Imidazo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine derivatives as tlr9 inhibitors for the treatment of fibrosis

Abstract

The present invention relates to imidazo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine derivatives of Formula (I): or a salt or prodrug thereof. These compounds are TLR9 inhibitors useful for the treatment, prevention or slowing of a fibrotic disease, such as liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 067,452, filed on August 19, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention generally relates to substituted bicyclic compounds suitable as inhibitors of Toll-like receptor 9 (TLR9) signaling. Substituted bicyclic compounds, compositions comprising such compounds, and methods of using them are provided herein. The invention further relates to pharmaceutical compositions containing at least one compound according to the invention, which can be used to treat conditions associated with TLR9 regulation, such as inflammatory diseases and autoimmune diseases; and methods for inhibiting TLR9 activity in mammals. Background Technology

[0004] Toll-like receptors (TLRs) are transmembrane proteins that can trigger an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs) or microbe-associated molecular patterns (MAMPs). A total of 10 human TLRs have been identified, which may be located on the cell surface or, in the case of TLR7, TLR8, and TLR9, in lysosomes. TLR9 recognizes unmethylated single-stranded DNA containing the cytosine-phosphate-guanine (CpG) motif, which is commonly found in bacterial and mitochondrial DNA (mtDNA). TLR9 can promote inflammation via the MyD88-dependent signaling pathway, ultimately mediating the activation of IL-6, IFN-α, IL-1β, TNF-α, and other cytokines, thereby promoting fibrosis. (Barton GM, Kagan JC (2009) Nat. Rev. Immunol. 9(8), 535-42; Li X, Jiang S, Tapping RI (2010), Cytokine 49(1), 1-9).

[0005] TLR9 levels in lung biopsies of rapid progressors of idiopathic pulmonary fibrosis (IPF) are higher than in healthy or stable IPF progressors (Sci. Transl. Med. 2010, 2(57): 57ra82). Recently, the ligand of TLR9, circulating mtDNA, has been identified as a mechanism-based IPF prognostic biomarker (Am J. Resp. and Crit. Care Med. 2017, 196(12), 1502). In addition, it has been observed that TLR9 is upregulated in human and murine nonalcoholic steatohepatitis (NASH) (Clin. Sci. 2017, 131(16), 2145), and activation of hepatocyte mitochondrial DNA via TLR9 causes NASH (J. Clin. Inv. 2016, 126(3), 859). Therefore, inhibitors / antagonists of TLR9 are predicted to have efficacy as novel therapeutic agents for treating fibrotic diseases.

[0006] TLR9 inhibition has been recognized as a potential approach to treat fibrotic diseases, including idiopathic pulmonary fibrosis (Trujillo et al. Sci. Transl. Med. 2010, 2(57): 57ra82; Yoshizaki et al. Ann Rheum Dis. October 2016; 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. October 2016; 75(10): 1858-65); as well as heart failure (Oka et al. Nature 485, pp. 251-255 (2012)) and hypertension (McCarthy et al. Cardiovascular Research, 2015, pp. 119-130).

[0007] There remains a need for compounds useful as TLR9 inhibitors. In addition, there remains a need for compounds useful as TLR9 inhibitors selective for TLR7 or TLR8.

[0008] In view of the conditions that can benefit from treatment involving modulation of Toll-like receptors, novel compounds capable of inhibiting TLR9 and methods of using these compounds can clearly provide substantial therapeutic benefit to a wide variety of patients.

[0009] Applicants have discovered potent compounds having TLR9 inhibitor activity. In addition, Applicants have discovered compounds having activity as TLR9 inhibitors and selectivity for TLR7 or TLR8. The compounds provided are useful as pharmaceuticals having the requisite stability, bioavailability, therapeutic index, and toxicity values that are critical to their usefulness as pharmaceuticals. SUMMARY

[0010] The present invention relates to a novel class of substituted bicyclic compounds discovered to be potent inhibitors of TLR9 signaling. The compounds provided are useful as pharmaceuticals having the requisite stability, bioavailability, therapeutic index, and toxicity values that are critical to their usefulness as pharmaceuticals.

[0011] The present invention provides a compound of Formula (I), or a stereoisomer, N-oxide, tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, useful as an inhibitor of Toll-like Receptor 9 signaling and useful in the treatment of fibrotic diseases.

[0012] The present invention also provides a pharmaceutical composition 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.

[0013] The present invention also provides a method of inhibiting Toll-like Receptor 9 comprising administering to a subject 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 of treating a fibrotic disease comprising administering to a subject 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.

[0015] The present invention also provides a method of treating a disease or disorder associated with Toll-like Receptor 9 activity, the method comprising administering to a mammal in need thereof at least one compound of Formula (I) or salts, solvates, and prodrugs thereof.

[0016] The present invention also provides processes and intermediates for making the compounds of Formula (I), including salts, solvates, and prodrugs thereof.

[0017] The present invention also provides at least one compound of Formula (I) or salts, solvates, and prodrugs thereof, for use in therapy.

[0018] The present application also provides the use of at least one compound of Formula (I), or salts, solvates, and prodrugs thereof, for the manufacture of a medicament for treating or preventing a Toll-like Receptor 9 associated condition, such as an allergic disease, an autoimmune disease, an inflammatory disease, and a proliferative disease.

[0019] The compounds of Formula (I) and compositions comprising the compounds of Formula (I) are useful for treating, preventing, or curing various Toll-like Receptor 9 associated conditions. Pharmaceutical compositions comprising these compounds are suitable 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.

[0020] These and other features of the present application will be set forth in the continuation of the specification. DETAILED DESCRIPTION

[0021] A first aspect of the present application provides at least one compound of Formula (I):

[0022]

[0023] or a stereoisomer, tautomer, solvate, or salt thereof, wherein:

[0024] two dashed lines represent two single bonds or one double bond; and R 5a and R 5b is present only when the two dashed lines represent two single bonds; X is N or CR3;

[0025] one of Q1and Q2is A and the other of Q1and Q2is R5;

[0026] G is:

[0027] (i) phenyl substituted with one to three substituents independently selected from 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 ;

[0028]

[0029]

[0030] (v) a 9-membered heterocycle selected from:

[0031]

[0032]

[0033]

[0034] (vi) a 10-membered heterocyclic ring selected from:

[0035]

[0036] A is cyclohexyl, piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octyl, or azabicyclo[3.2.1]octyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituents;

[0037] L is a bond, -CR x R x - or -C(O)(CR x R x ) 0-2 -;

[0038] each R2is 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 hydroxyalkyl), -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 1-3 alkyl), -S(O)2N(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, dioxidothiomorpholinyl, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or -C(O)(thiazolyl);

[0039] 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;

[0040] each R 2b is independently hydrogen, halo, -CN, -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)NRx (C 1-3 alkyl), -CR x =CR x R x or -CR x =CH(C 3-6 cycloalkyl);

[0041] R 2c is R 2a or R 2b ;

[0042] R 2d is R 2a or R 2b ; provided that one of R 2c and R 2d is R 2a , and the other of R 2c and R 2d is R 2b ;

[0043] R3is hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl;

[0044] R4is:

[0045] (i) -N(CH3)2;

[0046] (ii) pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, pyridinyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with zero to 2 R 4a ; or

[0047]

[0048] 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 1-4 alkyl), oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl;

[0049] R 4b is F, Cl, or -CH3;

[0050] 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 cycloalkyl;

[0051] each R5is independently hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl;

[0052] R 5a and R 5b are independently hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl;

[0053] each R x is independently hydrogen or -CH3;

[0054] each R y is independently hydrogen or C 1-6 alkyl;

[0055] m is 0, 1, or 2;

[0056] n is 0, 1, or 2;

[0057] p is 0, 1, 2, 3, or 4; and

[0058] q is 1 or 2.

[0059] A second aspect of the application provides at least one compound of Formula (I):

[0060]

[0061] or salts thereof, wherein:

[0062] both dashed lines represent two single bonds or two double bonds; and R 5a and R 5b are present only when both dashed lines represent two single bonds; X is N or CR3;

[0063] one of Q1and Q2is A and the other of Q1and Q2is R5;

[0064] G is:

[0065] (i) phenyl substituted with 1 to 3 substituents independently selected from F, CI, 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 ;

[0066]

[0067] (v) a 9-membered heterocyclic ring selected from:

[0068]

[0069]

[0070]

[0071]

[0072] (vi) a 10-membered heterocyclic ring selected from:

[0073]

[0074]

[0075] A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituents;

[0076] L is a bond, -CR x R x - or -C(O)(CR x R x ) 0-2 -;

[0077] each R2is 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), C1-3 Fluoroalkoxy, -(CH2) 1-4 O(C 1-3 Alkyl group), -O(CH2) 1-2 OC(O)(C 1-3 Alkyl group), -O(CH2) 1-2 NR x R x -C(O)O(C 1-3 Alkyl group), -(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 1-3 Alkyl), -S(O)2N(C 1-3 Alkyl)2、-S(O)(NH)N(C 1-3 Alkyl group 2, -(CH2) 0-2 (C 3-6 cycloalkyl), -(CH2) 0-2 (phenyl), morpholino, dioxothiomorpholino, dimethylpyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl or -C(O)(thiazolyl);

[0078] R 2a 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)NRx R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;

[0079] each R 2b is independently hydrogen, halo, -CN, -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);

[0080] R 2c is R 2a or R 2b ;

[0081] R 2d is R 2a or R 2b ; provided that one of R 2c and R 2d is R 2a , and the other of R 2c and R 2d is R 2b ;

[0082] R3is hydrogen, F, Cl, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl;

[0083] R4is:

[0084] (i) -N(CH3)2;

[0085] (ii) pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octyl, each of which is substituted with 0 to 2 R4a Replace; or

[0086]

[0087] Each R 4a Independently for 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);

[0088] R 4b It can be F, Cl, or -CH3;

[0089] Each R 4c Independently for 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 cycloalkyl;

[0090] Each R5 is independently hydrogen, F, Cl, or C. 1-3 Alkyl, C 1-2 fluoroalkyl or C 3-4 cycloalkyl;

[0091] R 5a and R 5b Independently hydrogen, F, Cl, C 1-3 Alkyl, C 1-2 fluoroalkyl or C 3-4 cycloalkyl;

[0092] Each R x Independently hydrogen or -CH3;

[0093] Each R y Independently hydrogen or C 1-6 alkyl;

[0094] m is 0, 1, or 2;

[0095] n is 0, 1, or 2;

[0096] p is 0, 1, 2, 3, or 4; and

[0097] q is 1 or 2.

[0098] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond. Compounds of this embodiment have the structure of Formula (II):

[0099]

[0100] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond and X is CR3. Compounds of this embodiment have the structure of Formula (IIa):

[0101]

[0102] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond and X is N. Compounds of this embodiment have the structure of Formula (IIb):

[0103]

[0104] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond; X is CR3; Q1 is A; and Q2 is R5. Compounds of this embodiment have the structure of Formula (IIa-1):

[0105]

[0106] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond; X is CR3; Q1 is R5; and Q2 is A. Compounds of this embodiment have the structure of Formula (IIa-2):

[0107]

[0108] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a double bond; X is N; Q1 is A; and Q2 is R5. Compounds of this embodiment have the structure of Formula (IIb-1):

[0109]

[0110] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds; X is CR3; Q1 is A; and Q2 is R5. Compounds of this embodiment have the structure of Formula (IIIa-1):

[0111]

[0112] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds. Compounds of this embodiment have the structure of Formula (III):

[0113]

[0114] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds and X is CR3. Compounds of this embodiment have the structure of Formula (Ilia):

[0115]

[0116] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds and X is CR3. Compounds of this embodiment have the structure of Formula (Ilia):

[0117]

[0118] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds; X is CR3; Q1 is A; and Q2 is R5. Compounds of this embodiment have the structure of Formula (IIIa-1):

[0119]

[0120] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent two single bonds; X is CR3; Q1 is A; and Q2 is R5. Compounds of this embodiment have the structure of Formula (IIIa-1):

[0121]

[0122] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a single bond; X is N; Q1is A; and Q2is R5. Compounds of this embodiment have the structure of Formula (IIIb-1):

[0123]

[0124] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein both dashed lines represent a single bond; X is N; Q1is R5; and Q2is A. Compounds of this embodiment have the structure of Formula (IIIb-2):

[0125]

[0126] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein G is phenyl substituted with one to two substituents independently selected from F, -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2. Also included in this embodiment are compounds in which G is phenyl substituted with one to two substituents independently selected from F, -OCH3, and -S(O)2CH3. Also included in this embodiment are compounds in which G is:

[0127] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein G is Included in this embodiment are compounds in which each R2is 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 in which each R2is independently F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl. Additionally, included in this embodiment are compounds in which p is 2; one R2is -CH3; and the other R2is F, Cl, -CN, -CH3, -OCH3, -NH2, or cyclopropyl.

[0128] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a 9-membered heterocycle selected from:

[0129]

[0130]

[0131]

[0132] Included in this embodiment are compounds in which G is:

[0133]

[0134] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is a 10-membered heterocycle selected from:

[0135]

[0136] Included in this embodiment are compounds in which G is:

[0137]

[0138] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is:

[0139] (i) phenyl substituted with 1 to 2 substituents independently selected from the group consisting of -OCH3, -S(O)2CH3, -S(O)2N(CH3)2, and -S(O)(NH)N(CH3)2;

[0140]

[0141]

[0142] Included in this embodiment are compounds in which each R2is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3.

[0143] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein p is 0, 1, 2, or 3. Included in this embodiment are compounds in which p is 1 or 2.

[0144] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein A is cyclohexyl, piperidinyl, phenyl, pyridinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted. Included in this embodiment are compounds in which A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4.

[0145] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted. Included in this embodiment are compounds in which A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4. Also included in this embodiment are compounds in which A is piperidinyl or 6-azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4.

[0146] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein A is piperidinyl, phenyl, or pyridinyl, each of which is substituted with -L-R4and 0 to 1 R 4bsubstituted. Included in this embodiment are compounds in which A is piperidinyl or phenyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted. Also included in this embodiment are compounds in which A is phenyl or pyridinyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted.

[0147] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein A is piperidinyl, phenyl, pyridinyl, or pyrimidinyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted; and L is a bond. Included in this embodiment are compounds in which A is piperidinyl, phenyl, or pyridinyl, each of which is substituted with -L-R4and 0 to 1 R 4b substituted; and L is a bond.

[0148] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein L is a bond.

[0149] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein L is -CR x R x -. Included in this embodiment are compounds in which L is -CH2-.

[0150] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein L is -C(O)(CR x R x ) 0-2 -. Included in this embodiment are compounds in which L is -C(O)(CH2) 0-2 -. Also included in this embodiment are compounds in which L is -C(O)(CH2) 0-1 -. Additionally, included in this embodiment are compounds in which L is -C(O)-.

[0151] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein L is -CR x R x - or -C(O)(CR x R x ) 0-2 -. Included in this embodiment are compounds in which L is -CR x R x - or -C(O)(CR x R x ) 0-1-CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. Included in this embodiment are compounds in which L is -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. x R x -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. Included in this embodiment are compounds in which L is -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. x -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. Included in this embodiment are compounds in which L is -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2.

[0152] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein L is a bond, -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. Included in this embodiment are compounds in which L is -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. 0-2 -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2. Included in this embodiment are compounds in which L is -CH2- or -C(O)(CH2)n-; n is 1 or 2; and R4is -N(CH3)2.

[0153] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein R4is -N(CH3)2.

[0154] In one embodiment, a compound of Formula (I), or a salt thereof, is provided wherein R4is pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octyl, each substituted with zero to 2 R 4a Included in this embodiment are compounds in which R4is piperidinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octyl, each substituted with R 4a Included in this embodiment are compounds in which R4is piperidinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octyl, each substituted with R

[0155] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein R4is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to 2 R 4a Included in this embodiment are compounds in which R4is piperidinyl, piperazinyl, or pyridinyl. Also included in this embodiment are compounds in which R4is piperidinyl or piperazinyl.

[0156] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein R4is Included in this embodiment are compounds in which n is 1 or 2. Also included in this embodiment are compounds in which n is 1. Further included in this embodiment are compounds in which n is 2.

[0157] In one embodiment, a compound of Formula (I), or a stereoisomer, tautomer, solvate, or salt thereof, is provided wherein R4is pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to 2 R 4a ; or

[0158] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided: 4a independently C 1-5 alkyl, C 1-2 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 1-3 alkyl), oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. Included in this embodiment are compounds in which each R 4a independently -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OCH3, -C(O)CH(CH3)2, -C(O)(cyclopropyl), -CH2(cyclopropyl), -CH2(cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl or tetrahydropyranyl. Also included in this embodiment are compounds in which each R 4a independently -CH(CH3)2, -CH2CH(CH3)2, -C(O)CH(CH3)2, -C(O)(cyclopropyl) or -CH2(cyclopropyl), cyclopropyl or cyclobutyl.

[0159] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided: 4b is F or Cl. Included in this embodiment are compounds in which R 4b is F.

[0160] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided: 4c independently C 1-4 alkyl, C 1-2 fluoroalkyl, -(CH2) 3-6 cycloalkyl), -C(O)(C 1-3 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3 or C 3-6 cycloalkyl. Included in this embodiment are compounds in which each R 4c independently C 1-3 alkyl, C 1-2 fluoroalkyl, -(CH2) 3-4cycloalkyl), -C(O)(C 1-2 alkyl), -C(O)(phenyl), -C(O)CH2(phenyl), -C(O)OCH2CH3, or C 3-4 cycloalkyl.

[0161] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R2is 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 cycloalkyl), -CH2(phenyl), or phenyl. Included in this embodiment are compounds in which each R2is independently Cl, -CH3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2CN, -OCH3, -CH2OCH3, or -CH2CH2S(O)2CH3. Also included in this embodiment are compounds in which each R2is independently Cl, -CH3, -CH2OH, or -OCH3.

[0162] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R 2a is C 1-4 alkyl, C 1-2 fluoroalkyl, C 1-4 hydroxyalkyl, -(CH2) 1-3 OCH3, C 3-6 cycloalkyl, -CH2C(O)NR x R x , -CH2(C 3-6 cycloalkyl), -CH2(phenyl), tetrahydrofuranyl, or phenyl; and each R 2b is 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 cycloalkyl). Also included in this embodiment are compounds in which R 2a is -CH3; and each R 2b is independently H, Cl or -CH3.

[0163] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein R3is hydrogen, F, Cl, C 1-2 alkyl or C 3-4 cycloalkyl. Included in this embodiment are compounds in which R3is hydrogen, C 1-2 alkyl or cyclopropyl. Also included in this embodiment are compounds in which R3is hydrogen or -CH3. Further, included in this embodiment are compounds in which R3is hydrogen.

[0164] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein each R5is independently hydrogen, F, Cl, -CH3or cyclopropyl. Included in this embodiment are compounds in which each R5is independently hydrogen, -CH3or cyclopropyl. Also included are compounds in which each R5is hydrogen or -CH3.

