Heterocyclic compounds, compositions thereof, and methods of treatment therewith

Abstract

Provided herein are compounds having the following structure, compositions comprising an effective amount of the compounds, and methods for modulating immune cell activity. Provided herein are pharmaceutical compositions comprising an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, and a pharma- ceutically acceptable carrier, excipient, or vehicle. Provided herein are methods of modulating immune cell activity, comprising contacting a cell with an effective amount of a compound provided herein, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof. JPEG2025505688000888.jpg3869

Description

[Technical Field]

[0001] Provided herein are compounds of formula (I) for activating T cells, NK cells, and / or cells that exhibit anti-tumor activity, methods of using the compounds disclosed herein for treating cancer, and pharmaceutical compositions comprising the same. [Background technology]

[0002] Casitas B-lineage lymphoma proto-oncogene b (Cbl-b) is a member of the Cbl family of ubiquitin ligases. Cbl family proteins share similar structural features: a highly conserved tyrosine kinase-binding (TKB) domain that recognizes substrates and a C3HC4 RING (really interesting new gene) finger domain that is responsible for E3 ubiquitin ligase activity (Tsygankov, A., Cbl proteins. 2008, New York: Nova Science Publishers, vi, 210 p). The first member of the Cbl family in mammalian cells, c-Cbl (Cbl or RNF55), was identified as a proto-oncogene protein in 1989 (Langdon, WY, et al., Proc Natl Acad Sci USA, 1989. 86(4): pp. 1168-72), whereas Cbl-b (RNF56) and Cbl-c (Cbl-3 or RNF57) were subsequently cloned and characterized, sharing high sequence homology with c-Cbl at their N-termini (Keane, MM, et al., Oncogene, 1995. 10(12): pp. 2367-77; Kim, M., et al., Gene, 1999. 239(1): pp. 145-54). Within the Cbl family, both c-Cbl and Cbl-b have been well studied and are ubiquitously expressed in mammalian tissues. On the other hand, Cbl-c is less well known, has weak E3 activity, and shows restricted expression in epithelial cells (Swaminathan, G. and A.Y. Tsygankov, Journal of Cellular Physiology, 2006. 209(1): pp. 21-43).

[0003] Cbl family members exhibit similar mechanisms of autoinhibition and phosphorylation-induced activation. Structural and biochemical studies have revealed that inactive c-Cbl and Cbl-b adopt an autoinhibitory conformation in which the RING domain position confers low binding affinity to the E2 ubiquitin-conjugating enzyme (UbcH5B). Tyrosine phosphorylation (Y371 in c-Cbl and Y363 in Cbl-b) induces a large conformational change, unshielding the RING domain from the TKB domain and creating a surface that enhances the binding affinity of c-Cbl and Cbl-b to E2s (Kobashigawa, Y., et al., Proc Natl Acad Sci USA, 2011. 108(51): pp. 20579-84; Dou, H., et al., Nat Struct Mol Biol, 2012. 19(2): pp. 184-92). Upon activation, structural rearrangements of c-Cbl and Cbl-b position E2 toward the substrate, facilitating the transfer of poly- or mono-ubiquitin to lysine residues. Ubiquitinated membrane proteins may then bind to ESCRT complexes, be internalized into endosomes, and attenuate receptor-mediated cell signaling (Ma, K., et al., 2013, p. 219-244).

[0004] Among these three Cbl family members, Cbl-b has been extensively studied and has emerged as a key intracellular checkpoint regulator in antitumor immunity. Cbl-b knockout mice exhibited potent rejection of EL4, EG7, TC-1, and B16F10 syngeneic tumors, as well as ATM knockout or UVB-induced spontaneous tumors (Loeser, S., et al., J Exp Med, 2007. 204(4): pp. 879-91; Chiang, JY, et al., J Clin Invest, 2007. 117(4): pp. 1029-36; Paolino, M., et al., Nature, 2014. 507(7493): pp. 508-12). CD8+ T cells and NK cells were found to play important roles in tumor elimination in Cbl-b knockout mice, as depletion of either cell population abrogated Cbl-b knockout-induced tumor rejection (Loeser, S., et al., J Exp Med, 2007. 204(4): p. 879-91; Paolino, M., et al., Nature, 2014. 507(7493): p. 508-12). Cbl-b deficiency lowered the T cell activation threshold and modulated costimulatory pathways to enhance TCR signaling (Fang, D. and YC Liu, Nat Immunol, 2001.2(9):pp.870-5; Bachmaier, K., et al., Nature, 2000.403(6766):pp.211-6; Braun, M., et al., 2020.53(4):pp.805-823 e15; Zhang, J., et al., 2002.169(5):pp.2236-40). Cbl-b depletion or E3-inactivating mutations were shown to enhance NK cell function by blocking ligand-induced TAM receptor internalization (Paolino, M., et al., Nature, 2014.507(7493):pp.508-12).Bone marrow-derived dendritic cells (BMDCs) and macrophages lacking Cbl-b expression in mice also exhibit stronger activation after stimulation, which may contribute to Cbl-b deficiency-induced tumor regression (Abe, T., et al., Diabetes, 2013. 62(6): p. 1957-69; Wallner, S., et al., PLoS One, 2013. 8(6): p. e65178.). Collectively, targeting Cbl-b is a potential novel immunotherapy for cancer.

[0005] Although some literature has shown that knockout of both c-Cbl and Cbl-b can induce stronger T cell activation than single c-Cbl or Cbl-b knockout, c-Cbl may not be an optimal immuno-oncological target because it functions as a tumor suppressor by downregulating activating receptor tyrosine kinases (RTKs). Clinically, heterozygous germline mutations (LOF) in CBL are associated with Noonan syndrome and RAS disease, and increase the risk of acute myeloid leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia (Grand, FH, et al., Blood, 2009. 113(24): pp. 6182-92; Becker, H., et al., Blood, 2014. 123(12): pp. 1883-6; Loh, ML, et al., Blood, 2009. 114(9): pp. 1859-63; Martinelli, S., et al., Am J Hum Genet, 2010. 87(2): pp. 250-7). In contrast to Cbl-b knockout, c-Cbl knockout altered the tumor microenvironment and promoted tumor growth in B16F10 and MC38 syngeneic models (Meyer, R.D., D. Husain, and N. Rahimi, Oncogene, 2011. 30(19): p. 2198-206; Lyle, C., et al., Sci Rep, 2019. 9(1): p. 20257). Knockout of both c-Cbl and Cbl-b results in embryonic lethality in mice. Hematopoietic c-Cbl and Cbl-b double knockout induced severe autoimmune disease and early-onset fatal myeloproliferative disorder (Naramura, M., et al., Nat Immunol, 2002.3(12):p.1192-9; Naramura, M., et al., Proc Natl Acad Sci USA, 2010.107(37):p.16274-9). Therefore, selective inhibition of Cbl-b over c-Cbl should be achieved to avoid potential tumor-promoting effects and safety risks.

[0006] Although existing anti-CTLA-4 and anti-PD-1 therapies have demonstrated clear clinical benefits in subsets of patients with various tumor types, there remains an unmet need to develop novel immunotherapies to achieve robust and durable clinical antitumor responses. Preclinical data strongly suggest the great potential of developing selective Cbl-b-targeted therapies to improve antitumor immunity. Citation or identification of any reference in this section shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Tsygankov, A., Cbl proteins.2008, New York: Nova Science Publishers, vi, 210 p. [Non-patent document 2] Langdon, WY, et al., Proc Natl Acad Sci USA, 1989.86(4):p.1168-72 [Non-patent document 2] Keane, MM, et al., Oncogene, 1995.10(12):p.2367-7 Summary of the Invention [Means for solving the problem]

[0008] Provided herein are compounds having formula (I): [ka] During the ceremony, V, W, X, Y, and Z are each independently CH or N; R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1-8alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, or R 1 and R 2 But R 1 and R 2 together with the atom to which it is attached form a substituted or unsubstituted cycloalkyl or non-aromatic heterocyclyl; R 3 is hydrogen, halogen, -CN, hydroxyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 4 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 5 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 6 is hydrogen, or substituted or unsubstituted C 1-8 is alkyl, R 7 is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; Ring A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; the moiety B is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted saturated spiro bicyclic ring, or substituted or unsubstituted non-aromatic heterocyclyl; m, n, and p are each independently 0, 1, or 2, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopic substitution, or enantiomer thereof.

[0009] In one embodiment, the compound having formula (I) is a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof.

[0010] In one embodiment, the compound having formula (I) is a compound of formula (IIb): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof.

[0011] In one embodiment, the compound having formula (I) is a compound of formula (IIIa): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof; wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R 8 is hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R 8 together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3.

[0012] In one embodiment, the compound having formula (I) is a compound of formula (IIIb): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof; wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R 8 is hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R 8 together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3; Other variables R 3 , R 4 , R 5 , R 6 , R 7 , ring A, moiety B, p, and n are as defined in formula (I).

[0013] Provided herein are pharmaceutical compositions comprising an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0014] Provided herein is a method of modulating the activity of an immune cell, comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic substitute, stereoisomer, or prodrug thereof.

[0015] Provided herein is a method for treating or preventing cancer responsive to Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound provided herein. In one embodiment, the cancer is a blood cancer. In one embodiment, the blood cancer is lymphoma, leukemia, myeloma, or glioblastoma. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition As used herein, the term "Cbl-b" refers to a Cbl-b protein. This term also includes naturally occurring variants of Cbl-b, including splice variants or allelic variants. This term also includes non-naturally occurring variants of Cbl-b, such as recombinant Cbl-b proteins or truncated variants thereof, that generally retain the binding ability (e.g., the ability to bind to E2 enzymes) of naturally occurring Cbl-b or naturally occurring variants of Cbl-b.

[0017] As used herein and in the specification and appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural as well as singular referents unless the context clearly dictates otherwise.

[0018] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0019] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, for example, a particular temperature or temperature range (such as those describing melting, dehydration, desolvation, or glass transition temperature), mass change (e.g., as a function of temperature or humidity), solvent or water content (e.g., in terms of mass or percentage), or peak position (such as, for example, in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art, but still describe the solid form. Techniques for characterizing crystalline forms and amorphous solids include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately" when used in this context indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position can vary by up to ±0.2 degrees 2θ (or ±0.2 degrees 2θ) and still describe a particular XRPD peak.

[0020] An "alkyl" group is a saturated, partially saturated, or unsaturated straight- or branched-chain acyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbon atoms, and in some embodiments from 1 to 6, 1 to 4, or 2 to 6 carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl, and the like. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH), -CH=C(CH), -C(CH)=CH, -C(CH)=CH(CH), -C(CHCH)=CH, -C≡CH, -C≡C(CH), -C≡C(CHCH), -CHC≡CH, -CHC≡C(CH), and -CHC≡C(CHCH), among others. Alkyl groups can be substituted or unsubstituted. When alkyl groups described herein are said to be "substituted," they may be substituted with any substituent or substituents found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamino, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, B(OH), or O(alkyl)aminocarbonyl.

[0021] A "cycloalkyl" group is a saturated, partially saturated, or unsaturated cyclic alkyl group having 3 to 10 carbon atoms, having a single cyclic ring or multiple fused or bridged rings, which may be optionally substituted with 1 to 3 alkyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups containing more than one ring may be fused, spiro, or bridged, or combinations thereof. Such cycloalkyl groups include, by way of example, single ring structures, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring or bridged ring structures, such as 1-bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of unsaturated cycloalkyl groups include, among others, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl. The cycloalkyl groups may be substituted or unsubstituted. Examples of such substituted cycloalkyl groups include cyclohexanol and the like.

