Pure fractions were combined, concentrated, and dried under reduced pressure to give the title compound (2.1 g, 4.8 mmol, 84% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 7.34 (d, J=1.9 Hz, 1H), 7.26-7.23 (m, 1H), 7.22 (s, 1H), 6.97-6.93 (m, 1H), 4.20-4.13 (m, 3H), 3.90 (s, 3H), 3.85 (s, 3H), 3.79-3.71 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.72 (m, 3H), 2.24-2.15 (m, 1H), 1.93-1.85 (m, 2H), 1.83-1.75 (m, 1H), 1.71-1.54 (m, 2H), 1.49-1.46 (m, 9H), 1.34-1.24 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 442.5; Retention time: 0.78 min

[0232] Step B. Intermediate 31B. Preparation of 2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine hydrochloride [ka] To a 200 mL recovery flask was added Intermediate 31A (2.1 g, 4.8 mmol), THF (10 mL), and 4 M HCl in dioxane (20 mL). After stirring for 18 h, the solvent was concentrated and the residue was co-evaporated with toluene. The product was dried under reduced pressure to give the title compound (1.8 g, 4.8 mmol, 100% yield) as a light tan solid. 1 H NMR (500 MHz, methanol-d4) δ 7.70 (s, 1H), 7.27-7.26 (m, 1H), 7.30-7.26 (m, 1H), 7.11-7.08 (m, 1H), 4.43-4.37 (m, 1H), 4.01-3.94 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.63-3.58 (m, 4H), 3.53-3.47 (m, 2H), 3.30-3.26 (m, 1H), 3.25-3.22 (m, 1H), 3.11-3.03 (m, 3H), 2.34-2.27 (m, 1H), 2.19-2.04 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 342.4; Retention time: 0.50 min

[0233] Step C. Preparation of the compound of Example 31 To a 40 mL vial was added Intermediate 31B (120 mg, 0.27 mmol), 1-isobutylpiperidin-4-one (220 mg, 1.4 mmol), AcOH (0.017 mL, 0.3 mmol), magnesium sulfate (490 mg, 4.1 mmol), and DMF (5 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (170 mg, 0.81 mmol) was added and the reaction mixture was stirred. After 24 hours, the reaction mixture was filtered, and the filter cake was washed with 10% IPA / chloroform (20 mL). The filtrate was washed with 10% aqueous NaOH (10 mL), brine, dried over MgSO, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (69 mg, 0.14 mmol, 52% yield). Analytical LC / MS (Method 1): Purity: 96.8 %; Observed mass: 481.23; Retention time: 1.38 min (Method 2): Purity: 97.6 %; Observed mass: 481.22; Retention time: 0.91 min

[0234] Examples 32 and 33 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The individual enantiomers, Example 32 and Example 33, were obtained by separation of the racemic mixture, Example 31 (68 mg, 0.14 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 1000 μL 68 mg dissolved in 3 mL MeOH. Example 32 (21 mg, 0.044 mmol, 31% yield) was isolated as the first eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.58-7.48 (m, 1H), 7.34-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.00-6.93 (m, 1H), 4.18-4.09 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.00-2.89 (m, 9H), 2.84-2.76 (m, 1H), 2.05 (br s, 4H), 1.89 (br s, 5H), 1.68-1.45 (m, 5H), 0.93-0.89 (m, 6H) (3 protons ambiguous). Analytical LC / MS (Method 1): Purity: 98.2%; Observed Mass: 481.18; Retention Time: 1.38 min. (Method 2): Purity: 97.1%; Observed Mass: 480.98; Retention Time: 1.05 min. Chiral Analysis (SFC Method 1): Chiral purity > 95%. Retention Time: 1.89 min. Example 33 (11 mg, 0.023 mmol, 16% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.35 (s, 1H), 7.30 (d, J=1.2 Hz, 1H), 7.21 (s, 1H), 6.92 (d, J=8.2 Hz, 1H), 4.11-4.01 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.69-3.60 (m, 1H), 3.05-2.98 (m, 2H), 2.91-2.83 (m, 3H), 2.72-2.63 (m, 1H), 2.40-2.30 (m, 1H), 2.28-2.18 (m, 2H), 2.09-1.99 (m, 3H), 1.92-1.81 (m, 3H), 1.79-1.68 (m, 5H), 1.59-1.43 (m, 3H), 1.38-1.24 (m, 3H), 0.85 (d, J=6.4 Hz, 6H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 481.17; Retention time: 1.38 min. (Method 2): Purity: 97.2 %; Observed mass: 481.01; Retention time: 1.05 min. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 5.19 min

[0235] Example 34 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Example 34 was prepared according to the general method described in the synthesis of Example 31 (Step C), using Intermediate 31B (120 mg, 0.27 mmol) as the starting material, substituting 1-isopropylpiperidin-4-one (190 mg, 1.3 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (70 mg, 0.15 mmol, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.30 (d, J=1.8 Hz, 1H), 7.21 (dd, J=8.2, 1.8 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 4.09-4.01 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.70-3.59 (m, 1H), 2.95-2.86 (m, 2H), 2.86-2.79 (m, 2H), 2.73-2.61 (m, 2H), 2.19-2.13 (m, 1H), 2.08 (br s, 5H), 1.80-1.64 (m, 5H), 1.58-1.47 (m, 1H), 1.45-1.34 (m, 2H), 1.32-1.18 (m, 3H), 0.96 (d, J=6.7 Hz, 6H) (1 proton obscured). Analytical LC / MS (method 1): Purity: 90.7 %; Observed mass: 467.13; Retention time: 1.2 min. (Method 2): Purity: 95.1 %; Observed mass: 467.65; Retention time: 0.64 min

[0236] Examples 35 and 36 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The individual enantiomers, Example 35 and Example 36, were obtained by separation of the racemic mixture, Example 34 (26 mg, 0.056 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 1000 μL 26 mg dissolved in 3 mL MeOH. Example 35 (6.4 mg, 0.014 mmol, 25% yield) was isolated as the first eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.32 (s, 1H), 7.29 (d, J=1.7 Hz, 1H), 7.19 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.08-3.98 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 2.94-2.88 (m, 2H), 2.87-2.79 (m, 3H), 2.73-2.60 (m, 2H), 2.21-1.98 (m, 6H), 1.79-1.70 (m, 4H), 1.69-1.61 (m, 1H), 1.57-1.46 (m, 1H), 1.45-1.34 (m, 2H), 1.33-1.19 (m, 3H), 0.95 (d, J=6.5 Hz, 6H) (1 proton obscured). Analytical LC / MS (Method 1): Purity: 97.7 %; Observed mass: 467.21; Retention time: 1.25 min. (Method 2): Purity: 100 %; Observed mass: 467.19; Retention time: 0.97 min. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 1.85 min Example 36 (7.4 mg, 0.016 mmol, 29% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.30 (s, 1H), 7.23-7.18 (m, 1H), 6.94-6.89 (m, 1H), 4.10-4.02 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.71-3.61 (m, 1H), 2.98-2.86 (m, 4H), 2.80-2.71 (m, 1H), 2.70-2.61 (m, 1H), 2.29-2.08 (m, 6H), 2.07-2.00 (m, 1H), 1.83-1.65 (m, 5H), 1.57-1.39 (m, 3H), 1.36-1.21 (m, 3H), 1.01-0.98 (m, 6H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 467.21; Retention time: 1.25 min. (Method 2): Purity: 98.4 %; Observed mass: 467.19; Retention time: 0.97 min. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 3.68 min

[0237] Examples 37 and 38 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The racemic mixture was prepared according to the general method described for the synthesis of Example 31 (Step C), using Intermediate 31B (300 mg, 0.62 mmol) as the starting material, substituting 1-cyclopropylpiperidin-4-one (430 mg, 3.1 mmol) as needed. The crude material was purified by preparative HPLC (Preparative Method 1) to give the racemic mixture (65 mg, 0.14 mmol, 23% yield).

[0238] The individual enantiomers, Example 37 and Example 38, were obtained by separation of the racemic mixture (65 mg, 0.14 mmol) under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral AD, 30 x 250 mm. 5 micron; Mobile phase: 60% CO2 / 40% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 1200 μL 65 mg dissolved in 3 mL MeOH. Example 37 (25 mg, 0.054 mmol, 39% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.08 (s, 1H), 7.04 (d, J=1.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.66 (s, 1H), 3.82-3.77 (m, 1H), 3.53 (s, 3H), 3.49 (s, 3H), 3.43-3.36 (m, 1H), 2.75-2.69 (m, 3H), 2.63-2.57 (m, 1H), 2.45-2.36 (m, 1H), 2.15-2.04 (m, 1H), 2.02-1.91 (m, 2H), 1.91-1.81 (m, 2H), 1.81-1.74 (m, 1H), 1.57-1.42 (m, 5H), 1.34-1.23 (m, 2H), 1.19-0.96 (m, 6H), 0.17-0.11 (m, 2H), 0.05--0.03 (m, 2H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 465.28; Retention time: 1.37 min. (Method 2): Purity: 100 %; Observed mass: 465.28; Retention time: 0.95 min. Chiral analysis (SFC method 2): Chiral purity > 95 %. Retention time: 3.60 min Example 38 (23 mg, 0.043 mmol, 31% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.08 (s, 1H), 7.04 (d, J=1.9 Hz, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J=8.5 Hz, 1H), 3.84-3.76 (m, 1H), 3.53 (s, 3H), 3.49 (s, 3H), 3.43-3.34 (m, 1H), 2.77-2.68 (m, 4H), 2.65-2.56 (m, 1H), 2.45-2.36 (m, 1H), 2.15-2.05 (m, 1H), 2.01-1.91 (m, 2H), 1.90-1.82 (m, 2H), 1.81-1.74 (m, 1H), 1.57-1.42 (m, 5H), 1.34-1.24 (m, 2H), 1.18-0.98 (m, 5H), 0.17-0.11 (m, 2H), 0.04--0.02 (m, 2H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 465.29; Retention time: 1.37 min. (Method 2): Purity: 87.7 %; Observed mass: 465.29; Retention time: 0.95 min. Chiral analysis (SFC Method 2): Chiral purity > 95 %. Retention time: 5.58 min

[0239] Example 39 1-(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)-2-methylpropan-1-one (racemic mixture) [ka] Step A. Intermediate 39A. Preparation of 6-([1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride [ka] To a 40 mL vial was added Intermediate 31B (600 mg, 1.6 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (950 mg, 4.8 mmol), AcOH (0.10 mL, 1.7 mmol), magnesium sulfate (2900 mg, 24 mmol), and DMF (15 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (1000 mg, 4.8 mmol) was added and the reaction mixture was stirred. After 24 hours, the reaction mixture was filtered, and the filter cake was washed with 10% MeOH / DCM (20 mL). The filtrate was concentrated, and the crude product was purified by flash column chromatography (100 g reverse-phase C18 GOLD silica gel cartridge; A = water:MeCN:TFA 90:10:0.05%, B = water:MeCN:TFA 10:90:0.05%; 20 min gradient; 0% B to 400% B; flow rate = 60 mL / min). Pure fractions were combined and concentrated. The resulting residue was dissolved in THF (20 mL) and 4 M HCl in dioxane (20 mL) and stirred. After 3 h, the solvent was concentrated, the residue co-evaporated with toluene, and the product was dried under reduced pressure to give the title compound (790 mg, 1.6 mmol, 100% yield) as a yellow solid. Analytical LC / MS (Method 5): Observed mass: 425.4; Retention time: 0.48 min

[0240] Step B. Preparation of the compound of Example 39 To a 40 mL vial was added Intermediate 39A (200 mg, 0.22 mmol), isobutyric acid (39 mg, 0.44 mmol), TEA (0.062 mL, 0.44 mmol), HOBt (85 mg, 0.44 mmol), and DMF (2 mL). To this mixture was added EDC (85 mg, 0.44 mmol), the vial was capped, and the reaction mixture was stirred. After 18 h, the crude reaction mixture was purified by preparative HPLC (Preparative Method 2) to give the title compound (30 mg, 0.061 mmol, 28% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.36 (s, 2H), 7.11 (br d, J=8.5 Hz, 1H), 4.62-4.52 (m, 1H), 4.29-4.21 (m, 1H), 4.17-4.08 (m, 1H), 3.92-3.87 (m, 1H), 3.86-3.83 (m, 3H), 3.83-3.80 (m, 3H), 3.58-3.50 (m, 1H), 3.20-2.86 (m, 6H), 2.14-2.02 (m, 4H), 1.99-1.91 (m, 2H), 1.74-1.38 (m, 7H), 1.04-0.99 (m, 6H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 98.6 %; Observed mass: 495.19; Retention time: 1.25 min. (Method 2): Purity: 98.8 %; Observed mass: 495.16; Retention time: 1.05 minutes

[0241] Examples 40 and 41 1-(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)-2-methylpropan-1-one [ka] The individual enantiomers, Example 40 and Example 41, were obtained by separation of the racemic mixture, Example 39 (14 mg, 0.028 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH-ACN-50-50; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 2000 μL 14 mg dissolved in 3 mL MeOH. Example 40 (3.7 mg, 0.0075 mmol, 27% yield) was isolated as the first eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.30 (s, 1H), 7.24-7.19 (m, 1H), 6.94-6.89 (m, 1H), 4.49-4.38 (m, 1H), 4.09-4.03 (m, 1H), 4.01-3.93 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.70-3.61 (m, 1H), 3.04-2.90 (m, 3H), 2.90-2.82 (m, 2H), 2.72-2.60 (m, 1H), 2.22-2.13 (m, 2H), 2.07-2.01 (m, 1H), 1.85-1.72 (m, 4H), 1.71-1.65 (m, 1H), 1.59-1.48 (m, 1H), 1.39-1.17 (m, 6H), 0.99 (br s, 6H) (1 proton unclear). Analytical LC / MS (Method 1): Purity: 95.3 %; Observed mass: 495.15; Retention time: 1.28 min. (Method 2): Purity: 97.2 %; Observed mass: 495.13; Retention time: 1.06 min. Chiral analysis (SFC Method 1): Chiral purity > 95 %. Retention time: 1.25 minutes Example 41 (3.8 mg, 0.0077 mmol, 28% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.36-7.33 (m, 1H), 7.32-7.29 (m, 1H), 7.24-7.19 (m, 1H), 6.94-6.89 (m, 1H), 4.47-4.39 (m, 1H), 4.10-4.02 (m, 1H), 4.00-3.93 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.69-3.61 (m, 1H), 3.54-3.44 (m, 1H), 3.02-2.94 (m, 1H), 2.94-2.83 (m, 4H), 2.72-2.60 (m, 1H), 2.50-2.43 (m, 2H), 2.07-2.00 (m, 1H), 1.84-1.71 (m, 4H), 1.70-1.65 (m, 1H), 1.57-1.48 (m, 1H), 1.36-1.14 (m, 6H), 0.99 (br t, J=7.2 Hz, 6H). Analytical LC / MS (Method 1): Purity: 96 %; Observed mass: 495.16; Retention time: 1.28 min. (Method 2): Purity: 96.7 %; Observed mass: 495.12; Retention time: 1.06 min. Chiral analysis (SFC Method 1): Chiral purity > 95 %. Retention time: 3.40 minutes