[0165] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof is provided, wherein G is phenyl substituted with one to two substituents independently selected from F, -OCH3and -S(O)2CH3; A is cyclohexyl, piperidinyl, phenyl or 6-azabicyclo[3.2.1]octyl, each of which is substituted with -L-R4; L is a bond; R3is hydrogen; R4is piperidinyl, piperazinyl, azepanyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl or diazabicyclo[3.2.1]octanyl, each of which is substituted with R 4a ; R 4a is -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OCH3, -C(O)CH(CH3)2, -C(O)(cyclopropyl), -CH2(cyclopropyl), -CH2(cyclobutyl), cyclopropyl, cyclobutyl, oxetanyl or tetrahydropyranyl; and each R5is hydrogen, F or -CH3.

[0166] In one embodiment, a compound of Formula (I) or a stereoisomer, tautomer, solvate or salt thereof is provided, wherein G is phenyl substituted with one to two substituents independently selected from F, -OCH3, and -S(O)2CH3; A is piperidinyl or 6-azabicyclo[3.2.1]octanyl, each of which is substituted with -L-R4; L is a bond; R3 is hydrogen; R4 is piperidinyl, azaspiro[3.3]heptyl, or azabicyclo[3.2.1]octanyl, each of which is substituted with R 4a ; and each R5 is hydrogen or -CH3. 4a ; and each R5 is hydrogen or -CH3.

[0167] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is: 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]-4-yl)-8-methylimidazo[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 (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)-8-6-(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-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-8- methylimidazo[1,2-a]pyridine (18-19); 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); 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'-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); 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[l,2- a]pyridine (65); 8-fluoro-6-(l'-isopropyl-[l,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine (67); 8-fluoro-6-(l-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (68-69); 7-fluoro-6-(l'-isopropyl-[l,4'-bipiperidin]-4-yl)- 2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (70); 8-fluoro-6-(l-(l-isopropylazepan-4-yl)piperidin- 4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (71-72); 5-fluoro-6-(l'-isopropyl-[l,4'- bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (73); 6-(l-(8-cyclobutyl-8- azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (83-84); 6-(l-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (85-86); 6-(l-(8-(cyclopropylmethyl)-8- azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine (87-88); 6-(l-(8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8- methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (89-90); 6-(l'-cyclobutyl-[l,4'- bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (91); 6-(l'-(cyclopropylmethyl)-[l,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine (92); 6-(l'-(cyclobutylmethyl)-[l,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl) imidazo[l,2-a]pyridine (93); 2-(3,4-dimethoxyphenyl)-6-(4-(4-isobutylpiperazin-l-yl)phenyl)-8- methylimidazo[l,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-l-yl)phenyl)imidazo[l,2-a]pyridine (97); 2-(3,4- dimethoxyphenyl)-6-(4-(4-(2-methoxyethyl)piperazin-l-yl)phenyl)-8-methylimidazo[l,2- a]pyridine (98); 6-(4-(4-isobutylpiperazin-l-yl)phenyl)-8-methyl-2-(4- (methylsulfonyl)phenyl)imidazo[l,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-l-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine (101); 6-(4-(4-cyclobutylpiperazin-l-yl)phenyl)-8-methyl-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (102); 8-methyl-2-(4- (methylsulfonyl)phenyl)-6-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)imidazo[l,2- a]pyridine (103); 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-l-yl)phenyl)imidazo[l,2-a]pyridine (104); 6-(4-(4-(2-methoxyethyl)piperazin-l- yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (105); 7-(l'- isobutyl-[l,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine (106); 8-fluoro-6-(l'-isobutyl-[l,4'-bipiperidin]-4-yl)-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (107); 6-(l'-cyclopropyl-[l,4'-bipiperidin]-4- yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine (108); 6-(l'-(cyclopropyl- methyl)-[l,4'-bipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[l,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]oct-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]oct-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]oct-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]oct-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]oct-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]oct-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); 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).

[0168] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is: 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 (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); 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 (45-47); 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 (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] (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[l,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[l,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[l,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[l,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[l,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[l,2-a]pyridine (140-141).

[0169] One embodiment provides 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[l,2-a]pyridine (58); or 2-(3,4- dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyridine (59).

[0170] One embodiment provides 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).

[0171] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is: 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-l-yl)phenyl)-8-methyl-[l,2,4]triazolo[l,5-a]pyridine (142); 6-(8-(l-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)- [l,2,4]triazolo[l,5-a]pyridine (146); 6-(4-(4-isopropylpiperazin-l-yl)phenyl)-8-methyl-2-(4- (methylsulfonyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridine (147); 2-(3,4-dimethoxyphenyl)-6-(8-(l- isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-[l,2,4]triazolo[l,5-a]pyridine (149); 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-8-methyl- [l,2,4]triazolo[l,5-a]pyridine (151); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)- 8-methyl-2-(4-(methylsulfonyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridine (153); 6-(8-(l- cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-8-methyl- [l,2,4]triazolo[l,5-a]pyridine (155); 2-(3,4-dimethoxyphenyl)-6-(8-(l-isopropylpiperidin-4- yl)-8-azabicyclo[3.2.1]oct-3-yl)-8-methyl-[l,2,4]triazolo[l,5-a]pyridine (156); 6-(l'- cyclopropyl-[l,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-8-methyl-[l,2,4]triazolo[l,5- a]pyridine (157); 2-(3,4-dimethoxyphenyl)-6-(l'-isopropyl-[l,4'-bipiperidin]-4-yl)-8- methyl-[l,2,4]triazolo[l,5-a]pyridine (158); 6-(8-(l-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-[l,2,4]triazolo[l,5-a]pyridine (159); 6-(8-(l-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-8-methyl-2-(4-1] 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'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (164); 2-(3,4-dimethoxyphenyl)-6-(4-(8-isopropyl-8-azabicyclo[3.2.1]oct-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).

[0172] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, solvate, or salt thereof, wherein the compound is: 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]oct-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]oct-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]oct-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]oct-3- yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[1,5-a]pyridine (154).

[0173] One embodiment provides 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).

[0174] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.6 μM.

[0175] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.1 μΜ.

[0176] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.05 μΜ.

[0177] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.025 μΜ.

[0178] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.015 μΜ.

[0179] One embodiment provides a TLR9 IC 50 a compound of Formula (I) having a value < 0.01 μΜ.

[0180] In another embodiment, the present application provides a composition comprising at least one compound of the present application or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0181] In another embodiment, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present application or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0182] In another embodiment, the present application provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present application or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0183] In another embodiment, the present application provides a method of making a compound of the present application.

[0184] In another embodiment, the present application provides an intermediate useful for making a compound of the present application.

[0185] In another embodiment, the present application provides a pharmaceutical composition as defined above, further comprising one or more other therapeutic agents.

[0186] Definitions

[0187] The features and advantages of the present application can be better understood with respect to the following detailed description. It should be appreciated that certain features and advantages of the application are readily apparent and include, among others, the provision of compounds and methods that can be used to treat or prevent diseases or conditions associated with the activity of the protein kinase. It should also be appreciated that the features and advantages of the application described herein are not all-inclusive and are deemed to include all equivalents thereof known to those skilled in the art.

[0188] Reference to singular can include plural unless otherwise specifically stated. For example, "a" or "an" can refer to one or more.

[0189] As used herein, the phrase "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).

[0190] Unless otherwise indicated, any heteroatom possessing an unsatisfied valence number is assumed to have the hydrogen atom sufficient to satisfy the valence number.

[0191] The definitions set forth herein control over any definitions set forth in any patents, patent applications, and / or patent application publications incorporated herein by reference.

[0192] The following definitions are listed below for the various terms used to describe the present application. These definitions apply to the terms as they are used throughout the specification unless otherwise indicated by the specific context.

[0193] Throughout the specification, groups and substituents thereof can be chosen from any of the groups disclosed herein or known in the art, provided that the indication of the group or substituent is compatible with the remainder of the group or substituent.

[0194] According to the usual practice in the art,

[0195]

[0196] A bond used in structural formulas herein to depict a point of attachment of a moiety or substituent to a core or backbone structure.

[0197] As used herein, the terms "halo" and "halogen" refer to F, CI, Br, and I.

[0198] The term "cyano" refers to the group -CN.

[0199] The term "amino" refers to the group -NH2.

[0200] The term "oxo" refers to the group =0.

[0201] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 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, i-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl). When numbers appear in a subscript after the symbol "C", the subscript defines the number of carbon atoms that a particular group can contain. For example, "C1-C4alkyl" means an alkyl group containing from 1 to 4 carbon atoms. 1-6 "Alkyl" means a straight-chain and branched-chain alkyl group having one to six carbon atoms.

[0202] 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 C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3and -CH2CF3.

[0203] The term "hydroxyalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH2OH, -CH2CH2OH, and C 1-4 hydroxyalkyl groups.

[0204] The term "aminoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more amino groups. For example, "aminoalkyl" includes -CH2NH2, -CH2CH2NH2, and C 1-4 aminoalkyl groups.

[0205] The term "cyanoalkyl" includes both branched and straight-chain saturated alkyl groups substituted with one or more cyano groups. For example, "cyanoalkyl" includes -CH2CN, -CH2CH2CN, and C 1-4 cyanoalkyl groups.

[0206] As used herein, the term "alkoxy" refers to an alkyl group connected to the parent molecular moiety through an oxygen atom, for example methoxy (-OCH3). For example, "C 1-3 "Alkoxy" means an alkoxy group having one to three carbon atoms.

[0207] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" mean a fluoroalkyl group as defined above connected via an oxygen bond (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0208] As used herein, the term "alkoxyalkyl" refers to an alkoxy group attached to an alkyl group through an oxygen atom of the alkoxy group, which alkyl group is attached to the parent molecular moiety through a carbon atom, for example, methoxymethyl (-CH2OCH3). For example, "C 2-4 "Alkoxyalkyl" denotes an alkoxyalkyl group having two to four carbon atoms, such as -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, and -CH2CH2OCH2CH3.

[0209] As used herein, the term "cycloalkyl" refers to a radical derived by the removal of one hydrogen atom from a saturated ring carbon atom of a non-aromatic monocyclic or polycyclic hydrocarbon molecule. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When numbers appear in a subscript after the symbol "C", the subscript defines with more specificity the number of carbon atoms that a particular cycloalkyl group can contain. For example, "C 3-6 "Cycloalkyl" denotes a cycloalkyl group having three to six carbon atoms.

[0210] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0211] The compound of Formula (I) can be provided as an amorphous solid or a crystalline solid. Lyophilization can be employed to provide the compound of Formula (I) as an amorphous solid.

[0212] It is further understood that solvates (e.g., hydrates) of the compound of Formula (I) are within the scope of the present application. The term "solvate" means the

[0213] Various forms of prodrugs are well known in the art and described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0214] Additionally, compounds of Formula (I) can be isolated and purified after preparation to obtain compositions containing an amount equal to or greater than 99% by weight of the compound of Formula (I) ("substantially pure"), respectively, which are then used or formulated as described herein. Such "substantially pure" compounds of Formula (I) are also contemplated herein as part of the present application.

[0215] "Stable compound" and "stable structure" are meant to refer to compounds that are sufficiently robust to survive isolation from a reaction mixture into a useful purity and formulation into an efficacious therapeutic.

[0216] "Therapeutically effective amount" is intended to include an amount of a sole compound of the present application, or an amount of a combination of compounds as claimed, or an amount of a compound of the present application in combination with other active ingredients effective to act as a TLR9 inhibitor or to treat or prevent a condition associated with a fibrotic disease or disorder (bile acid disorder), such as pathological fibrosis.

[0217] As used herein, "treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and includes: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and / or (c) relieving the disease-state, i.e., causing the disease-state to regress.

[0218] The compounds of the present application are intended to include all isotopes of atoms occurring in the compounds. Isotopes include those 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 include 13 C and 14 C. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. By way of example, methyl (-CH3) also includes deuterated methyl, such as -CD3.

[0219] Utility

[0220] The compounds of the present application are useful for inhibiting the TLR9 receptor.

[0221] One embodiment provides a method for treating a disease, disorder, or condition associated with a bile acid disorder in a patient in need of such treatment, and the method comprises administering to the patient a therapeutically effective amount of a compound of the present application or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0222] One embodiment provides a method for treating a disease, disorder, or condition associated with the activity of the TLR9 receptor in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound of the application, alone or in optional combination with another compound of the application and / or at least one other type of therapeutic agent.

[0223] One embodiment provides a method 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 application, alone or in optional combination with another compound of the application and / or at least one other type of therapeutic agent.

[0224] One embodiment provides a method for eliciting agonism of the TLR9 receptor in a patient comprising administering to the patient a therapeutically effective amount of a compound of the application, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0225] In some embodiments, the disease, disorder, or condition is associated with TLR9 dysfunction, including pathologic fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

[0226] In some embodiments, the disease, disorder, or condition is associated with fibrosis, including liver fibrosis, biliary fibrosis, kidney fibrosis, heart fibrosis, skin fibrosis, eye fibrosis, and pancreatic fibrosis.

[0227] In other embodiments, the disease, disorder, or condition is associated with a cell proliferative disorder, such as cancer. In some embodiments, the cancer includes solid tumor growth or neoplasia. In other embodiments, the cancer includes tumor metastasis. In some embodiments, the cancer is a cancer of the liver, gall bladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, genitalia, 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 a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0228] Examples of diseases, disorders, or conditions associated with FXR activity that can be prevented, modulated, or treated in accordance with the present application include, but are not limited to, transplant rejection, fibrotic disorders (e.g., liver fibrosis, kidney fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, nonalcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and cell proliferative disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0229] Fibrotic disorders, inflammatory disorders, and cell proliferative disorders suitable for prevention or treatment by the compounds of the application include, but are not limited to, nonalcoholic fatty liver disease (NAFLD), alcoholic or nonalcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, aplasia, hypofunction, liver blood flow disorder, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic exocrine insufficiency, benign prostatic hyperplasia, neuropathic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplantation-induced nephropathy, autoimmune nephropathy, lupus nephritis liver fibrosis, kidney fibrosis, chronic kidney disease (CKD), diabetic kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, idiopathic pulmonary fibrosis (IPF), 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 cord tumors, herniated intervertebral disc, spinal canal 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, solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, Crohn's disease, or systemic lupus erythematosus; keloid formation resulting from abnormal wound healing; fibrosis occurring after organ transplantation, myelofibrosis, and myoma. In one embodiment, the present application provides a method for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present application, alone or optionally in combination with another compound of the present application and / or at least one other type of therapeutic agent.

[0230] In another embodiment, the present application provides a compound of the present application for use in therapy.

[0231] In another embodiment, the present application provides a compound of the present application for use in therapy for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder thereof.

[0232] In another embodiment, the present application also provides the use of a compound of the present application for the manufacture of a medicament for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder thereof.

[0233] In another embodiment, the present application provides a method for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present application.

[0234] In another embodiment, the present application provides a combined preparation of a compound of the present application and another therapeutic agent for simultaneous, separate or sequential use in therapy.

[0235] In another embodiment, the present application provides a combined preparation of a compound of the present application and another therapeutic agent for simultaneous, separate or sequential use in the treatment of a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder.

[0236] The compounds of the present application can be used in combination with other therapeutic agents, such as one or more anti-fibrotic and / or anti-inflammatory therapeutic agents.

[0237] In one embodiment, the other therapeutic agent for use in a combined pharmaceutical composition or a combined method or a combined use is one or more (preferably one to three) selected from the following therapeutic agents: TGF receptor inhibitors (e.g. galunisertib); TGF synthesis inhibitors (e.g. pirfenidone); inhibitors of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinases (e.g. nintedanib); humanized anti-alpha V integrin monoclonal antibodies (e.g. 3G9); human recombinant profinilin-2; recombinant human serum amyloid P; recombinant human antibodies against TGF beta-1, TGF beta-2 and TGF beta-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-purin-2-yl]amino]-trans-cyclohexanol); 3-pentylbenzeneacetic acid (PBI-4050); tetrasubstituted porphyrin derivatives containing manganese (III); monoclonal antibodies targeting eotaxin-2; 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); Cintredekin Besudotox; human recombinant DNA-derived IgGl kappa monoclonal antibody to connective tissue growth factor; and fully human IgGl kappa antibody selective for CC-chemokine ligand 2 (e.g., carlumab, CCX140); antioxidants (e.g., N-acetylcysteine); phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil); agents for the treatment of obstructive airway disease, such as muscarinic antagonists (e.g., tiotropium, ipatropium bromide); adrenergic beta2 agonists (e.g., salbutamol, salmeterol); corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone); immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus); and therapeutic agents useful for the treatment of fibrotic conditions (such as liver fibrosis, biliary fibrosis, and kidney fibrosis), nonalcoholic fatty liver disease (NALFD), nonalcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Therapeutic agents useful for the treatment of these fibrotic conditions include, but are not limited to, FXR agonists (e.g., OCA, GS-9674, and LJN452); LOXL2 inhibitors (e.g., simtuzumab); LPA1 antagonists (e.g., BMS-986020 and SAR 100842); PPAR modulators (e.g., elafibrinor, pioglitazone, and saroglitazar, IVA337); SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302); ASK-1 inhibitors (e.g., GS-4997 or selonsertib); ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976); FGF21 mimics (e.g., LY2405319 and BMS-986036); apoptin inhibitors (e.g., emricasan); NOX4 inhibitors (e.g., GKT137831); MGAT2 inhibitors (e.g., BMS-963272); alphaV integrin inhibitors (e.g., abituzumab); and bile acid / fatty acid binders (e.g., aramchol).The FXR agonists of the various embodiments of the application can also be used in combination with one or more therapeutic agents such as CCR2 / 5 inhibitors (e.g., cenicriviroc); galectin-3 inhibitors (e.g., TD-139, GR-MD-02); leukotriene receptor antagonists (e.g., tipelukast, montelukast); SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin); GLP-1 receptor agonists (e.g., liraglutide and semaglutide); FAK 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., halofugenone); FPR2 agonists (e.g., ZK-994); and THR agonists (e.g., MGL:3196). In another embodiment, the other therapeutic agent for use in a combination pharmaceutical composition or a combination method or a combination use is one or more (preferably one to three) selected from immunooncology agents such as Alemtuzumab, Atezolizumab, Ipilimumab, Nivolumab, Ofatumumab, Pembrolizumab, and Rituximab.

[0238] When the term "TLR9-related condition" or "TLR9-related disease or disorder" is used herein, each is intended to encompass all of the above-identified conditions, as if repeated in detail, as well as any other condition affected by TLR9 inhibition.

[0239] The above other therapeutic agents, when used in combination with the compounds of the application, can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the application, such other therapeutic agents can be administered prior to, simultaneously with, or following the administration of the compounds of the application. The present application also provides pharmaceutical compositions capable of treating a TLR9-related condition.

[0240] The compositions of the present application can contain other therapeutic agents, as described above, and can be formulated, e.g., according to techniques well known in the art of pharmaceutical formulation, by employing conventional solid or liquid vehicles or diluents, and adding appropriate pharmaceutical additives including, but not limited to, compatible

[0241] Accordingly, the present application further includes compositions comprising one or more compounds of Formula (I) and a pharmaceutically acceptable carrier.

[0242] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal. Pharmaceutically acceptable carriers are formulated in accordance with a number of factors relevant to the field of the ordinarily skilled artisan. These factors include, but are not limited to: the type and nature of the active agent being formulated; the individual to whom the composition containing the agent is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. 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 can include a variety of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., to stabilize the active agent, binder, etc.). A description of suitable pharmaceutically acceptable carriers and factors involved in their selection is found in a variety of readily available sources, such as Remington: The Science and Practice of Pharmacy, 22ndEd. (2013).