[0022] An "aryl" group is an aromatic carbocyclic group having 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups have 6 to 14 carbons, and in other embodiments, 6 to 12 or even 6 to 10 carbon atoms, in the ring portion of the group. Specific aryl groups include phenyl, biphenyl, naphthyl, and the like. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" also includes groups containing condensed rings, for example, fused aromatic aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0023] A "heterocyclyl" is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which 1 to 4 of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. In some embodiments, a heterocyclyl group contains 3 to 10 ring members, while other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. A heterocyclyl can also be attached to another group at any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. A heterocyclyl group can contain multiple fused rings, including, but not limited to, bicyclic, tricyclic, and tetracyclic rings, as well as bridged or spirocyclic ring systems. Heterocyclyl groups encompass unsaturated, partially saturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dioneyl) groups. The phrase heterocyclyl includes fused ring species, including those containing fused aromatic and non-aromatic groups, such as 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing heteroatoms, including, but not limited to, quinuclidyl. Representative examples of heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl ), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithionyl, dihydrodithionyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoin dolyl, isoindolinyl, azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or 1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzo Thiazinyl, benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl (e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl), imidazopyridyl (e.g., azabenzimidazolyl or 1H-imidazo[4,5-b]pyridyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,Representative non-aromatic heterocyclyl groups include, but are not limited to, 4-dihydroisoquinolin-1(2H)-onyl), quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one, and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species containing fused aromatic groups. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidinyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representative substituted heterocyclyl groups may be mono- or multiply substituted, for example, but not limited to, pyridyl or morpholinyl groups may be di-, 3-, 4-, 5-, or 6-substituted or di-substituted with various substituents such as those described below.

[0024] A "heteroaryl" group is an aryl ring system having 1 to 4 heteroatoms as ring atoms in the heteroaromatic ring system, with the remaining atoms in the ring system being carbon atoms. In some embodiments, heteroaryl groups have 3 to 6 ring atoms, and in other embodiments, 6 to 9 or 6 to 10 atoms in the ring portion of the group. Suitable heteroatoms include oxygen, sulfur, and nitrogen. In certain embodiments, heteroaryl ring systems are monocyclic or bicyclic. Non-limiting examples include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pyrrolopyridyl or 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo[d]imidazolyl), imidazopyridyl (e.g., azaindolyl), Examples of such groups include, but are not limited to, benzimidazolyl or 1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-1(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0025] As used herein, "spirocyclic ring" refers to two or more rings in which adjacent rings are connected via a single atom. The individual rings within a spirocyclic ring may be the same or different. The individual rings within a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings within a set of spirocyclic rings.

[0026] A "cycloalkylalkyl" group is a radical of the formula -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, cycloalkyl, or both the alkyl and cycloalkyl portions of the group. Representative cycloalkylalkyl groups include, but are not limited to, methylcyclopropyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propylcyclopentyl, propylcyclohexyl, and the like.

[0027] An "aralkyl" group is a radical of the formula -alkyl-aryl, where alkyl and aryl are as defined above. Substituted aralkyl groups can be substituted on the alkyl, aryl, or both the alkyl and aryl portions of the group. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups, such as 4-ethyl-indanyl.

[0028] A "heterocyclylalkyl" group is a radical of the formula -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined above. Substituted heterocyclylalkyl groups can be substituted on the alkyl, heterocyclyl, or both the alkyl and heterocyclyl portions of the group. Representative heterocyclylalkyl groups include, but are not limited to, 4-ethylmorpholinyl, 4-propylmorpholinyl, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl.

[0029] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0030] A "hydroxyalkyl" group is an alkyl group as defined above that is substituted with one or more hydroxy groups.

[0031] An "alkoxy" or "alkoxyl" group is an --O-(alkyl), where alkyl is as defined above.

[0032] An "alkoxyalkyl" group is an -(alkyl)-O-(alkyl), where alkyl is defined above.

[0033] An "amino" group is a radical of the formula -NH2.

[0034] An "alkylamino" group is a radical of the formula -NH-alkyl or -N(alkyl)2, where each alkyl is independently as defined above.

[0035] A "carboxy" group is a radical of the formula --C(O)OH.

[0036] An "aminocarbonyl" group is a group of the formula -C(O)N(R # )2, -C(O)NH(R # ), or a radical of —C(O)NH2, where each R # are independently substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclyl groups as defined herein.

[0037] An "acylamino" group is a group of the formula -NHC(O)(R # ) or -N(alkyl)C(O)(R # ) radical, where each alkyl and R # are independently as defined above.

[0038] A "sulfonylamino" group is a group of the formula -NHSO2(R # ) or -N(alkyl)SO2(R # ) radical, where each alkyl and R # is as defined above.

[0039] A "urea" group is a group of the formula -N(alkyl)C(O)N(R #)2, -N(alkyl)C(O)NH(R # ), -N(alkyl)C(O)NH2, -NHC(O)N(R # )2, -NHC(O)NH(R # ), or -NH(CO)NHR # where each alkyl and R # are independently as defined above.

[0040] With the exception of alkyl groups, when groups described herein are said to be "substituted," they can be substituted with any suitable substituent(s). Illustrative examples of substituents include those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro), alkyl, hydroxyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, nitro, cyano, thiol, thioether, imine, imide, amidine, guanidine, enamine, aminocarbonyl, acylamino, phosphonate, phosphine, thiocarbonyl, sulfonyl, sulfone, sulfonamide, ketone, aldehyde, ester, urea, urethane, oxime, hydroxylamino, alkoxyamine, aralkoxyamine, N-oxide, hydrazine, hydrazide, hydrazone, azide, isocyanate, isothiocyanate, cyanate, thiocyanate, oxo(-O), B(OH), O(alkyl)aminocarbonyl, monocyclic or fused or non-fused alkyl groups. cycloalkyl, which may be fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy.

[0041] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases, and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, those well known in the art, and are described, for example, in Remington's Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).

[0042] As used herein, and unless otherwise indicated, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of that compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of that compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of that compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of that compound. The compounds may contain chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein.

[0043] The use of stereomerically pure forms of such compounds, as well as mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. See, for example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0044] It should also be noted that the compounds can include E and Z isomers, or mixtures thereof, as well as cis and trans isomers, or mixtures thereof. In certain embodiments, the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of E and Z isomers.

[0045] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms may vary depending on the environment in which the compound is found, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other: [ka]

[0046] As will be readily understood by one of ordinary skill in the art, a wide variety of functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of the invention.

[0047] It should also be noted that the compounds may contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may contain unnatural proportions of atomic isotopes, such as tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 It may be radiolabeled with a radioisotope such as C) or deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15 An isotope may be enriched with an isotope, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 120, 121, 132, 133, 144, 155, 166, 170, 171, 182, 192, 193, 194, 195, 196, 197, 198, 19

[0048] As used herein, "treating" means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or halting further progression or worsening of the symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In some embodiments, "treating" refers to alleviating, in whole or in part, a disorder, disease, or condition, or slowing or halting further progression or worsening of the symptoms. In another embodiment, "treating" refers to alleviating, in whole or in part, a disease, disease, or condition, or symptoms associated with a condition, which condition is treatable or preventable by inhibition of Cbl-b.

[0049] As used herein, "preventing" refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, a method of inhibiting a subject from acquiring a disorder, disease, or condition, or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the condition is one that is treatable or preventable by inhibition of Cbl-b.

[0050] The term "effective amount" in reference to a compound means an amount that is capable of treating or preventing a disorder, disease, or condition disclosed herein, or a symptom thereof.

[0051] The term "subject" includes animals, including, but not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment includes mammals, and in another embodiment includes humans.

[0052] compound Aspect 1: Provided herein are compounds having the following formula (I): [ka] During the ceremony, V, W, X, Y, and Z are each independently CH or N; R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, or R 1 and R 2 But R 1 and R 2 together with the atom to which it is attached form a substituted or unsubstituted cycloalkyl or non-aromatic heterocyclyl; R 3 is hydrogen, halogen, -CN, hydroxyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 4 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 5 is hydrogen, halogen, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; R 6 is hydrogen, or substituted or unsubstituted C 1-8 is alkyl, R 7 is hydrogen, deuterium, halogen, or substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl; Ring A is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; the moiety B is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted saturated spiro bicyclic ring, or substituted or unsubstituted non-aromatic heterocyclyl; and compounds, and pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers, isotopic substitutions, and prodrugs thereof, wherein m, n, and p are each independently 0, 1, or 2.

[0053] In one embodiment, R 7 is hydrogen, halogen, or substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted saturated cycloalkyl.

[0054] Aspect 2: In one embodiment, the compound having formula (I) is a compound of formula (IIa): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof.

[0055] In one embodiment, the compound having formula (I) is a compound of formula (IIb): [ka] or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopically substituted derivative, or prodrug thereof.

[0056] In one embodiment, R 1 is a substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl.

[0057] In one embodiment, R 1is 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl, 3,3-difluoro-cyclohexyl, 3-trifluoromethylcyclohexyl, or 1-methylbicyclo[1.1.1]pentyl, preferably 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 3,3-difluoro-cyclopentyl, cyclohexyl, 3,3-difluoro-cyclohexyl, 3-trifluoromethylcyclohexyl, or 1-methylbicyclo[1.1.1]pentyl.

[0058] In one embodiment, R 1 is a substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted cyclobutylmethyl, substituted or unsubstituted cyclopentylmethyl, substituted or unsubstituted cyclohexylmethyl; More preferred are 2-methylpropyl, neopentyl, (R)-(sec-butyl), 1-methylcyclopropyl, 1-methylcyclobutyl, (1S,3S)-3-methylcyclobutyl, 3-methylcyclobutyl, (R)-3,3-difluorocyclopentyl, cyclopropylmethyl, (S)-3,3-difluorocyclopentyl, (S)-1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-fluorocyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (S)-1-cyclobutylethyl, (1-methylcyclopropyl)methyl, (1-fluorocyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (S)-1-cyclobutylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, (1-fluorocyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (1-methylcyclopropyl)methyl ...methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (1-methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-methylcyclopropyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-methylcyclopropyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-methylcyclopropyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-methylcyclopropyl, (1-methylcyclopropyl)methyl, cyclobutylmethyl, 1-methylcyclopropyl, (1-methyl (4,4-difluorocyclohexyl)methyl, (3,3-difluorocyclohexyl)methyl, (3,3-difluorocyclopentyl)methyl, cyclohexyl, and cycloheptyl.

[0059] In one embodiment, R 2 is hydrogen.

[0060] Aspect 3: In one embodiment, the compound having formula (I) is a compound of formula (IIIa): [ka] wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R 8 is hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R 8together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3.

[0061] In one embodiment, the compound having formula (I) is a compound of formula (IIIb): [ka] wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R 8 is hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R 8 together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3.

[0062] Aspect 4: In one embodiment, ring A is a substituted or unsubstituted bicyclic heteroaryl.

[0063] Aspect 5: In one embodiment, ring A is [ka] is.

[0064] In one embodiment, ring A is [ka] is.

[0065] In one embodiment, R 3 is hydrogen, halogen, or substituted or unsubstituted C 1-8It is alkyl, preferably hydrogen, F, Cl, or methyl.

[0066] In one embodiment, [ka] is.

[0067] In one embodiment, moiety B is [ka] is.

[0068] In one embodiment, moiety B is [ka] and preferably [ka] is.

[0069] In one embodiment, the moiety C is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, or a substituted or unsubstituted saturated spiro-bicyclic ring, wherein one ring of the spiro-bicyclic ring is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, and the other ring of the spiro-bicyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0070] In one embodiment, the moiety C is substituted or unsubstituted aminoalkyl, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino.