[0242] Example 42 Cyclopropyl(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)methanone (racemic mixture) [ka] To a 40 mL vial was added Intermediate 39A (200 mg, 0.22 mmol), TEA (0.34 mL, 2.4 mmol), DMAP (98 mg, 0.80 mmol), and DCM (2 mL). To this mixture was added cyclopropanecarbonyl chloride (0.073 mL, 0.80 mmol), the vial was capped, and the reaction mixture was stirred. After 2 h, the solvent was concentrated, and the crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (59 mg, 0.12 mmol, 55% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.34-7.32 (m, 1H), 7.30-7.28 (m, 1H), 7.22-7.18 (m, 1H), 6.92-6.88 (m, 1H), 4.45-4.35 (m, 1H), 4.33-4.24 (m, 1H), 4.09-4.01 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.09-2.94 (m, 3H), 2.91-2.81 (m, 1H), 2.72-2.60 (m, 2H), 2.30-2.18 (m, 2H), 2.07-2.00 (m, Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 493.08; Retention time: 1.14 min. (Method 2): Purity: 100 %; Observed mass: 493.28; Retention time: 1.02 min

[0243] Examples 43 and 44 Cyclopropyl(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)-[1,4'-bipiperidin]-1'-yl)methanone [ka] The individual enantiomers, Example 43 and Example 44, were obtained by separation of the racemic mixture, Example 42 (59 mg, 0.12 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 75% CO2 / 25% IPA-ACN 50-50 w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 1000 μL 59 mg dissolved in 3 mL MeOH. Example 43 (21 mg, 0.043 mmol, 36% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.30 (s, 1H), 7.21 (br d, J=8.2 Hz, 1H), 6.91 (br d, J=8.2 Hz, 1H), 4.42-4.33 (m, 1H), 4.32-4.24 (m, 1H), 4.10-4.02 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.68-3.57 (m, 2H), 3.46-3.37 (m, 1H), 3.09-2.98 (m, 1H), 2.94-2.81 (m, 3H), 2.70-2.60 (m, 1H), 2.11 (br d, J=2.7 Hz, 3H), 2.07-2.01 (m, 1H), 1.99-1.92 (m, 2H), 1.84-1.62 (m, 2H), 1.59-1.47 (m, 2H), 1.29-1.23 (m, 2H), 1.19 (br s, 3H), 0.70 (br d, J=6.7 Hz, 4H). Analytical LC / MS (Method 1): Purity: 95.4 %; Observed mass: 493.14; Retention time: 1.24 min. (Method 2): Purity: 97.3 %; Observed mass: 493.13; Retention time: 1.03 min. Chiral analysis (SFC method 3): Chiral purity > 95 %. Retention time: 5.99 minutes Example 44 (22 mg, 0.0045 mmol, 38% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.30 (s, 1H), 7.21 (br d, J=7.9 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.43-4.34 (m, 1H), 4.33-4.23 (m, 1H), 4.09-4.01 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.59-3.53 (m, 1H), 3.47-3.36 (m, 1H), 3.09-2.99 (m, 1H), 2.96-2.90 (m, 2H), 2.89-2.83 (m, 1H), 2.70-2.61 (m, 1H), 2.16 (s, 2H), 2.08-2.01 (m, 2H), 1.99-1.93 (m, 2H), 1.86-1.66 (m, 4H), 1.56-1.49 (m, 1H), 1.27 (br s, 2H), 1.22-1.10 (m, 3H), 0.73-0.68 (m, 4H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 493.34; Retention time: 1.24 min. (Method 2): Purity: 95.9 %; Observed mass: 493.13; Retention time: 1.04 min. Chiral analysis (SFC method 3): Chiral purity > 95 %. Retention time: 7.30 minutes

[0244] Example 45 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Step A. Intermediate 45A. Preparation of 6-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine bis(2,2,2-trifluoroacetate) [ka] A 250 mL round-bottom flask was charged with Intermediate 31A (1.0 g, 2.7 mmol), tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.7 g, 7.9 mmol), AcOH (0.17 mL, 2.9 mmol), magnesium sulfate (4.8 g, 40 mmol), and DMF (20 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (1.7 g, 7.9 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with DCM / MeOH, and the filtrate was concentrated. The remaining crude DMF solution was purified by flash column chromatography (275 g reverse-phase C18 GOLD silica gel cartridge; A = water:MeCN:TFA 90:10:0.05%, B = water:MeCN:TFA 10:90:0.05%; 20 min gradient; 10% B to 100% B; flow rate = 125 mL / min). Pure fractions were combined and concentrated. The resulting residue was dissolved in DCM (20 mL) and TFA (20 mL). After stirring for 2 h, the solvent was concentrated under reduced pressure at 35 °C, the residue was co-evaporated with toluene, and the product was dried under reduced pressure to give the title compound (1.3 g, 2.0 mmol, 74% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 7.69-7.66 (m, 1H), 7.27 (s, 2H), 7.11-7.07 (m, 1H), 4.40-4.33 (m, 1H), 3.98-3.94 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.67-3.54 (m, 3H), 3.28-3.20 (m, 1H), 3.10-3.01 (m, 1H), 2.82-2.75 (m, 3H), 2.70-2.61 (m, 3H), 2.32-2.25 (m, 1H), 2.16-2.06 (m, 3H), 1.85-1.66 (m, 4H). Analytical LC / MS (Method 5): Observed mass: 437.5; Retention time: 0.58 min

[0245] Step B. Preparation of the compound of Example 45 To a 40 mL vial was added Intermediate 45A (320 mg, 0.48 mmol), acetone (140 mg, 2.4 mmol), AcOH (0.030 mL, 0.53 mmol), magnesium sulfate (870 mg, 7.2 mmol), and DMF (5 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (310 mg, 1.5 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with 10% MeOH / DCM, and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (180 mg, 0.21 mmol, 44% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.29 (d, J=1.7 Hz, 1H), 7.23-7.18 (m, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.09-4.01 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69-3.59 (m, 1H), 3.33-3.15 (m, 1H), 2.88-2.77 (m, 3H), 2.70-2.61 (m, 1H), 2.47-2.37 (m, 1H), 2.21-2.13 (m, 2H), 2.06-1.99 (m, 1H), 1.89-1.83 (m, 2H), 1.79-1.70 (m, 2H), 1.68-1.59 (m, 3H), 1.58-1.47 (m, 1H), 1.30-1.17 (m, 3H), 0.87 (d, J=6.1 Hz, 6H) (4 protons unclear). Analytical LC / MS: (Method 1): Purity: 95.4 %; Observed mass: 479.26; Retention time: 1.2 min. (Method 2): Purity: 97.5 %; Observed mass: 478.90; Retention time: 0.98 min

[0246] Examples 46 and 47 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The individual enantiomers, Example 46 and Example 47, were obtained by separation of the racemic mixture, Example 45 (130 mg, 0.27 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 300 μL 130 mg dissolved in 3 mL MeOH. Example 46 (59 mg, 0.12 mmol, 44% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.38-8.22 (m, 1H), 7.91-7.81 (m, 1H), 7.36-7.24 (m, 1H), 7.08 (br d, J=8.5 Hz, 1H), 4.27-4.19 (m, 1H), 4.15-4.04 (m, 2H), 4.02-3.94 (m, 1H), 3.88-3.84 (m, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.74-3.63 (m, 2H), 3.44-3.30 (m, 1H), 3.25-3.07 (m, 1H), 3.02-2.88 (m, 4H), 2.79-2.61 (m, 2H), 2.49-2.46 (m, 1H), 2.46-2.35 (m, 1H), 2.15-1.88 (m, 3H), 1.76-1.55 (m, 2H), 1.55-1.34 (m, 1H), 1.30-1.22 (m, 1H), 1.09 (br d, J=6.3 Hz, 6H) (2 protons ambiguous). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 479.26; Retention time: 1.29 min. (Method 2): Purity: 100 %; Observed mass: 478.94; Retention time: 0.94 min. Chiral analysis (SFC method 1): Chiral purity > 95%. Retention time: 1.41 min Example 47 (22 mg, 0.046 mmol, 17% yield) was isolated as the second eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.34-7.32 (m, 1H), 7.31-7.28 (m, 1H), 7.22-7.18 (m, 1H), 6.90 (d, J=8.5 Hz, 1H), 4.08-4.01 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.67-3.60 (m, 1H), 3.35-3.17 (m, 2H), 2.89-2.76 (m, 3H), 2.69-2.61 (m, 1H), 2.48-2.41 (m, 1H), 2.19-2.13 (m, 2H), 2.06-1.99 (m, 1H), 1.90-1.84 (m, 2H), 1.79-1.70 (m, 2H), 1.69-1.59 (m, 3H), 1.57-1.47 (m, 1H), 1.31-1.16 (m, 3H), 0.87 (br d, J=6.2 Hz, 6H) (3 protons ambiguous). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 479.26; Retention time: 1.29 (Method 2): Purity: 100 %; Observed mass: 479.26; Retention time: 0.94 min. Chiral analysis (SFC Method 1): Chiral purity > 95 %. Retention time: 4.05 minutes

[0247] Example 48 6-(1-(2-cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Example 48 was prepared according to the general method described for the synthesis of Example 45 (Step B), using Intermediate 45A (320 mg, 0.48 mmol) as the starting material, substituting cyclobutanone (170 mg, 2.4 mmol) where necessary. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (170 mg, 0.35 mmol, 73% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.37-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.23-7.18 (m, 1H), 6.92-6.88 (m, 1H), 4.15-4.02 (m, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.48-3.43 (m, 3H), 3.06-2.93 (m, 3H), 2.88-2.76 (m, 3H), 2.72-2.61 (m, 3H), 2.49-2.43 (m, 1H), 2.17-1.92 (m, 6H), 1.87-1.82 (m, Analytical LC / MS (Method 1): Purity: 93.6 %; Observed Mass: 491.22; Retention Time: 1.19 min. (Method 2): Purity: 96.3 %; Observed mass: 491.26; Retention time: 1.04 min

[0248] Examples 49 and 50 6-(1-(2-cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The individual enantiomers, Example 49 and Example 50, were obtained by separation of the racemic mixture, Example 48 (77 mg, 0.16 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 300 μL 77 mg dissolved in 3 mL MeOH. Example 49 (13 mg, 0.026 mmol, 16% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.34-7.31 (m, 1H), 7.30-7.27 (m, 1H), 7.22-7.17 (m, 1H), 6.92-6.88 (m, 1H), 4.07-4.00 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.11 (s, 2H), 3.00 (s, 3H), 2.89-2.82 (m, 1H), 2.81-2.75 (m, 2H), 2.70-2.59 (m, 1H), 2.49-2.44 (m, 1H), 2.16-2.10 (m, 2H), 2.05-1.97 (m, 1H), 1.89-1.80 (m, 4H), 1.77-1.47 (m, 11H), 1.30-1.15 (m, 3H). Analytical LC / MS (Method 1): Purity: 98.5 %; Observed mass: 491.19; Retention time: 1.31 min. (Method 2): Purity: 95.8 %; Observed mass: 491.21; Retention time: 0.99 min. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 1.80 min Example 50 (11 mg, 0.022 mmol, 14% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.33-7.31 (m, 1H), 7.30-7.27 (m, 1H), 7.21-7.17 (m, 1H), 6.91-6.88 (m, 1H), 4.07-4.01 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.72-3.68 (m, 2H), 3.61-3.60 (m, 1H), 3.03-2.99 (m, 1H), 2.87-2.82 (m, 1H), 2.80-2.73 (m, 2H), 2.69-2.59 (m, 1H), 2.49-2.43 (m, Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 491.10; Retention time: 1.32 min. (Method 2): Purity: 100 %; Observed mass: 491.19; Retention time: 0.98 min. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 5.30 min

[0249] Example 51 6-(1-(2-(cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Example 51 was prepared according to the general method described for the synthesis of Example 45 (Step B), using Intermediate 45A (320 mg, 0.48 mmol) as the starting material, substituting cyclopropanecarbaldehyde (170 mg, 2.4 mmol) as needed. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (190 mg, 0.39 mmol, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.27-7.25 (m, 1H), 7.24-7.21 (m, 1H), 7.16-7.11 (m, 1H), 6.86-6.81 (m, 1H), 4.00-3.94 (m, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.61-3.54 (m, 1H), 3.23-3.18 (m, 1H), 3.12-3.07 (m, 1H), 2.82-2.68 (m, 3H), 2.63-2.54 (m, 1H), 2.43-2.39 (m, 1H), 2.25-2.20 (m, 2H), 2.13-2.07 (m, 2H), 1.98-1.92 (m, 1H), 1.82-1.75 (m, 2H), 1.72-1.63 (m, 2H), 1.61-1.52 (m, 3H), 1.50-1.41 (m, 1H), 1.24-1.10 (m, 3H), 0.68-0.59 (m, 1H), 0.33-0.29 (m, 2H), 0.01 (br d, J=4.6 Hz, 2H) (2 protons obscured). Analytical LC / MS (method 1): Purity: 96.3 %; Observed mass: 491.20; Retention time: 1.2 min. (Method 2): Purity: 97.3 %; Observed mass: 491.19; retention time: 0.98 min

[0250] Example 52 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Example 52 was prepared according to the general method described for the synthesis of Example 45 (Step B), using Intermediate 45A (320 mg, 0.48 mmol) as the starting material, substituting isobutyraldehyde (170 mg, 2.4 mmol) as needed. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (190 mg, 0.39 mmol, 81% yield).1 H NMR (500 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.23-7.18 (m, 1H), 6.93-6.87 (m, 1H), 4.08-4.02 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.68-3.61 (m, 1H), 3.31-3.15 (m, 1H), 2.88-2.77 (m, 3H), 2.71-2.60 (m, 1H), 2.32-2.22 (m, 2H), 2.21-2.14 (m, 2H), 2.11-2.05 (m, 1H), 2.04-1.98 (m, 1H), 1.89-1.84 (m, 2H), 1.79-1.71 (m, 2H), 1.69-1.60 (m, 3H), 1.57-1.47 (m, 2H), 1.32-1.16 (m, 3H), 0.82 (d, J=6.6 Hz, 6H) (3 protons obscured). Analytical LC / MS (Method 1): Purity: 97.6 %; Observed mass: 493.20; Retention time: 1.24 min. (Method 2): Purity: 97.5 %; Observed mass: 493.22; Retention time: 0.99 min