[0243] The compounds according to Formula (I) can be administered by any means suitable to the condition to be treated, which can be determined by a need for targeted treatment or the amount of the compound of Formula (I) to be delivered.

[0244] The compounds of Formula (I) can be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and compositions of the present application can, for example, be administered orally, mucosally, or parenterally (including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally) in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants, and vehicles, which are generally known in the art of pharmaceutical formulation. For example, the pharmaceutical carrier can contain a mixture of mannitol or lactose with microcrystalline cellulose. The mixture can contain additional components such as a lubricant, e.g., magnesium stearate, and a disintegrant, e.g., crospovidone. The carrier mixture can be filled into a gelatin capsule or compressed into a tablet. The pharmaceutical composition can be administered, for example, in oral dosage forms or infusion forms.

[0245] For oral administration, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit, i.e., a unit that can be administered in whole form or in divided form. For example, the pharmaceutical composition can be provided in the form of tablets or capsules each containing an amount of active ingredient that is suitable for administration of a specified amount. Suitable daily dosages for humans or other mammals can vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.

[0246] Any of the pharmaceutical compositions contemplated herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, dragees, troches, 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 according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. In order to provide pharmaceutically elegant and palatable preparations, the pharmaceutical compositions according to the application can contain at least one agent selected from the group consisting of sweetening agents, flavoring agents, coloring agents, demulcent agents, antioxidants, and preserving agents.

[0247] Tablets can be prepared, for example, by admixing at least one compound of Formula (I) with at least one pharmaceutically acceptable, non-toxic excipient suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, sodium starch glycolate, corn starch, and alginic acid; binding agents, such as starch, gelatin, polyvinylpyrrolidone, and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. Additionally, the tablets can be uncoated or they can be coated by known techniques to mask the bad taste of the medicine or delay the disintegration and absorption of the active ingredient in the gastrointestinal tract and thereby provide a sustained action over a longer period. Exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl-cellulose. Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0248] Hard gelatin capsules can 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.

[0249] 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.

[0250] Aqueous suspensions can be made for example by dispersing at least one compound of Formula (I) in at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, tragacanth gum and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example, soy lecithin; condensed products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate; condensed products of alkylene oxides with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol; condensed products of alkylene oxides with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbitan monooleate; and condensed products of alkylene oxides with partial esters derived from fatty acids and a hexitol anhydride, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions can also contain at least one preservative such as ethyl and n-propyl p-hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, for example, sucrose, saccharin and aspartame.

[0251] Oil suspensions can be formulated for example by suspending at least one compound of Formula (I) in either a vegetable oil such as arachis oil, olive oil, sesame oil and coconut oil, or a mineral oil such as liquid paraffin. Oil suspensions can also contain at least one thickening agent such as beeswax, hard paraffin and cetyl alcohol. For purposes of providing an oral oil suspension, at least one sweetening agent and / or at least one flavoring agent described above can be added to the oil suspension. The oil suspensions can additionally contain at least one preservative including, but not limited to, for example, antioxidants such as butylated hydroxyanisole and alpha-tocopherol.

[0252] Dispersible powders and granules can be prepared for example by admixing at least one compound of Formula (I) with at least one dispersing agent and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersing agents, wetting agents and suspending agents are as described above. Exemplary preservatives include, but are not limited to, for example, antioxidants such as ascorbic acid. Additionally, dispersible powders and granules can also contain at least one excipient including, but not limited to, for example, a sweetening agent, a flavoring agent and a coloring agent.

[0253] An emulsion of at least one compound of Formula (I) can be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion comprising a compound of Formula (I) can be constituted from known ingredients in known fashion. The oil phase can be provided, without limitation, by, for example, vegetable oils, such as olive oil and peanut oil; mineral oil, such as liquid paraffin; and mixtures thereof. While this phase can contain only an emulsifying agent, it can also contain a mixture of at least one emulsifying agent with a fat or oil or both a fat and an oil. Suitable emulsifying agents include, but are not limited to, for example, naturally occurring phosphatides, e.g., soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monoleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monoleate. Preferably, a hydrophilic emulsifying agent is included together with a lipophilic emulsifying agent which acts as a stabilizer. It is also preferable to include both an oil and a fat. Together the emulsifying agents, with or without stabilizer, constitute so-called emulsifying wax, and this wax, together with the oil and fat, constitutes so-called emulsifying ointment base, which forms the oily dispersed phase of a cream emulsion formulation. The emulsions can also contain sweetening agents, flavoring agents, preservatives and / or antioxidants. Suitable emulsifying agents and emulsion stabilizers that can be used in the formulation of the application include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl stearate or other materials well known in the art.

[0254] The compounds of Formula (I) can also be delivered intravenously, subcutaneously, and / or intramuscularly, for example, via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0255] Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from a sterile powder or granule having one or more of the above-mentioned carriers or diluents, or from a previously prepared sterile solution or suspension using one or more of the above-mentioned carriers or diluents. The compounds can 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 modes of administration are well and widely known in the pharmaceutical art. The active ingredient can also be administered by injection as a composition in suitable vehicles including saline, dextrose or water or in compositions containing cyclodextrin (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol), or micelle solubilization (i.e., Tween 80).

[0256] The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0257] Sterile injectable aqueous and oleaginous suspensions can be formulated according to known methods. For example, sterile injectable solutions or suspensions can be prepared using non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol; and sterile oleaginous suspensions can be formulated using acceptable, sterile, non-toxic diluents or solvents such as a sterile, fixed oil (e.g., synthetic mono- or diglycerides) and fatty acids, such as oleic acid.

[0258] Sterile aqueous or oleaginous suspensions can be prepared according to methods 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 oleaginous suspensions can be prepared using acceptable, sterile, non-toxic diluents or suspending media, such as sterile, fixed oils (e.g., synthetic mono- or diglycerides) and fatty acids, such as oleic acid.

[0259] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as a-cyclodextrin, β-cyclodextrin and γ-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-hydroxypropyl-β-cyclodextrin and 3-hydroxypropyl-β-cyclodextrin or other solubilized derivatives can also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0260] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce pharmaceutical preparations for administration to patients, including humans and other mammals. The pharmaceutical compositions may undergo conventional pharmaceutical processes such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, humectants, emulsifiers, buffers, etc. Tablets and pills may be additionally prepared with enteric coatings. Such compositions may also contain adjuvants such as humectants, sweeteners, flavoring agents, and aromatizers.

[0261] The amount of compound applied and the dosing regimen for treating disease conditions with the compounds and / or compositions of the present invention depend on a variety of factors, including an individual's age, weight, sex, medical condition; disease type; disease severity; route and frequency of administration; and the specific compound used. Therefore, dosing regimens can vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg per kilogram of body weight, preferably between about 0.0025 and about 50 mg per kilogram of body weight, and optimally between about 0.005 and 10 mg per kilogram of body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosing schedules include cycles of weekly and every two days.

[0262] For therapeutic purposes, the active compounds of the present invention are generally combined with one or more adjuvants suitable for the specified route of administration. For oral administration, the compounds may be blended with lactose, sucrose, starch powder, cellulose esters of alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and subsequently tableted or encapsulated for convenient administration. These capsules or tablets may contain a controlled-release formulation, such as a dispersion of the active compound in hydroxypropyl methylcellulose.

[0263] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) and optionally include additional agents selected from pharmaceutically acceptable carriers, adjuvants, and mediators. Alternative compositions of the present invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0264] This invention also covers an article of manufacture. As used herein, the article of manufacture is intended to include, but is not limited to, kits and packaging. The article of manufacture of this invention comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a product information label stating that the pharmaceutical composition can be used to treat cardiovascular disease, polyuria, and / or nauria. In another embodiment, the product information label states that the pharmaceutical composition can be used in combination with a second therapeutic agent for treating cardiovascular disease, polyuria, and / or nauria (as defined above). The article of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located inside or outside the second container. Located within the first and second containers means that each container contains the article within its boundaries.

[0265] The first container is a vessel for containing a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually or in whole. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream formulations), or any other container used for manufacturing, containing, storing, or dispensing pharmaceutical products.

[0266] The second container is a container for holding the first container and optionally, any accompanying instruction leaflets. 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), sachets, and large bags. The instruction leaflets may be physically attached to the outside of the first container by tape, glue, U-straps, or another attachment method, or they may remain inside the second container without being physically attached to the first container. Alternatively, the instruction leaflets may be located on the outside of the second container. When located on the outside of the second container, the instruction leaflets are preferably physically attached by tape, glue, U-straps, or another attachment method. Alternatively, they may be adjacent to or in contact with the outside of the second container but not physically attached.

[0267] A drug package insert is a label, tag, mark, or other written piece of paper that describes information relating to the drug composition located within a first container. The information described is typically determined by the regulatory agency in the jurisdiction where the product is sold (e.g., the United States Food and Drug Administration). Preferably, the drug package insert specifically describes the indications for which the drug composition has been approved. The drug package insert can be made of any material from which an individual can read the information contained herein. Preferably, the drug package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper, or plastic) on which the desired information has been formed (e.g., printed or coated).

[0268] Preparation method

[0269] The compounds of the present application can be prepared in a number of ways that are well known to one skilled in the art of organic synthesis. The compounds of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.

[0270] The reactions and techniques described in this section are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Additionally, in the descriptions of the synthetic methods described below, it is understood that all proposed reactions are performed at temperatures appropriate to reactants and reagents employed, and that the reaction conditions are chosen to give the desired results. It will be appreciated by one skilled in the art that the functionality present on the various moieties of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that can be present on the molecule are well known to one skilled in the art. It will also be recognized by one skilled in the art that the order of synthesis can be modified to give the desired result. It will also be recognized that another important consideration in the planning of any synthetic route is the judicious choice of protecting groups for protecting reactive functional groups present in the compounds described in the present application. An authoritative account of the design and use of ligands is found in Greene et al. (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0271] Scheme 1

[0272]

[0273] Scheme 1 describes the synthesis of compounds of the subset of Formula II, Formula II-A and II-B. The term "halo" in this scheme refers to any halogen that the ordinarily skilled artisan would consider suitable for effecting the desired transformation. The term "PG" refers to any suitable amino protecting group such as an alkyl carbamate, alkyl amide or alkyl group. Ring A as shown in Formula II-A and II-B is substituted at the 6 position of the imidazo[l,2-a]pyridine ring, however the ordinarily skilled artisan can readily modify this synthetic scheme to place ring A in the 7 position by using the appropriate starting material.

[0274] Compound la can be reacted with an a-halo-ketone lb in the presence or absence of a base such as potassium carbonate or sodium bicarbonate in any typical reaction solvent such as EtOH, DMF, DMSO with or without heating. Compound lc can be coupled with boronate Id under standard Suzuki coupling conditions. The resulting olefin can be reduced by catalytic hydrogenation using a catalyst such as Pd or Pt. The protecting group PG can be removed by the appropriate reagent and conditions generally known to one skilled in the art. Reductive amination of amine If with ketone Ig or Ih can be achieved with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence or absence of an acid catalyst (i.e., AcOH) to give compounds of Formula II-A and II-B.

[0275] Scheme 2

[0276]

[0277] Scheme 2 describes the synthesis of compounds of Formula III for a subset of Formula III-A and III-B. The term "PG" refers to any suitable amino protecting group such as an alkyl carbamate group, an alkyl amide group, or an alkyl group. Ring A as shown in Formula III-A and III-B is substituted at the 6 position of the 5,6,7,8-tetrahydroimidazo[l,2- a]pyridine ring, however one of ordinary skill can readily modify this synthetic scheme to place ring A in the 7 position by using the appropriate starting material.

[0278] Compound le (see Scheme 1) can be reduced by catalytic hydrogenation using a catalyst such as Pd or Pt at 1 atm or greater atmospheric pressure. Reaction times can vary, but are generally greater than 24 h. Reductive amination of amine 2a with ketone 2b or 2c can be achieved with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence or absence of an acid catalyst (i.e., AcOH) to give compounds of Formula III-A and III-B.

[0279] Examples

[0280] The compounds of the present application and intermediates used in the preparation of the compounds of the present application can be prepared using the procedures 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 the compounds of the present application can be prepared. When not prepared by the procedures described herein, the starting materials and reagents used in these examples are generally either commercially available or reported in the chemical literature or can be prepared by using procedures described in the chemical literature. The present application is further defined in the following examples. It should be understood that these examples are provided by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of the present application, and without departing from the spirit and scope thereof, can make various changes and modifications of the various embodiments to adapt the present application to various uses and conditions. Thus, the present application is not intended to be limited to the illustrative examples described in the following detailed description. The following examples further define the present application but are not intended to limit its scope.

[0281] In the examples given, the phrase "dried and concentrated" generally means drying of the solution over sodium sulfate or magnesium sulfate in an organic solvent, followed by filtration of the filtrate and removal of the solvent, generally under reduced pressure and at a temperature appropriate for the stability of the material.

[0282] Chemical names were determined using ChemDraw Ultra, Version 9.0.5 (CambridgeSoft). The following abbreviations were used:

[0283] aq. aqueous

[0284] br. brine saturated aqueous sodium chloride solution

[0285] DCM dichloromethane

[0286] DMAP dimethylaminopyridine

[0287] DMF N,N-dimethylformamide

[0288] DMSO dimethyl sulfoxide

[0289] EtOAc ethyl acetate

[0290] EtOH ethanol

[0291] g grams

[0292] h hours

[0293] HPLC high performance liquid chromatography

[0294] LCMS liquid chromatography-mass spectrometry

[0295] MeCN acetonitrile

[0296] MeOH methanol

[0297] Pet ether petroleum ether

[0298] TEA triethylamine

[0299] TFA trifluoroacetic acid

[0300] THF tetrahydrofuran

[0301] Preparation

[0302] Unless otherwise noted, all reagents were purchased from commercial sources and used without further purification. All reactions involving air- or moisture-sensitive reagents were carried out under an inert atmosphere. Proton magnetic resonance spectra were recorded on a Bruker Avance 400 or JEOLEclipse 500 spectrometer. LCMS analysis was performed on a Waters Acquity UPLC system coupled with Waters TUV and SQ mass detectors (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: 2-98% B over 1.6 min; flow rate: 0.8 mL / min); HPLC analysis was performed on a Shimadzu LC10-AT HPLC system coupled with SPD-10AV UV detector (column YMCS5 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: 0-100% B over 40 min followed by 1 min at 100% B; flow rate: 1 mL / min); preparative HPLC purification was performed on a Shimadzu LC-8 preparative HPLC system coupled with SPD 20 UV detector. Detailed conditions are described in the experimental procedures.

[0303] Analytical LC / MS method

[0304] 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, followed by 0.50 min at 100% B; flow rate: 1 mL / min; detection: MS and UV (220 nm).

[0305] 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 a 0.50 min hold at 100% B; Flow: 1 mL / min; Detection: MS and UV (220 nm).

[0306] Method 3: Column: Waters Acquity BEH 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 a 0.50 min hold at 100% B; Flow: 1 mL / min; Detection: MS and UV (220, 254 nm).

[0307] Method 4: Column: Waters Acquity BEH C18, 2.1 mm 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 a 0.50 min hold at 100% B; Flow: 1 mL / min; Detection: MS and UV (220, 254 nm).

[0308] Method 5: Column: Waters Acquity BEH C18, 2.1 mm 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 a 0.50 min hold at 98% B; Flow: 0.8 mL / min; Detection: MS and UV (220 nm).

[0309] Chiral analytical method

[0310] SFC Method 1: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0311] SFC Method 2: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 60% CO2 / 40% MeOH with 0.1% DEA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0312] SFC Method 3: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 75% CO2 / 25% IPA-acetonitrile 50-50 with 0.1% DEA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0313] SFC Method 4: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 55% CO2 / 45% IPA with 0.1% DEA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0314] SFC Method 5: Instrument: Berger SFC; Column: Chiral OD 4.6 x 250 mm, 5 microns; Mobile Phase: 70 / 30 CO2 / EtOH-0.1% DEA; Flow conditions: 4 mL / min; Detector wavelength: 220 nm.

[0315] SFC Method 6: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 65% CO2 / 35% IPA with 0.6% DEA / 0.1% TFA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0316] SFC Method 7: Instrument: Shimadzu Nexera UC SFC; Column: Chiral OD, 4.6 x 100 mm, 5 microns; Mobile Phase: 80% CO2 / 20% MeOH with 0.1% DEA; Flow conditions: 2 mL / min; Detector wavelength: 220 nm.

[0317] SFC Method 8: Instrument: Agilent SFC; Column: Chiralcel OD-H, 4.6 x 250 mm, 5 microns; Mobile Phase: 55% CO2 / 40% MeOH-0.1% DEA; Flow conditions: 2.0 mL / min, 120 bar, RT; Detector wavelength: 220 nm

[0318] SFC Method 9: Instrument: Agilent SFC; Column: Chiralcel OD-H, 4.6 x 250 mm, 5 microns; Mobile Phase: 65% CO2 / 45% EtOH-0.1% DEA; Flow Conditions: 2.0 mL / min; Detector Wavelength: 220 nm

[0319] Preparative HPLC Method

[0320] Preparative Method 1: Column: XBridge C18, 200 mm x 19 mm, 5-μιη particles; Mobile Phase A: 5:95 Acetonitrile:water with Ammonium acetate; Mobile Phase B: 95:5 Acetonitrile:water with Ammonium acetate; Gradient: (variable; depending on substrate) %B over 20 minutes, followed by a 0 minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fractions were collected by MS and UV signals.

[0321] Preparative Method 2: Column: XBridge C18, 200 mm x 19 mm, 5-μιη 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: (variable; depending on substrate) %B over 20 minutes, followed by a 0 minute hold at 100% B; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fractions were collected by MS signals.

[0322] Example 1

[0323] 6-(1'-Cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-8- methylimidazo[1,2-a]pyridine

[0324]

[0325] Step A. Preparation of 6-bromo-2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2- a]pyridine

[0326]

[0327] 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 under reflux. After 18 h, a precipitate formed. The reaction mixture was allowed to cool, stored at -20 °C for 1 h, and the precipitate was collected by vacuum filtration. The filter cake was washed with a minimum amount of diethyl ether and the product was dried under vacuum to give the title compound as a tan solid (4.6 g, 13 mmol, 99% yield).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): mass found: 349.1 ; retention time: 0.66 min.

[0328] Step B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[l,2- a]pyridin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0329]

[0330] To a 200 mL pear-shaped flask was added Intermediate 1A (2.8 g, 8.0 mmol), tert- butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(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 N2(2x), followed by addition of l,l'-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (0.30 g, 0.37 mmol). The vessel was evacuated and purged again, and stirred at 75 °C. After 18 h, the reaction mixture was allowed to cool, diluted with water (200 mL) and extracted with EtOAc (2x 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 = 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 vacuum to give the title compound as a light yellow solid (3.5 g, 7.8 mmol, 98% yield). 1H 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): mass observed: 450.4; retention time: 0.81 min.