[0071] In one embodiment, [ka] [ka] is.

[0072] In one embodiment, [ka] and preferably [ka] and more preferably, [ka] is.

[0073] Aspect 6: In one embodiment, ring A is [ka] is.

[0074] In one embodiment, ring A is [ka] is.

[0075] In one embodiment, R 3 is hydrogen, halogen, -CN, -CF3, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted cycloalkyl.

[0076] In one embodiment, R 3 is H, F, Cl, Br, or methyl.

[0077] In one embodiment, [ka] is.

[0078] In one embodiment, [ka] is.

[0079] In one embodiment, moiety B is [ka] and preferably [ka] is.

[0080] In one embodiment, moiety B is [ka] and preferably [ka] is.

[0081] In one embodiment, the moiety C is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, or substituted or unsubstituted 5-azaspiro[2.4]heptyl.

[0082] In one embodiment, the moiety C is substituted or unsubstituted alkylamino, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl.

[0083] In one embodiment, [ka] is.

[0084] In one embodiment, [ka] and preferably [ka] and more preferably, [ka] is.

[0085] Aspect 7: In one embodiment, ring A is [ka] and preferably [ka] is.

[0086] In one embodiment, R 3 is hydrogen, halogen, hydroxyl, or substituted or unsubstituted C 1-4 It is alkyl, preferably methyl, F, or spiro-cyclopropyl.

[0087] In one embodiment, p is 0, 1, or 2, or preferably 2.

[0088] In one embodiment, [ka] is.

[0089] In one embodiment, moiety B is [ka] and preferably [ka] is.

[0090] In one embodiment, moiety B is [ka] and preferably [ka] is.

[0091] In one embodiment, the moiety C is substituted or unsubstituted alkylamino, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl.

[0092] In one embodiment, [ka] is.

[0093] In one embodiment, [ka] and more preferably, [ka] More preferably, [ka] is.

[0094] In one embodiment, R 5 is hydrogen, substituted or unsubstituted C 1-8 It is alkyl, or substituted or unsubstituted saturated cycloalkyl, preferably hydrogen or methyl.

[0095] In one embodiment, R 6 is methyl or ethyl.

[0096] In one embodiment, R 6 is methyl-d3.

[0097] In one embodiment, n and p are each independently 0 or 1.

[0098] In one embodiment, m is 1.

[0099] In one embodiment, R 7 is hydrogen, substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted cycloalkyl.

[0100] In one embodiment, R 7 is hydrogen, deuterium, methyl, ethyl, isopropyl, or 2-hydroxyethyl, preferably R 7 is hydrogen or methyl.

[0101] Aspect 8: In one embodiment, the compound is selected from Table 1, Table 2, and Table 3. In one embodiment, the compound having formula (I) is a compound selected from Table 1, Table 2, and Table 3.

[0102] Aspect 9: Provided herein is a pharmaceutical composition comprising an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

[0103] Aspect 10: Provided herein is a method of modulating immune cell activity, comprising contacting the cell with an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, tautomer, isotopic substitute, stereoisomer, or prodrug thereof. In one embodiment, the activity is Cbl-b activity. In one embodiment, the immune cell is a T cell. In one embodiment, the immune cell is a B cell. In one embodiment, the immune cell is an NK cell.

[0104] Aspect 11: Provided herein is a method for treating or preventing a cancer responsive to Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound provided herein. In one embodiment, the cancer is a blood cancer. In one embodiment, the blood cancer is lymphoma, leukemia, myeloma, or glioblastoma.

[0105] Aspect 12: Provided herein is a kit for treating cancer, the kit including: (a) a pharmaceutical composition comprising a compound provided herein; and (b) instructions for administering an effective amount of the pharmaceutical composition comprising a Cbl-b inhibitor to treat cancer in an individual.

[0106] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments.

[0107] Compound manufacturing method The compounds can be made using conventional organic synthesis and commercially available starting materials. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in Schemes 1-12 shown below, as well as in the Examples described herein. It should be noted that one skilled in the art would know how to modify the procedures described in the illustrative Schemes and Examples to arrive at the desired products.

[0108] Scheme 1 [ka]

[0109] Scheme 1 outlines an approach to synthesizing compounds defined as Formula I (where m is 1 and V is a nitrogen atom). Halogen-substituted compound A is converted to compound B under Suzuki coupling conditions (e.g., K2CO3, Pd(dppf)Cl2), which is then oxidized to compound C under an oxidizing agent (e.g., KOsO4, NaIO4), which further undergoes reductive amination with amine A under a reducing agent (e.g., STAB) to give compound D, which is prepared by hydrolysis of compound D under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl), which is then acylated with a substituted aromatic amine under standard amide bond formation conditions (e.g., active ester formation (HATU or EDCI, DIPEA)) to give compound I (where m is 1 and V is a nitrogen atom).

[0110] Scheme 2 [ka]

[0111] Scheme 2 illustrates an approach for synthesizing compound A-7. Halogen-substituted compound A-1 is converted to compound A-2 under Suzuki coupling conditions (e.g., KCO, Pd(dppf)Cl), which is then oxidized to compound A-3 (e.g., KOsO, NaIO), which further undergoes reductive amination with amine A under a reducing agent (e.g., STAB) to give compound A-4, which is prepared by hydrolysis of compound A-4 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl), which is then acylated with a substituted aromatic amine under standard amide bond-forming conditions (e.g., active ester formation (HATU or EDCI, DIPEA)) to give compound A-7.

[0112] Compound A-5 is acylated to compound A-6 under standard amide bond forming conditions (e.g., activated ester forming HATU or EDCI, DIPEA), and then A-6 is reacted with a substituted aromatic halogen under standard carbon-nitrogen bond forming conditions using an appropriate Pd catalyst (e.g., tBuXPhospd-G3) and ligand (e.g., tBuXPhos) to give compound A-7.

[0113] Scheme 3 [ka]

[0114] Scheme 3 outlines an alternative preparation of compound A-7. Compound A-2-1 is prepared by hydrolysis of compound A-2 in a basic solution (e.g., KOH, NaOH, or LiOH), which is then acylated with a substituted aromatic amine under standard amide bond forming conditions (e.g., active ester formation, HATU or EDCI, DIPEA) to give compound A-3-1, which is then oxidized (e.g., KOsO, NaIO) to give compound A-3-2, which further undergoes reductive amination (e.g., STAB) with amine A to give compound A-7.

[0115] Scheme 4 [ka]

[0116] Scheme 4 illustrates an approach for synthesizing compound A-4-9. Halogen-substituted compound A-4-1 is converted to compound A-4-2 under Suzuki coupling conditions (e.g., K2CO3, Pd(dppf)Cl2), which is then brominated under basic conditions (e.g., TMPMgCl.LiCl, 1,2-dibromo-1,1,2,2-tetrachloroethane) to give compound A-4-3, which is treated with a cyanating agent (ZnCN) with an appropriate Pd catalyst (e.g., Pd(OAc)2) and ligand (e.g., XantPhos) to form compound A-4-5, which is then brominated under basic conditions (e.g., TMPMgCl.LiCl, 1,2-dibromo-1,1,2,2-tetrachloroethane) to give compound A-4-3, which is then treated with a cyanating agent (ZnCN) with an appropriate Pd catalyst (e.g., Pd(OAc)2) and ligand (e.g., XantPhos) to form compound A-4-5. Compound A-4-6 is oxidized (e.g., KOsO, NaIO) to give compound A-4-6, which is reductively aminated (e.g., STAB) with amine A to give compound A-4-7, compound A-4-8 is prepared by hydrolysis of compound A-4-7 in a basic solution (e.g., KOH, NaOH, or LiOH) or an acidic solution (e.g., HCl), and compound A-4-8 is acylated with a substituted aromatic amine under standard amide-forming conditions (e.g., ester-forming HATU or EDCI, DIPEA) to give compound A-4-9. Scheme 5 [ka]

[0117] Scheme 5 shows an approach for synthesizing compound B-9. Halogen-substituted compound B-1 is converted to compound B-2 under suitable oxidation conditions (e.g., m-PCBA or HO), compound B-2 is converted to the corresponding compound B-3 by treatment with a cyanating agent (e.g., TMSCN) under basic conditions (e.g., EtN), compound B-3 is reacted with a suitable protecting group (e.g., SEM-, Boc-) under basic conditions (e.g., NaH, DIPEA, CsCO) to give compound B-4, compound B-5 is obtained using compound B-4 under Suzuki coupling conditions (e.g., KCO, Pd(dppf)Cl), compound B-5 is oxidized (e.g., KOsO, NaIO) to give compound B-6, and compound B-6 undergoes reductive amination with amine A (e.g., STAB) to give compound B-7. Compound B-8 is prepared by hydrolysis and deprotection of compound B-7 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl or TFA), and compound B-8 is acylated with a substituted aromatic amine under standard amide bond forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound B-9.

[0118] Scheme 6 [ka]

[0119] Scheme 6 outlines an alternative preparation of compound B-9. Compound B-8 is hydrolyzed under basic conditions (e.g., NaOH) to give compound B-8-1, which is then reacted with a substituted aromatic halogen under standard carbon-nitrogen bond-forming conditions using an appropriate Pd catalyst (e.g., tBuXPhospd-G3) and ligand (e.g., tBuXPhos) under basic conditions (e.g., t-BuONa) to give compound B-9.

[0120] Scheme 7 [ka]

[0121] Scheme 7 outlines an alternative preparation of compound B-8. Compound B-8-1 is prepared by hydrolysis of compound B-3 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA), which is then esterified under acidic conditions (e.g., HSO) to give compound B-8-2, which is reacted with an appropriate protecting group (e.g., SEM-, Boc-) under basic conditions (e.g., NaH, DIPEA, CsCO) to give compound B-8-3, which is then subjected to Suzuki coupling conditions (e.g., KCO, Pd(dppf)Cl) using compound B-8-3, which is then oxidized (e.g., KOsO, NaIO) to give compound B-8-5, which is further subjected to reductive amination with an amine (e.g., STAB) to give compound B-8-6. Compound B-8 is prepared by hydrolysis and deprotection of compound B-8-6 under basic conditions (eg, KOH, NaOH, or LiOH) or acidic conditions (eg, HCl or TFA).

[0122] Scheme 8 [ka]

[0123] Scheme 8 illustrates an approach for synthesizing compound B-11. Compound B-10-1 is obtained using compound B-10 under Suzuki coupling conditions (e.g., K2CO3, Pd(dppf)Cl2), which is then oxidized (e.g., K2OsO4, NaIO4) to give compound B-10-2, which is further subjected to reductive amination (e.g., STAB) with amine A to give compound B-10-3. Compound B-10-3 is then reacted with carbon monoxide using a suitable Pd catalyst (e.g., Pd(dppf)Cl) under basic conditions (e.g., EtN) in solution (e.g., methanol, ethanol) to give compound B-10-4, and compound B-10-5 is prepared by hydrolysis of compound B-10-4 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA), and compound B-10-5 is acylated with a substituted aromatic amine under standard amide bond forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound B-11.