[0251] Examples 53 and 54 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] (53-54) The individual enantiomers, Example 53 and Example 54, were obtained by separation of the racemic mixture, Example 52 (94 mg, 0.19 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 600 μL 94 mg dissolved in 3 mL MeOH. Example 53 (17 mg, 0.035 mmol, 18% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.32 (s, 1H), 7.29 (s, 1H), 7.22-7.17 (m, 1H), 6.91 (s, 1H), 4.09-3.99 (m, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.13 (s, 2H), 3.02 (s, 2H), 2.88-2.80 (m, 1H), 2.80-2.73 (m, 2H), 2.70-2.58 (m, 1H), 2.49-2.41 (m, 1H), 2.18-2.09 (m, 4H), 2.06-1.98 (m, 1H), 1.90-1.80 (m, 2H), 1.78-1.69 (m, 2H), 1.67-1.56 (m, 3H), 1.55-1.43 (m, 2H), 1.30-1.15 (m, 3H), 0.80 (d, J=6.6 Hz, 6H) (1 proton ambiguous). Analytical LC / MS (Method 1): Purity: 97.8 %; Observed mass: 493.21; Retention time: 1.29 min. (Method 2): Purity: 97.6 %; Observed mass: 493.23; Retention time: 0.98 min. Chiral analysis (SFC Method 1): Chiral purity > 95 %. Holding time: 1.45 minutes Example 54 (16 mg, 0.032 mmol, 17% yield) was isolated as the second eluting enantiomer. 1H NMR (500 MHz, DMSO-d6) δ 7.33-7.31 (m, 1H), 7.30-7.27 (m, 1H), 7.21-7.17 (m, 1H), 6.92-6.87 (m, 1H), 4.07-3.99 (m, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.18-3.13 (m, 2H), 3.06-3.00 (m, 2H), 2.88-2.81 (m, 1H), 2.80-2.74 (m, 2H), 2.67-2.58 (m, 1H), 2.49-2.42 (m, 1H), 2.18-2.10 (m, 4H), 2.06-1.97 (m, 1H), 1.87-1.79 (m, 2H), 1.76-1.69 (m, 2H), 1.65-1.57 (m, 3H), 1.54-1.43 (m, 2H), 1.30-1.17 (m, 3H), 0.79 (d. Chiral analysis (SFC method 1): Chiral purity > 95 %. Retention time: 4.10 minutes

[0252] Example 55 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] To a 40 mL vial was added Intermediate 39A (380 mg, 0.42 mmol), cyclopropanecarbaldehyde (150 mg, 2.1 mmol), AcOH (0.026 mL, 0.46 mmol), magnesium sulfate (760 mg, 6.3 mmol), and DMF (5 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (270 mg, 1.3 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with 10% MeOH / DCM (20 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (100 mg, 0.21 mmol, 50% yield). 1 H NMR (500 MHz, DMSO-d6) δ 7.32-7.28 (m, 1H), 7.27-7.23 (m, 1H), 7.18-7.13 (m, 1H), 6.89-6.83 (m, 1H), 4.05-3.95 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.01-2.93 (m, 2H), 2.91-2.84 (m, 2H), 2.84-2.77 (m, 1H), 2.66-2.56 (m, 1H), 2.10 (br d, J=6.3 Hz, 3H), 2.07-1.95 (m, 3H), 1.89-1.80 (m, 3H), 1.65 (br d, J=13.6 Hz, 5H), 1.53-1.44 (m, 1H), 1.40 (br s, 2H), 1.21 (br s, 3H), 0.83-0.70 (m, 1H), 0.44-0.37 (m, 2H), 0.01 (br d, J=4.3 Hz, 2H). Analytical LC / MS (Method 1): Purity: 98 %; Observed mass: 479.12; Retention time: 1.22 min. (Method 2): Purity: 97.1 %; Observed mass: 478.97; Retention time: 1.03 min

[0253] Examples 56 and 57 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [ka] The individual enantiomers, Example 56 and Example 57, were obtained by separation of the racemic mixture, Example 55 (68 mg, 0.14 mmol), under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 55% CO2 / 45% MeOH w / 0.1% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 1500 μL 68 mg dissolved in 2 mL MeOH. Example 56 (2.7 mg, 0.0056 mmol, 4.0% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.25-7.22 (m, 1H), 7.21-7.17 (m, 1H), 7.13-7.09 (m, 1H), 6.82-6.78 (m, 1H), 3.99-3.91 (m, 1H), 3.68 (s, 3H), 3.64 (s, 3H), 3.60-3.49 (m, 1H), 3.04-2.97 (m, 1H), 2.94-2.86 (m, 1H), 2.80-2.72 (m, 1H), 2.60-2.51 (m, 1H), 2.30-2.24 (m, 1H), 2.23-2.16 (m, 2H), 2.15-2.07 (m, 2H), 2.04-1.89 (m, 3H), 1.75-1.64 (m, 4H), 1.64-1.57 (m, 1H), 1.51-1.37 (m, 3H), 1.28-1.13 (m, 3H), 0.79-0.70 (m, 1H), 0.41-0.35 (m, 2H), 0.05--0.03 (m, 2H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 91.1 %; Observed mass: 479.21; Retention time: 1.26 min. (Method 2): Purity: 93.1 %; Observed mass: 479.20; Retention time: 0.89 min. Chiral analysis (SFC Method 1): Chiral purity > 95%. Retention time: 2.20 min. Example 57 (2.4 mg, 0.0050 mmol, 3.6% yield) was isolated as the second eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.24-7.21 (m, 1H), 7.20-7.16 (m, 1H), 7.12-7.07 (m, 1H), 6.81-6.77 (m, 1H), 3.99-3.89 (m, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.58-3.50 (m, 1H), 3.05-3.00 (m, 1H), 2.88 (s, 2H), 2.78-2.71 (m, 1H), 2.59-2.49 (m, 1H), 2.34-2.27 (m, 1H), 2.25-2.19 (m, 2H), 2.17-2.08 (m, 2H), 2.07-1.98 (m, 2H), 1.96-1.87 (m, 1H), 1.75-1.56 (m, 5H), 1.43 (br s, 3H), 1.19 (br s, 3H), 0.80-0.70 (m, Analytical LC / MS (Method 1): Purity: 96.6 %; Observed mass: 479.22; Retention time: 1.26 min. %; Observed mass: 479.20; Retention time: 0.90 min. Chiral analysis (SFC method 1): Chiral purity > 95%. Retention time: 4.70 min

[0254] Example 58 2-(3,4-Dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Step A. Intermediate 58A. Preparation of 7-bromo-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine [ka] Intermediate 58A was prepared according to the general method described for the synthesis of Intermediate 1A, substituting 4-bromopyridin-2-amine (500 mg, 2.9 mmol) as needed to afford the title compound (0.98 g, 2.9 mmol, 100% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J=7.2 Hz, 1H), 8.70 (s, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.62-7.57 (m, 1H), 7.56-7.53 (m, 1H), 7.56-7.50 (m, 1H), 7.18 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 333.0; Retention time: 0.62 min

[0255] Step B. Intermediate 58B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Intermediate 58B was prepared following the general method described for the synthesis of Intermediate 1B, starting from Intermediate 58A (0.98 g, 2.9 mmol) to afford the title compound (1.2 g, 2.8 mmol, 97% yield) as a white solid. 1 H NMR (500 MHz, methanol-d4) δ 8.35-8.31 (m, 1H), 8.09 (s, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.48 (s, 2H), 7.16-7.11 (m, 1H), 7.06-7.02 (m, 1H), 6.45-6.33 (m, 1H), 4.19-4.12 (m, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.74-3.67 (m, 2H), 2.65-2.57 (m, 2H), 1.53 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 436.2; Retention time: 0.79 minutes

[0256] Step C. Intermediate 58C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)piperidine-1-carboxylate [ka] Intermediate 58C was prepared following the general method described for the synthesis of Intermediate 31A, starting from Intermediate 58B (1.2 g, 2.8 mmol) to afford the title compound (0.56 g, 1.3 mmol, 46% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 7.35-7.32 (m, 1H), 7.22 (s, 2H), 6.97-6.92 (m, 1H), 4.20-4.12 (m, 3H), 3.97-3.91 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.06-2.98 (m, 1H), 2.85-2.68 (m, 2H), 2.61-2.49 (m, 1H), 2.26-2.14 (m, 1H), 1.92-1.69 (m, 4H), 1.57-1.50 (m, 1H), 1.48 (s, 9H), 1.26 (s, 2H). Analytical LC / MS (Method 5): Observed mass: 442.4; Retention time: 0.77 min

[0257] Step D. Intermediate 58D. Preparation of 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine hydrochloride [ka] Intermediate 58D was prepared following the general method described for the synthesis of Intermediate 31B, starting from Intermediate 58C (0.56 g, 1.3 mmol) to afford the title compound (420 mg, 1.1 mmol, 85% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 7.72 (s, 1H), 7.30 (s, 2H), 7.12-7.06 (m, 1H), 4.42-4.33 (m, 1H), 4.20-4.11 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.54-3.48 (m, 2H), 3.31-3.25 (m, 1H), 3.10-3.02 (m, 2H), 2.89-2.81 (m, 1H), 2.36-2.30 (m, 1H), 2.19-2.13 (m, 1H), 2.12-2.01 (m, 2H), 1.94-1.84 (m, 1H), 1.84-1.75 (m, 1H), 1.71-1.56 (m, 2H). Analytical LC / MS (Method 5): Observed mass: 342.4; Retention time: 0.49 min

[0258] Step E. Preparation of the compound of Example 58 To a 2-dram vial was added Intermediate 58D (110 mg, 0.29 mmol), 1-isopropylpiperidin-4-one (120 mg, 0.85 mmol), AcOH (0.017 mL, 0.31 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (1 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (180 mg, 0.83 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with 10% MeOH / DCM (10 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (15 mg, 0.032 mmol, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.29 (s, 1H), 7.23-7.18 (m, 1H), 6.92-6.88 (m, 1H), 4.10-4.04 (m, 1H), 3.87-3.80 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.05-2.96 (m, 3H), 2.94-2.84 (m, 2H), 2.47-2.30 (m, 4H), 2.29-2.19 (m, 2H), 2.08-2.02 (m, 1H), 1.87-1.73 (m, 4H), 1.72-1.47 (m, 5H), 1.31-1.23 (m, 3H), 1.04 (br d, J=6.5 Hz, 6H). Analytical LC / MS (Method 1): Purity: 95 %; Observed mass: 467.20; Retention time: 1.21 min. (Method 2): Purity: 100 %; Observed mass: 467.20; Retention time: 0.98 min

[0259] Example 59 2-(3,4-Dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture) [ka] Example 59 was synthesized according to the general method described for the preparation of Example 58 (Step E), using Intermediate 58D (110 mg, 0.29 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (130 mg, 0.84 mmol) as needed. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (15 mg, 0.031 mmol, 11% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.25-7.20 (m, 1H), 6.92 (d, J=8.5 Hz, 1H), 4.12-4.03 (m, 1H), 3.88-3.81 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.50-3.40 (m, 1H), 3.01-2.90 (m, 2H), 2.90-2.83 (m, 2H), 2.46-2.38 (m, 1H), 2.27-2.21 (m, 1H), 2.20-2.12 (m, Analytical LC / MS (Method 1): Purity: 97.4 %; Observed mass: 480.99; Retention time: 1.31 min. (Method 2): Purity: 92.7 %; Observed mass: 481.03; Retention time: 1.03 min

[0260] Example 60 2-(3,4-Dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Step A. Intermediate 60A. Preparation of 7-bromo-2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine [ka] A 50 mL three-neck flask was charged with 4-bromopyridin-2-amine (1.0 g, 5.8 mmol), 3,4-dimethoxybenzonitrile (1.1 g, 6.7 mmol), copper(I) bromide (0.041 g, 0.29 mmol), zinc iodide (0.18 g, 0.56 mmol), 1,10-phenanthroline (0.052 g, 0.29 mmol), and 1,2-dichlorobenzene (12 mL). Air was gently bubbled through the mixture, the system was closed, and the reaction mixture was heated to 130 °C and stirred. After 18 h, the reaction mixture was cooled, diluted with DCM, filtered, and the filter cake was washed with copious amounts of DCM. The filtrate was concentrated, and the residue was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min). The pure fractions were combined, concentrated and dried under vacuum to give the title compound (1.4 g, 4.2 mmol, 72% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.73-8.69 (m, 1H), 8.00-7.98 (m, 1H), 7.86-7.83 (m, 1H), 7.82-7.81 (m, 1H), 7.37-7.31 (m, 1H), 7.13-7.10 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 335.9; Retention time: 0.86 min

[0261] Step B. Intermediate 60B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a 40 mL vial were added Intermediate 60A (0.66 g, 2.0 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.73 g, 2.4 mmol), followed by potassium phosphate (1.3 g, 6.1 mmol) dissolved in 1,4-dioxane (10 mL) and water (2 mL). The vial was purged with N2, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.081 g, 0.099 mmol) was added. The vial was again purged with N2, and the reaction was stirred at 70 °C. After 18 h, the reaction mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (2 × 50 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min). Pure fractions were combined, concentrated, and dried under reduced pressure to give the title compound (0.61 g, 1.4 mmol, 70% yield) as a pale yellow solid. Analytical LC / MS (Method 5): Observed mass: 437.1; Retention time: 0.96 min

[0262] Step C. Intermediate 60C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)piperidine-1-carboxylate [ka] To a 100 mL recovery flask was added Intermediate 60B (0.61 g, 1.4 mmol) and MeOH (20 mL). The vessel was evacuated and purged with N2, then Pd-C (10% on carbon) (0.15 g, 0.14 mmol) was added and the reaction mixture was stirred under 1 atmosphere of hydrogen. After 2 h, the catalyst was filtered and the filtrate was concentrated. The product was dried under reduced pressure to give the title compound (0.61 g, 1.4 mmol, 99% yield) as a white solid. Analytical LC / MS (Method 5): Observed mass: 439.1; Retention time: 0.94 min

[0263] Step D. Intermediate 60D. Preparation of 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine hydrochloride [ka] To a 100 mL recovery flask was added Intermediate 60C (610 mg, 1.4 mmol), THF (2 mL), and 4 M HCl in dioxane (5 mL). A white precipitate formed immediately. The suspension was stirred. After 18 h, the solvent was concentrated, and the solid was purified by trituration from MeOH. The product was collected by vacuum filtration and dried under reduced pressure to give the title compound (520 mg, 1.4 mmol, 100% yield) as an off-white solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.81-7.76 (m, 1H), 7.73 (s, 1H), 7.65-7.63 (m, 1H), 7.12 (s, 2H), 3.87 (s, 3H), 3.84 (s, Analytical LC / MS (Method 5): Observed mass: 339.0; Retention time: 0.60 min

[0264] Step E. Preparation of the compound of Example 60 To a 40 mL vial was added Intermediate 60D (60 mg, 0.16 mmol), 1-isopropylpiperidin-4-one (68 mg, 0.48 mmol), AcOH (0.010 mL, 0.18 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (100 mg, 0.48 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was filtered, the filter cake was washed with 10% MeOH / DCM (20 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (71 mg, 0.15 mmol, 94% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=7.0 Hz, 1H), 7.76 (dd, J=8.2, 1.8 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.15-7.08 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.55-3.48 (m, 3H), 3.20-3.16 (m, 1H), 3.15-3.02 (m, 3H), 2.75-2.67 (m, 1H), 2.40-2.29 (m, 3H), 1.94-1.86 (m, 3H), 1.76-1.65 (m, 3H), 1.64-1.52 (m, 2H), 1.10 (br d, J=5.8 Hz, 6H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 464.31; Retention time: 1.26 min. (Method 2): Purity: 100 %; Observed mass: 464.15; retention time: 1.07 minutes