[0331] Step C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[l,2- a]pyridin-6-yl)piperidine-l-carboxylate

[0332]

[0333] To a 1 L round bottom flask was added Intermediate IB (3.5 g, 7.8 mmol) and MeOH (150 mL). The vessel was evacuated and purged with N2, then Pd-C (5% on carbon) (1.7 g, 0.78 mmol) was added and the reaction mixture was evacuated and purged again. The reaction mixture was stirred under 1 atm of hydrogen. After 1 h, 1 H NMR showed complete conversion of starting material. The reaction mixture was filtered, the filtrate was concentrated and the product was dried under vacuum to give the title compound as a light yellow solid (3.1 g, 6.9 mmol, 88% yield). 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): mass observed: 450.4; retention time: 0.81 min.

[0334] Step D. Preparation of 2-(3,4-dimethoxyphenyl)-8-methyl-6-(piperidin-4-yl)imidazo[l,2- a]pyridine hydrochloride

[0335]

[0336] 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 HC1 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 vacuum to yield the title compound as an off-white solid (2.1 g, 5.4 mmol, 78% yield). 1 H 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): mass found: 352.2; retention time: 0.68 min.

[0337] Step E. Preparation of Example 1

[0338] 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 MgSO4(220 mg, 1.8 mmol). The reaction mixture was stirred for 20 min, then sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added and the reaction mixture was stirred. After 24 h, 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 MgSO4, filtered, and concentrated. The crude material was purified via preparative HPLC (Preparative Method 1) to yield 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 99.2%; mass observed: 474.91; retention time: 1.38 min. (Method 2): purity: 98.9%; mass observed: 475.36; retention time: 0.99 min.

[0339] Example 2

[0340] 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8- methylimidazo[1,2-a]pyridine

[0341]

[0342] Example 2 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 1D (70 mg, 0.18 mmol) as starting material and 1-isopropylpiperidin-4-one (130 mg, 0.90 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 477.29; retention time: 1.42 min. (Method 2): purity: 100%; mass observed: 477.03; retention time: 0.97 min.

[0343] Example 3

[0344] 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8- methylimidazo[1,2-a]pyridine

[0345]

[0346] Example 3 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 1D (70 mg, 0.18 mmol) as starting material and 1-isobutylpiperidin-4-one (140 mg, 0.90 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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 not clear). Analytical LC / MS (Method 1): purity: 97%; mass observed: 491.18; retention time: 1.51 min. (Method 2): purity: 100%; mass observed: 491.27; retention time: 0.94 min.

[0347] Example 4

[0348] 6-(1'-Cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3-fluoro-4-methoxyphenyl)-8- methylimidazo[1,2-a]pyridine

[0349]

[0350] Step A. Preparation of 6-bromo-2-(3-fluoro-4-methoxyphenyl)-8- methylimidazo[1,2-a]pyridine

[0351]

[0352] Intermediate 4A was prepared according to the general procedure described for the synthesis of Intermediate 1A, using 5-bromo-3-methylpyridin-2-amine (0.76 g, 4.1 mmol) as starting material and 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethan-1-one (1.0 g, 4.1 mmol) as a replacement where appropriate, to give the title compound as a tan solid (1.0 g, 3.0 mmol, 73% yield). 1 H 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): mass observed: 337.0; retention time: 0.75 min.

[0353] Step B. Preparation of tert-butyl 4-(2-(3-fluoro-4-methoxyphenyl)-8- methylimidazo[l,2-a]pyridin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0354]

[0355] Intermediate 4B was prepared according to the general procedure described for the synthesis of Intermediate IB using Intermediate 4A (500 mg, 1.5 mmol) as starting material to afford the title compound as a light yellow solid (480 mg, 1.1 mmol, 73% yield). 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): mass observed: 438.4; retention time: 0.88 min.

[0356] Step C. Preparation of 2-(3-fluoro-4-methoxyphenyl)-8-methyl-6-(piperidin-4- yl)imidazo[l,2-a]pyridine hydrochloride

[0357] Intermediate 4C was prepared according to the general procedure described for the synthesis of Intermediate ID (steps C to D) using Intermediate 4B (480 mg, 1.1 mmol) as starting material to afford the title compound as a tea colored solid (410 mg, 1.1 mmol, 100% yield). 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): mass observed: 438.4; retention time: 0.88 min.

[0358] Step D. Preparation of Example 4

[0359] Example 4 was synthesized according to the general procedure described for Preparation Example 1 (step E) using intermediate 4C (60 mg, 0.15 mmol) as starting material. The crude material was purified via preparative HPLC (preparative method 1) to afford the title compound (40 mg, 0.086 mmol, 57% yield). 1 H 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 not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 463.14; retention time: 1.53 min. (Method 2): purity: 100%; mass observed: 463.16; retention time: 0.99 min.

[0360] Example 5

[0361] 2-(3-Fluoro-4-methoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8- methylimidazo[1,2-a]pyridine

[0362]

[0363] Example 5 was synthesized according to the general procedure described for Preparation Example 1 (step E) using intermediate 4C (60 mg, 0.15 mmol) as starting material and 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as a replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (two protons not clear). Analytical LC / MS: (Method 1): purity: 100%; mass observed: 465.01; retention time: 1.54 min. (Method 2): purity: 100%; mass observed: 465.29; retention time: 1.04 min.

[0364] Example 6

[0365] 2-(3-Fluoro-4-methoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8- methylimidazo[1,2-a]pyridine

[0366]

[0367] Example 6 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 4C (60 mg, 0.15 mmol) as starting material and 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 479.13; retention time: 1.77 min. (Method 2): purity: 98.8%; mass observed: 479.05; retention time: 1.04 min.

[0368] Example 7

[0369] 6-(1'-Cyclopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0370]

[0371] Step A. Preparation of 6-bromo-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0372]

[0373] Intermediate 7A was prepared as follows: according to the general procedure described for the synthesis of Intermediate 1A, with 5-bromo-3-methylpyridin-2-amine (0.60 g, 3.2 mmol) as starting material and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethan-1-one (0.89 g, 3.2 mmol) as replacement where appropriate, to give the title compound as a tan solid (1.0 g, 2.7 mmol, 84% yield). 1 H 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): mass observed: 367.1; retention time: 0.72 min.

[0374] Step B. Preparation of tert-butyl 4-(8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0375]

[0376] Intermediate 7B was prepared according to the general procedure described for the synthesis of Intermediate IB (steps C to D) using Intermediate 7A (1.0 g, 2.7 mmol) as starting material to afford the title compound as a light yellow solid (1.2 g, 2.6 mmol, 96% yield). 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): mass observed: 468.4; retention time: 0.81 min.

[0377] Step C. Preparation of 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)imidazo[l,2- a]pyridine hydrochloride

[0378]

[0379] Intermediate 7C was prepared according to the general procedure described for the synthesis of Intermediate ID (steps C to D) using Intermediate 7B (1.2 g, 2.5 mmol) as starting material to afford the title compound as a brown solid (1.0 g, 2.5 mmol, 100% yield). 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): mass observed: 370.4; retention time: 0.51 min.

[0380] Step D. Preparation of Example 7

[0381] Example 7 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 7C (70 mg, 0.16 mmol) as starting material. The crude material was purified via preparative HPLC (preparative method 1) to afford the title compound (61 mg, 0.12 mmol, 75% yield). 1 H 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 not clear). Analytical LC / MS (method 1): purity: 96.8%; mass observed: 493.14; retention time: 1.45 min. (method 2): purity: 94.9%; mass observed: 493.15; retention time: 0.90 min.

[0382] Example 8

[0383] 6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0384]

[0385] Example 8 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 7C (70 mg, 0.16 mmol) as starting material and 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as a replacement when appropriate. The crude material was purified via 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%; mass observed: 494.90; retention time: 1.19 min. (Method 2): purity: 95%; mass observed: 495.17; retention time: 0.90.

[0386] Example 9

[0387] 6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0388]

[0389] Example 9 was synthesized according to the general procedure described for Preparation Example 1 (step E) using intermediate 7C (70 mg, 0.16 mmol) as starting material and 1- isobutylpiperidin-4-one (120 mg, 0.77 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 509.17; retention time: 1.38 min. (Method 2): purity: 99.3%; mass observed: 509.18; retention time: 0.94 min.

[0390] Example 10

[0391] 6-(1'-Cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)imidazo[1,2- a]pyridine

[0392]

[0393] Step A. Preparation of intermediate 10A. 6-Bromo-2-(3,4-dimethoxyphenyl)imidazo[1,2- a]pyridine

[0394]

[0395] Intermediate 10A was prepared according to the general procedure described for the synthesis of intermediate 1A, using 5-bromopyridin-2-amine (5.0 g, 29 mmol) instead where appropriate, to give the title compound as a tan solid (9.5 g, 29 mmol, 100% yield). 1 H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 509.17; retention time: 1.38 min. (Method 2): purity: 99.3%; mass observed: 509.18; retention time: 0.94 min.

[0396] Step B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[l,2- a]pyridin-6-yl)piperidine- 1 -carboxylate, Intermediate 10B

[0397]

[0398] Intermediate 10B was prepared according to the general procedure described for the synthesis of Intermediate IB using Intermediate 10A (2.5 g, 7.5 mmol) as starting material according to the general procedure described for the synthesis of Intermediate IB to give the title compound as a yellow solid (3.2 g, 7.4 mmol, 99% yield). 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): mass observed: 436.4; retention time: 0.78 min.

[0399] Step C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[l,2- a]pyridin-6-yl)piperidine- 1 -carboxylate, Intermediate 10C

[0400]

[0401] To a 100 mL pear-shaped flask was added Intermediate 10B (3.2 g, 7.4 mmol) and MeOH (40 mL). The vessel was evacuated and purged with N2(2x) followed by the addition of platinum (IV) oxide (0.68 g, 3.0 mmol) and the reaction mixture was stirred under 1 atm 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). The pure fractions were combined, concentrated and dried under vacuum to give the title compound as a white solid (1.0 g, 2.3 mmol, 31% yield). 1H 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): mass observed: 438.4; retention time: 0.78 min.

[0402] Step D. Preparation of 2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)imidazo[l,2- a]pyridine 2,2,2-trifluoroacetate

[0403]

[0404] To a 100 mL pear-shaped 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 vacuum to give the title compound as a tan solid (1.0 g, 2.2 mmol, 96% yield). 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): mass observed: 438.4; retention time: 0.78 min.

[0405] Step E. Preparation of Example 10

[0406] Example 10 was synthesized according to the general procedure described for the preparation of Example 1 (Step E) using intermediate 10D (70 mg, 0.16 mmol) as the starting material. The crude material was purified via 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, 2H), 1.75-1.65 (m, 2H), 1.64-1.56 (m, 1H), 1.50-1.38 (m, 2H), 0.45-0.39 (m, 2H), 0.32-0.26 (m, 2H) (two protons not clear). Analytical LC / MS (Method 1): purity: 95.9%; mass observed: 461.27; retention time: 1.35 min. (Method 2): purity: 96.7%; mass observed: 460.99; retention time: 1.02 min.

[0407] Example 11

[0408] 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2- a]pyridine

[0409]

[0410] Example 11 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 10D (70 mg, 0.16 mmol) as starting material and 1-isopropylpiperidin-4-one (110 mg, 0.78 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 463.29; retention time: 1.33 min. (Method 2): purity: 100%; mass observed: 463.16; retention time: 0.96 min.

[0411] Example 12

[0412] 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)imidazo[1,2- a]pyridine

[0413]

[0414] Example 12 was synthesized according to the general procedure described for the preparation of Example 1 (step E) using intermediate 10D (70 mg, 0.16 mmol) as starting material and 1-isobutylpiperidin-4-one (120 mg, 0.77 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 477.03; retention time: 1.39 min. (Method 2): purity: 100%; mass observed: 477.02; retention time: 1.04 min.

[0415] Example 13

[0416] 2-(3,4-Dimethoxyphenyl)-6-(1-(2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-8- methylimidazo[1,2-a]pyridine

[0417]

[0418] Step A. 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 salt

[0419]

[0420] To a 40 mL vial was added Intermediate 1D (0.50 g, 1.3 mmol), 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (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). The pure fractions were combined, concentrated, and the intermediate was dissolved in a minimum amount of MeOH and diluted with 4 M HC1 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 vacuum dried to give the title compound as a white solid (0.40 g, 0.77 mmol, 59% yield). 1 HNMR (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) (one proton not clear). Analytical LC / MS (Method 5): mass observed: 447.4; retention time: 0.50 min.

[0421] Step B. Preparation of Example 13

[0422] 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 min, then sodium triacetoxyborohydride (87 mg, 0.41 mmol) was added and the reaction mixture was stirred. After stirring for 24 h, 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 MgS04, filtered, and concentrated. The crude material was purified via preparative HPLC (Preparative Method 1) to afford 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 489.07; retention time: 1.2 min. (Method 2): purity: 95.2%; mass observed: 489.29; retention time: 0.98 min.

[0423] Example 14

[0424] 6-(1-(2-Cyclobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8- methylimidazo[1,2-a]pyridine

[0425]

[0426] Example 14 was synthesized according to the general procedure described for Preparation Example 13 (step B) using intermediate 13A (70 mg, 0.14 mmol) as starting material and cyclobutanone (98 mg, 1.4 mmol) as replacement where appropriate. The crude material was purified via 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, 6H), 2.07-1.87 (m, 4H), 1.84-1.66 (m, 4H) (4 protons not clear). Analytical LC / MS (Method 1): purity: 96.7%; mass observed: 501.22; retention time: 1.31 min. (Method 2): purity: 95.2%; mass observed: 501.21; retention time: 0.95 min.

[0427] Example 15

[0428] 2-(3,4-Dimethoxyphenyl)-6-(1-(2-isobutyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-8- methylimidazo[1,2-a]pyridine

[0429]

[0430] Example 15 was synthesized according to the general procedure described for Preparation Example 13 (step B) using intermediate 13A (90 mg, 0.17 mmol) as starting material and isobutyraldehyde (63 mg, 0.87 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford the title compound (32 mg, 0.064 mmol, 38% yield). 1H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 99.2%; mass observed: 502.96; retention time: 1.46 min. (Method 2): purity: 100%; mass observed: 502.96; retention time: 1.03 min.

[0431] Example 16

[0432] 6-(1-(2-(Cyclopropylmethyl)-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4- dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine

[0433]

[0434] Example 16 was synthesized according to the general procedure described for the preparation of Example 13 (step B) using intermediate 13A (90 mg, 0.17 mmol) as starting material and cyclopropanecarboxaldehyde (61 mg, 0.87 mmol) as a replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford the title compound (49 mg, 0.098 mmol, 58% yield). 1H 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, 2H), 1.94-1.86 (m, 2H), 1.69-1.56 (m, 2H), 0.72-0.61 (m, 1H), 0.34-0.28 (m, 2H), 0.10-0.03 (m, 2H) (three protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 501.25; retention time: 1.01 min. (Method 2): purity: 100%; mass observed: 501.28; retention time: 1.52 min.

[0435] Example 17

[0436] 6-(1-(2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)piperidin-4-yl)-2-(3,4-dimethoxyphenyl)-8- methylimidazo[1,2-a]pyridine

[0437]

[0438] To a 40 mL vial was added Intermediate 13A (100 mg, 0.19 mmol), (1-ethoxycyclopropoxy)trimethylsilane (100 mg, 0.58 mmol), activated molecular sieves (500 mg) and MeOH (5 mL). The reaction mixture was flushed with N2and stirred at 80 °C for 1 h, cooled to room temperature, then sodium cyano borohydride (36 mg, 0.58 mmol) was added, the vessel was flushed with N2and the reaction mixture was stirred at 40 °C. After 18 h, the vessel was cooled, recharged with (1-ethoxycyclopropoxy)trimethylsilane (100 mg, 0.58 mmol), AcOH (0.066 mL, 1.2 mmol), sodium cyano borohydride (36 mg, 0.58 mmol) and additional molecular sieves. The vessel was flushed with N2, heated to 50 °C and stirred. After 18 h, the reaction mixture was cooled, filtered and concentrated. The crude material was purified via preparative HPLC (Preparative Method 1) to give the title compound (10 mg, 0.021, 11% yield). 1H 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%; mass observed: 487.23; retention time: 1.5 min. (Method 2): purity: 100%; mass observed: 487.22; retention time: 1.0 min.

[0439] Examples 18 and 19

[0440] 2-(3,4-Dimethoxyphenyl)-6-(l-(8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8- methylimidazo[l,2-a]pyridine

[0441]

[0442] Step A. Preparation of 6-(l-(8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(3,4- dimethoxyphenyl)-8-methylimidazo[l,2-a]pyridine bis(2,2,2-trifluoroacetate)

[0443]

[0444] To a 40 mL vial was added Intermediate 1D (400 mg, 1.0 mmol), 3-oxo-8- azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (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 min, then sodium triacetoxyborohydride (660 mg, 3.1 mmol) was added and the reaction mixture was stirred. After 18 h, the reaction mixture was diluted with DCM / MeOH and filtered. To the filtrate was added water (0.5 mL), then concentrated. The remaining DMF solution was filtered and the crude product was purified by flash column chromatography (100 g of 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 fractions corresponding to the intermediate were combined and concentrated. The resulting residue was dissolved in THF (20 mL) and TFA (20 mL) and stirred. After 3 h, the solvents were concentrated and the residue was purified by flash column chromatography (100 g of 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, concentrated and the product was dried under vacuum to give the title compound as a colorless residue (120 mg, 0.26 mmol, 26% yield). 1 H 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): mass observed: 461.3; retention time: 0.50 min.

[0445] Step B. Preparation of Example 18 and Example 19

[0446] 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 min, then sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added and the reaction mixture was stirred. After 18 h, the reaction mixture was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated. The crude isomeric mixture was purified via preparative HPLC with 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 for 0 min, 15-70% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS signal triggers. Fractions containing the respective desired product were combined and dried via centrifugal evaporation.

[0447] Example 18 (12 mg, 0.023 mmol, 40% yield) was isolated as the 1st eluting isomer. 1 H 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 not clear). Analytical LC / MS (Method 1): purity: 97.7%; mass observed: 516.90; retention time: 1.59 min. (Method 2): purity: 96.1%; mass observed: 517.24; retention time: 1.09 min.

[0448] Example 19 (3.6 mg, 0.0070 mmol, 12% yield) was isolated as the 2nd eluting isomer. 1H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 98.9%; mass observed: 517.01; retention time: 1.69 min. (Method 2): purity: 100%; mass observed: 517.33; retention time: 1.1 min.

[0449] Examples 20 and 21

[0450] 6-(1-(8-(Cyclopropylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(3,4- dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine

[0451]

[0452] Examples 20 and 21 were synthesized according to the general procedure described for the synthesis of Examples 18 and 19 using Intermediate 18A (40 mg, 0.058 mmol) as starting material and cyclopropanecarboxaldehyde (20 mg, 0.29 mmol) as a replacement where appropriate. The crude isomeric mixture was purified via preparative HPLC with 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: 13% B for 0 minutes, 13-53% B over 20 minutes, followed by 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions containing the respective desired product were combined and dried via centrifugal evaporation.

[0453] 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 95.9%; mass observed: 514.94; retention time: 1.52 min. (Method 2): purity: 96.2%; mass observed: 514.33; retention time: 1.08 min.

[0454] Example 21 (4.1 mg, 0.0080 mmol, 14% yield) was isolated as the second eluting isomer. 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) (four protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 515.25; retention time: 1.74 min. (Method 2): purity: 96.1%; mass observed: 515.41; retention time: 1.08 min.