[0124] Scheme 9 [ka]

[0125] Scheme 9 outlines the preparation of compound C-12. Compound C-1 is treated with compound C-1A under basic conditions (e.g., CHONa or CHONa) to give compound C-2. Compound C-2 reacts with compound C-1B to give compound C-3, followed by a cyclization reaction to give compound C-4. Compound C-5 is prepared by hydrolysis of compound C-4 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA). The hydroxyl group of compound C-5 is halogenated by treatment with a halogenating agent (e.g., POCl3 or POBr3) to give compound C-6. Reduction of compound C-6 using a reducing agent (such as NaBH4) gives compound C-7 as an alcohol. Compound C-7 is then oxidized by precipitation with an appropriate Pd ion under basic conditions (e.g., Et3N) in a solution (e.g., methanol or ethanol). Reaction with carbon monoxide using a catalyst (e.g., Pd(dppf)Cl) gives compound C-8, which is oxidized with an oxidizing agent (e.g., MnO or DMP) to give compound C-9, which further undergoes reductive amination (e.g., STAB) with amine A to give compound C-10, which is prepared by hydrolysis of compound C-10 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA), which is acylated with a substituted aromatic amine under standard amide bond forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound C-12.

[0126] Scheme 10 [ka]

[0127] Scheme 10 illustrates an approach for synthesizing compound D-11. Compound D-2 is obtained by alkylation using an alkyl halide under alkylation conditions (e.g., TMEDA / n-BuLi, NaH, or LDA), and then compound D-2 is reduced (e.g., BH, LAH conditions) to obtain compound D-3. Compound D-3 is further subjected to halogenation reaction conditions (e.g., NBS, Br) to obtain compound D-4. Compound D-4 is then converted to compound D-5 under Suzuki coupling conditions (e.g., KCO, Pd(dppf)Cl), and compound D-5 is reacted with an appropriate protecting group (e.g., acetyl-, SEM-, Boc-) under basic conditions (e.g., TEA, DMAP, NaH, DIPEA, CsCO) to obtain compound D-6. Compound D-6 is then converted to compound D-7 under a suitable Pd catalyst (e.g., t-BuXphos). Compound D-7 is formed by treatment with a cyanating agent (ZnCN) using G3, Zn, Pd(OAc)2) and a ligand (e.g., XantPhos), which is then oxidized (conditions: e.g., KOsO4, NaIO4, NMO) to give compound D-8, which further undergoes reductive amination (e.g., STAB, NaCNBH3) with amine A to give compound D-9, compound D-10 is prepared by hydrolysis of compound D-9 in basic solution (e.g., KOH, NaOH, or LiOH) or acidic solution (e.g., HCl, H2SO4), and compound D-10 is acylated with a substituted aromatic amine under standard amide bond forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound D-11.

[0128] Scheme 11 [ka] Scheme 11 outlines the preparation of compound E-10. Compound E-2 is obtained by alkylation conditions (e.g., NaH or LDA) by treating E-1 with an alkyl halide, followed by radical cyclization conditions (e.g., Bu3SnH, AIBN) to give compound E-3, which is converted to compound E-4 under appropriate oxidation conditions (e.g., m-PCBA or HO), which is halogenated by treatment with a halogenating agent (e.g., POCl3 or POBr3) to give compound E-5, and compound E-6 is obtained by Suzuki coupling conditions (e.g., K2CO3, Pd(dppf)Cl2). Compound E-6 is then oxidized (e.g., KOsO, NaIO) to give compound E-7, which further undergoes reductive amination (e.g., STAB) with amine A to give compound E-8, compound E-9 is prepared by hydrolysis of compound E-8 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA), and compound E-9 is acylated with a substituted aromatic amide under standard amide-forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound E-10.

[0129] Scheme 12 [ka] Scheme 12 outlines the preparation of compound F-18. Compound F-4 is obtained in three sequential steps: F-4 is treated with hydrolysis conditions (e.g., HCl) to give compound F-5, which is then subjected to halogenation conditions (e.g., POCl3 or POBr3) to give compound F-6, which is converted to compound F-7 under appropriate oxidation conditions (e.g., m-PCBA or H2O2), which is acylated by treatment with acetic anhydride to give compound F-8, which is then hydrolyzed to compound F-8 (e.g., NaOH, LiOH), which is esterified to give compound F-10, which is then oxidized (e.g., HCl) to give compound F-10. Compound F-11 is then obtained by fluorination, reduction, carbonylation, and oxidation to give compound F-15, which is further subjected to reductive amination (e.g., STAB) with amine A to give compound F-16, compound F-17 is prepared by hydrolysis of compound F-16 under basic conditions (e.g., KOH, NaOH, or LiOH) or acidic conditions (e.g., HCl, TFA), and compound F-17 is acylated with a substituted aromatic amine under standard amide-forming conditions (e.g., active ester forming HATU or EDCI, DIPEA) to give compound F-18.

[0130] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to exemplify non-limiting embodiments. [Example]

[0131] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Unless otherwise specified, experimental methods in the examples described below are conventional. Unless otherwise specified, all reagents and materials are commercially available. All solvents and chemicals used are of analytical grade or chemical purity. All solvents are redistilled before use. All anhydrous solvents are prepared according to standard or reference methods. Silica gel (100-200 mesh) for column chromatography and silica gel (GF254) for thin-layer chromatography (TLC) are commercially available from Tsingdao Haiyang Chemical Co., Ltd. or Yantai Chemical Co., Ltd., China. Unless otherwise specified, all elutions were performed with petroleum ether (60-90°C) / ethyl acetate (v / v) and visualized with iodine or molybdophosphoric acid / ethanol solution. Unless otherwise specified, all extraction solvents were dried over anhydrous Na2SO4. 1 H NMR spectra were recorded on a Bruck-400, Varian 400MR nuclear magnetic resonance spectrometer using TMS (tetramethylsilane) as the internal standard. Coupling constants are given in Hertz. Peaks are reported as singlets (s), doublets (d), triplets (t), quartets (q), quintets (p), sextets (h), septets (hept), multiplets (m), or combinations thereof, with br representing broad. LC / MS data were recorded using an Agilent 1100 or 1200 high-performance liquid chromatography-ion trap mass spectrometer (LC-MSD trap) equipped with a diode array detector (DAD) detecting at 214 nm and 254 nm and an ion trap (ESI source). All compound names, other than those of reagents, were generated by ChemDraw® 18.0 or Chemaxon-Marvin JS. All mobile phase ratios for preparative HPLC were given as B% (organic phase), and the corresponding aqueous phase was A% = 100% - B%.

[0132] In the examples below, the following abbreviations are used: JPEG2025505688000059.jpg140147JPEG2025505688000060.jpg222164JPEG2025505688000061.jpg189165

[0133] Synthesis of intermediate compounds

[0134] Compound INT1: (3R,4S)-4-fluoro-3-methylpiperidine, HCl [ka]

[0135] Step 1: (R)-1-benzyl-3-methylpiperidin-4-one DTTA. [ka]

[0136] 1-Benzyl-3-methyl-piperidin-4-one (600 g, 2.95 mol, 1.00 equiv.) and ACN (3.00 L) were charged to reactor R-1 under N2 at 20-25 °C. The reaction mixture was warmed to 40-45 °C. (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid (1.37 kg, 3.54 mol, 1.20 equiv.) was charged to reactor R-1 at 40-45 °C. The reaction mixture was stirred at 40-45 °C for 18 h. The reaction mixture was filtered, and the filter cake was collected. The filter cake was washed with MeCN (1.00 L) to give (3R)-1-benzyl-3-methyl-piperidin-4-one DTTA (1.20 kg, crude).

[0137] Step 2: (R)-1-benzyl-3-methylpiperidin-4-one [ka]

[0138] 1-Benzyl-3-methyl-piperidin-4-one DTTA (1.20 kg, 1.00 equiv.) and DCM (8.40 L) were charged to reactor R-1 at 20-25°C. HO (2.40 L) was charged to reactor R-1 at 20-25°C. The reaction mixture was stirred at 20-25°C for 0.5 h. NHHO (500 mL) was added and the reaction mixture was adjusted to pH = 10. Extraction was performed with DCM (500 mL) and the organic phase was collected. The organic phase was concentrated in vacuo. (3R)-1-benzyl-3-methyl-piperidin-4-one (410 g, 2.02 mol, 68.3% yield) was obtained.

[0139] Step 3: tert-Butyl (R)-3-methyl-4-oxopiperidine-1-carboxylate [ka]

[0140] Reactor R-1 (250 mL) was installed. Pd / C (6.5 g, 639 mmol, 10% purity, 1.00 equiv.) and EtOAc (910 mL) were charged to reactor R-1 under argon (Ar) at 15-20 °C. (3R)-1-benzyl-3-methyl-piperidin-4-one (130 g, 639 mmol, 1.00 equiv.) was charged to reactor R-1 at 15-25 °C. BocO (167 g, 767 mmol, 176 mL, 1.20 equiv.) was charged to reactor R-1 at 15-25 °C. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (50 psi) at 15-25 °C for 6 h. LCMS indicated complete consumption of the reactants. The three reactions were worked up together. The reaction mixture was filtered, and the filtrate was collected. The filtrate was concentrated in vacuo. The crude product was completely dissolved in n-heptane (200 mL). The mixture was cooled to 0-5°C and stirred for 2 hours. The reaction mixture was filtered, and the filter cake was collected and concentrated in vacuo to give tert-butyl (3R)-3-methyl-4-oxo-piperidine-1-carboxylate (200 g, 937 mmol, 48.8% yield, 100% purity).

[0141] Step 4: tert-Butyl (3R)-4-hydroxy-3-methylpiperidine-1-carboxylate [ka]

[0142] Reactor R-1 (2.00 L) (2 batches) was set up. tert-Butyl (3R)-3-methyl-4-oxo-piperidine-1-carboxylate (100 g, 468 mmol, 1.00 equiv.) and MeOH (700 mL) were charged to reactor R-1 under N2 at 15-20 °C. After cooling to 0-5 °C, NaBH4 (26.6 g, 703 mmol, 1.50 equiv.) was charged to reactor R-1 under N2. The reaction mixture was stirred at 0-5 °C for 1 h. The reaction mixture was stirred at 20-25 °C for 2 h. LCMS indicated complete consumption of the reactant. The reaction mixture was quenched with saturated NH4Cl (100 mL). The reaction mixture was concentrated in vacuo. The mixture was extracted with DCM (200 mL) and the organic phase was collected. The organic phase was concentrated in vacuo. tert-Butyl (3R)-4-hydroxy-3-methylpiperidine-1-carboxylate (184 g, purity 93.5%) was obtained.

[0143] Step 5: tert-Butyl (3R,4R)-4-hydroxy-3-methylpiperidine-1-carboxylate [ka]

[0144] The crude product (184 g, purity 93.5%) was purified by SFC separation (column: DAICELCHIRALPAKAD (250 mm × 50 mm, 10 μm), mobile phase: [0.1% NH3HO ETOH], B%: 13%-13%, 3.5 min) to give tert-butyl (3R,4S)-4-hydroxy-3-methyl-piperidine-1-carboxylate (85.0 g, 394 mmol, yield 46.2%, purity 100%).

[0145] Step 6: tert-Butyl (3R,4R)-3-methyl-4-(tosyloxy)piperidine-1-carboxylate [ka]

[0146] Reactor R-1 (1.00 L) was installed. tert-Butyl (3R,4R)-4-hydroxy-3-methyl-piperidine-1-carboxylate (80.0 g, 371 mmol, 1.00 equiv.) and pyridine (560 mL) were charged to reactor R-1 at 20-25 °C. TsCl (92.1 g, 483 mmol, 1.30 equiv.) was charged to reactor R-1 under N2. The reaction mixture was stirred at 20-25 °C for 12 h. LCMS showed complete consumption of the reactants. The reaction mixture was quenched with HO (200 mL) at 15-20 °C. The mixture was extracted with DCM (300 mL) and the organic phase was collected. The organic phase was washed with HCl (0.5 M aqueous solution, 500 mL × 2) and adjusted to pH = 6. The mixture was extracted with DCM (200 mL) and the organic phase was collected. The organic phase was concentrated in vacuo. The crude product was triturated with n-heptane (100 mL) at 15-20°C for 1 hour. The reaction mixture was filtered, and the filter cake was collected. The filter cake was dried at 40-45°C for 4 hours. tert-Butyl (3R,4R)-3-methyl-4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (100 g, 270 mmol, 72.8% yield) was obtained.