[0265] Example 61 2-(3,4-Dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Example 61 was synthesized according to the general method described for the preparation of Example 60 (Step E), using Intermediate 60D (60 mg, 0.16 mmol) as the starting material, substituting 1-isobutylpiperidin-4-one (75 mg, 0.48 mmol) as needed. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (54 mg, 0.11 mmol, 69% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.86-8.78 (m, 1H), 7.79-7.75 (m, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.61 (s, 1H), 7.12 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.57-3.50 (m, 2H), 3.13-3.05 (m, 1H), 2.97-2.90 (m, 1H), 2.78-2.68 (m, 1H), 2.44-2.34 (m, 2H), 2.15-2.02 (m, 2H), 1.98-1.87 (m, 3H), 1.83-1.64 (m, 5H), 1.58-1.47 (m, 2H), 0.86 (d, J=6.4 Hz, 6H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 99.3 %; Observed mass: 478.17; Retention time: 1.39 min. (Method 2): Purity: 97%; Observed mass: 478.17; Retention time: 1.1 min

[0266] Examples 62 and 63 6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 62A. Preparation of 6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine dihydrochloride [ka] A 250 mL round-bottom flask was charged with Intermediate 7C (0.58 g, 1.4 mmol), MeOH (50 mL), and DOWEX 550A anion exchange resin (10 g). The mixture was stirred for 15 min, the resin was filtered, and the filtrate was concentrated. The resulting free amine was dissolved in DCE (15 mL) and DME (15 mL), and then tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 5.7 mmol) was added, followed by titanium(IV) isopropoxide (2.1 mL, 7.1 mmol). The reaction mixture was stirred at 40 °C under N2. After 18 h, the mixture was cooled to rt, and then sodium triacetoxyborohydride (1.2 g, 5.7 mmol) was added, and the reaction was continued. After 3 h, the reaction mixture was partitioned between 1M KOH (saturated with solid NaCl) (150 mL) and 10% IPA / chloroform (150 mL). The layers were separated, the aqueous phase was extracted with 10% IPA / chloroform (75 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 15% B; flow rate = 80 mL / min). The product fractions were combined, concentrated, and dried under reduced pressure. The resulting residue was dissolved in MeOH (20 mL) and 4 M HCl in dioxane (10 mL) and stirred. After 0.5 h, the solvent was concentrated, and the residue was coevaporated with toluene (2x). The product was dried under vacuum to give the title compound (0.47 g, 0.85 mmol, 61% yield) as an off-white solid. 1H NMR (500 MHz, methanol-d4) δ 8.70-8.66 (m, 1H), 8.22 (br d, J=6.8 Hz, 4H), 7.92-7.84 (m, 1H), 7.19-7.15 (m, 1H), 4.31-4.18 (m, 3H), 4.11-3.98 (m, 3H), 3.89-3.79 (m, 3H), 3.23 (s, 3H), 2.78 (s, 3H), 2.50-2.42 (m, 2H), 2.17-2.13 (m, 3H), 2.01 (br d, J=8.5 Hz, 6H). Analytical LC / MS (Method 4): Observed mass: 479.1; Retention time: 0.832 minutes

[0267] Step B. Examples 62 and 63 To a 40 mL vial was added Intermediate 62A (90 mg, 0.16 mmol), propan-2-one (47 mg, 0.82 mmol), AcOH (10 μL, 0.18 mmol), magnesium sulfate (300 mg, 2.5 mmol), and DMF (2 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (170 mg, 0.82 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative LC / MS using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 5% B at 0 min hold, 5-55% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by MS and UV signals. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 62 (11 mg, 0.021 mmol, 13% yield) was isolated as the first eluting isomer.1 H NMR (500 MHz, DMSO-d6) δ 8.51-8.44 (m, 1H), 8.25-8.14 (m, 3H), 8.02-7.93 (m, 2H), 7.14-7.04 (m, 1H), 3.23 (s, 2H), 3.00 (s, 2H), 2.83-2.75 (m, 1H), 2.69-2.59 (m, 1H), 2.52 (br d, J=1.8 Hz, 5H), 2.17 (br s, 2H), 1.81 (br d, J=11.0 Hz, 4H), 1.70-1.52 (m, 6H), 1.51-1.42 (m, 2H), 1.03 (d, J=6.1 Hz, 6H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 98.2 %; Observed mass: 521.01; Retention time: 0.84 min. (Method 2): Purity: 98 %; Observed mass: 520.95; Retention time: 1.28 min Example 63 (11 mg, 0.021 mmol, 13% yield) was isolated as the second eluting isomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.52-8.43 (m, 1H), 8.29-8.17 (m, 3H), 8.03-7.91 (m, 2H), 7.13-7.05 (m, 1H), 3.49-3.37 (m, 1H), 3.24 (s, Analytical LC / MS (Method 1): Purity: 97.9 %; Observed mass: 521.32; Retention time: 0.84 min. (Method 2): Purity: 96.7 %; Observed Mass: 521.31; Retention Time: 1.35 min

[0268] Example 64 2-(3,4-dimethoxyphenyl)-8-methyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 64A. Preparation of tert-butyl 4-(4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate [ka] To a 40 mL vial was added Intermediate 1A (500 mg, 1.4 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (620 mg, 1.6 mmol), XPhos Pd G3 (120 mg, 0.14 mmol), 1,4-dioxane (20 mL), followed by potassium phosphate tribasic (1100 mg, 5.0 mmol) dissolved in water (3 mL). The vessel was flushed with N2, capped, and the reaction mixture was stirred at 85 °C. After 18 h, the reaction mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (2 × 50 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 80 mL / min). Fractions corresponding to the desired product were combined, concentrated, and dried under reduced pressure to give the title compound (610 mg, 1.2 mmol, 86% yield) as a pale yellow solid. 1 H NMR (500 MHz, chloroform-d) δ 8.18-8.05 (m, 1H), 7.86-7.79 (m, 1H), 7.67-7.59 (m, 1H), 7.54-7.47 (m, 3H), 7.26-7.19 (m, 1H), 7.07-7.01 (m, 2H), 7.00-6.94 (m, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.70-3.60 (m, 4H), 3.30-3.17 (m, 4H), 2.74 (s, 3H), 1.52 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 529.3; Retention time: 0.86 minutes

[0269] Step B. Intermediate 64B. Preparation of 2-(3,4-dimethoxyphenyl)-8-methyl-6-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine dihydrochloride [ka] To a 200 mL recovery flask was added Intermediate 64A (610 mg, 1.2 mmol), MeOH (10 mL), followed by 4 M HCl in dioxane (10 mL). After stirring for 30 min, the solvent was concentrated, the residue was co-evaporated with toluene, and the product was dried under reduced pressure to give the title compound (600 mg, 1.2 mmol, 100% yield) as a tan solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.49-9.44 (m, 1H), 9.03-8.97 (m, 1H), 8.70-8.64 (m, 1H), 8.16-8.12 (m, 1H), 7.88-7.81 (m, 1H), 7.77-7.71 (m, 2H), 7.70-7.66 (m, 1H), 7.21-7.15 (m, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 3.75-3.65 (m, 1H), 3.56-3.48 (m, 3H), 3.29-3.20 (m, 4H), 2.81 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 429.3; Retention time: 0.57 min

[0270] Step C. Example 64 To a 40 mL vial was added Intermediate 64B (60 mg, 0.12 mmol), oxetan-3-one (43 mg, 0.60 mmol), AcOH (7.5 μL, 0.13 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 10 min, then sodium triacetoxyborohydride (130 mg, 0.60 mmol) was added and the reaction mixture was stirred. After 18 h, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (33 mg, 0.068 mmol, 57% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.67-8.58 (m, 1H), 8.34-8.30 (m, 1H), 7.63-7.55 (m, 3H), 7.54-7.50 (m, 1H), 7.48-7.42 (m, 1H), 7.11-7.01 (m, 3H), 4.66-4.59 (m, 2H), 4.58-4.49 (m, 2H), 3.87 (s, 3H), 3.81-3.76 (m, 3H), 3.61-3.46 (m, 1H), 3.36-3.23 (m, 2H), 2.60 (s, 5H), 2.51 (br s, 4H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 485.17; Retention time: 1.12 min. (Method 2): Purity: 100 %; Observed mass: 485.16; Retention time: 1.80 min

[0271] Example 65 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 65A. Preparation of 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine dihydrochloride [ka] Intermediate 65A was synthesized according to the method described for the preparation of Intermediate 64B (Steps A-B), substituting Intermediate 7A (0.75 g, 2.1 mmol) as needed to afford the title compound (0.81 g, 1.6 mmol, 76% yield over two steps) as a tan solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.25 (br s, 1H), 9.02-8.93 (m, 1H), 8.82-8.74 (m, 1H), 8.41-8.29 (m, 2H), 8.17-8.08 (m, 2H), 8.05-7.93 (m, 1H), 7.79-7.63 (m, 2H), 7.21-7.09 (m, 2H), 3.52-3.48 (m, 4H), 3.31 (s, 3H), 3.27-3.23 (m, 4H), 2.73 (s, 3H) Analytical LC / MS (Method 4): Observed mass: 447.1; Retention time: 0.927 min

[0272] Step B. Example 65 Example 65 was synthesized according to the method described for the preparation of Example 64 (Step C) using Intermediate 65A (70 mg, 0.14 mmol) as the starting material. The crude mixture was purified by preparative HPLC (Preparative Method 1) to give the title compound (15 mg, 0.031 mmol, 22% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.62 (m, 1H), 8.54 (s, 1H), 8.25 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.5 Hz, 2H), 7.58 (br d, J=8.9 Hz, 2H), 7.46 (s, 1H), 7.04 (br d, J=8.9 Hz, 2H), 3.45-3.33 (m, 1H), 3.25 (s, 4H), 2.78-2.67 (m, 1H), 2.61 (s, 7H), 2.55 (s, 2H), 1.03 (d, J=6.7 Hz, 6H). Analytical LC / MS (Method 1): Purity: 100%; Observed Mass: 489.35; Retention Time: 1.06 min. (Method 2): Purity: 100%; Observed Mass: 489.35; Retention Time: 1.45 min.

[0273] Example 66 7-(1'-Isopropyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 66A. Preparation of tert-butyl 2'-amino-6'-methyl-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate [ka] A 200 mL recovery flask was charged with 4-bromo-6-methylpyridin-2-amine (1.0 g, 5.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.0 g, 6.4 mmol), XPhos Pd G3 (0.23 g, 0.27 mmol), 1,4-dioxane (50 mL), followed by potassium phosphate tribasic (4.0 g, 19 mmol) dissolved in water (10 mL). The vessel was flushed with N2, and the reaction mixture was stirred at 85 °C. After 24 h, the reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2 × 100 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 15% B; flow rate = 60 mL / min). The product-containing fractions were combined, concentrated, and dried under reduced pressure to give the title compound (1.3 g, 4.5 mmol, 83% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 6.62-6.55 (m, 1H), 6.46-6.37 (m, 1H), 6.31-6.23 (m, 1H), 4.08 (br s, 2H), 3.72-3.57 (m, 2H), 2.53-2.43 (m, 2H), 2.33 (s, 3H), 1.51 (s, 9H). Analytical LC / MS (Method 4): Observed mass: 289.9; Retention time: 1.318 min

[0274] Step B. Intermediate 66B. Preparation of tert-butyl 4-(5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a 20 mL microwave reaction vial was added Intermediate 66A (0.6 g, 2.1 mmol), 2,2-dimethoxy-2-(4-(methylsulfonyl)phenyl)ethyl 4-methylbenzenesulfonate (1.0 g, 2.5 mmol), MeCN (15 mL), followed by scandium(III) triflate (0.051 g, 0.10 mmol). The vial was capped and irradiated at 120 °C. After 15 h, the solvent was concentrated, and the residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 10% B; flow rate = 80 mL / min). The fractions corresponding to the product were combined, concentrated, and dried under reduced pressure to give the title compound (100 mg, 0.21 mmol, 10% yield) as a tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.38-8.32 (m, 1H), 8.30-8.19 (m, 2H), 8.08-8.00 (m, 2H), 7.51-7.44 (m, 1H), 7.14-7.07 (m, 1H), 6.48-6.38 (m, 1H), 4.22-4.08 (m, 2H), 3.77-3.66 (m, 2H), 3.19 (s, 3H), 2.74 (s, 3H), 2.68-2.59 (m, 2H), 1.53 (s, 9H). analytical LC / MS (Method 4): Observed mass: 468.1; Retention time: 1.508 minutes

[0275] Step C. Intermediate 66C. Preparation of 5-methyl-2-(4-(methylsulfonyl)phenyl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride [ka] To a 250 mL round-bottom flask was added Intermediate 66B (90 mg, 0.19 mmol), MeOH (30 mL), and Pd—C (wt % on carbon, wet) (41 mg, 0.019 mmol). The vessel was evacuated, purged with N (3×), and stirred under 1 atmosphere of H. After 6 h, the catalyst was filtered, and 4 M HCl in dioxane (20 mL) was added to the filtrate, and the mixture was stirred. After 20 min, the solvent was concentrated, the residue was coevaporated with toluene (2×), and the product was dried under reduced pressure to give the title compound (78 mg, 0.19 mmol, 100% yield) as a tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.88-8.79 (m, 1H), 8.28-8.19 (m, 4H), 7.78-7.69 (m, 1H), 7.47-7.41 (m, 1H), 3.78-3.75 (m, 2H), 3.69 (br Analytical LC / MS (Method 4): Observed mass: 369.9; Retention time: 0.821 min

[0276] Step D. Example 66 To a 40 mL vial was added Intermediate 66C (50 mg, 0.12 mmol), 1-isopropylpiperidin-4-one (87 mg, 0.62 mmol), AcOH (7.8 μL, 0.14 mmol), magnesium sulfate (220 mg, 1.8 mmol), and DMF (2 mL). The reaction mixture was stirred for 10 minutes, and then sodium triacetoxyborohydride (130 mg, 0.62 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1) to give the title compound (16 mg, 0.032 mmol, 27% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.51-8.42 (m, 1H), 8.31-8.24 (m, 2H), 8.06-7.91 (m, 2H), 7.35-7.26 (m, 1H), 6.86-6.73 (m, 1H), 3.66-3.62 (m, 6H), 3.25-3.21 (m, 2H), 3.07-2.97 (m, 3H), 2.95-2.86 (m, 1H), 2.64-2.61 (m, 2H), 2.46-2.22 (m, 4H), 1.89-1.80 (m, 3H), 1.74-1.48 (m, 4H), 1.19-0.99 (m, 6H). Analytical LC / MS (Method 1): Purity: 95.4 %; Observed mass: 495.17; Retention time: 0.92 min. (Method 2): Purity: 95.6 %; Observed mass: 495.17; Retention time: 1.28 min

[0277] Example 67 8-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 67A. Preparation of 6-bromo-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] To a 40 mL vial was added 5-bromo-3-fluoropyridin-2-amine (1.0 g, 5.2 mmol), 2-bromo-1-(4-(methylsulfonyl)phenyl)ethan-1-one (1.6 g, 5.8 mmol), and EtOH (15 mL). The vessel was capped, and the reaction mixture was stirred at 75° C. After 18 h, a precipitate formed. The reaction vessel was stored at −20° C. for 1 h, and the precipitate was collected by vacuum filtration. The filter cake was washed with a minimal amount of ether, and the product was dried under reduced pressure to give the title compound (1.0 g, 2.8 mmol, 54% yield) as a light tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.88-8.81 (m, 1H), 8.73-8.64 (m, 1H), 8.30-8.23 (m, 2H), 8.06-7.97 (m, 2H), 7.62-7.53 (m, 1H), 3.26 (s, 3H). Analytical LC / MS (Method 4): Observed mass: 370.7; Retention time: 1.562 min