[0455] Example 22

[0456] 2-(3,4-Dimethoxyphenyl)-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8- methylimidazo[1,2-a]pyridine

[0457]

[0458] Examples 22 and 23 were synthesized according to the general procedures described for the synthesis of Examples 18 and 19, using Intermediate 18A (40 mg, 0.058 mmol) as the starting material and prop-2-one (17 mg, 0.29 mmol) as a replacement where appropriate. The crude isomeric mixture was purified via preparative LC / MS with 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: 15-60% B over 20 minutes, then a 100% B hold for 0 minutes; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions containing individual desired products were combined and dried via centrifugal evaporation.

[0459] Example 22 (5.3 mg, 0.011 mmol, 19% yield) was isolated as the first eluting isomer. 1 H 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 503.18; retention time: 1.39 min. (Method 2): purity: 100%; mass observed: 503.21; retention time: 1.00 min.

[0460] Example 23 (2.6 mg, 0.0052 mmol, 9.0% yield) was isolated as the second eluting isomer. 1H 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) (5 protons not clear). Analytical LC / MS (Method 1): purity: 97%; mass observed: 502.90; retention time: 1.65 min. (Method 2): purity: 98.6%; mass observed: 503.16; retention time: 1.07 min.

[0461] Example 24

[0462] 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)-8- methylimidazo[1,2-a]pyridine (mixture of isomers)

[0463]

[0464] Step A. 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

[0465]

[0466] 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 allowed to cool, diluted with water (100 mL) and extracted with EtOAc (2 x 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). The pure fractions were combined, concentrated and dried under vacuum to give the title compound as a light yellow solid (270 mg, 0.56 mmol, 75% yield). 1 H NMR (500 MHz, Methanol-d4) d 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): mass observed: 476.4; retention time: 0.88 min.

[0467] Step B. Preparation of Intermediate 24B. 6-(8-Azabicyclo[3.2.1]oct-3-yl)-2-(3,4- dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine hydrochloride

[0468]

[0469] To a 100 mL pear-shaped 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 atm of hydrogen. After 18 h, the catalyst was filtered and to the filtrate was added 4 M HC1 in dioxane (30 mL). After stirring for 30 min, the solvent was concentrated, the residue was co-evaporated with toluene (2x), and the product was dried under vacuum to yield the title compound as a tan solid (230 mg, 0.56 mmol, 98% yield). 1 H 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 (s, 3H), 3.94 (s, 3H), 3.78 - 3.58 (m, 2H), 3.48 - 3.40 (m, 1H), 2.77 - 2.72 (m, 3H), 2.25 (br s, 4H), 2.16 - 2.08 (m, 2H). Analytical LC / MS (Method 5): mass observed: 378.3; retention time: 0.58 min.

[0470] Step C. Preparation of Example 24

[0471] 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 min, then sodium triacetoxyborohydride (99 mg, 0.47 mmol) was added and the reaction mixture was stirred. After 18 h, the reaction mixture was filtered and partitioned in 10% NaOH (20 mL) and extracted with 10% IPA / chloroform (3 x 10 mL). The organic phases were combined, dried over Na2S04, filtered, and concentrated. The crude material was purified via preparative HPLC (Preparative Method 1) to yield 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%; mass observed: 501.17; retention time: 1.52 min. (Method 2): purity: 100%; mass observed: 500.96; retention time: 1.16 min.

[0472] Examples 25 and 26

[0473] 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4- dimethoxyphenyl)-8-methylimidazo[1,2-a]pyridine

[0474]

[0475] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% C02 / 45% IPA with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 600 uL, 21 mg, dissolved in 3 mL MeOH.

[0476] 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 not clear). Analytical LC / MS (Method 1): purity: 99.3%; mass observed: 501.21; retention time: 1.46 min. (Method 2): purity: 100%; mass observed: 500.98; retention time: 1.01 min. Chiral analytical (SFC Method 4): chiral purity >95%. Retention time: 2.2 min.

[0477] Example 26 (4.1 mg, 0.0082 mmol, 20% yield) was isolated as the second eluting isomer. 1 H 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%; mass observed: 500.93; retention time: 1.46 min. (Method 2): purity: 98.6%; mass observed: 500.96; retention time: 0.99 min. Chiral analytical (SFC Method 4): chiral purity >95%. Retention time: 4.2 min.

[0478] Example 27

[0479] 2-(3,4-dimethoxyphenyl)-6-(8-(1-isobutylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3- yl)-8-methylimidazo[1,2-a]pyridine (isomeric mixture)

[0480]

[0481] Example 27 was prepared according to the general procedure described for the synthesis of Example 24 (step C) using intermediate 24C (70 mg, 0.16 mmol) as starting material and 1 -isobutylpiperidin-4-one (120 mg, 0.77 mmol) as a replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1 ) to afford the title compound (76 mg, 0.15 mmol, 94% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 2H), 7.55-7.52 (m, 1 H), 7.51 -7.46 (m, 1 H), 7.07-6.99 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.69-3.62 (m, 1 H), 3.05-2.94 (m, 1 H), 2.88-2.79 (m, 2H), 2.56 (s, 4H), 2.33-2.23 (m, 1 H), 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 not clear). Analytical LC / MS (Method 1 ): purity: 97.9%; mass observed: 516.97; retention time: 1.59 min. (Method 2): purity: 100%; mass observed: 516.96; retention time: 1.1 min.

[0482] Examples 28 and 29

[0483] 2-(3,4-dimethoxyphenyl)-6-(8-(1-isobutylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3- yl)-8-methylimidazo[1,2-a]pyridine

[0484]

[0485] 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: Instrument: Berger SFC; Column: OD 30 x 250 mm ID, 5 pm; Temperature: 40 °C; Flow rate: 85.0 mL / min; Mobile phase: 75 / 25 C02 / EtOH-0.1% DEA; Detector wavelength: 220 nm; Injection volume: 500 pL; Sample preparation: 50 mg sample dissolved in 3 mL MeOH.

[0486] Example 28 (22 mg, 0.043 mmol, 44% yield) was isolated as the first eluting isomer. 1 H NMR (400 MHz, Methanol-d4) d 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, 4H), 1.86-1.76 (m, 3H), 1.68-1.47 (m, 4H), 1.29 (s, 3H), 0.93 (d, J = 6.7 Hz, 6H). Analytical LC / MS (Method 3): purity: 96.9%; mass observed: 517.55; retention time: 2.27 min. (Method 4): purity: 98.0%; mass observed: 517.20; retention time: 1.25 min. Chiral analytical (SFC Method 5): chiral purity >99%. retention time: 11.58 min.

[0487] 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%; mass observed: 517.50; retention time: 2.28 min. (Method 4): purity: 96.1%; mass observed: 517.20; retention time: 1.18 min. Chiral analytical (SFC Method 5): chiral purity >99%. Retention time: 19.81 min.

[0488] Example 30

[0489] 2-(3,4-Dimethoxyphenyl)-6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-8- methylimidazo[1,2-a]pyridine (mixture of isomers)

[0490]

[0491] Example 30 was prepared according to the general procedure described for the synthesis of Example 24 (step C) using intermediate 24C (70 mg, 0.16 mmol) as starting material and 1- isopropylpiperidin-4-one (110 mg, 0.78 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 502.90; retention time: 1.41 min. (Method 2): purity: 100%; mass observed: 502.96; retention time: 1.08 min.

[0492] Example 31

[0493] 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine (racemic mixture)

[0494]

[0495] Step A. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate

[0496]

[0497] To a 100 mL pear-shaped 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 atm 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). The pure fractions were combined, concentrated and dried under vacuum to afford the title compound as a light yellow solid (2.1 g, 4.8 mmol, 84% yield). 1H 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): mass observed: 442.5; retention time: 0.78 min.

[0498] Step B. Preparation of Intermediate 31B. 2-(3,4-Dimethoxyphenyl)-6-(piperidin-4- yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine hydrochloride

[0499]

[0500] To a 200 mL pear-shaped flask was added Intermediate 31A (2.1 g, 4.8 mmol), THF (10 mL), and 4 M HC1 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 vacuum to give the title compound as a light tea solid (1.8 g, 4.8 mmol, 100% yield). 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): mass observed: 442.5; retention time: 0.78 min.

[0501] Step C. Preparation of Example 31

[0502] 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 min, then sodium triacetoxyborohydride (170 mg, 0.81 mmol) was added and the reaction mixture was stirred. After 24 h, 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 MgS04, filtered, and concentrated. The crude material was purified via 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%; mass observed: 481.23; retention time: 1.38 min. (Method 2): purity: 97.6%; mass observed: 481.22; retention time: 0.91 min.

[0503] Examples 32 and 33

[0504] 2-(3,4-Dimethoxyphenyl)-6-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine

[0505]

[0506] The individual enantiomers Example 32 and Example 33 were obtained by separating the racemic mixture Example 31 (68 mg, 0.14 mmol) under the following conditions: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% C02 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 1000 uL, 68 mg dissolved in 3 mL MeOH.

[0507] Example 32 (21 mg, 0.044 mmol, 31% yield) was isolated as the 1steluting 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 98.2%; mass observed: 481.18; retention time: 1.38 min. (Method 2): purity: 97.1%; mass observed: 480.98; retention time: 1.05 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 1.89 min.

[0508] Example 33 (11 mg, 0.023 mmol, 16% yield) was isolated as the 2nd eluting enantiomer. 1 H 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 98.2%; mass observed: 481.18; retention time: 1.38 min. (Method 2): purity: 97.1%; mass observed: 480.98; retention time: 1.05 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 1.89 min.

[0509] Example 34

[0510] 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine (racemic mixture)

[0511]

[0512] Example 34 was prepared according to the general procedure described for the synthesis of Example 31 (step C) using intermediate 31B (120 mg, 0.27 mmol) as starting material and 1 -isopropylpiperidin-4-one (190 mg, 1.3 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to afford the title compound (70 mg, 0.15 mmol, 56% yield). 1 H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 90.7%; mass observed: 467.13; retention time: 1.2 min. (Method 2): purity: 95.1%; mass observed: 467.65; retention time: 0.64 min.

[0513] Examples 35 and 36

[0514] 2-(3,4-Dimethoxyphenyl)-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine

[0515]

[0516] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 1000 uL, 26 mg, dissolved in 3 mL MeOH.

[0517] Example 35 (6.4 mg, 0.014 mmol, 25% yield) was isolated as the 1steluting enantiomer. 1 H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 97.7%; mass observed: 467.21; retention time: 1.25 min. (Method 2): purity: 100%; mass observed: 467.19; retention time: 0.97 min. Chiral analytical (SFC Method 1): chiral purity >95%. retention time: 1.85 min.

[0518] Example 36 (7.4 mg, 0.016 mmol, 29% yield) was isolated as the 2ndeluting 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%; mass observed: 467.21; retention time: 1.25 min. (Method 2): purity: 98.4%; mass observed: 467.19; retention time: 0.97 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 3.68 min.

[0519] Examples 37 and 38

[0520] 6-(1'-Cyclopropyl-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine

[0521]

[0522] The racemic mixture was prepared according to the general procedure described for the synthesis of Example 31 (step C) using intermediate 31B (300 mg, 0.62 mmol) as starting material and 1-cyclopropylpiperidin-4-one (430 mg, 3.1 mmol) as replacement where appropriate. The crude material was purified via preparative HPLC (preparative method 1) to give the racemic mixture (65 mg, 0.14 mmol, 23% yield).

[0523] The individual enantiomeric Examples 37 and 38 were obtained by separation of the racemic mixture (65 mg, 0.14 mmol) under the following conditions: Instrument: Waters 100 Prep SFC; Column: Chiral AD, 30 x 250 mm. 5 micron; Mobile phase: 60% CO2 / 40% MeOH with 0.1% DEA; Flow conditions: 100 mL / min; Detector wavelength: 220 nm; Injection details: 1200 μL, 65 mg dissolved in 3 mL MeOH.

[0524] Example 37 (25 mg, 0.054 mmol, 39% yield) was isolated as the 1st 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%; mass observed: 465.28; retention time: 1.37 min. (Method 2): purity: 100%; mass observed: 465.28; retention time: 0.95 min. Chiral analytical (SFC Method 2): chiral purity > 95%. retention time: 3.60 min.

[0525] Example 38 (23 mg, 0.043 mmol, 31% yield) was isolated as the 2nd 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%; mass observed: 465.29; retention time: 1.37 min. (Method 2): purity: 87.7%; mass observed: 465.29; retention time: 0.95 min. Chiral analytical (SFC Method 2): chiral purity > 95%. Retention time: 5.58 min.

[0526] Example 39

[0527] 1-(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-6-yl)-[l,4'- bipiperidin]-l'-yl)-2-methylpropan-l-one (racemic mixture)

[0528]

[0529] Step A. Preparation of intermediate 39A. 6-([l,4'-bipiperidin]-4-yl)-2-(3,4- dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine dihydrochloride salt

[0530]

[0531] 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 min, then sodium triacetoxyborohydride (1000 mg, 4.8 mmol) was added and the reaction mixture was stirred. After 24 h, 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). The pure fractions were combined and concentrated. The resulting residue was dissolved in THF (20 mL) and 4 M HC1 in dioxane (20 mL) and stirred. After 3 h, the solvents were concentrated, the residue was co-evaporated with toluene and the product was dried under vacuum to give the title compound as a yellow solid (790 mg, 1.6 mmol, 100% yield). Analytical LC / MS (Method 5): mass observed: 425.4; retention time: 0.48 min.

[0532] Step B. Preparation of Example 39

[0533] 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 via 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 98.6%; mass observed: 495.19; retention time: 1.25 min. (Method 2): purity: 98.8%; mass observed: 495.16; retention time: 1.05 min. Examples 40 and 41

[0534] 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

[0535]

[0536] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH-ACN-50-50; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 2000 μL, 14 mg, dissolved in 3 mL MeOH.

[0537] Example 40 (3.7 mg, 0.0075 mmol, 27% yield) was isolated as the 1steluting 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 95.3%; mass observed: 495.15; retention time: 1.28 min. (Method 2): purity: 97.2%; mass observed: 495.13; retention time: 1.06 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 1.25 min.

[0538] Example 41 (3.8 mg, 0.0077 mmol, 28% yield) was separated as the 2nd 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%; mass observed: 495.16; retention time: 1.28 min. (Method 2): purity: 96.7%; mass observed: 495.12; retention time: 1.06 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 3.40 min.

[0539] Example 42

[0540] Cyclopropyl(4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyridin-6-yl)-[l,4’-bipiperidin]-l’-yl)methanone (racemic mixture)

[0541]

[0542] 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 via preparative HPLC (Preparative Method 1) to afford the title compound (59 mg, 0.12 mmol, 55% yield). 1H 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, 1H), 1.98 - 1.93 (m, 1H), 1.91 - 1.66 (m, 6H), 1.58 - 1.47 (m, 1H), 1.44 - 1.19 (m, 6H), 0.69 (br d, J=7.3 Hz, 4H). Analytical LC / MS (Method 1): purity: 100%; mass observed: 493.08; retention time: 1.14 min. (Method 2): purity: 100%; mass observed: 493.28; retention time: 1.02 min.

[0543] Examples 43 and 44

[0544] Cyclopropyl (4-(2-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyridin-6-yl)-[l,4'-bipiperidin]-l'-yl)methanone

[0545]

[0546] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 75% CO2 / 25% IPA-ACN 50-50 with 0.1% DEA; Flow conditions: 100 mL / min; Detector wavelength: 220 nm; Injection details: 1000 uL, 59 mg dissolved in 3 mL MeOH.

[0547] Example 43 (21 mg, 0.043 mmol, 36% yield) was isolated as the first eluting enantiomer. 1H 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%; mass observed: 493.14; retention time: 1.24 min. (Method 2): purity: 97.3%; mass observed: 493.13; retention time: 1.03 min. Chiral analytical (SFC Method 3): chiral purity >95%. Retention time: 5.99 min.

[0548] Example 44 (22 mg, 0.0045 mmol, 38% yield) was separated as the 2nd 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%; mass observed: 493.34; retention time: 1.24 min. (Method 2): purity: 95.9%; mass observed: 493.13; retention time: 1.04 min. Chiral analytical (SFC Method 3): chiral purity >95%. Retention time: 7.30 min.

[0549] Example 45

[0550] 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)

[0551]

[0552] Step A. 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)

[0553]

[0554] To a 250 mL round bottom flask was added Intermediate 31A (1.0 g, 2.7 mmol), 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (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 min, then sodium triacetoxyborohydride (1.7 g, 7.9 mmol) was added and the reaction mixture was stirred. After 18 h, 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). The 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 vacuum to yield the title compound as a light yellow solid (1.3 g, 2.0 mmol, 74% yield). 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): mass observed: 437.5; retention time: 0.58 min.

[0555] Step B. Preparation of Example 45

[0556] 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 min, then sodium triacetoxyborohydride (310 mg, 1.5 mmol) was added and the reaction mixture was stirred. After 18 h, 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 not clear). Analytical LC / MS: (Method 1): purity: 95.4%; mass observed: 479.26; retention time: 1.2 min. (Method 2): purity: 97.5%; mass observed: 478.90; retention time: 0.98 min.

[0557] Examples 46 and 47

[0558] 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

[0559]

[0560] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 300 uL, 130 mg, dissolved in 3 mL MeOH.

[0561] Example 46 (59 mg, 0.12 mmol, 44% yield) was isolated as the 1st 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 479.26; retention time: 1.29 min. (Method 2): purity: 100%; mass observed: 478.94; retention time: 0.94 min. Chiral analytical (SFC Method 1): chiral purity >95%. retention time: 1.41 min.

[0562] Example 47 (22 mg, 0.046 mmol, 17% yield) was isolated as the 2nd eluting enantiomer. 1H 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 479.26; retention time: 1.29 (Method 2): purity: 100%; mass observed: 479.26; retention time: 0.94 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 4.05 min.

[0563] Example 48

[0564] 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)

[0565]

[0566] Example 48 was prepared according to the general procedure described for the synthesis of Example 45 (step B) using intermediate 45A (320 mg, 0.48 mmol) as starting material and cyclobutanone (170 mg, 2.4 mmol) as replacement where appropriate. The crude product was purified by preparative HPLC (preparative method 1) to afford the title compound (170 mg, 0.35 mmol, 73% yield). 1H 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, 2H), 1.77-1.72 (m, 2H), 1.70-1.47 (m, 5H), 1.30-1.15 (m, 3H). Analytical LC / MS (Method 1): purity: 93.6%; mass observed: 491.22; retention time: 1.19 min. (Method 2): purity: 96.3%; mass observed: 491.26; retention time: 1.04 min.

[0567] Examples 49 and 50

[0568] 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

[0569]

[0570] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 300 uL, 77 mg, dissolved in 3 mL MeOH.

[0571] Example 49 (13 mg, 0.026 mmol, 16% yield) was isolated as the first eluting enantiomer. 1H 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%; mass observed: 491.19; retention time: 1.31 min. (Method 2): purity: 95.8%; mass observed: 491.21; retention time: 0.99 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 1.80 min.

[0572] Example 50 (11 mg, 0.022 mmol, 14% yield) was isolated as the 2nd 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), 3.72 - 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, 1H), 2.16 - 2.09 (m, 2H), 2.05 - 1.97 (m, 1H), 1.88 - 1.79 (m, 4H), 1.78 - 1.47 (m, 11H), 1.30 - 1.15 (m, 3H) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 491.10; retention time: 1.32 min. (Method 2): purity: 100%; mass observed: 491.19; retention time: 0.98 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 5.30 min.