[0147] Step 7: tert-Butyl (3R,4S)-4-fluoro-3-methylpiperidine-1-carboxylate [ka]

[0148] Reactor R-1 (2.00 L) was installed. tert-Butyl (3R,4R)-3-methyl-4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (100 g, 270 mmol, 1.00 equiv.) was charged to Reactor R-1 at 15-20 °C. Tetrabutylammonium fluoride trihydrate (1 M, 1.35 L, 5.00 equiv.) was charged to Reactor R-1 at 15-20 °C. The reaction mixture was stirred at 60-65 °C for 8 h. HPLC and TLC (petroleum ether: EtOAc = 8:1, Rf = 0.65) showed complete consumption of the reactants and detected the product. After cooling to 15-20 °C, the reaction mixture was quenched with HO (100 mL). The mixture was extracted with DCM (200 mL), and the organic phase was collected. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 60 / 1 to 20 / 1) to give tert-butyl (3R,4S)-4-fluoro-3-methyl-piperidine-1-carboxylate (20.0 g, 92.0 mmol, yield 34.0%).

[0149] Step 8: (3R,4S)-4-Fluoro-3-methylpiperidine, HCl [ka]

[0150] Reactor R-1 (100 mL) was installed. tert-Butyl (3R,4S)-4-fluoro-3-methyl-piperidine-1-carboxylate (20.0 g, 92.0 mmol, 1.00 equiv.) and HCl / EtOAc (4 M solution, 140 mL) were charged to reactor R-1 at 20-25°C. The reaction mixture was stirred at 20-25°C for 1 hour. LCMS and TLC (petroleum ether: EtOAc = 8:1) showed complete consumption of the reactants, and the product was detected. The reaction mixture was concentrated in vacuo. The crude product was triturated with n-heptane (40.0 mL) at 25°C for 1 hour. The reaction mixture was filtered, and the filter cake was collected. The filter cake was dried at 40-45°C for 2 hours. (3R,4S)-4-Fluoro-3-methyl-piperidine (11.0 g, 71.60 mmol, 77.79% yield, 100% purity, HCl) was obtained.

[0151] Compound INT2: 3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]aniline [ka]

[0152] Step 1: Ethyl 2-(oxetan-3-ylidene)acetate [ka]

[0153] Ethyl 2-(triphenyl-λ) in DCM (400 mL) 5 To a solution of 2-(oxetan-3-ylidene)acetate (406 g, 1.17 mol, 1.05 equiv.) was added a solution of oxetan-3-one (80.0 g, 1.11 mol, 1.00 equiv.) in DCM (200 mL) at 0-10 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether (500 mL) at 25 °C for 2 h. Ethyl 2-(oxetan-3-ylidene)acetate (250 g, 1.76 mol, 79.2% yield) was obtained.

[0154] Step 2: Ethyl 2-(3-(3-nitrophenyl)oxetan-3-yl)acetate [ka]

[0155] To a solution of ethyl 2-(oxetan-3-ylidene)acetate (20.0 g, 140 mmol, 1.00 equiv) in dioxane (80.0 mL) was added chlororhodium (1Z,5Z)-cycloocta-1,5-diene (6.74 g, 14.03 mmol, 0.1 equiv) and KOH (1.50 M, 140 mL, 1.50 equiv) in HO (20.0 mL), followed by the addition of (3-nitrophenyl)boronic acid (30.5 g, 182 mmol, 1.30 equiv) in small portions. The mixture was stirred at 15 °C for 4 h. The mixture was filtered through Celite, extracted with EtOAc (200 mL × 3) and HO (300 mL), separated, and the organic layer was washed with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness in vacuo. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1-1 / 1). Ethyl 2-[3-(3-nitrophenyl)oxetan-3-yl]acetate (10 g) was obtained. 1 H NMR: (400 MHz, CDCl3-d) δ ppm 8.15 (m, 1H), 8.10 - 8.03 (m, 1H), 7.67 - 7.50 (m, 2H), 5.02 (d, J = 6.4 Hz, 2H), 4.91 (d, J = 6.4 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.20 (s, 2H), 1.16 (t, J = 7.2 Hz, 3H)ppm; MS:M / e 266 (M+1) + .

[0156] Step 3: 2-(3-(3-nitrophenyl)oxetan-3-yl)acetohydrazide [ka]

[0157] To a solution of ethyl 2-[3-(3-nitrophenyl)oxetan-3-yl]acetate (40.0 g, 150 mmol, 1.00 equiv.) in EtOH (200 mL) was added N2H4 . HO (49.1 g, 961 mmol, 47.6 mL, 98.0% purity, 6.38 equiv.) was added. The mixture was stirred at 80° C. for 16 h. TLC (dichloromethane / methanol=10 / 1, R f( 2-(3-(3-nitrophenyl)oxetan-3-yl)acetohydrazide) = 0.20, I2) indicated that 60% of reactant 1 was not consumed. The mixture was then added with N2H4 . HO (24.3 g, 477 mmol, 23.6 mL, 98% purity, 3.16 equivalents) was added at 25° C. The mixture was stirred at 80° C. for 16 hours. TLC (dichloromethane / methanol=10 / 1, R f( 2-(3-(3-nitrophenyl)oxetan-3-yl)acetohydrazide) = 0.20, I2) indicated that all of the reactants had been consumed. The mixture was concentrated under reduced pressure to give 2-[3-(3-nitrophenyl)oxetan-3-yl]acetohydrazide (32.0 g).

[0158] Step 4: 1-methyl-3-[[2-[3-(3-nitrophenyl)oxetan-3-yl]acetyl]amino]thiourea [ka]

[0159] To a solution of 2-[3-(3-nitrophenyl)oxetan-3-yl]acetohydrazide (75.0 g, 298 mmol, 1.00 equiv) in THF (450 mL) was added methylimino(thioxo)methane (43.6 g, 597 mmol, 40.8 mL, 2.00 equiv). The mixture was stirred at 70° C. for 5 hours. The mixture was concentrated to give the crude product. The crude product (80.0 g) was obtained and used in the next step without further purification.

[0160] Step 5: 4-methyl-5-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole-3-thiol [ka]

[0161] To a solution of 1-methyl-3-[[2-[3-(3-nitrophenyl)oxetan-3-yl]acetyl]amino]thiourea (80.0 g, 246 mmol, 1.00 equiv.) in NaOH (1 M, 2.47 L, 10.0 equiv.) was added. The mixture was stirred at 25 °C for 8 hours. The reaction was diluted with water, and then the pH of the solution was adjusted to 5 with HCl (1 N, 2.00 L) and extracted with EtOAc (1.00 L × 3). The combined organic layers were washed with 800 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. 4-methyl-5-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole-3-thiol (90.0 g, crude) was obtained.

[0162] Step 6: 4-Methyl-3-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole [ka]

[0163] To a solution of 4-methyl-5-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole-3-thiol (30.0 g, 97.9 mmol, 1.00 equiv.) in THF (450 mL) and HO (450 mL) was added NaNO (67.5 g, 979 mmol, 4.90 mL, 10.0 equiv.) and HNO (94.9 g, 979 mmol, 67.8 mL, 65% purity, 10.0 equiv.) at 0 °C. The mixture was basified with saturated aqueous NaHCO (0.5 L), diluted with water, and extracted with EtOAc (200 mL × 4). The organic phases were combined and concentrated to give a residue. The residue was purified by column chromatography (SiO, dichloromethane / methanol = 100 / 1-0 / 1). 4-Methyl-3-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole (20 g) was obtained. 1 HNMR: (400 MHz, CDCl3-d) δ ppm 8.18 - 8.05 (m, 1H), 7.98 - 7.85 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.35 (m, 1H), 5.18 - 4.99 (m, 4H), 3.58 (s, 2H), 3.11 (s, 3H)ppm; MS:M / e 275 (M+1) + .

[0164] Step 7: 3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]aniline [ka]

[0165] To a solution of 4-methyl-3-[[3-(3-nitrophenyl)oxetan-3-yl]methyl]-1,2,4-triazole (10.0 g, 36.4 mmol, 1.00 equiv.) in EtOH (100 mL) and HO (30.0 mL) was added NH4Cl (9.75 g, 182 mmol, 5.00 equiv.). Then, Fe (6.11 g, 109 mmol, 3.00 equiv.) was added to the mixture at 80 °C. The mixture was stirred at 80 °C for 2 h. Four batches were combined and worked up. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with water (100 mL), and then the pH of the solution was adjusted to 8 with NaHCO3 (150 mL) and extracted with dichloromethane / methanol = 10 / 1 (200 mL × 3). The combined organic layers were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, dichloromethane / methanol = 100 / 1-0 / 1) to give 3-[3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl]aniline (31.4 g). 1 H NMR: (400 MHz, CDCl3-d) δ ppm 8.20 (s, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.40 (br d, J = 7.6 Hz, 1H), 6.04 (s, 1H), 5.94 (br d, J = 7.2 Hz, 1H), 5.02 (br s, 2H), 4.84 (d, J = 5.6 Hz, 2H), 4.75 (d, J = 5.6 Hz, 2H), 3.39 (s, 2H), 2.83 (s, 3H)ppm; MS:M / e 245 (M+1) + .

[0166] Compound INT3: (1r,3r)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile [ka]

[0167] Step 1: Methyl 2-(3-cyanocyclobutylidene)acetate [ka]

[0168] To a solution of NaH (13.9 g × 6, 347 mmol, 60%) in THF (900 mL) was added methyl 2-(dimethoxyphosphoryl)acetate (57.5 g × 6, 315.5 mmol) under N2 at 0 °C. The mixture was stirred at 25 °C for 1 h, and then 3-oxocyclobutane-1-carbonitrile (30 g × 6, 315.5 mmol) in THF (90 mL) was added at 0 °C under N2. The mixture was stirred at 25 °C for 13 h. The mixture was poured into saturated aqueous NH4Cl (1000 mL) and extracted with EtOAc (1000 mL, 500 mL). The combined organic phase was washed with brine (100 mL), dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography (SiO, PE:EA=100 / 1, 0 / 1) to give the product (192.0 g, 67% yield). MS: M / e 152 (M+1) + .

[0169] Step 2: Methyl 2-((1r,3r)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate [ka]

[0170] To a solution of methyl 2-(3-cyanocyclobutylidene)acetate (75.0 × 2 g, 496 mmol) in dioxane (750 mL) was added (3-((tert-butoxycarbonyl)amino)phenyl)boronic acid (176 g × 2, 744 mmol), KOH (430 × 2 mL, 545 mmol, 1.5 M), and chloro(1,5-cyclooctadiene)rhodium(I) dimer (CAS: 12092-47-6) (24.5 g × 2, 49.6 mmol) under N at 25 °C. The mixture was stirred under N at 25 °C for 15 h. The mixture was poured into water (800 mL) and extracted with EtOAc (1000 mL, 500 mL). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a residue that was purified by column chromatography (SiO2, PE:EA = 100 / 1, 0 / 1) to give methyl 2-((1r,3r)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate (50 g, 14.6% yield) and methyl 2-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate (98 g, CIS:TRANS = 1:1). MS: M / e 345 (M+1) + .