[0278] Step B. Intermediate 67B. Preparation of benzyl 4-(8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] To a 40 mL vial was added Intermediate 67A (1.0 g, 2.8 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.2 g, 3.4 mmol), XPhos Pd G3 (0.12 g, 0.14 mmol), 1,4-dioxane (15 mL), followed by potassium phosphate tribasic (2.1 g, 9.9 mmol) dissolved in water (3 mL). The vessel was flushed with N2, and the reaction mixture was stirred at 85 °C. After 18 h, the reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (2 × 100 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 15% B; flow rate = 80 mL / min). The product fractions were combined, concentrated, and dried under reduced pressure to give the title compound (0.41 g, 0.81 mmol, 29% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 8.50-8.45 (m, 1H), 8.40-8.37 (m, 1H), 8.22 (s, 2H), 8.09-8.01 (m, 2H), 7.47-7.31 (m, 6H), 6.39-6.25 (m, Analytical LC / MS (Method 4): Observed mass: 506.1; Retention time: 1.947 min

[0279] Step C. Intermediate 67C. Preparation of 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine [ka] To a 250 mL round-bottom flask was added Intermediate 67B (0.41 g, 0.81 mmol), MeOH (30 mL), and DCM (10 mL). The vessel was evacuated and purged with N. Pd—C (5 wt% on carbon, wet) (0.086 g, 0.081 mmol) was then added, the vessel was evacuated and purged with N, and the reaction mixture was stirred under 1 atmosphere of H. After 18 h, the catalyst was filtered, and the filtrate was concentrated. The product was dried under reduced pressure to give the title compound (0.30 g, 0.81 mmol, 100% yield) as a light tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.50-8.45 (m, 1H), 8.30-8.27 (m, 1H), 8.26-8.20 (m, 2H), 8.07-8.03 (m, 2H), 7.22-7.13 (m, 1H), 3.58-3.52 (m, 2H), 3.19 (s, 5H), 3.06-2.99 (m, 1H), 2.25-2.18 (m, 2H), 2.00-1.89 (m, 2H). Analytical LC / MS (method 4): Observed mass: 373.9; Retention time: 0.890 min

[0280] Step D. Example 67 To a 40 mL vial was added Intermediate 67C (75 mg, 0.17 mmol), 1-isopropylpiperidin-4-one (120 mg, 0.84 mmol), AcOH (11 μL, 0.19 mmol), magnesium sulfate (300 mg, 2.5 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (180 mg, 0.84 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 2) to give the title compound (47 mg, 0.065 mmol, 38% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.72-8.63 (m, 1H), 8.34-8.28 (m, 1H), 8.25-8.19 (m, 2H), 8.05-7.97 (m, 2H), 7.23-7.17 (m, 1H), 3.70-3.43 (m, 3H), 3.24 (s, 3H), 3.21-3.12 (m, 1H), 3.10-2.92 (m, 3H), 2.55-2.52 (m, 2H), 2.40-2.29 (m, 2H), 2.18 (br d, J=11.0 Hz, 2H), 2.08-1.84 (m, 4H), 1.26 (br d, J=6.7 Hz, 6H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 499.21; Retention time: 0.91 min. (Method 2): Purity: 100 %; Observed mass: 498.94; Retention time: 1.12 min

[0281] Examples 68 and 69 8-Fluoro-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 68A. Preparation of 6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine dihydrochloride [ka] To a 250 mL round-bottom flask was added Intermediate 67C (0.41 g, 1.1 mmol), DCE (10 mL), 1,4-dioxane (10 mL), tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.99 g, 4.4 mmol), followed by titanium(IV) isopropoxide (1.6 mL, 5.5 mmol). The reaction mixture was stirred at 40 °C under N2. After 18 h, the mixture was cooled to rt, and then sodium triacetoxyborohydride (0.93 g, 4.4 mmol) was added and the reaction continued. After 1 h, the reaction mixture was filtered and partitioned between 1 M KOH (150 mL) (saturated with solid NaCl) and 10% IPA / chloroform (150 mL). The layers were separated, the aqueous phase was extracted with 10% IPA / chloroform (75 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 30% B; flow rate = 80 mL / min). Fractions corresponding to the desired intermediate were combined, concentrated, and dried under reduced pressure. The resulting residue was dissolved in MeOH (20 mL) and 4 M HCl in dioxane (10 mL) and stirred. After 0.5 h, the solvent was concentrated, the residue was coevaporated with toluene (2x), and the product was dried under reduced pressure to give the title compound (0.50 g, 0.90 mmol, 82% yield) as a tan solid. Analytical LC / MS (Method 4): Observed mass: 483.1; Retention time: 0.896 min

[0282] Step B. Examples 68 and 69 The compounds of Examples 68 and 69 were synthesized according to the method described for the preparation of the compounds of Examples 62 and 63 (Step B), using Intermediate 68A (100 mg, 0.18 mmol) as the starting material. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 2% B at 0 min hold, 2 to 42% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fraction collection was initiated by MS signal. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 68 (8.4 mg, 0.016 mmol, 9% yield) was isolated as the first eluting isomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.63-8.57 (m, 1H), 8.31-8.27 (m, 1H), 8.25-8.20 (m, 2H), 8.02-7.96 (m, 2H), 7.26-7.20 (m, 1H), 3.55-3.37 (m, 2H), 3.24 (s, 2H), 3.05-2.96 (m, 2H), 2.95-2.85 (m, 1H), 2.76-2.65 (m, 1H), 2.59-2.56 (m, 1H), 2.25-2.17 (m, 2H), 1.93-1.81 (m, 5H), 1.63 (br s, 8H), 1.09 (br d, J=6.1 Hz, 6H). Analytical LC / MS (Method 1): Purity: 97.5 %; Observed mass: 525.20; Retention time: 0.95 min. (Method 2): Purity: 100 %; Observed mass: 525.30; Retention time: 1.23 min Example 69 (11 mg, 0.021 mmol, 12% yield) was isolated as the second eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.58 (m, 1H), 8.34-8.30 (m, 1H), 8.27-8.21 (m, 2H), 8.06-7.96 (m, 2H), 7.31-7.22 (m, 1H), 3.69-3.60 (m, 1H), 3.36-3.30 (m, 1H), 3.25 (s, 2H), 2.90-2.81 (m, 1H), 2.55-2.52 (m, 3H), 2.41-2.32 (m, 1H), 2.05-1.76 (m, 10H), 1.74-1.56 (m, 3H), 1.12 (br d, J=6.1 Hz, 6H) (2 protons obscured). Analytical LC / MS (Method 1): Purity: 96.5 %; Observed mass: 525.20; Retention time: 0.98 min. (Method 2): Purity: 95.3 %; Observed mass: 525.20; Retention time: 1.36 min

[0283] Example 70 7-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 70A. Preparation of 7-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine [ka] Intermediate 70A was synthesized according to the method described for the preparation of Intermediate 67C (Steps A-C) using 5-bromo-4-fluoropyridin-2-amine (1.0 g, 5.2 mmol) as the starting material to afford the title compound (0.38 g, 1.0 mmol, 19% yield over three steps) as a light tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.96-8.75 (m, 1H), 8.59-8.49 (m, 2H), 8.25-8.16 (m, 2H), 7.99 (d, J=8.6 Hz, 2H), 7.59-7.49 (m, 1H), 3.44-3.38 (m, 2H), 3.25 (s, 3H), 3.13-3.04 (m, 3H), 2.11-2.02 (m, 2H), 1.96-1.86 (m, 2H). Analytical LC / MS (Method 4): Observed mass: 373.9; Retention time: 0.992 min

[0284] Step B. Example 70 Example 70 was synthesized according to the method described for the preparation of Example 67 (Step D) using Intermediate 70A (65 mg, 0.17 mmol) as the starting material. The crude mixture was purified by preparative HPLC (Preparative Method 1) to give the title compound (14 mg, 0.028 mmol, 17% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.53-8.46 (m, 2H), 8.21-8.16 (m, 2H), 8.02-7.95 (m, 2H), 7.46-7.42 (m, 1H), 3.24-3.22 (m, 2H), 3.17 (s, 3H), 3.02-2.97 (m, 2H), 2.87-2.82 (m, 2H), 2.73-2.62 (m, 3H), 1.79-1.64 (m, 6H), 1.49-1.39 (m, 4H), 0.96 (br d, J=6.7 Hz, 6H). Analytical LC / MS (Method 1): Purity: 97.4%; Observed mass: 499.12; Retention time: 0.89 min. (Method 2): Purity: 98.7%; Observed mass: 499.0; Retention time: 1.20 min.

[0285] Examples 71 and 72 8-Fluoro-6-(1-(1-isopropylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 108A. Preparation of 6-(1-(azepan-4-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine dihydrochloride [ka] To a 200 mL recovery flask was added Intermediate 67C (1.2 g, 3.3 mmol), tert-butyl 4-oxoazepane-1-carboxylate (3.5 g, 17 mmol), AcOH (0.21 mL, 3.6 mmol), magnesium sulfate (7.9 g, 66 mmol), and DMF (40 mL). The reaction mixture was stirred for 20 min, then sodium triacetoxyborohydride (3.5 g, 17 mmol) was added, and the reaction mixture was stirred under N2. After 18 h, the reaction mixture was diluted with 2 M KOH (saturated with solid NaCl) (200 mL) and extracted with 10% IPA / CHCl3 (2 × 100 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (80 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 10% B; flow rate = 60 mL / min). Fractions corresponding to the product were combined, concentrated, and dried under reduced pressure. The resulting intermediate was dissolved in MeOH (20 mL) and 4 M HCl in dioxane (20 mL) and stirred. After 30 min, the solvent was concentrated, the residue was coevaporated with toluene (2x), and the product was dried under reduced pressure to give the title compound (1.1 g, 2.1 mmol, 64% yield) as a light tan solid. 1H NMR (500 MHz, methanol-d4) δ 8.83-8.76 (m, 1H), 8.69-8.64 (m, 1H), 8.24-8.17 (m, 4H), 7.92-7.84 (m, 1H), 3.74-3.62 (m, 3H), 3.60-3.53 (m, 1H), 3.48-3.38 (m, 3H), 3.31-3.24 (m, 2H), 3.22 (s, 3H), 2.65-2.55 (m, 1H), 2.50-2.43 (m, 1H), 2.33 (br d, J=2.9 Hz, 5H), 2.26-2.16 (m, 1H), 2.10-1.90 (m, 2H) (1 proton obscured). Analytical LC / MS (Method 4): Observed mass: 471.3; Retention time: 0.889 min

[0286] Step B. Examples 71 and 72 To a 40 mL vial was added Intermediate 71A (220 mg, 0.41 mmol), propan-2-one (120 mg, 2.0 mmol), AcOH (0.025 mL, 0.45 mmol), magnesium sulfate (730 mg, 6.1 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, and then sodium triacetoxyborohydride (430 mg, 6.1 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 1). The resulting racemic mixture was further purified by SFC-chiral chromatography using the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiral AD, 30 x 250 mm, 5 micron; Mobile phase: 65% CO2 / 35% IPA with 0.5% DEA; Flow conditions: 100 mL / min; Detection wavelength: 220 nm; Injection details: 500 μL, 100 mg dissolved in 4 mL MeOH. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 71 (26 mg, 0.051 mmol, 12% yield) was isolated as the first eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.65-8.56 (m, 1H), 8.32-8.27 (m, 1H), 8.25-8.20 (m, 2H), 8.05-7.96 (m, 2H), 7.27-7.21 (m, 1H), 3.25 (s, 2H), 2.95-2.82 (m, 2H), 2.73-2.64 (m, 2H), 2.63-2.53 (m, 2H), 2.41-2.28 (m, 2H), 1.91 (s, 2H), 1.87-1.69 (m, 5H), 1.69-1.41 (m, 5H), 0.98 (dd, J=6.3, 3.8 Hz, 6H) (2 protons unclear). Analytical LC / MS (Method 1): Purity: 100%; Observed Mass: 513.20; Retention Time: 0.95 min. (Method 2): Purity: 100%; Observed Mass: 513.30; Retention Time: 1.23 min. Chiral analysis (SFC Method 6): Purity: >95%; Retention Time: 13.52 min. Example 72 (18 mg, 0.035 mmol, 9% yield) was isolated as the second eluting enantiomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.1 Hz, 1H), 8.28 (s, 1H), 8.23 ​​(d, J=8.2 Hz, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.24 (br d, J=12.2 Hz, 1H), 3.25 (s, 2H), 2.89-2.79 (m, 3H), 2.72-2.58 (m, 3H), 2.39-2.26 (m, 3H), 1.90 (s, 3H), 1.86-1.68 (m, 5H), 1.67-1.37 (m, 5H), 0.95 (dd, J=6.4, 3.7 Hz, 6H). Chiral analysis (SFC method 6): Purity: >92%; Retention time: 16.16 min

[0287] Example 73 5-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 73A. Preparation of tert-butyl 6-amino-2-fluoro-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate [ka] Intermediate 73A was synthesized according to the method described for the preparation of Intermediate 66A using 5-bromo-6-fluoropyridin-2-amine (1.5 g, 7.9 mmol) as the starting material to afford the title compound (2.3 g, 7.8 mmol, 99% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 7.60-7.39 (m, 1H), 6.39 (dd, J=8.2, 1.8 Hz, 1H), 5.88 (br s, 1H), 4.09-4.01 (m, 2H), 3.69-3.57 (m, 2H), 2.52-2.39 (m, 2H), 1.51 (s, 9H). Analytical LC / MS (Method 4): Observed mass: 294.1; Retention time: 1.684 min

[0288] Step B. Intermediate 73B. Preparation of tert-butyl 4-(6-amino-2-fluoropyridin-3-yl)piperidine-1-carboxylate [ka] To a 500 mL recovery flask was added Intermediate 73A (2.3 g, 7.8 mmol), DCM (30 mL), MeOH (30 mL), followed by Pd-C (5 wt% on carbon, wet) (1.7 g, 0.78 mmol). The vessel was evacuated and purged with N2, then stirred under 1 atmosphere of H2. After 18 h, the catalyst was filtered and the filtrate was concentrated. The product was dried under reduced pressure to give the title compound (2.3 g, 7.8 mmol, 100% yield) as a pale yellow solid.1 H NMR (500 MHz, methanol-d4) δ 7.51-7.38 (m, 1H), 6.45-6.31 (m, 1H), 4.28-4.15 (m, 2H), 2.96-2.76 (m, 3H), 1.81-1.72 (m, 2H), 1.65-1.51 (m, 2H), 1.49 (s, 9H). Analytical LC / MS (Method 4): Observed mass: 240.1 (-t-Bu); Retention time: 1.676 min