[0573] Example 51

[0574] 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)

[0575]

[0576] Example 51 was prepared according to the general procedure described for the synthesis of Example 45 (step B) using intermediate 45A (320 mg, 0.48 mmol) as starting material and cyclopropanecarboxaldehyde (170 mg, 2.4 mmol) as replacement where appropriate. 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 7.27-7.25 (m, 1 H), 7.24-7.21 (m, 1 H), 7.16-7.11 (m, 1 H), 6.86-6.81 (m, 1 H), 4.00-3.94 (m, 1 H), 3.71 (s, 3 H), 3.67 (s, 3 H), 3.61 -3.54 (m, 1 H), 3.23-3.18 (m, 1 H), 3.12-3.07 (m, 1 H), 2.82-2.68 (m, 3 H), 2.63-2.54 (m, 1 H), 2.43-2.39 (m, 1 H), 2.25-2.20 (m, 2 H), 2.13-2.07 (m, 2 H), 1.98-1.92 (m, 1 H), 1.82-1.75 (m, 2 H), 1.72-1.63 (m, 2 H), 1.61 -1.52 (m, 3 H), 1.50-1.41 (m, 1 H), 1.24-1.10 (m, 3 H), 0.68-0.59 (m, 1 H), 0.33-0.29 (m, 2 H), 0.01 (br d, J = 4.6 Hz, 2 H) (two protons not clear). Analytical LC / MS (Method 1): purity: 96.3%; mass observed: 491.20; retention time: 1.2 min. (Method 2): purity: 97.3%; mass observed: 491.19; retention time: 0.98 min.

[0577] Example 52

[0578] 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)

[0579]

[0580] Example 52 was prepared according to the general procedure described for the synthesis of Example 45 (step B) using intermediate 45A (320 mg, 0.48 mmol) as starting material and isobutyraldehyde (170 mg, 2.4 mmol) as replacement where appropriate. 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) (three protons not clear). Analytical LC / MS (Method 1): purity: 97.6%; mass observed: 493.20; retention time: 1.24 min. (Method 2): purity: 97.5%; mass observed: 493.22; retention time: 0.99 min.

[0581] Examples 53 and 54

[0582] 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

[0583]

[0584] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 600 uL, 94 mg, dissolved in 3 mL MeOH.

[0585] Example 53 (17 mg, 0.035 mmol, 18% yield) was isolated as the 1st 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 97.8%; mass observed: 493.21; retention time: 1.29 min. (Method 2): purity: 97.6%; mass observed: 493.23; retention time: 0.98 min. Chiral analytical (SFC Method 1): chiral purity >95%. retention time: 1.45 min.

[0586] Example 54 (16 mg, 0.032 mmol, 17% yield) was isolated as the 2nd 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, J = 6.6 Hz, 6H) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 492.90; retention time: 1.35 min. (Method 2): purity: 100%; mass observed: 493.22; retention time: 1.00 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 4.10 min.

[0587] Example 55

[0588] 6-(1'-(Cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (racemic mixture)

[0589]

[0590] To a 40 mL vial was added Intermediate 39A (380 mg, 0.42 mmol), cyclopropanecarboxaldehyde (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 min, then sodium triacetoxyborohydride (270 mg, 1.3 mmol) was added and the reaction mixture was stirred. After 18 h, 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). 1H 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%; mass observed: 479.12; retention time: 1.22 min. (Method 2): purity: 97.1%; mass observed: 478.97; retention time: 1.03 min.

[0591] Examples 56 and 57

[0592] 6-(1'-(Cyclopropylmethyl)-[1,4'-bipiperidin]-4-yl)-2-(3,4-dimethoxyphenyl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine

[0593]

[0594] 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: Instrument: Waters 100 Prep SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 100 mL / min; Detector Wavelength: 220 nm; Injection Details: 1500 uL, 68 mg, dissolved in 2 mL MeOH.

[0595] Example 56 (2.7 mg, 0.0056 mmol, 4.0% yield) was isolated as the first eluting enantiomer. 1H 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 91.1%; mass observed: 479.21; retention time: 1.26 min. (Method 2): purity: 93.1%; mass observed: 479.20; retention time: 0.89 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 2.20 min.

[0596] Example 57 (2.4 mg, 0.0050 mmol, 3.6% yield) was isolated as the 2ndeluting enantiomer. 1H 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, 1H), 0.37 (br d, J = 8.0 Hz, 2H), 0.01 (br d, J = 4.6 Hz, 2H) (one proton not clear). Analytical LC / MS (Method 1): purity: 96.6%; mass observed: 479.22; retention time: 1.26 min. (Method 2): purity: 95.7%; mass observed: 479.20; retention time: 0.90 min. Chiral analytical (SFC Method 1): chiral purity >95%. Retention time: 4.70 min.

[0597] Example 58

[0598] 2-(3,4-Dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine (racemic mixture)

[0599]

[0600] Step A. Preparation of 7-bromo-2-(3,4-dimethoxyphenyl)imidazo[1,2- a]pyridine

[0601]

[0602] Intermediate 58A was prepared as follows: according to the general procedure described for the synthesis of Intermediate 1A, using 4-bromopyridin-2-amine (500 mg, 2.9 mmol) as a replacement where appropriate, to give the title compound as a white solid (0.98 g, 2.9 mmol, 100% yield). 1H 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): mass observed: 333.0; retention time: 0.62 min.

[0603] Step B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)imidazo[l,2- a]pyridin-7-yl)piperidine-l-carboxylate

[0604]

[0605] Intermediate 58B was prepared according to the general procedure described for the synthesis of Intermediate IB using Intermediate 58A (0.98 g, 2.9 mmol) as starting material to give the title compound as a white solid (1.2 g, 2.8 mmol, 97% yield). 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): mass observed: 333.0; retention time: 0.62 min.

[0606] Step C. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-5,6,7,8- tetrahydroimidazo[l,2-a]pyridin-7-yl)piperidine-l-carboxylate

[0607]

[0608] Intermediate 58C was prepared according to the general procedure described for the synthesis of Intermediate 31A using Intermediate 58B (1.2 g, 2.8 mmol) as starting material to give the title compound as a white solid (0.56 g, 1.3 mmol, 46% yield). 1H 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): mass observed: 442.4; retention time: 0.77 min.

[0609] Step D. Preparation of intermediate 58D, 2-(3,4-dimethoxyphenyl)-7-(piperidin-4- yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine hydrochloride

[0610]

[0611] Intermediate 58D was prepared according to the general procedure described for the synthesis of intermediate 31B using intermediate 58C (0.56 g, 1.3 mmol) as starting material to give the title compound as a light yellow solid (420 mg, 1.1 mmol, 85% yield). 1 H 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): mass observed: 342.4; retention time: 0.49 min.

[0612] Step E. Preparation of Example 58

[0613] 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 min, then sodium triacetoxyborohydride (180 mg, 0.83 mmol) was added and the reaction mixture was stirred. After 18 h, 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 afford the title compound (15 mg, 0.032 mmol, 11% yield). 1 H 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%; mass observed: 467.20; retention time: 1.21 min. (Method 2): purity: 100%; mass observed: 467.20; retention time: 0.98 min.

[0614] Example 59

[0615] 2-(3,4-Dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine (racemic mixture)

[0616]

[0617] Example 59 was synthesized according to the general procedure described for the preparation of Example 58 (step E) using Intermediate 58D (110 mg, 0.29 mmol) as starting material and 1-isobutylpiperidin-4-one (130 mg, 0.84 mmol) as a replacement where appropriate. 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, 2H), 2.11-2.04 (m, 1H), 2.00 (s, 2H), 1.91-1.56 (m, 9H), 1.49-1.40 (m, 2H), 1.24 (br s, 3H), 0.85 (d, J = 6.4 Hz, 6H). Analytical LC / MS (Method 1): purity: 97.4%; mass observed: 480.99; retention time: 1.31 min. (Method 2): purity: 92.7%; mass observed: 481.03; retention time: 1.03 min.

[0618] Example 60

[0619] 2-(3,4-Dimethoxyphenyl)-7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5- a]pyridine

[0620]

[0621] Step A. Preparation of 7-bromo-2-(3,4-dimethoxyphenyl)-[1,2,4]triazolo[1,5- a]pyridine

[0622]

[0623] To a 50 mL three necked flask was added 4-bromo-pyridin-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 sealed, and the reaction mixture was heated to 130 °C and stirred. After 18 h, the reaction mixture was allowed to cool, 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 afford the title compound as a light yellow solid (1.4 g, 4.2 mmol, 72% yield). 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): mass found: 335.9; retention time: 0.86 min.

[0624] Step B. Preparation of tert-butyl 4-(2-(3,4-dimethoxyphenyl)-[l,2,4]triazolo[l,5- a]pyridin-7-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0625]

[0626] Intermediate 60A (0.66 g, 2.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.73 g, 2.4 mmol), 1,4-dioxane (10 mL), and potassium phosphate dissolved in water (2 mL) (1.3 g, 6.1 mmol) were added. The vial was purged with N2, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.081 g, 0.099 mmol). The vial was purged again with N2, and the reaction mixture 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 rapid column chromatography (80 g silica gel filter cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 60 mL / min). The pure eluates were combined, concentrated, and dried under vacuum to give the title compound (0.61 g, 1.4 mmol, 70% yield) as a pale yellow solid. Analytical LC / MS (Method 5): Mass observation: 437.1; retention time: 0.96 min.

[0627] 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

[0628]

[0629] Intermediate 60B (0.61 g, 1.4 mmol) and MeOH (20 mL) were added to a 100 mL pear-shaped flask. The flask was evacuated and purged with N2, followed by the addition of Pd-C (10% on carbon) (0.15 g, 0.14 mmol), and the reaction mixture was stirred at 1 atm of hydrogen. After 2 h, the catalyst was filtered off and the filtrate was concentrated. The product was dried under vacuum to give the title compound as a white solid (0.61 g, 1.4 mmol, 99% yield). Analytical LC / MS (Method 5): Mass observation: 439.1; Retention time: 0.94 min.

[0630] Step D. Intermediate 60D. Preparation of 2-(3,4-dimethoxyphenyl)-7-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine hydrochloride

[0631]

[0632] To a 100 mL pear-shaped flask was added intermediate 60C (610 mg, 1.4 mmol), THF (2 mL), and 4 M HC1 in dioxane (5 mL). A white precipitate immediately formed. 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 vacuum to yield the title compound as an off-white solid (520 mg, 1.4 mmol, 100% yield). 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, 3H), 3.44-3.38 (m, 2H), 3.11-2.98 (m, 3H), 2.11-2.04 (m, 2H), 2.01-1.89 (m, 2H). Analytical LC / MS (Method 5): mass observed: 339.0; retention time: 0.60 min.

[0633] Step E. Preparation of Example 60

[0634] 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 min, then sodium triacetoxyborohydride (100 mg, 0.48 mmol) was added and the reaction mixture was stirred. After 18 h, 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 yield the title compound (71 mg, 0.15 mmol, 94% yield). 1H 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%; mass observed: 464.31; retention time: 1.26 min. (Method 2): purity: 100%; mass observed: 464.15; retention time: 1.07 min.

[0635] Example 61

[0636] 2-(3,4-Dimethoxyphenyl)-7-(1'-isobutyl-[1,4'-bipiperidin]-4-yl)-[1,2,4]triazolo[1,5- a]pyridine

[0637]

[0638] Example 61 was synthesized according to the general procedure described for the preparation of Example 60 (step E) using intermediate 60D (60 mg, 0.16 mmol) as starting material and 1-isobutylpiperidin-4-one (75 mg, 0.48 mmol) as replacement where appropriate. The crude product was purified by preparative HPLC (preparative method 1) to give the title compound (54 mg, 0.11 mmol, 69% yield). 1H 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 99.3%; mass observed: 478.17; retention time: 1.39 min. (Method 2): purity: 97%; mass observed: 478.17; retention time: 1.1 min.

[0639] Examples 62 and 63

[0640] 6-(l-(8-Isopropyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine

[0641]

[0642] Step A. Preparation of intermediate 62A. 6-(l-(8-Azabicyclo[3.2. l]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine dihydrochloride

[0643]

[0644] To a 250 mL round bottom flask was added Intermediate 7C (0.58 g, 1.4 mmol), MeOH (50 mL), and DOWEX 50A 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), followed by the addition of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.3 g, 5.7 mmol), followed by the addition of 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, followed by the addition of sodium triacetoxyborohydride (1.2 g, 5.7 mmol) and the reaction was continued. After 3 h, the reaction mixture was partitioned between 1 M 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), 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 fractions corresponding to the product were combined, concentrated, and dried in vacuo. The resulting residue was dissolved in MeOH (20 mL) and 4 M HC1 in dioxane (10 mL) and stirred. After 0.5 h, the solvent was concentrated, and the residue was co-evaporated with toluene (2x). The product was dried in vacuo to yield the title compound as an off-white solid (0.47 g, 0.85 mmol, 61% yield). 1 H 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): mass observed: 479.1; retention time: 0.832 min.

[0645] Step B. Examples 62 and 63

[0646] 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 min, then sodium triacetoxyborohydride (170 mg, 0.82 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 in 10% KOH (aq, saturated with solid NaCl) (20 mL) and the layers separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), the organic phases were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified via preparative LC / MS with the following conditions: Column: XBridge CI 8, 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 for 0 min, 5-55% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS and UV signals. Fractions corresponding to individual desired products were combined and dried via centrifugal evaporation.

[0647] Example 62 (11 mg, 0.021 mmol, 13% yield) was isolated as the 1st 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 98.2%; mass observed: 521.01; retention time: 0.84 min. (Method 2): purity: 98%; mass observed: 520.95; retention time: 1.28 min.

[0648] Example 63 (11 mg, 0.021 mmol, 13% yield) was isolated as the 2nd eluting isomer. 1H 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, 3H), 2.62 - 2.45 (m, 7H), 2.39 - 2.29 (m, 1H), 1.94 - 1.58 (m, 15H), 1.00 (br d, J=6.1 Hz, 6H). Analytical LC / MS (Method 1): purity: 97.9%; mass observed: 521.32; retention time: 0.84 min. (Method 2): purity: 96.7%; mass observed: 521.31; retention time: 1.35 min.

[0649] Example 64

[0650] 2-(3,4-Dimethoxyphenyl)-8-methyl-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)imidazo[1,2- a]pyridine

[0651]

[0652] Step A. Preparation of tert-butyl 4-(4-(2-(3,4-dimethoxyphenyl)-8-methylimidazo[1,2- a]pyridin-6-yl)phenyl)piperazine-1-carboxylate

[0653]

[0654] 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 allowed to cool, diluted with water (100 mL) and extracted with EtOAc (2 x 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). The fractions corresponding to the desired product were combined, concentrated and dried under vacuum to give the title compound as a light yellow solid (610 mg, 1.2 mmol, 86% yield). 1H 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): mass observed: 529.3; retention time: 0.86 min.

[0655] Step B. Preparation of 2-(3,4-dimethoxyphenyl)-8-methyl-6-(4-(piperazin-l- yl)phenyl)imidazo[l,2-a]pyridine dihydrochloride salt

[0656]

[0657] To a 200 mL pear-shaped flask was added intermediate 64A (610 mg, 1.2 mmol), MeOH (10 mL) and 4 M HC1 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 vacuum to give the title compound as a tea-colored solid (600 mg, 1.2 mmol, 100% yield). 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): mass observed: 429.3; retention time: 0.57 min.

[0658] Step C. Example 64

[0659] 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 between 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), 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%; mass observed: 485.17; retention time: 1.12 min. (Method 2): purity: 100%; mass observed: 485.16; retention time: 1.80 min.

[0660] Example 65

[0661] 6-(4-(4-Isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0662]

[0663] Step A. Preparation of 8-methyl-2-(4-(methylsulfonyl)phenyl)-6-(4-(piperazin-1- yl)phenyl)imidazo[1,2-a]pyridine dihydrochloride salt

[0664]

[0665] Intermediate 65A was synthesized according to the procedure described for the preparation of Intermediate 64B (steps A to B, using Intermediate 7A (0.75 g, 2.1 mmol) as a replacement where appropriate, to give the title compound as a tan solid (0.81 g, 1.6 mmol, 76% yield over 2 steps). 1 H NMR (500 MHz, DMSO-d6) δ 9.25 (br s, 1 H), 9.02-8.93 (m, 1 H), 8.82-8.74 (m, 1 H), 8.41-8.29 (m, 2 H), 8.17-8.08 (m, 2 H), 8.05-7.93 (m, 1 H), 7.79-7.63 (m, 2 H), 7.21-7.09 (m, 2 H), 3.52-3.48 (m, 4 H), 3.31 (s, 3 H), 3.27-3.23 (m, 4 H), 2.73 (s, 3 H) Analytical LC / MS (Method 4): Mass found: 447.1 ; Retention time: 0.927 min.

[0666] Step B. Example 65

[0667] Example 65 was synthesized according to the procedure described for the preparation of Example 64 (step C), using Intermediate 65A (70 mg, 0.14 mmol) as a 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). 1 H NMR (500 MHz, DMSO-d6) δ 8.68-8.62 (m, 1 H), 8.54 (s, 1 H), 8.25 (d, J = 8.5 Hz, 2 H), 8.00 (d, J = 8.5 Hz, 2 H), 7.58 (br d, J = 8.9 Hz, 2 H), 7.46 (s, 1 H), 7.04 (br d, J = 8.9 Hz, 2 H), 3.45-3.33 (m, 1 H), 3.25 (s, 4 H), 2.78-2.67 (m, 1 H), 2.61 (s, 7 H), 2.55 (s, 2 H), 1.03 (d, J = 6.7 Hz, 6 H). Analytical LC / MS (Method 1): purity: 100%; mass found: 489.35; retention time: 1.06 min. (Method 2): purity: 100%; mass found: 489.35; retention time: 1.45 min.

[0668] Example 66

[0669] 7-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0670]

[0671] Step A. Preparation of tert-butyl 2'-amino-6'-methyl-3,6-dihydro-[4,4'- bipyridine]-l(2H)-carboxylate

[0672]

[0673] To a 200 mL pear-shaped flask was added 4-bromo-6-methylpyridin-2-amine (1.0 g, 5.4 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)3,6- dihydropyridine-l(2H)-carboxylate (2.0 g, 6.4 mmol), XPhosPd 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 N2and the reaction mixture was stirred at 85 °C. After 24 h, the reaction mixture was allowed to cool, diluted with water (200 mL) and extracted with EtOAc (2 x 100 mL). The organic phases were combined, washed with brine, dried over MgS04, 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 vacuum to give the title compound as a light yellow solid (1.3 g, 4.5 mmol, 83% yield). 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): Mass observed: 289.9; Retention time: 1.318 min.

[0674] Step B. Preparation of tert-butyl 4-(5-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridin-7-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0675]

[0676] 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) trifluoromethanesulfonate (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 vacuum to give the title compound as a tan solid (100 mg, 0.21 mmol, 10% yield). 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): mass observed: 468.1; retention time: 1.508 min.