[0171] Step 3: 2-((1r,3r)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetic acid [ka]

[0172] To a solution of methyl 2-((1r,3r)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate (46.0 g, 133.6 mmol) in THF / MeOH / HO (450 mL, 1:1:1) was added LiOH.HO (16.8 g, 400.7 mmol) at 20 °C. The mixture was stirred under N at 20 °C for 12 h. The mixture was adjusted to pH = 6.0 with HCl (1 M) and extracted with EtOAc (900 mL, 500 mL). The combined organic phases were washed with brine (200 mL), dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (35 g, 80% yield). MS:M / e 329 (M-1) - . 1 H NMR: (400 MHz, CDCl3-d) δ 7.24-7.27 (m, 4H) 6.89-6.91 (m, 1H) 2.89-2.30 (m, 5H) 2.65-2.78 (m, 2H) 1.51 (s, 9H).

[0173] Step 4: tert-butyl (3-((1r,3r)-3-cyano-1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate [ka]

[0174] To a solution of 2-((1r,3r)-1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetic acid (35 g, 106 mmol) in DMF (350 mL) at 20 °C was added DIEA (15.1 g, 116.5 mmol), HATU (52.4 g, 137.7 mmol), and N-methylhydrazinecarbothioamide (16.7 g, 159.0 mmol). The mixture was stirred at 25 °C for 13 h, after which NaOH (222.5 mL, 222.5 mmol, 1 M) was added. The mixture was stirred at 60 °C for 12 h. The mixture was poured into water (500 mL), adjusted to pH = 6.0 with HCl (1 M), and extracted with EtOAc (500 mL, 300 mL). The combined organic phase was washed with brine (200×2 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA=100 / 1, 0 / 1) to give the product (36 g, 86% yield). MS: M / e 400 (M+1) + .

[0175] Step 5: tert-butyl (3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate [ka]

[0176] To a solution of tert-butyl (3-((1r,3r)-3-cyano-1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate (36 g, 90.1 mmol) in DCM (720 mL) was added AcOH (72 mL) and HO (40.8 g, 360.1 mmol, 30%) at 0 °C. The mixture was stirred at 20 °C for 6 h. The mixture was poured into water (500 mL), adjusted to pH = 8.0 with NaOH (1 M), and extracted with DCM (500 mL, 300 mL). The combined organic phase was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA=100 / 1, 0 / 1) to give the product (30 g, 91% yield). MS: M / e 368 (M+1) + .

[0177] Step 6: (1r,3r)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile [ka]

[0178] To a solution of tert-butyl (3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate (30 g, 81.6 mmol) in DCM (600 mL) was added TMSI (32.7 g, 163.3 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was adjusted to pH=8.0 with saturated NaHCO3 and extracted with DCM (800 mL, 500 mL). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by preparative HPLC (column = Xtimate C18 10u 250 mm x 80 mm), mobile phase = water (NH4HCO3)-ACN, B% = 0%-40%, 25 min) to give the product (16 g, 73% yield). MS: M / e 268 (M+1) + .1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H) 6.87-6.91 (t, J=7.6 Hz, 1H) 6.38-6.40 (d, J=7.6 Hz, 1H) 6.15 (s, 1H) 6.04-6.06 (d, J=7.6 Hz, 1H) 5.14 (s, 2H) 3.18 (s, 3H) 2.67-2.79 (m, 7H).

[0179] Compound INT4: (1s,3s)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile [ka]

[0180] Step 1: 2-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetic acid [ka]

[0181] To a solution of methyl 2-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetate (80 g, 232.3 mmol) in THF / MeOH / HO (800 mL, 1:1:1) was added LiOH.HO (29.2 g, 696.2 mmol) at 20 °C. The mixture was stirred under N at 20 °C for 12 h. The mixture was adjusted to pH = 6.0 with HCl (1 M) and extracted with EtOAc (1.5 L, 1.0 L). The combined organic phases were washed with brine (500 mL), dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (70 g, 84% yield). MS: M / e 329 (M-1). - .

[0182] Step 2: tert-butyl (3-(3-cyano-1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate [ka]

[0183] To a solution of 2-(1-(3-((tert-butoxycarbonyl)amino)phenyl)-3-cyanocyclobutyl)acetic acid (35 g × 2, 106 mmol) in DMF (350 mL) at 20 °C was added DIEA (15.1 g, 116.5 mmol), HATU (52.4 g, 137.7 mmol), and N-methylhydrazinecarbothioamide (16.7 g, 159.0 mmol). The mixture was stirred at 25 °C for 13 h, and then NaOH (222.5 mL, 222.5 mmol, 1 M) was added. The mixture was stirred at 60 °C for 12 h. The mixture was poured into water (500 mL), adjusted to pH = 6.0 with HCl (1 M), and extracted with EtOAc (1.0 L, 500 mL). The combined organic phase was washed with brine (300×2 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA=100 / 1, 0 / 1) to give the product (80 g, 81% yield). MS: M / e 400 (M+1) + ..

[0184] Step 3: tert-butyl (3-(3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate [ka]

[0185] To a solution of tert-butyl (3-(3-cyano-1-((5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate (40 g, 100 mmol) in DCM (800 mL) were added AcOH (80 mL) and HO (45.4 g, 400 mmol, 30%) at 0 °C. The mixture was stirred at 20 °C for 6 h. The mixture was poured into water (500 mL), adjusted to pH = 8.0 with NaOH (1 M), and extracted with DCM (800 mL, 500 mL). The combined organic phases were washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (60 g, 82% yield). MS:M / e 368 (M+1) + .

[0186] Step 6: (1s,3s)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile [ka]

[0187] To a solution of tert-butyl (3-(3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)carbamate (20 g × 3, 54.4 mmol) in DCM (400 mL) was added TMSI (21.8 g, 108.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was adjusted to pH = 8.0 with saturated NaHCO3 and extracted with DCM (1500 mL, 1000 mL). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a residue, which was purified by preparative HPLC (column = Welch Xtimate C18 250 × 70 mm #10 um), mobile phase = water (NH4HCO3)-ACN, B% = 0%-30%, 20 min) to give the product (32 g, 73%). The product was purified by SFC (column = DAICEL CHIRALPAK IC (250 mm × 50 mm, 10 um)), mobile phase = 0.1% NH3H2O ​​ETOH, B% = 60%-60%, 5 min) to give (1s,3s)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (P1: 14.5 g, 45%). 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (s, 1H), 6.86-6.90 (t, J=7.6 Hz, 1H) 6.38-6.40 (d, J=7.6 Hz, 1H) 6.02 (s, 1H) 5.91-5.93 (d, J=7.6 Hz, 1H) 5.01 (s, 2H), 3.17-3.18 (m, 1H), 3.11 (s, 2H) 2.90-2.95 (m, 2H) 2.68 (s, 3H) 2.43-2.46 (m, 2H);

[0188] Compound INT5: 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0189] Step 1: Methyl 1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylate [ka]

[0190] To a solution of methyl 2-(3-bromophenyl)acetate (100 g, 436 mmol) in DMF (2000 mL) was added 1,3-dibromo-2-methylpropane (94.2 g, 436 mmol) and NaH (38.4 g, 960 mmol, 60%) under N at 0 °C. The mixture was stirred under N at 25 °C for 12 h. The mixture was poured into saturated aqueous NH Cl (2.0 L) and extracted with EtOAc (1000 mL, 500 mL). The combined organic phase was washed with brine (2.0 L × 2), dried over Na SO , filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (80 g, 65% yield). MS: M / e 283 (M+1). + .

[0191] Step 2: 1-(3-bromophenyl)-3-methylcyclobutane-1-carbohydrazide [ka]

[0192] To a solution of methyl 1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylate (80 g, 282 mmol) in EtOH (800 mL) was added NHNHHO (70.7 g, 1.4 mol) at 25 °C. The mixture was stirred under N at 80 °C for 48 h. The mixture was poured into water (1000 mL) and extracted with EtOAc (1000 mL, 500 mL). The combined organic phases were washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (60 g, 75% yield). MS: M / e 283 (M+1) + .

[0193] Step 3: 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol [ka]

[0194] To a solution of 1-(3-bromophenyl)-3-methylcyclobutane-1-carbohydrazide (60 g, 212 mmol) in THF (600 mL) was added isothiocyanatomethane (46.5 g, 635 mmol) under N at 20 °C. The mixture was stirred at 65 °C under N for 1 h, after which KOH (594 g, 1.1 mol, 10%) in HO was added at 20 °C. The mixture was heated to 65 °C and stirred at 65 °C under N for 12 h. The mixture was poured into water (600 mL), adjusted to pH = 5.0 with HCl (1 M), and extracted with EtOAc (800 mL, 500 mL). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA=100 / 1, 0 / 1) to give the product (50 g, 70% yield). MS: M / e 338 (M+1) +

[0195] Step 4: 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole [ka]

[0196] To a solution of 5-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (50 g, 148 mmol) in DCM (500 mL) was added HO (50 g, 443 mmol, 30%) and AcOH (50 mL) at 0 °C. The mixture was stirred at 25 °C for 3 h. The mixture was poured into water (500 mL), adjusted to pH = 8.0 with NaOH (2 M), and extracted with DCM (1000 mL, 500 mL). The combined organic phases were washed with NaSO (500 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (35 g, 78% yield). MS: M / e 306 (M+1). + .

[0197] Step 5: 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole [ka]

[0198] The compound 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (35 g, 114 mmol) was purified by pre-SFC-2 (DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm, 0.1% NH3HO ETOH)) to give the product (13 g, 37% yield). MS: M / e 306 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) 8.31 (m, 1H) δ 7.45-7.48 (m, 2H) 7.34-7.35 (m, 2H) 3.17 (s, 3H) 2.79-2.82 (m, 2H) 2.47-2.52 (m, 3H) 1.04-1.07 (m, 3H)ppm.

[0199] Step 6: tert-butyl (3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate [ka]

[0200] To a solution of 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (4 g, 13.07 mmol), tert-butyl carbamate (1.5 g, 12.82 mmol) in dioxane (50 mL) was added Pd(OAc) (300 mg, 1.34 mmol), Xantphos (1.5 g, 2.59 mmol), and CsCO (8.5 g, 26.07 mmol) under N. The reaction mixture was stirred at 110 °C for 12 h. After completion, the mixture was filtered and the filtrate was collected and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with methanol (10%) in dichloromethane to give the title compound (3.7 g, 83%). MS: M / e 343. (M+H) + .

[0201] Step 7: 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0202] tert-Butyl (3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamate (3.7 g, 10.82 mmol) was dissolved in HCl (60 mL, 4 M dioxane solution). The reaction mixture was stirred at 25° C. for 5 h. After completion, the solvent was concentrated in vacuo. The residue was diluted with DCM (50 mL), quenched with aqueous NaHCO (30 mL), extracted with DCM / MeOH (10 / 1, 3×80 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol (10%) in dichloromethane to give the title compound (1.9 g, 73%). 1 H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.09 (t, J = 8.4 Hz, 1H), 6.69-6.65 (m, 2H), 6.61 (d, J = 8.0 Hz, 1H), 3.24 (s, 3H), 2.89-2.79 (m, 2H), 2.69-2.56 (m, 1H), 2.53-2.44 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H)ppm.MS:M / e 243(M+H) + .