[0289] Step C. Intermediate 73C. Preparation of 5-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine [ka] To a 20 mL microwave reaction vial was added Intermediate 73B (1.0 g, 3.4 mmol), 2,2-dimethoxy-2-(4-(methylsulfonyl)phenyl)ethyl 4-methylbenzenesulfonate (1.4 g, 3.4 mmol), MeCN (20 mL), followed by scandium(III) triflate (0.083 g, 0.17 mmol). The vial was capped, and the reaction mixture was irradiated at 120 °C. After 12 h, the desired cyclization reaction was observed in addition to Boc cleavage. The solvent was concentrated, and the residue was purified by flash column chromatography (120 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 10% B; flow rate = 80 mL / min). The fractions corresponding to the product were combined, concentrated, and dried under reduced pressure to give the title compound (0.14 g, 0.37 mmol, 11% yield) as a light tan solid. Analytical LC / MS (Method 4): Observed mass: 374.1; Retention time: 1.008 min

[0290] Step D. Example 73 To a 40 mL vial was added Intermediate 73C (72 mg, 0.19 mmol), 1-isopropylpiperidin-4-one (140 mg, 0.96 mmol), AcOH (0.012 mL, 0.21 mmol), magnesium sulfate (350 mg, 2.9 mmol), and DMF (2 mL). The reaction mixture was stirred for 20 minutes, then sodium triacetoxyborohydride (200 mg, 0.96 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by preparative HPLC (Preparative Method 2) to give the title compound (29 mg, 0.040 mmol, 21% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.76 (br s, 1H), 8.32 (br d, J=7.6 Hz, 2H), 8.01 (br d, J=8.2 Hz, 2H), 7.59 (br d, J=9.2 Hz, 1H), 7.38-7.30 (m, 1H), 3.63-3.45 (m, 4H), 3.26 (br s, 2H), 3.14-3.04 (m, 2H), 2.99-2.90 (m, 3H), 2.40-2.31 (m, 2H), 2.07 (br d, J=12.8 Hz, 8H), 1.57-1.52 (m, 1H), 1.21-1.12 (m, 6H). Analytical LC / MS (Method 1): Purity: 98.1 %; Observed mass: 499.30; Retention time: 0.91 min. (Method 2): Purity: 97.8 %; Observed mass: 499.30; Retention time: 1.21 min

[0291] Example 74 8-Fluoro-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine [ka] Step A. Intermediate 74A. Preparation of 8-fluoro-2-(4-(methylsulfonyl)phenyl)-7-(piperidin-4-yl)imidazo[1,2-a]pyridine hydrochloride [ka] Intermediate 74A was synthesized according to the method described for the preparation of Intermediate 66C (Steps A-C) using 4-bromo-3-fluoropyridin-2-amine (0.50 g, 2.6 mmol) as the starting material to afford the title compound (0.34 g, 0.83 mmol, 32% yield over three steps) as a light tan solid. 1 H NMR (500 MHz, methanol-d4) δ 8.81-8.78 (m, 1H), 8.70-8.65 (m, 1H), 8.23-8.16 (m, 4H), 7.50-7.44 (m, 1H), 3.64-3.58 (m, 3H), 3.32-3.24 (m, 2H), 3.22 (s, 3H), 2.22-2.16 (m, 4H). Analytical LC / MS (Method 4): Observed mass: 374.1; Retention time: 0.894 min

[0292] Step B. Example 74 Example 74 was synthesized according to the method described for the preparation of Example 66 (Step D) using Intermediate 74A (70 mg, 0.17 mmol) as the starting material. The crude mixture was purified by preparative HPLC (Preparative Method 2) to give the title compound (33 mg, 0.064 mmol, 38% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.66-8.61 (m, 1H), 8.41-8.34 (m, 1H), 8.27-8.21 (m, 2H), 8.05-7.95 (m, 2H), 6.99-6.91 (m, 1H), 3.39-3.28 (m, 2H), 3.05-2.84 (m, 5H), 2.39-2.13 (m, 3H), 2.11-1.95 (m, 2H), 1.91-1.69 (m, 10H), 1.57-1.43 (m, 2H), 0.85 (d, J=6.5 Hz, 6H).

[0293] Examples 75 and 76 (6R)-2-(3,4-dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (Absolute stereochemistry is optional) [ka] (75-76) Step A. Intermediate 75A. Preparation of (R)-2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry shown optionally) [ka] (75A) Intermediate 75A was obtained as the first-eluting enantiomer of intermediate 31B (1.0 g, 2.9 mmol) by chiral separation using SFC-chiral chromatography under the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiralcel OD-H, 21 × 250 mm. 5 microns; Mobile phase: 55% CO / 45% MeOH w / 0.1% DEA; Flow conditions: 45 mL / min, 120 bar, 30 °C; Detection wavelength: 220 nm; Injection details: 1000 μL, 1000 mg dissolved in 8 mL MeOH-MeCN. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.36 g, 1.1 mmol, 38% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 7.36-7.31 (m, 1H), 7.27-7.19 (m, 2H), 6.98-6.92 (m, 1H), 4.19-4.13 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.77-3.69 (m, 1H), 3.19-3.09 (m, 2H), 3.04-2.96 (m, 1H), 2.83-2.71 (m, 1H), 2.70-2.58 (m, 2H), 2.24-2.14 (m, 1H), 1.94-1.76 (m, 3H), 1.70-1.49 (m, 2H), 1.45-1.27 (m, 2H). Analytical LC / MS (Method 4): Observed mass: 342.1; Retention time: 0.857 min. Chiral analysis (SFC Method 8): Purity: >95 %; Retention time: 6.729 min

[0294] Step B. Intermediate 75B. Preparation of (6R)-6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride (absolute stereochemistry shown optionally) [ka] (75B) To a 40 mL vial was added Intermediate 75A (0.36 g, 1.1 mmol), tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.95 g, 4.2 mmol), DCE (8 mL), and 1,4-dioxane (8 mL). To this mixture was added titanium(IV) isopropoxide (1.6 mL, 5.3 mmol), and the vessel was flushed with N, capped, and stirred at 40 °C. After 18 h, the mixture was cooled to rt, and then sodium triacetoxyborohydride (0.89 g, 4.2 mmol) was added and the reaction continued. After 3 h, the reaction mixture was partitioned between 10% KOH (aqueous, saturated with solid NaCl) (150 mL) and 10% IPA / chloroform (150 mL). The layers were separated, the aqueous phase was extracted with 10% IPA / chloroform (75 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (40 g silica gel cartridge; A = DCM, B = MeOH; 30 min gradient; 0% B to 20% B; flow rate = 80 mL / min). Fractions corresponding to the desired product were combined, concentrated, and dried under reduced pressure. The resulting residue was dissolved in MeOH (10 mL) and 4 M HCl in dioxane (5 mL) and stirred. After 15 min, the solvent was concentrated, the residue was coevaporated with toluene, and the product was dried under reduced pressure to give the title compound (0.11 g, 0.21 mmol, 19% yield) as an off-white solid. 1 H NMR (500 MHz, methanol-d4) δ 7.72-7.69 (m, 1H), 7.30-7.25 (m, 2H), 7.12-7.08 (m, 1H), 4.41-4.35 (m, 1H), 4.28-4.23 (m, 1H), 4.22-4.15 (m, 1H), 4.01-3.95 (m, 1H), 3.91 (d, J=12.9 Hz, 6H), 3.79-3.67 (m, 5H), 3.62-3.59 (m, 1H), 3.29-3.06 (m, 6H), 2.31-2.01 (m, 8H), 1.92-1.77 (m, 4H). Analytical LC / MS (Method 4): Observed mass: 451.1; Retention time: 0.858 min

[0295] Step C. Examples 75 and 76 To a 40 mL vial was added Intermediate 75B (60 mg, 0.12 mmol), isobutyraldehyde (41 mg, 0.57 mmol), AcOH (7.2 μL, 0.13 mmol), magnesium sulfate (210 mg, 1.7 mmol), and DMF (2 mL). The reaction mixture was stirred for 10 minutes, then sodium triacetoxyborohydride (120 mg, 0.57 mmol) was added and the reaction mixture was stirred. After 18 hours, the reaction mixture was diluted with 10% IPA / CHCl3 (40 mL) and filtered. The filtrate was partitioned with 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3 (10 mL), and the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 10% B at 0 min hold, 10-60% B over 20 min, then 100% B at 0 min hold; Flow rate: 20 mL / min; Column temperature: 25 °C. Fraction collection was initiated by MS signal. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 75 (28 mg, 0.055 mmol, 46% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 7.37-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.21 (br d, J=7.9 Hz, 1H), 6.94-6.88 (m, 1H), 4.05 (br s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.62-3.47 (m, 1H), 3.26-3.13 (m, 2H), 3.10-2.93 (m, 1H), 2.92-2.83 (m, 1H), 2.72-2.59 (m, 1H), 2.49-2.31 (m, 3H), 1.91 (s, 5H), 1.78 (br d, J=5.8 Hz, 7H), 1.65 (br d, J=7.6 Hz, 2H), 1.58-1.46 (m, 2H), 1.38 (br d, J=8.2 Hz, 3H), 0.91 (d, J=6.4 Hz, 6H) (1 proton unknown). LC / MS analysis (Method 1): Purity: 100%; Observational quality: 507.29; Holding time: 0.98 min. (Method 2): Purity: 94.2%; Observational quality: 506.99; Holding time: 1.24 min. The compound of Example 76 (25 mg, 0.049 mmol, 41% yield) was dissolved in 2nd order and the opposite body was dissolved. 1 H NMR (500 MHz, DMSO-d6) δ 7.92-7.85 (m, 1H), 7.35-7.24 (m, 2H), 7.15-7.05 (m, 1H), 4.30-4.20 (m, 1H), 4.00-3.85 (m, 2H), 3.82 (d, J=11.6 Hz, 6H), 3.55-3.41 (m, 2H), 3.18 (s, 2H), 3.04-2.91 (m, 2H), 2.80-2.65 (m, 2H), 2.28-1.72 (m, 12H), 1.71-1.34 (m, 5H), 0.97 (br d, J=6.4 Hz, 6H) (Proton 2 unknown). LC / MS analysis (Method 1): Purity: 100%; Observational quality: 507.01; Holding time: 0.98 min. (Method 2): Purity: 100%; Observational quality: 507.0; Holding time: 1.47 min.

[0296] Examples 77 and 78 (6S)-2-(3,4-Dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (Absolute stereochemistry is optional) [ka] Step A. Intermediate 77A. Preparation of (S)-2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry shown optionally) [ka] Intermediate 77A was obtained as the second-eluting enantiomer of chiral separation of Intermediate 31B (1.0 g, 2.9 mmol) by SFC-chiral chromatography using the following conditions: Apparatus: Waters 100 Preparative SFC; Column: Chiralcel OD-H, 21 × 250 mm. 5 microns; Mobile phase: 55% CO / 45% MeOH w / 0.1% DEA; Flow conditions: 45 mL / min, 120 bar, 30 °C; Detection wavelength: 220 nm; Injection details: 1000 μL, 1000 mg dissolved in 8 mL MeOH-MeCN. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.33 g, 0.97 mmol, 33% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 7.36-7.32 (m, 1H), 7.28-7.19 (m, 2H), 6.98-6.91 (m, 1H), 4.25-4.10 (m, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.78-3.72 (m, 1H), 3.22-3.16 (m, 2H), 3.05-2.98 (m, 1H), 2.81-2.67 (m, 3H), 2.24-2.16 (m, 1H), 1.98-1.81 (m, 3H), 1.71-1.53 (m, 2H), 1.47-1.32 (m, 2H). Analytical LC / MS (Method 4): Observed mass: 342.1; Retention time: 0.859 min. Chiral analysis (SFC Method 8): Purity: >95 %; Retention time: 16.297 min

[0297] Step B. Intermediate 77B. Preparation of (6S)-6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride (absolute stereochemistry given optionally) [ka] Intermediate 77B was synthesized according to the method described for the preparation of Intermediate 75B using Intermediate 77A (0.33 g, 0.97 mmol) as the starting material to afford the title compound (0.10 g, 0.19 mmol, 20% yield) as an off-white solid. 1H NMR (500 MHz, methanol-d4) δ 7.71-7.67 (m, 1H), 7.28-7.25 (m, 2H), 7.24-7.21 (m, 1H), 4.43-4.36 (m, 1H), 4.30-4.24 (m, 1H), 4.22-4.13 (m, 1H), 3.99-3.95 (m, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.76 (br s, 2H), 3.69 (br d, J=5.5 Hz, 5H), 3.61 (br d, J=5.0 Hz, 2H), 3.28-3.20 (m, 2H), 3.14-3.01 (m, 3H), 2.45-1.98 (m, 6H), 1.92-1.74 (m, 3H). Analytical LC / MS (Method 4): Observed mass: 451.1; Retention time: 0.857 min

[0298] Step C. Examples 77 and 78 The compounds of Examples 77 and 78 were synthesized according to the method described for the preparation of the compounds of Examples 75 and 76, using Intermediate 77B (50 mg, 0.096 mmol) as the starting material. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 11% B at 0 min hold, 11–58% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was initiated by MS signal. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 77 (22 mg, 0.043 mmol, 45% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 7.36-7.31 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.18 (m, 1H), 6.95-6.87 (m, 1H), 4.10-4.00 (m, 1H), 3.76 (d, J=18.3 Hz, 6H), 3.63-3.46 (m, 3H), 3.21-3.15 (m, 2H), 2.99-2.78 (m, 3H), 2.72-2.60 (m, 1H), 2.18-2.08 (m, 2H), 2.07-1.96 (m, 3H), 1.93-1.69 (m, 5H), 1.68–1.43 (m, 7H), 1.32–1.16 (m, 3H), 0.92–0.77 (m, 6H). Analytical LC / MS (Method 1): Purity: 95.8%; Visual quality: 507.05; Holding time: 1.01 min. (Method 2): Purity: 96.6%; Visual quality: 507.02; Holding time: 1.38 min. The compound of Example 78 (21 mg, 0.041 mmol, 43% yield) was dissolved in 2nd order and the opposite body was dissolved. 1 H NMR (500 MHz, DMSO-d6) δ 7.35-7.32 (m, 1H), 7.31-7.28 (m, 1H), 7.22-7.19 (m, 1H), 6.92-6.89 (m, 1H), 3.77 (s, 3H), 3.75-3.71 (m, 2H), 3.19-3.05 (m, 5H), 2.91-2.78 (m, 3H), 2.71-2.61 (m, 3H), 2.41-2.28 (m, 3H), 2.03-1.88 (m, 6H), 1.77-1.58 (m, 8H), 1.23 (br s, 3H), 0.86 (br d, J = 6.7 Hz, 6H). LC / MS analysis (Method 1): Purity: 99.1%; Observational quality: 506.9; Holding time: 0.94 min. (Method 2): Purity: 100%; Observational quality: 506.9; Holding time: 1.55 min.