[0677] Step C. Preparation of intermediate 66C. 5-methyl-2-(4-(methylsulfonyl)phenyl)-7- (piperidin-4-yl)imidazo[l,2-a]pyridine hydrochloride

[0678]

[0679] 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 and purged with N2(3x) and stirred under 1 atm of H2. After 6 h, the catalyst was filtered, and to the filtrate was added 4 M HC1 in dioxane (20 mL) and the mixture was stirred. After 20 min, the solvent was concentrated, the residue was co-evaporated with toluene (2x), and the product was dried under vacuum to give the title compound as a tan solid (78 mg, 0.19 mmol, 100% yield). 1H 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 s, 4H), 3.62 - 3.59 (m, 3H), 3.23 (s, 3H), 2.96 - 2.89 (m, 3H). Analytical LC / MS (Method 4): Mass found: 369.9; Retention time: 0.821 min.

[0680] Step D. Example 66

[0681] To a 40 mL vial was added Intermediate 66C (50 mg, 0.12 mmol), l-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 min, then sodium triacetoxyborohydride (130 mg, 0.62 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 in 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), 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). 1 H 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%; Mass found: 495.17; Retention time: 0.92 min. (Method 2): Purity: 95.6%; Mass found: 495.17; Retention time: 1.28 min.

[0682] Example 67

[0683] 8-fluoro-6-(l'-isopropyl-[l,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine

[0684]

[0685] Step A. Preparation of 6-bromo-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine

[0686]

[0687] To a 40 mL vial was added 5-bromo-3-fluoropyridin-2-amine (1.0 g, 5.2 mmol), 2-bromo-l-(4-(methylsulfonyl)phenyl)ethan-l-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 minimum amount of diethyl ether and the product was dried under vacuum to give the title compound as a light tan solid (1.0 g, 2.8 mmol, 54% yield). 1 H 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): mass observed: 370.7; retention time: 1.562 min.

[0688] Step B. Preparation of 4-(8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylic acid benzyl ester

[0689]

[0690] To a 40 mL vial was added intermediate 67A (1.0 g, 2.8 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate benzyl ester (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 N2and the reaction mixture was stirred at 85 °C. After 18 h, the reaction mixture was allowed to cool, diluted with water (200 mL) and extracted with EtOAc (2 x 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 fractions corresponding to the product were combined, concentrated and dried under vacuum to give the title compound as a light yellow solid (0.41 g, 0.81 mmol, 29% yield). 1 H 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, 1H), 5.20 (s, 2H), 4.29-4.17 (m, 2H), 3.86-3.73 (m, 2H), 3.18 (s, 3H), 2.65-2.57 (m, 2H). Analytical LC / MS (Method 4): mass observed: 506.1; retention time: 1.947 min.

[0691] Step C. Intermediate 67C. Preparation of 8-fluoro-2-(4-(methylsulfonyl)phenyl)-6- (piperidin-4-yl)imidazo[1,2-a]pyridine

[0692]

[0693] 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 N2, followed by the addition of Pd-C (5% wt. on carbon, wet) (0.086 g, 0.081 mmol), the vessel was evacuated and purged with N2, and the reaction mixture was stirred under 1 atm of H2. After 18 h, the catalyst was filtered and the filtrate was concentrated. The product was dried under vacuum to give the title compound as a light tan solid (0.30 g, 0.81 mmol, 100% yield). 1H 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): Mass found: 373.9; Retention time: 0.890 min.

[0694] Step D. Example 67

[0695] To a 40 mL vial was added Intermediate 67C (75 mg, 0.17 mmol), l-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 min, then sodium triacetoxyborohydride (180 mg, 0.84 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 between 10% KOH (aqueous, saturated with solid NaCl) (20 mL) and the layers separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; Mass found: 499.21; Retention time: 0.91 min. (Method 2): purity: 100%; Mass found: 498.94; Retention time: 1.12 min.

[0696] Examples 68 and 69

[0697] 8-fluoro-6-(l-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)imidazo[l,2-a]pyridine

[0698]

[0699] Step A. Preparation of 6-(l-(8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-fluoro-2- (4-(methylsulfonyl)phenyl)imidazo[l,2-a]pyridine dihydrochloride

[0700]

[0701] 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, then sodium triacetoxyborohydride (0.93 g, 4.4 mmol) was added and the reaction was continued. After 1 h, the reaction mixture was filtered, 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), the organic phases were combined, washed with brine, dried over MgS04, 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). The fractions corresponding to the desired intermediate were combined, concentrated and dried under vacuum. The resulting residue was dissolved in MeOH (20 mL) and 4 M HC1 in dioxane (10 mL) and stirred. After 0.5 h, the solvents were concentrated, the residue was co-evaporated with toluene (2x) and the product was dried under vacuum to give the title compound as a tan solid (0.50 g, 0.90 mmol, 82% yield). Analytical LC / MS (Method 4): mass observed: 483.1; retention time: 0.896 min.

[0702] Step B. Examples 68 and 69

[0703] Examples 68 and 69 were synthesized according to the procedures described for the preparation 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 via preparative HPLC with 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: 2% B for 0 minutes, 2-42% B over 20 minutes, followed by 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions corresponding to the respective desired product were combined and dried via centrifugal evaporation.

[0704] Example 68 (8.4 mg, 0.016 mmol, 9% yield) was isolated as the 1st 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%; mass observed: 525.20; retention time: 0.95 min. (Method 2): purity: 100%; mass observed: 525.30; retention time: 1.23 min.

[0705] Example 69 (11 mg, 0.021 mmol, 12% yield) was isolated as the 2nd 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 96.5%; mass observed: 525.20; retention time: 0.98 min. (Method 2): purity: 95.3%; mass observed: 525.20; retention time: 1.36 min.

[0706] Example 70

[0707] 7-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0708]

[0709] Step A. Preparation of intermediate 70A, 7-Fluoro-2-(4-(methylsulfonyl)phenyl)-6- (piperidin-4-yl)imidazo[1,2-a]pyridine

[0710]

[0711] Intermediate 70A was synthesized as follows: according to the procedure described for the preparation of intermediate 67C (steps A to C), using 5-bromo-4-fluoropyridin-2-amine (1.0 g, 5.2 mmol) as starting material to give the title compound as a light greenish solid (0.38 g, 1.0 mmol, 19% yield over 3 steps). 1 H 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 96.5%; mass observed: 525.20; retention time: 0.98 min. (Method 2): purity: 95.3%; mass observed: 525.20; retention time: 1.36 min.

[0712] Step B. Example 70

[0713] Example 70 was synthesized according to the procedure described for the preparation of Example 67 (step D) using intermediate 70A (65 mg, 0.17 mmol) as 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%; mass observed: 499.12; retention time: 0.89 min. (Method 2): purity: 98.7%; mass observed: 499.0; retention time: 1.20 min.

[0714] Examples 71 and 72

[0715] 8-Fluoro-6-(1-(1-isopropylazepan-4-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)imidazo[1,2-a]pyridine

[0716]

[0717] 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

[0718]

[0719] To a 200 mL pear-shaped 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 x 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). The fractions corresponding to the product were combined, concentrated, and dried in vacuo. The resulting intermediate was dissolved in MeOH (20 mL) and 4 M HC1 in dioxane (20 mL) and stirred. After 30 min, the solvent was concentrated and the residue was co-evaporated with toluene (2x) and the product was dried in vacuo to give the title compound as a light tan solid (1.1 g, 2.1 mmol, 64% yield). 1 H 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) (one proton not clear). Analytical LC / MS (Method 4): mass observed: 471.3; retention time: 0.889 min.

[0720] Step B. Examples 71 and 72

[0721] 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 min, then sodium triacetoxyborohydride (430 mg, 6.1 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 in 10% KOH (aq, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), 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 under the following conditions: Instrument: Waters 100 Prep 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; Detector Wavelength: 220 nm; Injection Details: 500 uL, 100 mg dissolved in 4 mL MeOH. The fractions corresponding to the individual desired products were combined and dried via centrifugal evaporation.

[0722] Example 71 (26 mg, 0.051 mmol, 12% yield) was isolated as the 1st 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 513.20; retention time: 0.95 min. (Method 2): purity: 100%; mass observed: 513.30; retention time: 1.23 min. Chiral analytical (SFC Method 6): purity: >95%; retention time: 13.52 min.

[0723] Example 72 (18 mg, 0.035 mmol, 9% yield) was isolated as the 2nd 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 Analytical (SFC Method 6): purity: >92%; Retention time: 16.16 min.

[0724] Example 73

[0725] 5-Fluoro-6-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[1,2- a]pyridine

[0726]

[0727] Step A. Preparation of Intermediate 73A. tert-Butyl 6-amino-2-fluoro-3',6'-dihydro-[3,4'- bipiridin]-1'(2'H)-carboxylate

[0728]

[0729] Intermediate 73A was synthesized as follows: according to the procedure described for the preparation of Intermediate 66A, using 5-bromo-6-fluoropyridin-2-amine (1.5 g, 7.9 mmol) as starting material to give the title compound (2.3 g, 7.8 mmol, 99% yield) as a light 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): mass observed: 294.1; retention time: 1.684 min.

[0730] Step B. Preparation of Intermediate 73B. tert-Butyl 4-(6-amino-2-fluoropyridin-3-yl)piperidine- 1-carboxylate

[0731]

[0732] To a 500 mL pear-shaped 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 atm of H2. After 18 h, the catalyst was filtered and the filtrate was concentrated. The product was dried under vacuum to yield the title compound as a light yellow solid (2.3 g, 7.8 mmol, 100% yield). 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): mass observed: 240.1 (-t-Bu); retention time: 1.676 min.

[0733] Step C. Preparation of intermediate 73C. 5-Fluoro-2-(4-(methylsulfonyl)phenyl)-6- (piperidin-4-yl)imidazo[l,2-a]pyridine

[0734]

[0735] 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) trifluoromethanesulfonate (0.083 g, 0.17 mmol). The vial was capped and the reaction mixture was irradiated at 120 °C. After 12 h, in addition to Boc cleavage, the desired cyclization reaction was also observed. 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 vacuum to yield the title compound as a light tan solid (0.14 g, 0.37 mmol, 11% yield). Analytical LC / MS (Method 4): mass observed: 374.1; retention time: 1.008 min.

[0736] Step D. Example 73

[0737] To a 40 mL vial was added intermediate 73C (72 mg, 0.19 mmol), l-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 min, then sodium triacetoxyborohydride (200 mg, 0.96 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 in 10% KOH (aq, saturated with solid NaCl) (20 mL) and the layers were separated. The aqueous phase was extracted with 10% IPA / CHCl3(10 mL), 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%; mass observed: 499.30; retention time: 0.91 min. (Method 2): purity: 97.8%; mass observed: 499.30; retention time: 1.21 min.

[0738] Example 74

[0739] 8-Fluoro-7-(l'-isobutyl-[l,4'-bipiperidin]-4-yl)-2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridine

[0740]

[0741] Step A. Preparation of 8-fluoro-2-(4-(methylsulfonyl)phenyl)-7-(piperidin-4-yl)imidazo[l,2- a]pyridine hydrochloride salt

[0742]

[0743] Intermediate 74A was synthesized according to the methods described for the preparation of Intermediate 66C (steps A to C) using 4-bromo-3-fluoropyridin-2-amine (0.50 g, 2.6 mmol) as starting material to give the title compound as a light green solid (0.34 g, 0.83 mmol, 32% yield over 3 steps). 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): mass found: 374.1 ; retention time: 0.894 min.

[0744] Step B. Example 74

[0745] Example 74 was synthesized according to the methods described for the preparation of Example 66 (step D) using Intermediate 74A (70 mg, 0.17 mmol) as 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).

[0746] Examples 75 and 76

[0747] (6R)-2-(3,4-Dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0748] (absolute stereochemistry arbitrarily drawn)

[0749]

[0750] Step A. Preparation of (R)-2-(3,4-dimethoxyphenyl)-6-(piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[l,2-a]pyridine (absolute stereochemistry drawn arbitrarily)

[0751]

[0752] Intermediate 75A was obtained as the first eluting enantiomer of a chiral separation of Intermediate 31B (1.0 g, 2.9 mmol) by SFC chiral chromatography under the following conditions: Instrument: Waters 100 Prep SFC; Column: ChiralCel OD-H, 21 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow Conditions: 45 mL / min, 120 bar, 30 °C; Detector Wavelength: 220 nm; Injection Details: 1000 uL, 1000 mg dissolved in 8 mL MeOH-MeCN. The fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound as a light yellow solid (0.36 g, 1.1 mmol, 38% yield). 1 H 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): mass observed: 342.1; retention time: 0.857 min. Chiral analytical (SFC Method 8): purity: >95%; retention time: 6.729 min.

[0753] Step B. Preparation of (6R)-6-(l-(8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-2-(3,4- dimethoxyphenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine dihydrochloride (absolute stereochemistry drawn arbitrarily)

[0754]

[0755] 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), the vessel was flushed with N2, capped, and stirred at 40 °C. After 18 h, the mixture was cooled to rt, then sodium triacetoxyborohydride (0.89 g, 4.2 mmol) was added, and the reaction was continued. After 3 h, the reaction mixture was partitioned between 10% KOH (aq, 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), 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). The fractions corresponding to the desired product were combined, concentrated, and dried in vacuo. The resulting residue was dissolved in MeOH (10 mL) and 4 M HC1 in dioxane (5 mL) and stirred. After 15 min, the solvent was concentrated, the residue was co-evaporated with toluene, and the product was dried in vacuo to give the title compound as an off-white solid (0.11 g, 0.21 mmol, 19% yield). 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): mass observed: 451.1; retention time: 0.858 min.

[0756] Step C. Examples 75 and 76

[0757] To a 40 mL vial was added intermediate 75B (60 mg, 0.12 mmol), isobutyraldehyde (41 mg, 0.57 mmol), AcOH (7.2 μί, 0.13 mmol), magnesium sulfate (210 mg, 1.7 mmol), and DMF (2 mL). The reaction mixture was stirred for 10 min, then sodium triacetoxyborohydride (120 mg, 0.57 mmol) was added and the reaction mixture was stirred. After 18 h, the reaction mixture was diluted with 10% IPA / CHCI3(40 mL) and filtered. The filtrate was partitioned in 10% KOH (aq, saturated with solid NaCI) (20 mL) and the layers separated. The aqueous phase was extracted with 10% IPA / CHCI3(10 mL), the organic phases were combined, washed with brine, dried over MgS04, filtered, and concentrated. The crude isomeric mixture was purified via preparative HPLC with 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 for 0 min, 10-60% B over 20 min, then 100% B for 0 min; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions corresponding to the individual desired products were combined and dried via centrifugal evaporation.

[0758] Example 75 (28 mg, 0.055 mmol, 46% yield) was isolated as the 1st eluting isomer. 1 H 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) (one proton not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 507.29; retention time: 0.98 min. (Method 2): purity: 94.2%; mass observed: 506.99; retention time: 1.24 min.

[0759] Example 76 (25 mg, 0.049 mmol, 41% yield) was isolated as the 2ndeluting isomer. 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 507.01; retention time: 0.98 min. (Method 2): purity: 100%; mass observed: 507.0; retention time: 1.47 min.

[0760] Examples 77 and 78

[0761] (6S)-2-(3,4-Dimethoxyphenyl)-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0762] (absolute stereochemistry arbitrarily drawn)

[0763]

[0764] Step A. Preparation of (S)-2-(3,4-Dimethoxyphenyl)-6-(piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry arbitrarily drawn)

[0765]

[0766] Intermediate 77A, the 2nd eluting enantiomer of the chiral separation of intermediate 31B (1.0 g, 2.9 mmol) was obtained by SFC chiral chromatography under the following conditions: Instrument: Waters 100 Prep SFC; Column: ChiralCel OD-H, 21 x 250 mm. 5 micron; Mobile Phase: 55% CO2 / 45% MeOH with 0.1% DEA; Flow conditions: 45 mL / min, 120 bar, 30 °C; Detector wavelength: 220 nm; Injection details: 1000 uL, 1000 mg dissolved in 8 mL MeOH-MeCN. The fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound as a light yellow solid (0.33 g, 0.97 mmol, 33% yield). 1 H NMR (500 MHz, Methanol-d4) d 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): Mass found: 342.1; Retention time: 0.859 min. Chiral analytical (SFC Method 8): Purity: >95%; Retention time: 16.297 min.

[0767] Step B. 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 salt (absolute stereochemistry arbitrarily drawn)

[0768]

[0769] Intermediate 77B was synthesized as follows: using intermediate 77A (0.33 g, 0.97 mmol) as starting material according to the method described for the preparation of intermediate 75B to afford the title compound as an off-white solid (0.10 g, 0.19 mmol, 20% yield). 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): mass observed: 451.1; retention time: 0.857 min.

[0770] Step C. Examples 77 and 78

[0771] Examples 77 and 78 were synthesized according to the procedures described for the preparation of Examples 75 and 76 using Intermediate 77B (50 mg, 0.096 mmol) as the starting material. The crude isomeric mixture was purified via preparative HPLC with 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: 11% B for 0 minutes, 11-58% B over 20 minutes, followed by 100% B for 0 minutes; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions corresponding to the individual desired products were combined and dried via centrifugal evaporation.

[0772] Example 77 (22 mg, 0.043 mmol, 45% yield) was isolated as the 1st 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%; mass observed: 507.05; retention time: 1.01 min. (Method 2): purity: 96.6%; mass observed: 507.02; retention time: 1.38 min.

[0773] Example 78 (21 mg, 0.041 mmol, 43% yield) was isolated as the 2ndeluting isomer. 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). Analytical LC / MS (Method 1): purity: 99.1%; mass observed: 506.9; retention time: 0.94 min. (Method 2): purity: 100%; mass observed: 506.9; retention time: 1.55 min.

[0774] Examples 79 and 80

[0775] (6R)-6-(1-(8-Isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0776] (absolute stereochemistry drawn arbitrarily)

[0777]

[0778] Step A. Preparation of tert-butyl 4-(2-(4-(methylsulfonyl)phenyl)imidazo[l,2- a]pyridin-6-yl)-3,6-dihydropyridine-l(2H)-carboxylate

[0779]

[0780] Intermediate 79A was synthesized as follows: according to the methods described for the preparation of Intermediate IB (steps A to B) using 5-bromopyridin-2-amine (1.3 g, 7.5 mmol) as starting material and 2-bromo-l-(4-(methylsulfonyl)phenyl)ethan-l-one as a replacement where appropriate, to give the title compound as a light yellow solid (2.8 g, 6.1 mmol, 81% yield over 2 steps). 1 HNMR (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): mass found: 454.1; retention time: 1.451 min.

[0781] Step B. Preparation of 2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)-5,6,7,8- tetrahydroimidazo[l,2-a]pyridine hydrochloride

[0782]

[0783] Intermediate 79B was synthesized as follows: according to the methods described for the preparation of Intermediate 31B (steps A to B) using Intermediate 79A (2.8 g, 6.1 mmol) as starting material, to give the title compound as an off-white solid (0.85 g, 2.1 mmol, 34% yield over 2 steps). 1H 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): mass observed: 360.0; retention time: 0.752 min.