[0203] Compound INT6: 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile [ka]

[0204] Step 1: 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile [ka]

[0205] To a solution of NaH (9.0 g, 224 mmol, 60%) in DMF (200 mL) was added 2-(3-bromophenyl)acetonitrile (20 g, 102 mmol) under N at 0 °C. The mixture was stirred for 10 min, and then 1,3-dibromo-2,2-dimethoxypropane (29.4 g, 112 mmol) was added under N at 0 °C. The mixture was stirred at 60 °C under N for 12 h. The mixture was poured into saturated aqueous NH Cl (200 mL) and extracted with EtOAc (200 mL, 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na SO , filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (14 g, 48% yield). 1 H NMR: (400 MHz, CDCl3-d) δ 7.55-7.56 (t, J = 2 Hz, 1H) 7.39-7.41 (d, J = 8 Hz, 1H) 7.33-7.35 (d, J = 8 Hz, 1H) 7.21-7.23 (m, 1H) 3.21 (s, 3H) 3.11 (s, 3H) 3.01-3.05 (m, 2H) 2.61-2.65 (m, 2H)ppm;

[0206] Step 2: 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarboxylic acid [ka]

[0207] To a solution of 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile (14 g, 47 mmol) in EtOH (60 mL) was added NaOH (56.7 g, 142 mmol, 10%) and stirred at 85 °C under N for 15 h. The mixture was poured into water (20 mL), adjusted to pH = 3.0 with HCl (2 M), and extracted with EtOAc (100 mL, 50 mL). The combined organic phases were washed with brine (20 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (9.0 g, 60% yield). 1 H NMR:(400 MHz, CDCl3-d) δ 7.46(s, 1H) 7.39-7.42 (m, 1H) 7.21-7.26 (m, 2H) 3.20 (s, 3H) 3.11-3.16 (m, 5H) 2.54-2.57 (m, 2H); MS:M / e 313 (M-1) -

[0208] Step 3: 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarbohydrazide [ka]

[0209] A solution of 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarboxylic acid (9.0 g, 28.6 mmol) in DCM (100 mL) was cooled to 0 °C, and EtN (5.8 g, 57 mmol) and isobutyl carbonochloridate (5.8 g, 42.8 mmol) were added dropwise at 0 °C under N. The mixture was stirred at 0 °C for 40 min, then NHNH 2.HO (5.7 g, 114 mmol) was added dropwise at −30° C. The mixture was stirred under N at 20° C. for 3 h. The mixture was poured into water (100 mL) and extracted with EtOAc (100 mL, 50 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography (SiO, PE:EA=100 / 1, 0 / 1) to give the product (6.0 g, yield 68%). 1 H NMR: (400 MHz, CDCl3-d) δ 7.40-7.43 (m, 2H) 7.21-7.23 (m, 2H) 6.87 (s, 1H) 3.69 (s, 2H) 3.21 (s, 3H) 3.10 (s, 3H) 3.05-3.08 (m, 2H) 2.61-2.64 (m, 2H)ppm.

[0210] Step 4: 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol [ka]

[0211] To a solution of 1-(3-bromophenyl)-3,3-dimethoxycyclobutanecarbohydrazide (6.0 g, 19.2 mmol) in THF (120 mL) was added isothiocyanatomethane (4.2 g, 57.4 mmol) under N at 20 °C. The mixture was stirred at 65 °C under N for 1 h, after which KOH (5.4 g, 95.7 mmol) in HO (12 mL) was added at 20 °C. The mixture was heated to 65 °C and stirred at 65 °C under N for 12 h. The mixture was poured into water (50 mL), adjusted to pH = 5.0 with HCl (1 M), and extracted with EtOAc (100 mL, 50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA=100 / 1, 0 / 1) to give the product (5.5 g, yield 79%). 1H NMR: (400 MHz, CDCl3-d) 11.20 (s, 1H) δ 7.42-7.44 (m, 2H) 7.21-7.25 (t, J = 8 Hz, 1H) 7.12-7.14 (d, J = 8 Hz, 1H) 3.18-3.22 (m, 11H) 2.81-2.84 (m, 2H)ppm.

[0212] Step 5: 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole

[0213] [ka]

[0214] To a solution of 5-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol (2.0 g, 5.2 mmol) in DCM (40 mL) was added HO (2.9 g, 26 mmol, 30%) and AcOH (4 mL) at 15 °C. The mixture was stirred at 15 °C for 3 h. The mixture was poured into water (10 mL), adjusted to pH = 8.0 with NaOH (1 M), and extracted with DCM (20 mL, 10 mL). The combined organic phases were washed with NaSO (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (1.4 g, 77% yield).

[0215] Step 6: 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanone [ka]

[0216] To a solution of 3-(1-(3-bromophenyl)-3,3-dimethoxycyclobutyl)-4-methyl-4H-1,2,4-triazole (1.4 g, 4.0 mmol) in acetone (20 mL) was added HCl (10 mL, 6 M) at 15 °C. The mixture was stirred at 15 °C for 12 h. The mixture was poured into water (10 mL), adjusted to pH = 8.0 with NaOH (2 M), and extracted with EtOAc (50 mL, 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a residue which was purified by column chromatography (SiO2, PE:EA = 100 / 1, 0 / 1) to give the product (1.0 g, 83% yield).

[0217] Step 7: 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutylidene)acetonitrile [ka]

[0218] To a solution of 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutanone (800 mg, 2.6 mmol) in THF (16 mL) was added diethyl(cyanomethyl)phosphonate (509 mg, 2.87 mmol) and t-BuOK (322 mg, 2.87 mmol) at 0 °C and stirred under N at 15 °C for 6 h. The mixture was poured into saturated aqueous NH Cl (10 mL) and extracted with EtOAc (20 mL, 10 mL). The combined organic phase was washed with brine (10 mL), dried over Na SO , filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE:EA = 100 / 1, 0 / 1) to give the product (600 mg, 70% yield). MS: M / e 329 (M+1). +

[0219] Step 8: 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile [ka]

[0220] To a solution of 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutylidene)acetonitrile (2.6 g, 8.0 mmol) in EtOH (25 mL) and iPrOH (25 mL) was added NaBH (896 mg, 23.7 mmol) at 15 °C. The mixture was stirred at 60 °C for 6 h. The mixture was poured into saturated aqueous NH Cl (50 mL) and extracted with EtOAc (50 mL, 30 mL). The combined organic phases were washed with brine (20 mL), dried over Na SO , filtered, and concentrated to give a residue which was purified by column chromatography (SiO, EA:MeOH = 100 / 1, 1 / 1) to give the product (2.0 g, 75% yield). MS: M / e 331 (M+1) + ;

[0221] 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (360 mg) was purified by SFC (column = ChiralPak IH, 250 × 30 mm, 10 μm, mobile phase = Neu-IPA, B% = 45%-45%, 4 min) to give two isomers P1 and P2. [ka]

[0222] 2-((1s,3s)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (P1, Rt=2.516, 103 mg, 28.7%), 1 H NMR (400 MHz, DMSO-d6) δ = 8.32 (s, 1H), 7.47-7.50 (m, 2H), 7.34-7.36 (m, 2H), 3.18 (s, 3H), 2.82-2.88 (m, 2H), 2.71-2.73 (m, 5H) ppm; MS:M / e 331 (M+1) +.

[0223] 2-((1r,3r)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (P2, Rt=2.676, 125 mg, 34.8%), 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.45-7.47 (m, 1H), 7.32-7.36 (m, 2H), 7.16-7.20 (m, 1H), 3.20 (s, 3H), 3.06-3.11 (m, 2H), 2.71-2.73 (m, 2H).2.40-2.50 (m, 3H) ppm.MS:M / e 331 (M+1) + .

[0224] Step 9: 2-(3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile [ka]

[0225] To a solution of 2-(3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (1.0 g, 3 mmol) in sulfolane (10 mL) was added dimethylethylenediamine (DMEDA, 53 mg, 604 μmol), CuI (115 mg, 604 μmol), and NH3HO (20 mL) under N2 at 25 °C. The mixture was heated to 100 °C and stirred at 100 °C in a sealed container for 16 h. The mixture was filtered to obtain a filtrate, which was purified by preparative HPLC (column = Welch Xtimate C18 250 × 70 mm #10 μm), mobile phase = water (NH4HCO3)-ACN, B% = 5%-35%, 20 min) to obtain the product (480 mg, 60%). MS: M / e 268 (M+1). + .

[0226] 2-(3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile was purified by SFC (column = DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), mobile phase = 0.1% NH3H2O ​​ETOH, B% = 24%-24%, 9 min) to give two isomers P1 and P2. [ka]

[0227] 2-((1r,3r)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (P1, Rt=3.399, 122 mg, 30%), 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (s, 1H), 6.97-7.01 (t, J =8.0 Hz, 1H) 6.37-6.42 (m, 2H) 6.26 (s, 1H) 5.09 (s, 2H) 3.19 (s, 3H), 2.95-3.00 (m, 2H), 2.67-2.69 (m, 2H) 2.51-2.52 (m, 1H) 2.32-2.35 (m, 2H)ppm.MS:M / e 268 (M+1) + .

[0228] 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (P2, Rt=3.641, 105 mg, 25%), 1 H NMR (400 MHz, DMSO-d6) δ = 8.28 (s, 1H), 6.96-7.01 (t, J =7.6 Hz, 1H), 6.43-6.50 (m, 3H) 5.09 (s, 2H) 3.16-3.17 (m, 4H), 2.65-2.73 (m, 5H), 2.51-2.52 (m, 1H) ppm; MS:M / e 268 (M+1) + .

[0229] Compound INT7: 3-((1s,3s)-3-methyl-1-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0230] Step 1: (E)-N'-(1-(3-bromophenyl)-3-methylcyclobutane-1-carbonyl)-N,N-dimethylformohydrazonamide [ka]

[0231] To a solution of 1-(3-bromophenyl)-3-methyl-cyclobutanecarbohydrazide (4 g, 14.13 mmol, 1 equiv.) in DCM (80 mL) was added DMFDMA (8.42 g, 70.63 mmol, 9.38 mL, 5 equiv.) at 20 °C. The mixture was stirred at 50 °C for 16 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 10 / 1 - DCM:MEOH = 10:1) to give the compound 1-(3-bromophenyl)-N-[(E)-dimethylaminomethyleneamino]-3-methyl-cyclobutanecarboxamide (4.6 g, 13.60 mmol) as a yellow solid. MS [M+41] 340.

[0232] Step 2: 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-(methyl-d3)-4H-1,2,4-triazole [ka]

[0233] To a solution of 1-(3-bromophenyl)-N-[(E)-dimethylaminomethyleneamino]-3-methyl-cyclobutanecarboxamide (5 g, 14.78 mmol, 1 equiv.) in THF (100 mL) was added trideuteriomethanamine hydrochloride (4.99 g, 73.91 mmol, 5 equiv.), CHCOOH (887.68 mg, 14.78 mmol, 846.21 μL, 1 equiv.), and TEA (7.48 g, 73.91 mmol, 10.29 mL, 5 equiv.). The mixture was stirred at 90 °C for 48 h. The reaction mixture was diluted with HO (100 mL), extracted with EA (150 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 180 x 70 mm #10 um, mobile phase: [HO (10 mM NH4HCO3) -ACN], gradient: 17%-47% B over 20.0 min). The residue was purified by preparative HPLC (column: Welch Xtimate C18 180 x 70 mm #10 um, mobile phase: [HO (10 mM NH4HCO3) -ACN], gradient: 17%-47% B over 20.0 min) to give the compound 3-[1-(3-bromophenyl)-3-methyl-cyclobutyl]-4-(trideuteriomethyl)-1,2,4-triazole (1.1 g, 3.56 mmol, 24.06% yield) as a brown solid. MS [M+1] 311; 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.97 (s, 1H), 7.53 (s, 1H), 7.44 - 7.31 (m, 1H), 7.26 - 7.06 (m, 2H), 2.88 - 2.74 (m, 2H), 2.72 - 2.57 (m, 3H), 1.14 (d, J = 5.4 Hz, 3H).