[0299] Example 79および80 (6R)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (Absolute stereochemistry is optional) [ka] Step A. Intermediate 79A. Preparation of tert-butyl 4-(2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] Intermediate 79A was prepared according to the procedure described for the preparation of Intermediate 1B (Steps A-B), using 5-bromopyridin-2-amine (1.3 g, 7.5 mmol) as the starting material, substituting 2-bromo-1-(4-(methylsulfonyl)phenyl)ethan-1-one as needed, to afford the title compound (2.8 g, 6.1 mmol, 81% yield over two steps) as a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.60-8.56 (m, 1H), 8.53-8.47 (m, 1H), 8.25-8.18 (m, 2H), 8.00-7.96 (m, 2H), 7.62-7.52 (m, 2H), 6.36-6.26 (m, 1H), 4.05 (br s, 2H), 3.58 (br s, 2H), 3.32 (s, 3H), 3.20-3.17 (m, 1H), 2.76-2.72 (m, 1H), 1.45 (s, 9H). Analytical LC / MS (Method 4): Observed mass: 454.1; Retention time: 1.451 min

[0300] Step B. Intermediate 79B. Preparation of 2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine hydrochloride [ka] Intermediate 79B was synthesized according to the method described for the preparation of Intermediate 31B (Steps A-B) using Intermediate 79A (2.8 g, 6.1 mmol) as the starting material to afford the title compound (0.85 g, 2.1 mmol, 34% yield over two steps) as an off-white solid. 1 H NMR (500 MHz, methanol-d4) δ 7.93 (s, 4H), 7.56-7.52 (m, 1H), 4.26-4.18 (m, 1H), 3.84-3.76 (m, 1H), 3.37 (s, 2H), 3.14 (s, 3H), 3.06-3.00 (m, 1H), 2.86-2.75 (m, 1H), 2.63 (br t, J=12.3 Hz, 2H), 2.25-2.17 (m, 1H), 1.89 (br d, J=12.2 Hz, 2H), 1.83-1.75 (m, 1H), 1.72-1.62 (m, 1H), 1.59-1.49 (m, 1H), 1.44-1.26 (m, 2H). Analytical LC / MS (Method 4): Observed mass: 360.0; Retention time: 0.752 min

[0301] Step C. Preparation of Intermediate 79C. (R)-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry shown optionally) [ka] Intermediate 79C was obtained as the first-eluting enantiomer of chiral separation of Intermediate 79B (0.85 g, 2.4 mmol) by SFC-chiral chromatography using the following conditions: Apparatus: Berger SFC; Column: Chiral OD, 30 × 250 mm, 5 micron; Mobile phase: 70% CO / 30% EtOH w / 0.1% DEA; Flow conditions: 85 mL / min; Detection wavelength: 220 nm; Injection details: 650 μL, 850 mg dissolved in 30 mL EtOH-DEA. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.35 g, 0.97 mmol, 41% yield) as a pale yellow solid. 1H NMR (500 MHz, methanol-d4) δ 7.96-7.89 (m, 4H), 7.57-7.53 (m, 1H), 4.27-4.19 (m, 1H), 3.85-3.74 (m, 1H), 3.14 (s, 4H), 3.08-3.00 (m, 1H), 2.85-2.76 (m, 1H), 2.70-2.61 (m, 2H), 2.25-2.17 (m, 1H), 1.95-1.85 (m, 2H), 1.84-1.77 (m, 1H), 1.73-1.63 (m, 1H), 1.60-1.51 (m, 1H), 1.42-1.30 (m, 3H). Analytical LC / MS (Method 4): Observed mass: 360.0; Retention time: 0.816 min. Chiral analysis (SFC Method 9): Purity: >99 %; Retention time: 12.01 min

[0302] Step D. Intermediate 79D. Preparation of (6R)-6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride (absolute stereochemistry shown optionally) [ka] Intermediate 79D was synthesized following the method described for the preparation of Intermediate 75B using Intermediate 79C (0.35 g, 0.97 mmol) as the starting material to afford the title compound (0.50 g, 0.92 mmol, 95% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.14-8.10 (m, 2H), 8.00 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 4.48-4.41 (m, 2H), 4.30-4.15 (m, 4H), 4.12-3.97 (m, 5H), 3.79-3.69 (m, 4H), 3.18-3.06 (m, 4H), 2.16-2.05 (m, 6H), 1.91-1.79 (m, 5H). Analytical LC / MS (Method): Observed mass: 469.1; Retention time: 0.825 min

[0303] Step E. Examples 79 and 80 The compounds of Examples 79 and 80 were synthesized according to the method described for the preparation of the compounds of Examples 75 and 76, using Intermediate 79D (110 mg, 0.20 mmol) as the starting material. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water with ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with ammonium acetate; Gradient: 12% B at 0 min hold, 12–52% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was initiated by MS signal. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 79 (7.4 mg, 0.014 mmol, 7% yield) was isolated as the first eluting isomer. 1 H NMR (500 MHz, DMSO-d6) δ 7.97-7.92 (m, 2H), 7.88-7.82 (m, 2H), 7.72-7.65 (m, 1H), 4.20-4.04 (m, 1H), 3.79-3.60 (m, 1H), 3.49-3.32 (m, 1H), 3.19 (s, 3H), 2.98-2.84 (m, 3H), 2.78-2.64 (m, 1H), 2.16-1.96 (m, 5H), 1.89-1.73 (m, 4H), 1.72-1.42 (m, 10H), 1.25 (br s, 4H), 0.87 (d, J=6.7 Hz, 6H). Analytical LC / MS (Method 1): Purity: 93.1 %; Observed mass: 524.93; Retention time: 0.89 min. (Method 2): Purity: 95.4 %; Observed mass: 525.21; Retention time: 1.17 min Example 80 (15 mg, 0.029 mmol, 15% yield) was isolated as the second eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 7.94 (br d, J=8.5 Hz, 2H), 7.85 (d, J=8.5 Hz, 2H), 7.68 (s, 1H), 4.18-4.07 (m, 1H), 3.78-3.66 (m, 1H), 3.49-3.35 (m, 1H), 3.19 (s, 5H), 2.93-2.85 (m, 1H), 2.76-2.62 (m, 2H), 2.38-2.28 (m, 1H), 2.03 (br s, 4H), 1.91 (br s, 3H), 1.86-1.49 (m, 11H), 1.25 (br s, (Method 2): Purity: 90.7 %; Observed mass: 525.21; Retention time: 1.41 min.

[0304] Examples 81 and 82 (6S)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (Absolute stereochemistry is optional) [ka] Step A. Intermediate 81A. Preparation of (S)-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry shown optionally) [ka] Intermediate 81A was obtained as the second-eluting enantiomer of intermediate 79B (0.85 g, 2.4 mmol) by chiral separation using SFC-chiral chromatography using the following conditions: Apparatus: Berger SFC; Column: Chiral OD, 30 × 250 mm, 5 microns; Mobile phase: 70% CO / 30% EtOH w / 0.1% DEA; Flow conditions: 85 mL / min; Detection wavelength: 220 nm; Injection details: 650 μL, 850 mg dissolved in 30 mL EtOH-DEA. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.35 g, 0.97 mmol, 41% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 7.98-7.89 (m, 4H), 7.58-7.52 (m, 1H), 4.29-4.16 (m, 1H), 3.87-3.70 (m, 1H), 3.14 (s, 5H), 3.07-3.00 (m, 1H), 2.86-2.75 (m, 1H), 2.67-2.58 (m, 2H), 2.24-2.18 (m, 1H), 1.94-1.86 (m, 2H), 1.81-1.75 (m, 1H), 1.74-1.62 (m, 1H), 1.59-1.50 (m, 1H), 1.43-1.33 (m, 2H). Analytical LC / MS (Method 4): Observed mass: 360.0; Retention time: 0.824 min. Chiral analysis (SFC Method 9): Purity: >99 %; Retention time: 16.21 min

[0305] Step B. Intermediate 81B. Preparation of (6S)-6-(1-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride (absolute stereochemistry shown optionally) [ka] Intermediate 81B was synthesized according to the method described for the preparation of Intermediate 75B using Intermediate 81A (0.35 g, 0.97 mmol) as the starting material to afford the title compound (0.52 g, 0.96 mmol, 99% yield) as a pale yellow solid. 1 H NMR (500 MHz, methanol-d4) δ 8.15-8.08 (m, 2H), 8.02-7.94 (m, 3H), 4.47-4.41 (m, 1H), 4.29-4.17 (m, 3H), 4.12-4.05 (m, 5H), 4.02-3.94 (m, 2H), 3.76-3.70 (m, 2H), 3.37 (s, 4H), 3.16-3.08 (m, 3H), 2.14-2.08 (m, 7H), 1.89-1.83 (m, 3H). Analytical LC / MS (Method 4): Observed mass: 469.1; retention time: 0.826 minutes

[0306] Step C. Examples 81 and 82 Compounds 81 and 81B were synthesized according to the method described for the preparation of compounds 75 and 76, using Intermediate 81B (100 mg, 0.19 mmol) as the starting material. The crude isomeric mixture was purified by preparative HPLC using the following conditions: Column: XBridge C18, 200 mm × 19 mm, 5 μm particles; Mobile Phase A: 5:95 acetonitrile:water containing ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water containing ammonium acetate; Gradient: 0% B at 0 min hold, 0–30% B over 20 min, then 100% B at 0 min hold; Flow Rate: 20 mL / min; Column Temperature: 25°C. Fraction collection was initiated by MS signal. Fractions corresponding to each desired product were combined and dried by centrifugal evaporation. Example 81 (1.1 mg, 0.0021 mmol, 1% yield) was isolated as the first eluting isomer. 1H NMR (500 MHz, DMSO-d6) δ 8.00-7.95 (m, 4H), 7.94-7.91 (m, 1H), 4.26-4.19 (m, 1H), 4.17-4.06 (m, 2H), 3.90-3.77 (m, 1H), 3.50-3.36 (m, 1H), 3.23 (s, 2H), 3.10-2.78 (m, 4H), 2.39-1.82 (m, 15H), 1.74-1.51 (m, 5H), 0.99 (br d, J=6.0 Hz, 6H) (2 protons unclear). Analytical LC / MS (Method 1): Purity: 100%; Observed mass: 525.29; Retention time: 0.86 min. (Method 2): Purity: 87.3%; Observed mass: 525.31; Retention time: 1.19 min. Example 82 (2.9 mg, 0.0055 mmol, 3% yield) was isolated as the second eluting isomer. 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 8.01 (br d, J=13.4 Hz, 4H), 4.31-4.20 (m, 1H), 4.02-3.93 (m, 1H), 3.90-3.81 (m, 1H), 3.64-3.43 (m, 1H), 3.25 (s, 3H), 3.16-3.06 (m, 1H), 2.99 (s, 2H), 2.77 (br s, 4H), 2.31-2.18 (m, 2H), 2.16-1.86 (m, 9H), 1.77-1.48 (m, 4H), 0.97 (br d, J=6.4 Hz, 6H) (4 protons ambiguous). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 524.97; Retention time: 0.8 min. (Method 2): Purity: 95.6 %; Observed mass: 525.30; Retention time: 1.42 min

[0307] The following example compounds were prepared according to the general procedures described herein using the appropriate starting materials, reactants and conditions. [Table 1] Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12

[0308] Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24]

[0309] Example 142 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine [ka] Step A. Intermediate 142A. Preparation of 6-bromo-2-(3,4-dimethoxyphenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine [ka] Intermediate 142A was synthesized following the general method described for the preparation of Intermediate 60A using 5-bromo-3-methylpyridin-2-amine (1.0 g, 5.6 mmol) as the starting material. The crude product was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min) to afford the title compound (1.3 g, 3.8 mmol, 67% yield) as an off-white solid. 1H NMR (chloroform-d) δ: 8.53-8.59 (m, 1H), 7.88 (dd, J=8.3, 1.9 Hz, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.36 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 347.8; Retention time: 0.99 min

[0310] Step B. Example 142 To a 20 mL vial was added Intermediate 142A (17 mg, 0.050 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (17 mg, 0.050 mmol), followed by 1,4-dioxane (3 mL) and 2 M potassium phosphate (88 μL, 0.18 mmol). The vial was purged with N2, and then XPhos Pd G3 (4.2 mg, 5.0 μmol) was added. The vial was purged again with N2, and the reaction was stirred at 85 °C. After 15 h, the reaction mixture was cooled, diluted with water (5 mL), and extracted with EtOAc (2 × 5 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 30 mL / min). Pure fractions were combined, concentrated, and dried under reduced pressure to afford the title compound (16 mg, 0.033 mmol, 67% yield) as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ 8.73-8.61 (m, 1H), 7.92 (dd, J=8.4, 2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 3.83 (m, 2H), 3.70 (m, 3H), 3.46 (m, 2H), 3.12 (m, 2H), 2.81 (s, 3H), 1.46 (d, J=6.7 Hz, 6H). Analytical LC / MS (Method 5): Observed mass: 472.1; Retention time: 0.80 min

[0311] Example 143 2-(3,4-Dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)cyclohexyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka] To a hydrogenation flask was added the compound from Example 142 (30 mg, 0.064 mmol), 3 M HCl in dioxane (0.21 mL, 0.64 mmol), platinum(IV) oxide (7 mg), methanol (5 mL), and THF (5 mL). The suspension was stirred under hydrogen at 30 PSI. After 3 hours, the reaction mixture was filtered, the filter cake was washed with MeOH (10 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (4.7 mg, 9.6 μmol, 15% yield). 1H NMR (DMSO-d6) δ: 7.53 (dd, J=8.4, 1.7 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.19-4.43 (m, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 2.89-3.05 (m, 4H), 2.50-2.53 (m, 6H), 2.14-2.30 (m, 2H), 1.82-1.96 (m, 4H), 1.68-1.82 (m, 6H), 1.55 (br s, 4H), 1.24 (d, J=6.6 Hz, 6H). Analytical LC / MS (Method 1): Purity: 98.5%; Observed Mass: 482.0; Retention Time: 1.46 min. (Method 2): Purity: 99.0%; Observed Mass: 482.0; Retention Time: 1.12 min.

[0312] Example 144 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka] To a hydrogenation flask was added the compound of Example 142 (30 mg, 0.064 mmol), Pd / C (7 mg), methanol (5 mL), and THF (5 mL). The suspension was stirred under hydrogen at 15 PSI. After 12 hours, the reaction mixture was filtered, the filter cake was washed with MeOH (10 mL), and the filtrate was concentrated. The crude product was purified by preparative HPLC (Preparative Method 1) to give the title compound (6.5 mg, 0.013 mmol, 21% yield). 1H NMR (DMSO-d6) δ: 7.56 (dd, J=8.2, 1.8 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.24 (br d, J=8.5 Hz, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.91 (br d, J=8.5 Hz, 2H), 4.26-4.40 (m, 1H), 4.05 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.44-3.61 (m, 2H), 3.30 (br s, 1H), 3.04-3.18 (m, 4H), 2.65 (dt, J=13.0, 6.3 Hz, Analytical LC / MS (Method 1): Purity: 98.1 %; Observed mass: 476.3.