[0784] Step C. Preparation of (R)-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[l,2-a]pyridine (absolute stereochemistry drawn arbitrarily)

[0785]

[0786] Intermediate 79C was obtained as the first eluting enantiomer of the chiral separation of Intermediate 79B (0.85 g, 2.4 mmol) by SFC chiral chromatography under the following conditions: Instrument: Berger SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 70% CO2 / 30% EtOH with 0.1% DEA; Flow conditions: 85 mL / min.; Detector wavelength: 220 nm; Injection details: 650 uL, 850 mg dissolved in 30 mL EtOH-DEA. The fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound as a light yellow solid (0.35 g, 0.97 mmol, 41% yield). 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): mass observed: 360.0; retention time: 0.816 min. Chiral analytical (SFC Method 9): purity: >99%; retention time: 12.01 min.

[0787] Step D. Preparation of (6R)-6-(1-(8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride salt (absolute stereochemistry drawn arbitrarily)

[0788]

[0789] Intermediate 79D was synthesized as follows: using intermediate 79C (0.35 g, 0.97 mmol) as starting material according to the procedure described for the preparation of intermediate 75B, the title compound was obtained as a light yellow solid (0.50 g, 0.92 mmol, 95% yield). 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): mass observed: 469.1; retention time: 0.825 min.

[0790] Step E. Examples 79 and 80

[0791] Examples 79 and 80 were synthesized according to the procedures described for the preparation of Examples 75 and 76 using Intermediate 79D (110 mg, 0.20 mmol) as the starting material. The crude isomeric mixture was purified via preparative HPLC with 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: 12% B for 0 minutes, 12-52% B over 20 minutes, followed by 100% B for 0 minutes; flow rate: 20 mL / min; column temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions corresponding to the respective desired product were combined and dried via centrifugal evaporation.

[0792] Example 79 (7.4 mg, 0.014 mmol, 7% yield) was isolated as the 1st 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%; mass observed: 524.93; retention time: 0.89 min. (Method 2): purity: 95.4%; mass observed: 525.21; retention time: 1.17 min.

[0793] Example 80 (15 mg, 0.029 mmol, 15% yield) was isolated as the 2nd 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, 3H), 0.87 (br d, J = 6.4 Hz, 6H). Analytical LC / MS (Method 1): purity: 91.7%; mass observed: 525.21; retention time: 0.89 min. (Method 2): purity: 90.7%; mass observed: 525.21; retention time: 1.41 min.

[0794] Examples 81 and 82

[0795] (6S)-6-(1-(8-Isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine

[0796] (absolute stereochemistry arbitrarily drawn)

[0797]

[0798] Step A. Preparation of (S)-2-(4-(methylsulfonyl)phenyl)-6-(piperidin-4-yl)- 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (absolute stereochemistry arbitrarily drawn)

[0799]

[0800] Intermediate 81A, the 2nd eluting enantiomer of the chiral separation of Intermediate 79B (0.85 g, 2.4 mmol) was obtained by SFC chiral chromatography under the following conditions: Instrument: Berger SFC; Column: Chiral OD, 30 x 250 mm. 5 micron; Mobile phase: 70% CO2 / 30% EtOH with 0.1% DEA; Flow conditions: 85 mL / min.; Detector wavelength: 220 nm; Injection details: 650 uL, 850 mg dissolved in 30 mL EtOH-DEA. The fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound as a light yellow solid (0.35 g, 0.97 mmol, 41% yield).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): mass observed: 360.0; retention time: 0.824 min. Chiral analytical (SFC Method 9): purity: >99%; retention time: 16.21 min.

[0801] Step B. Preparation of (6S)-6-(1-(8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4- (methylsulfonyl)phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine dihydrochloride salt (absolute stereochemistry drawn arbitrarily)

[0802]

[0803] Intermediate 81B was synthesized as follows: using intermediate 81A (0.35 g, 0.97 mmol) as starting material according to the procedure described for the preparation of intermediate 75B, the title compound was obtained as a light yellow solid (0.52 g, 0.96 mmol, 99% yield). 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): mass observed: 360.0; retention time: 0.824 min. Chiral analytical (SFC Method 9): purity: >99%; retention time: 16.21 min.

[0804] Step C. Examples 81 and 82

[0805] Example 81 and 81 were synthesized according to the procedures described for the preparation of Examples 75 and 76 using Intermediate 81B (100 mg, 0.19 mmol) as the starting material. The crude isomeric mixture was purified via preparative HPLC with 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: 0-30% B over 20 minutes, then a 100% B hold for 0 minutes; Flow Rate: 20 mL / min; Column Temperature: 25 °C. Fractions were collected by MS signal triggering. Fractions corresponding to the individual desired products were combined and dried via centrifugal evaporation.

[0806] Example 81 (1.1 mg, 0.0021 mmol, 1% yield) was isolated as the 1st eluting isomer. 1 H 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) (two protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 525.29; retention time: 0.86 min. (Method 2): purity: 87.3%; mass observed: 525.31; retention time: 1.19 min.

[0807] Example 82 (2.9 mg, 0.0055 mmol, 3% yield) was isolated as the 2nd eluting isomer. 1H 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) (four protons not clear). Analytical LC / MS (Method 1): purity: 100%; mass observed: 524.97; retention time: 0.8 min. (Method 2): purity: 95.6%; mass observed: 525.30; retention time: 1.42 min.

[0808] The following examples were prepared according to the general methods described herein using the appropriate starting materials, reagents and conditions.

[0809]

[0810] Eluting isomer

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836] Example 142

[0837] 2-(3,4-dimethoxyphenyl)-6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl- [1,2,4]triazolo[1,5-a]pyridine

[0838]

[0839] Step A. Preparation of 6-bromo-2-(3,4-dimethoxyphenyl)-8-methyl-[1,2,4]triazolo[1,5- a]pyridine

[0840]

[0841] Intermediate 142A was synthesized according to the general procedure described for the preparation of Intermediate 60A using 5-bromo-3-methylpyridin-2-amine (1.0 g, 5.6 mmol) as 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 as an off-white solid (1.3 g, 3.8 mmol, 67% yield). 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): mass observed: 472.1; retention time: 0.80 min.

[0842] Step B. Example 142

[0843] To a 20 mL vial was added Intermediate 142A (17 mg, 0.050 mmol), 1- isopropyl-4-(4-(4,4,5,5-tetramethyl-l,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, then XPhos Pd G3 (4.2 mg, 5.0 μmol) was added. The vial was again purged with N2 and the reaction stirred at 85 °C. After 15 h, the reaction mixture was allowed to cool, diluted with water (5 mL) and extracted with EtOAc (2 x 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). The pure fractions were combined, concentrated and dried under vacuum to afford the title compound as an off-white solid (16 mg, 0.033 mmol, 67% yield). 1 H 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): mass observed: 472.1; retention time: 0.80 min.

[0844] Example 143

[0845] 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

[0846]

[0847] To a hydrogenation flask was added Example 142 (30 mg, 0.064 mmol), 3M HC1 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 h, 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 pmol, 15% yield). 1 H 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%; mass observed: 482.0; retention time: 1.46 min. (Method 2): purity: 99.0%; mass observed: 482.0; retention time: 1.12 min.

[0848] Example 144

[0849] 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

[0850]

[0851] To a hydrogenation flask was added 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 h, 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 afford the title compound (6.5 mg, 0.013 mmol, 21% yield). 1 H 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, 2H), 2.13 (br d, J = 8.2 Hz, 2H), 1.79-1.94 (m, 2H), 1.40 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 6.4 Hz, 6H). Analytical LC / MS (Method 1): purity: 98.1%; mass observed: 476.3.

[0852] Example 145

[0853] 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)- 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine

[0854]

[0855] Step A. Preparation of intermediate 145A, 6-bromo-2-(3,4-dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridine

[0856]

[0857] Intermediate 145A was synthesized according to the general procedure described for the preparation of Intermediate 60A using 5-bromo-pyridin-2-amine (1.0 g, 5.8 mmol) as 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 as a light yellow solid (1.2 g, 3.7 mmol, 64% yield). 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): mass found: 334.0; retention time: 0.91 min.

[0858] 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

[0859]

[0860] Intermediate 145B was synthesized according to the general procedure described for the preparation of Example 142 (step B) using Intermediate 145A (100 mg, 0.30 mmol) as starting material and 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 a replacement where appropriate. 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 as a gum (130 mg, 0.27 mmol, 91% yield). 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): Mass found: 463.0; Retention time: 1.03 min.

[0861] Step C. Preparation of Intermediate 145C. tert-Butyl 3-(2-(3,4-dimethoxyphenyl)-5,6,7,8- tetrahydro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0862]

[0863] Intermediate 145C was synthesized according to the general procedure described for the preparation of Example 144 using Intermediate 145B (120 mg, 0.260 mmol) as starting material. The crude product was purified by preparative HPLC (preparative method 1) to give the title compound (63 mg, 0.130 mmol, 52% yield) as a gum. 1 H 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): Mass found: 469.1; Retention time: 0.938 min.

[0864] Step D. Preparation of Intermediate 145D. 6-(8-Azabicyclo[3.2.1]octan-3-yl)-2-(3,4- dimethoxyphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine hydrochloride

[0865]

[0866] Intermediate 145D was synthesized according to the general procedure described for the preparation of Example 60 (step D) using intermediate 145C (100 mg, 0.21 mmol) as starting material. The crude product was used as such without further purification. 1 H 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): mass found: 369.2; retention time: 0.663 min.

[0867] Step E. Example 145

[0868] Example 145 was synthesized according to the general procedure 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 give the title compound (17 mg, 0.035 mmol, 57% yield) as a gum. 1H NMR (DMSO-de) 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%; mass observed: 492.3; retention time: 1.284 min. (Method 2): purity: 100%; mass observed: 492.3; retention time: 1.048 min.

[0869] Example 146

[0870] 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4-dimethoxyphenyl)- [1,2,4]triazolo[1,5-a]pyridine

[0871]

[0872] Step A. Preparation of intermediate 146A. 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

[0873]

[0874] Intermediate 146A was synthesized according to the general procedure described for the preparation of Example 144, using intermediate 145B (120 mg, 0.26 mmol) as starting material. The crude product was purified by preparative HPLC (preparative method 1) to give the title compound (55 mg, 0.12 mmol, 47% yield) as a gum. 1H 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): mass observed: 465.1 ; retention time: 1.018 min.

[0875] Step B. Preparation of intermediate 146B. 6-(8-azabicyclo[3.2.1]oct-3-yl)-2-(3,4- dimethoxyphenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyridine hydrochloride

[0876]

[0877] Intermediate 146B was synthesized according to the general procedure described for the preparation of Example 60 (step D) using intermediate 146A (100 mg, 0.21 mmol) as starting material. The crude product was used without further purification. 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): mass observed: 465.1 ; retention time: 1.018 min.

[0878] Step C. Example 146

[0879] Example 146 was synthesized according to the general procedure 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 give the title compound (29 mg, 0.060 mmol, 96% yield) as a gum. 1 H 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%; mass observed: 488.3; retention time: 1.375 min. (Method 2): purity: 100%; mass observed: 488.3; retention time: 1.110 min.

[0880] Example 147

[0881] 6-(4-(4-Isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methylsulfonyl)phenyl)- [1,2,4]triazolo[1,5-a]pyridine

[0882]

[0883] Step A. Intermediate 147A. Preparation of 6-bromo-8-methyl-2-(4- (methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine

[0884]

[0885] Intermediate 147A was synthesized according to the general procedure 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): Mass observed: 365.7; Retention time: 0.936 min.

[0886] Step B. Example 147

[0887] Example 147 was synthesized according to the general procedure described for the preparation of Example 142 (step B) using Intermediate 147A (110 mg, 0.30 mmol) as starting material. The crude product was purified by preparative HPLC (Prep Method 1) to afford the title compound (120 mg, 0.24 mmol, 81% yield) as a white 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): Mass observed: 365.7; Retention time: 0.936 min.

[0888] The following examples were prepared according to the general procedures described elsewhere herein using the appropriate starting materials, reagents and conditions.

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899] Bioanalysis

[0900] The pharmacological properties of the compounds of the present invention can be confirmed by a variety of bioanalyses. The bioanalyses exemplified below have been performed on the compounds of the present invention.

[0901] TLR7 / 8 / 9 Suppression Report Subanalysis

[0902] HEK-Blue, which overexpresses human TLR7, TLR8, or TLR9 receptors TM Invivogen cells were used to screen for inhibitors of these receptors under the control of an IFN-β minimal promoter fused to five NF-κB and AP-1 binding sites, using an inducible SEAP (secreted embryonic alkaline phosphatase) reporter gene. In short, cells were seeded into Greiner 384-well discs (15,000 cells / well for TLR7; 20,000 cells / well for TLR8; and 25,000 cells / well for TLR9) and subsequently treated with DMSO containing the test compound to obtain a final dose-response concentration range from 0.05 nM to 50 μM. After pretreatment with the compound for 30 minutes at room temperature, cells were subsequently 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 induce SEAP production. After incubation at 37 °C and 5% CO2 for 22 hours, cells were cultured in HEK-Blue cell culture medium, which allows for the detection of SEAP, according to the manufacturer's specifications. TMThe percentage inhibition was determined in the form of a decrease in % of the HEK-Blue signal present in wells treated with agonist plus DMSO only, compared to wells treated with known inhibitors.

[0903] Table 1

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911] n.d.: not determined.

Claims

1. A compound of formula (II): Or its stereoisomers or salts, wherein: X is either N or CR3; One of Q1 and Q2 is A and the other of Q1 and Q2 is R5; G is a phenyl group substituted with -S(O)2CH3; A is cyclohexyl, piperidinyl, phenyl, pyridinyl or 6-azabicyclo[3.2.1]octyl, each of which is substituted with -L-R4; L represents the bond; R3 represents hydrogen, F, Cl, or C. 1-3 Alkyl or C 1-2 fluoroalkyl; R4 is: (i)-N(CH3)2; or (ii) piperidinyl, piperazinyl, azirrocycloheptyl, azirospiro[3.3]heptyl, azirbicyclo[3.2.1]octyl or diazirbicyclo[3.2.1]octyl, each with 0 to 1 R 4a replace; Each R 4a Independently for C 1-6 Alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, -CH2(C 3-6 cycloalkyl), oxetyl or tetrahydropyranyl; and Each R5 is independently hydrogen, F, or -CH3.

2. The compound of claim 1 or its stereoisomer or salt, wherein X is CR3.

3. The compound of claim 1 or its stereoisomer or salt, wherein X is N.

4. A compound of formula (II) or its stereoisomer or salt, wherein: Or its stereoisomers or salts, wherein: X is either N or CR3; One of Q1 and Q2 is A and the other of Q1 and Q2 is R5; G is a phenyl group substituted with -S(O)2CH3; A is cyclohexyl, piperidinyl, phenyl, or 6-azabicyclo[3.2.1]octyl, each of which is substituted with -L-R4; L represents the bond; R 3 It is hydrogen; R4 is piperidinyl, piperazinyl, azircyclic heptyl, azirospiro[3.3]heptyl, azirbicyclic[3.2.1]octyl, or diazirbicyclic[3.2.1]octyl, each via R 4a replace; R 4a The derivatives are -CH(CH3)2, -CH2CH(CH3)2, -CH2CH2OCH3, -C(O)CH(CH3)2, -C(O) (cyclopropyl), -CH2 (cyclopropyl), -CH2 (cyclobutyl), cyclopropyl, cyclobutyl, oxacyclobutyl, or tetrahydropyranyl; and Each R 5 It can be hydrogen, F, or -CH3.

5. The compound according to claim 1, or its stereoisomer or salt, wherein G is...

6. A compound or its stereoisomer or salt, wherein the compound is: 6-(1'-cyclopropyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (7); 6-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (8); 6-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (9); 7-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-5-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (66); 8-Fluoro-6-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (67); 8-Fluoro-6-(1-(8-isopropyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (68-69); 7-Fluoro-6-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (70); 8-Fluoro-6-(1-(1-isopropylazacycloheptyl-4-yl)piperidin-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (71-72); 5-Fluoro-6-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (73); 8-Fluoro-7-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (74); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (83-84); 6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (85-86); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[ 3.2.1] Oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (87-88); 6-(1-(8-(cyclobutylmethyl)-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (89-90); 6-(1'-cyclobutyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (91); 6-(1'-(cyclopropylmethyl)-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (92); 6-(1'-(cyclobutylmethyl)-[1,4'-dipiperidin]-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-(methanesulfonyl)phenyl)-6-(4-(4-(oxecyclobut-3-yl)piperazin-1-yl)phenyl)imidazo[1,2-a]pyridine (103); 8-Methyl-2-(4-(methanesulfonyl)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'-dipiperidin]-4-yl)-5-methyl-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (106); 8-Fluoro-6-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (107); 6-(1'-cyclopropyl-[1,4'-dipiperidin]-4-yl)-8-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (108); 6-(1'-(cyclopropylmethyl)-[1,4'-dipiperidin]-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (109); 6-(1'-cyclobutyl-[1,4'-dipiperidin]-4-yl)-8-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (110); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-6-(1'-(oxecyclobut-3-yl)-[1,4'-dipiperidin]-4-yl)imidazo[1,2-a]pyridine (111); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-6-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-dipiperidin]-4-yl)imidazo[1,2-a]pyridine (112); 8-Fluoro-6-(1-(8-isobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (113-114); 6-(1-(8-(cyclopropylmethyl)-8-azabicyclo[ 3.2.1] Oct-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (115-116); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (117); 6-(1-(8-cyclobutyl-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)-8-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (118); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-6-(1-(8-(oxacyclobut-3-yl)-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (119-120); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-6-(1-(8-(tetrahydro-2H-pyran-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (121-122); 7-Fluoro-6-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (123); 6-(1'-cyclopropyl-[1,4'-dipiperidin]-4-yl)-7-fluoro-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (124); 8-Fluoro-6-(1-(1-isobutylazacycloheptyl-4-yl)piperidin-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (125-126); 6-(1-(1-(cyclopropylmethyl)azacycloheptyl-4-yl)piperidin-4-yl)-8-fluoro-2-(4-(methylsulfonyl)phenyl)imidazo[1,2-a]pyridine (127-128); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-6-(1-(1-(tetrahydro-2H-pyran-4-yl)azacyclohept-4-yl)piperidin-4-yl)imidazo[1,2-a]pyridine (129-130); 5-Fluoro-6-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (131); 8-Fluoro-7-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-2-(4-(methanesulfonyl)phenyl)imidazo[1,2-a]pyridine (132); 8-Fluoro-2-(4-(methanesulfonyl)phenyl)-7-(1'-(tetrahydro-2H-pyran-4-yl)-[1,4'-dipiperidin]-4-yl)imidazo[1,2-a]pyridine (133); 6-(4-(4-isopropylpiperazin-1-yl)phenyl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (147); 6-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (153); 6-(8-(1-cyclopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (159); 6-(8-(1-isopropylpiperidin-4-yl)-8-azabicyclo[3.2.1]oct-3-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (160); 6-(1'-cyclopropyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (161); 6-(1'-isopropyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (162); 6-(1'-isobutyl-[1,4'-dipiperidin]-4-yl)-8-methyl-2-(4-(methanesulfonyl)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. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6, or stereoisomers thereof or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier.

8. Use of the compound of any one of claims 1 to 6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of pathological fibrosis.

9. The use according to claim 8, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.

10. Use of the compound of any one of claims 1 to 6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating non-alcoholic steatosis, non-alcoholic fatty liver disease, chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis, or primary biliary cirrhosis.

11. Use of a compound of any one of claims 1 to 6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of idiopathic pulmonary fibrosis.

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