[0313] Example 145 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine [ka] Step A. Preparation of Intermediate 145A 6-bromo-2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Intermediate 145A was synthesized following the general method described for the preparation of Intermediate 60A using 5-bromo-pyridin-2-amine (1.0 g, 5.8 mmol) as the starting material. The crude product was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min) to afford the title compound (1.2 g, 3.7 mmol, 64% yield) as a pale yellow solid.1 H NMR (chloroform-d) δ: 8.68-8.79 (m, 1H), 7.89 (dd, J=8.4, 1.7 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.63-7.68 (m, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 4.04 (s, 3H), 3.98 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 334.0; Retention time: 0.91 min

[0314] Step B. Intermediate 145B. Preparation of tert-butyl 3-(2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate [ka] Intermediate 145B was synthesized according to the general method described for the preparation of Example 142 (Step B), using Intermediate 145A (100 mg, 0.30 mmol) as the starting material, substituting tert-butyl-(1R,5S)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (100 mg, 0.30 mmol) as needed. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 20 min gradient; 0% B to 100% B; flow rate = 40 mL / min) to afford the title compound (130 mg, 0.27 mmol, 91% yield) as a gum. 1H NMR (chloroform-d) δ: 8.48 (s, 1H), 7.88 (dd, J=8.3, 1.9 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.58-7.69 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.57 (br s, 1H), 4.57 (br s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 2.14-2.34 (m, 2H), 1.91-2.12 (m, 2H), 1.60-1.78 (m, 2H), 1.46 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 463.0; Retention time: 1.03 minutes

[0315] Step C. Preparation of Intermediate 145C. tert-butyl 3-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Intermediate 145C was synthesized using Intermediate 145B (120 mg, 0.260 mmol) as the starting material according to the general method described for the preparation of Example 144. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (63 mg, 0.130 mmol, 52% yield). 1H NMR (chloroform-d) δ: 7.64-7.64 (m, 1H), 7.57 (d, J=1.7 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.19-4.48 (m, 3H), 3.96 (s, 3H), 3.95 (s, 3H), 3.73-3.94 (m, 2H), 3.37-3.73 (m, 1H), 3.35-3.35 (m, 1H), 2.94-3.15 (m, 1H), 2.25 (br d, J=8.5 Hz, 2H), 1.98-2.16 (m, 2H), 1.88-1.92 (m, 1H), 1.55-1.70 (m, 5H), 1.50 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 469.1; Retention time: 0.938 min

[0316] Step D. Intermediate 145D. Preparation of 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine hydrochloride [ka] Intermediate 145D was synthesized using Intermediate 145C (100 mg, 0.21 mmol) as the starting material following the general method described for the preparation of Example 60 (Step D). The crude product was used directly without further purification. 1H NMR (methanol-d4) δ: 8.16-8.25 (m, 1H), 7.81-7.84 (m, 1H), 7.73-7.77 (m, 1H), 4.29-4.48 (m, 3H), 4.16 (s, 3H), 4.05 (s, 3H), 3.73-3.99 (m, 2H), 3.37-3.73 (m, 1H), 3.05-3.35 (m, 1H), 2.98-3.15 (m, 1H), 2.45 (br d, J=8.5 Hz, 2H), 1.98-2.10 (m, 2H), 1.82-1.92 (m, 1H), 1.66-1.70 (m, 5H). Analytical LC / MS (Method 5): Observed mass: 369.2; Retention time: 0.663 min

[0317] Step E. Example 145 Example 145 was synthesized according to the general method described for the preparation of Example 60 (Step E) using Intermediate 145D (30 mg, 0.062 mmol) and 1-cyclopropylpiperidin-4-one (26 mg, 0.190) as starting materials. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (17 mg, 0.035 mmol, 57% yield). 1H NMR (DMSO-d6) δ: 7.50-7.55 (m, 1H), 7.41-7.49 (m, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.20 (br dd, J=12.2, 4.6 Hz, 1H), 3.81 (s, 3H), 3.78 (s,3H), 3.53-3.66 (m, 2H), 2.92 (br d, J=8.2 Hz, 3H), 2.27-2.46 (m, 1H), 2.16 (br t, J=11.1 Hz, 3H), 1.98-2.09 (m, 2H), 1.81-1.95 (m, 7H), 1.44-1.66 (m, 6H), 1.27 (br d, J=12.5 Hz, 3H), 0.33-0.46 (m, 2H), 0.29 (br s, 2H). Analytical LC / MS (Method 1): Purity: 100%; Observed mass: 492.3; Retention time: 1.284 min. 100 %; Observed mass: 492.3; Retention time: 1.048 min

[0318] Example 146 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Step A. Intermediate 146A. Preparation of tert-butyl 3-(2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Intermediate 146A was synthesized using Intermediate 145B (120 mg, 0.26 mmol) as the starting material according to the general method described for the preparation of Example 144. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (55 mg, 0.12 mmol, 47% yield). 1 H NMR (chloroform-d) δ: 8.51 (s, 1H), 8.27 (br d, J=9.3 Hz, 1H), 7.86 (br d, J=8.5 Hz, 1H), 7.78 (d, J=1.5 Hz, 2H), 7.04 (d, J=8.6 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.22-3.39 (m, 1H), 2.72-2.99 (m, 1H), 2.52-2.67 (m, 1H), 2.39 (br s, 1H), 2.05-2.24 (m, 3H), 1.86-1.95 (m, 3H), 1.63-1.69 (m, 1H), 1.53 (s, 9H). Analytical LC / MS (Method 5): Observed mass: 465.1; Retention time: 1.018 min

[0319] Step B. Intermediate 146B. Preparation of 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine hydrochloride [ka] Intermediate 146B was synthesized using Intermediate 146A (100 mg, 0.21 mmol) as the starting material following the general method described for the preparation of Example 60 (Step D). The crude product was used directly without further purification. 1H NMR (methanol-d4) δ: 8.57 (s, 1H), 8.25 (br d, J=9.3 Hz, 1H), 7.84 (br d, J=8.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.20-3.37 (m, 1H), 2.71-2.95 (m, 1H), 2.49-2.63 (m, 1H), 2.36 (br s, 1H), 2.00-2.16 (m, 3H), 1.80-1.91 (m, 3H), 1.60-1.66 (m, 1H). Analytical LC / MS (Method 5): Observed mass: 365.1; Retention time: 0.690 min

[0320] Step C. Example 146 Example 146 was synthesized according to the general method described for the preparation of Example 60 (Step E) using Intermediate 146B (30 mg, 0.063 mmol) and 1-cyclopropylpiperidin-4-one (26 mg, 0.19) as starting materials. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (29 mg, 0.060 mmol, 96% yield). 1H NMR (DMSO-d6) δ: 8.88 (s, 1H), 8.78 (s, 1H), 7.75 (br dd, J=9.5, 4.6 Hz, 2H), 7.64-7.72 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 3.05-3.23 (m, 2H), 2.88-2.97 (m, 2H), 2.08-2.24 (m, 3H), 1.74-1.98 (m, 8H), 1.53-1.63 (m, 2H), 1.42 (br d, J=7.3 Hz, 1H), 1.18-1.33 (m, 3H), 0.35-0.46 (m, 2H), 0.30 (br s, 2H). Analytical LC / MS (Method 1): Purity: 100 %; Observed mass: 488.3; Retention time: 1.375 min. (Method 2): Purity: 100 %; Observed mass: 488.3; Retention time: 1.110 minutes

[0321] Example 147 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Step A. Intermediate 147A. Preparation of 6-bromo-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Intermediate 147A was synthesized according to the general method described for the preparation of Intermediate 60A using 5-bromo-3-methylpyridin-2-amine (2.0 g, 11 mmol) and 4-(methylsulfonyl)benzonitrile (2.3 g, 13 mmol) as starting materials. The crude product was purified by flash column chromatography (80 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min) to afford the title compound (2.3 g, 6.3 mmol, 59% yield) as a tan solid. 1 H NMR (chloroform-d) δ: 8.63 (s, 1H), 8.46-8.56 (m, J=8.5 Hz, 2H), 8.08 (d, J=8.5 Hz, 2H), 7.45 (s, 1H), 3.13 (s, 3H), 2.72 (s, 3H). Analytical LC / MS (Method 5): Observed mass: 365.7; Retention time: 0.936 min

[0322] Step B. Example 147 Example 147 was synthesized according to the general method described for the preparation of Example 142 (Step B) using Intermediate 147A (110 mg, 0.30 mmol) as the starting material. The crude product was purified by preparative HPLC (Preparative Method 1) to afford the title compound (120 mg, 0.24 mmol, 81% yield). 1H NMR (chloroform-d) δ: 8.63 (s, 1H), 8.54 (d, J=8.2 Hz, 2H), 8.09 (d, J=8.3 Hz, 2H), 7.53-7.59 (m, 3H), 7.06 (d, J=8.6 Hz, 2H), 3.79 (br d, J=12.9 Hz, 2H), 3.63 (br d, J=10.7 Hz, 2H), 3.42-3.58 (m, 3H), 3.14 (s, 3H), 3.09 (s, 2H), 2.78 (s, 3H), 1.45 (d, J=6.7 Hz, 6H). Analytical LC / MS (Method 1): Purity: 100%; Observed mass: 492.3; Retention time: 1.284 min. (Method 2): Purity: 100%; Observed mass: 490.2; Retention time: 0.722 min.

[0323] The following example compounds were prepared according to the general procedures used elsewhere herein using the appropriate starting materials, reactants and conditions. [Table 25] [Table 26] [Table 27] [Table 28]

[0324] [Table 29] [Table 30] [Table 31] [Table 32]

[0325] Biological assays The pharmacological properties of the compounds of the invention may be confirmed by several biological assays. The following exemplary biological assays have been carried out with the compounds of the invention.

[0326] TLR7 / 8 / 9 inhibition reporter assay HEK-Blue overexpressing human TLR7, TLR8, or TLR9 receptors TM We used cells (Invivogen) to screen for inhibitors of these receptors using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites. Briefly, cells were seeded into Greiner 384-well plates (15,000 cells per well for TLR7, 20,000 cells per well for TLR8, and 25,000 cells per well for TLR9) and then treated with DMSO solutions of compounds at final dose-response concentrations ranging from 0.05 nM to 50 μM. After a 30-minute pretreatment with compounds at room temperature, cells were stimulated with TLR7 ligand (gardiquimod at a final concentration of 7.5 μM), TLR8 ligand (R848 at a final concentration of 15.9 μM), or TLR9 ligand (ODN2006 at a final concentration of 5 nM) to activate NF-κB and AP-1, which induces SEAP production. After 22 hours of incubation at 37°C and 5% CO2, SEAP levels were assessed using HEK-Blue, a cell culture medium that allows SEAP detection, according to the manufacturer's specifications. TM Detection reagent (Invivogen) is added and determined. Percent inhibition is determined as the % reduction in HEK-Blue signal present in wells treated with agonist and DMSO alone compared to wells treated with a known inhibitor.

[0327] [Table 33] [Table 34] [Table 35] [Table 36] nd: not measured

Claims

1. Formula (II): 【Chemistry 1】 [During the ceremony, X is N or CR ３ and Q １ and Q ２ One of them is A and the other is Q １ and Q ２ The other is R ５ and G is -S(O) ２ CH ３ , -S(O) ２ (phenyl), —S(O) ２ NR ｘ R ｘ or —S(O)(NH)NR ｘ R ｘ phenyl substituted with any one of A is cyclohexyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl or 8-azabicyclo[3.2.1]octanyl, each of which is -L-R ４ and 0 to 1 R ４ｂ is substituted with; L is a bond, -CR ｘ R ｘ - or -C(O)(CR ｘ R ｘ ) ０－２ - and; R ３ are hydrogen, F, Cl, C １－３ Alkyl, C １－２ Fluoroalkyl or C ３－４ is cycloalkyl; R ４ teeth: (i)-N(CH ３ ) ２ ; (ii) pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, pyridinyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with 0-2 R 4a ; or (iii) 【Chemistry 2】 and Each R ４ａ is independently C １－６ Alkyl, C １－３ Fluoroalkyl, -(CH ２ ) ０－２ O(C １－２ alkyl), C ３－６ Cycloalkyl, —CH ２ (C ３－６ cycloalkyl), -C(O)(C １－４ alkyl), -C(O)(C ３－６ -cycloalkyl), -C(O)(phenyl), -C(O)CH ２ (C ３－６ cycloalkyl), —C(O)CH ２ (phenyl), -C(O)O(C １－４ alkyl), oxetanyl, tetrahydrofuran or tetrahydropyranyl; R ４ｂ is F, Cl or -CH ３ and Each R ４ｃ is independently C １－６ Alkyl, C １－３ Fluoroalkyl, —CH ２ (C ３－６ cycloalkyl), -C(O)(C １－４ alkyl), —C(O)(phenyl), —C(O)CH ２ (phenyl), -C(O)OCH ２ CH ３ or C ３－６ is cycloalkyl; Each R ５ are independently hydrogen, F, Cl, C １－３ Alkyl, C １－２ Fluoroalkyl or C ３－４ is cycloalkyl; Each R ｘ are independently hydrogen or —CH ３ and m is 0, 1 or 2; and n is 0, 1 or 2. or a salt thereof.

2. X is CR ３ 2. The compound of claim 1, wherein:

3. 2. The compound of claim 1, or a salt thereof, wherein X is N.

4. G is -S(O) ２ CH ３ is phenyl substituted with; A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octanyl, and each is -L-R ４ is substituted with; L is a bond; R ３ is hydrogen; R ４ is piperidinyl, piperazinyl, azepanyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, and each R ４ａ is substituted with; R ４ａ -CH(CH ３ ) ２ , -CH ２ CH(CH ３ ) ２ , -CH ２ CH ２ OCH ３ , —C(O)CH(CH ３ ) ２ , —C(O)(cyclopropyl), —CH ２ (cyclopropyl), -CH ２ (cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl; and Each R ５ is hydrogen, F or -CH ３ That is, The compound of claim 1 or a salt thereof.

5. G 【Transformation 3】 2. The compound of claim 1, wherein:

6. 10. The compound of claim 1, which is: 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (7); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (8); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (9); 6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (62-63); 7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (66); 8-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (67); 8-fluoro-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (68-69); 7-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (70); 8-fluoro-6-(1-(1-isopropylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (71-72); 5-fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (73); 8-fluoro-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (74); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (83-84); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (85-86); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (87-88); 6-(1-(8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (89-90); 6-(1'-cyclobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (91); 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (92); 6-(1'-(cyclobutylmethyl)-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (93); 6-(4-(4-isobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (99); 6-(4-(4-(cyclopropylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (100); 6-(4-(4-(cyclobutylmethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (101); 6-(4-(4-cyclobutylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (102); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (103); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (104); 6-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (105); 7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (106); 8-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (107); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (108); 6-(1'-(cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (109); 6-(1′-cyclobutyl-[1,4′-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (110); 8-Fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1'-(oxetan-3-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (111); 8-Fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (112); 8-fluoro-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (113-114); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (115-116); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (117); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (118); 8-Fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(oxetan-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (119-120); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (121-122); 7-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (123); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-7-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (124); 8-fluoro-6-(1-(1-isobutylazepan-4-yl)piperidin-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (125-126); 6-(1-(1-(cyclopropylmethyl)azepan-4-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (127-128); 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6-(1-(1-(tetrahydro-2H-pyran-4-yl)azepan-4-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (129-130); 5-fluoro-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (131); 8-fluoro-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (132); 8-Fluoro-2-(4-(methylsulfonyl)phenyl)-7-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-bipiperidin]-4-yl)imidazo[1,2-a]pyridine (133); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (147); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (153); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (159); 6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]octan-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (160); 6-(1'-cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (161); 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (162); 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (163); or 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (167).

7. 10. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 6 or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for treating pathological fibrosis.

9. 9. The pharmaceutical composition of claim 8, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.

10. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for treating non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC).

11. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for treating idiopathic pulmonary fibrosis (IPF).

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