[0234] Step 5: 3-((1s,3s)-3-methyl-1-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0235] To a solution of 3-[1-(3-bromophenyl)-3-methyl-cyclobutyl]-4-(trideuteriomethyl)-1,2,4-triazole (400.00 mg, 1.29 mmol, 1 equiv.) in sulfolane (3 mL) and NH.HO (9 mL) was added CuI (246.36 mg, 1.29 mmol, 1 equiv.) and DMEDA (114.03 mg, 1.29 mmol, 139.23 μL, 1 equiv.). The mixture was stirred at 100° C. for 6 h. The reaction mixture was extracted with 30 mL of DCM (15 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100 x 40 mm x 3 um, mobile phase: [water (0.04% HCl)-ACN], gradient: 1%-20% B over 8.0 min). MS [M+1] 246; 1 H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 1H), 7.48 - 7.38 (m, 1H), 7.30 (br d, J = 7.8 Hz, 1H), 7.26 - 7.14 (m, 2H), 2.88 - 2.74 (m, 2H), 2.64 - 2.52 (m, 3H), 1.08 (br d, J = 5.8 Hz, 3H).

[0236] Compound INT8: 5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-amine [ka]

[0237] Step 1: 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbonitrile [ka]

[0238] To a stirred solution of NaH (2.19 g, 86.786 mmol, 2 equiv, 95%) in DMF (300 mL) was added 2-(5-bromopyridin-3-yl)acetonitrile (9 g, 43.393 mmol, 1 equiv, 95%) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for an additional 15 minutes. To the above mixture was added 1,3-dibromo-2-methylpropane (14.79 g, 65.090 mmol, 1.5 equiv, 95%) at 0 °C. The resulting mixture was stirred at 60 °C for an additional 16 hours. The reaction was quenched by the addition of saturated NH Cl (aq) (200 mL) at 0 °C. The aqueous layer was extracted with EtOAc (2 × 200 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbonitrile (9.0 g, 74.33%) as an off-white solid. LC-MS (M+H) + : =251.

[0239] Step 2: 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid [ka]

[0240] A solution of 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbonitrile (9 g, 34.047 mmol, 1 equiv., 95%) and NaOH (5.73 g, 136.188 mmol, 4 equiv., 95%) in EtOH (150 mL) / HO (50 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 2 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (10:1) to give 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid (8.2 g, 89.16%) as an off-white solid. LC-MS (M+H)+ : =270.

[0241] Step 3: 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbohydrazide [ka]

[0242] To a stirred solution of 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid (8.2 g, 28.838 mmol, 1 equiv, 95%) and EtN (7.07 g, 66.327 mmol, 2.3 equiv, 95%) in DCM (200 mL) was added 2-methylpropyl carbonochloridate (4.56 g, 31.722 mmol, 1.1 equiv, 95%) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 h. To the above mixture was added NHNH.HO (6.08 g, 115.352 mmol, 4 equiv, 95%) dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbohydrazide (6.42 g, 70.51%) as an off-white oil. LC-MS (M+H) + : =284.

[0243] Step 4: 5-(1-(5-bromopyridin-3-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol [ka]

[0244] A solution of 1-(5-bromopyridin-3-yl)-3-methylcyclobutane-1-carbohydrazide (6.42 g, 21.463 mmol, 1 equiv, 95%) and isothiocyanatomethane (4.96 g, 64.389 mmol, 3 equiv, 95%) in THF (200 mL) / HO (100 mL) was stirred at 65° C. for 1 h under a nitrogen atmosphere. To the above mixture was added NaOH (6.33 g, 150.241 mmol, 7 equiv, 95%) at room temperature. The resulting mixture was further stirred at 75° C. overnight. The mixture was acidified to pH 2 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give 5-[1-(5-bromopyridin-3-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazole-3-thiol (6.03 g, 82.81%) as an off-white oil. LC-MS (M+H) + : =339.

[0245] Step 5: 3-Bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine [ka]

[0246] A solution of 5-[1-(5-bromopyridin-3-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazole-3-thiol (6.03 g, 16.885 mmol, 1 equiv., 95%) and HO (30%) (8.23 g, 72.606 mmol, 4.3 equiv., 30%) in DCM (150 mL) / AcOH (20 mL) was stirred under a nitrogen atmosphere at 0 °C for 3 h. The mixture was basified to pH 8 with NaOH. The resulting mixture was extracted with EtOAc (2 × 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give 3-bromo-5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridine (5.0 g, 86.75%) as an off-white oil. LC-MS (M+H) + : =307.

[0247] Step 6: N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-1,1-diphenylmethanimine [ka]

[0248] To a stirred solution of 3-bromo-5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridine (5.0 g, 15.462 mmol, 1 equiv., 95%) and α-phenylbenzenemethanimine (5.90 g, 30.924 mmol, 2 equiv., 95%) in dioxane (250 mL) was added Pd(dba) (0.75 g, 0.773 mmol, 0.05 equiv., 95%), BINAP (1.01 g, 1.546 mmol, 0.1 equiv., 95%), and CsCO (15.91 g, 46.386 mmol, 3 equiv., 95%) under a nitrogen atmosphere at 100 °C. The crude product was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): Column, Kinetex EVO C18, 21.2 x 250 mm, 5 μm; Mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (15% ACN over 8 min - max. 45%); Detector, UV. The product was obtained as alpha. This gave N-{5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}-1,1-diphenylmethanimine (4.9 g, 69.99%) as an off-white solid. LC-MS (M+H) + : =408.CHIRALPAK IC-3 4.6×50mm 3um, mobile phase: Hex(0.1%DEA):EtOH=50:50, flow rate: 1.0mL / min, RT=6.27min.

[0249] Step 7: 5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-amine [ka]

[0250] A solution of 1,1-diphenyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}methanimine (400 mg, 0.932 mmol, 1 equiv., 95%) and HCl (3399.78 mg, 2.796 mmol, 3 equiv., 3%) in THF (10 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The mixture was basified to pH 8 with NaOH. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (210 mg, 83.30%) as an off-white solid. LC-MS (M+H) + : =244.

[0251] Compound synthesis Compound A1: N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0252] Step 1: Methyl 6-vinylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0253] To a solution of methyl 6-bromoimidazo[1,2-a]pyridine-8-carboxylate (10 g, 39.21 mmol) in dioxane (90 mL) / HO (30 mL) was added potassium ethenyl(trifluoro)boranide (13.1 g, 98.01 mmol), KCO (16.3 g, 117.6 mmol), and Pd(dppf)Cl (2.87 g, 3.92 mmol) at 15 °C. The mixture was stirred at 100 °C for 16 h. The reaction was filtered and concentrated. The crude was purified by column chromatography (SiO, petroleum ether / EtOAc = 5:1 to 0:1) to give the product (6.3 g, 79% yield). MS: M / e 203 (M+H). + ; 1 H NMR (400 MHz, CDCl3-d) δ = 8.24 (s, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 6.67 (dd, J = 12.0, 16.0 Hz, 1H), 5.85 (d, J = 16.0 Hz, 1H), 5.42 (d, J = 12.0Hz, 1H), 4.09 (s, 3H)ppm.

[0254] Step 2: Methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0255] To a solution of methyl 6-vinylimidazo[1,2-a]pyridine-8-carboxylate (6.3 g, 31.1 mmol) in dioxane (125 mL) / HO (25 mL) was added KOsOHO (1.15 g, 3.1 mmol) and NaIO (26.6 g, 124.6 mmol) in small portions. The mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into HO (100 mL) and extracted with EA (25 mL × 3). The combined organic phase was concentrated to give the crude product. Purification by column chromatography (SiO, petroleum ether / EtOAc = 5:1 to 0:1) gave the product (4 g, 62% yield). MS: M / e 205 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ = 9.99 (s, 1H), 9.54 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 3.92 (s, 3H)ppm.

[0256] Step 3: (S)-Methyl 6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0257] To a solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (1 g, 4.9 mmol), (S)-3-methylpiperidine hydrochloride (1.3 g, 9.8 mmol), and EtN (495 mg, 4.9 mmol) in DCM (10 mL) was added NaBH(OAc) (2.1 g, 9.8 mmol) in one portion. The mixture was stirred at 25 °C for 16 h. The reaction was concentrated. The crude material was purified by column chromatography (SiO, petroleum ether / EtOAc = 1:1 to 0:1) to give the product (700 mg, 49% yield). MS: M / e 288 (M+H). +; 1H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 3.90 (s, 3H) 3.51 - 3.43 (m, 2H), 1.96 - 1.87 (m, 1H), 1.96 - 1.86 (m, 1H), 1.71 - 1.40 (m, 6H), 0.92 - 0.78 (m, 4H)ppm.

[0258] Step 4: (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0259] A solution of (S)-ethyl 6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (1.3 g, 4.3 mmol) in NH3 / MeOH (15 mL, 3 M) was heated to 70 °C in a sealed tube. The mixture was stirred at 70 °C for 15 h. The mixture was concentrated to give the crude product (650 mg, crude), which was used in the next step without purification. MS: M / e 273 (M+H) + .

[0260] Step 5: (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0261] A solution of LiOH.HO (105 mg, 2.5 mmol, in 1 mL of water) was added to a solution of methyl (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (150 mg, 0.52 mmol) in MeOH (5 mL) and stirred overnight at room temperature. The reaction mixture was evaporated, dissolved in water (3 mL), acidified to pH = 5-6 with 1 M HCl solution, and lyophilized to give the product (142 mg, crude). MS: M / e 274 (M+1). +

[0262] Step 6: N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0263] To a solution of (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (140 mg, 0.51 mmol) and 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (123 mg, 0.51 mmol) in DMF (12 mL) was added HATU (233 mg, 0.61 mmol) and DIEA (129 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours, then quenched with water (5 mL), extracted with DCM (15 mL), and washed with brine (15 mL). The organic layer was dried, concentrated, and purified by CombiFlash® (DCM:MeOH=7%) to give the product (98 mg, 39%). 1H NMR (400 MHz, CD3OD) δ 8.76 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.24 (s, 2H), 3.41-3.35 (m, 2H), 3.32 (s, 3H), 2.97-2.93 (m, 2H), 2.78-2.57 (m, 4H), 2.48 (t, MS:M / e 498 (M+1) +

[0264] Compound A2: N-(3-((1r,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0265] Step A: 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline [ka]

[0266] To a solution of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (500 mg, 1.63 mmol) in ACN (10 mL) / NH3HO (20 mL) was added Cu2O (117 mg, 0.818 mmol) under N2. The reaction mixture was stirred at 100 °C for 12 h. After completion, the mixture was filtered and the filtrate was collected and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with methanol (20%) in dichloromethane to give the title compound (400 mg, crude). MS: M / e 243 (M+H) + .

[0267] Step B: (S)—N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0268] To a solution of (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (30 mg, 0.109 mmol), 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (70 mg, crude), DIEA (28 mg, 0.217 mmol) in DMF (2 mL) was added HATU (50 mg, 0.132 mmol). The reaction mixture was stirred at 25 °C for 1 h. After completion, the reaction mixture was quenched with water (10 mL) and extracted with DCM / MeOH (10 / 1, 3 × 30 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1 to 10 / 1) to give the title compound (40 mg, impure). MS: M / e 498 (M+H) + .

[0269] Step C: N-(3-((1r,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0270] (S)—N-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide was repurified by preparative HPLC (NH 3 HO conditions) to give N-(3-((1r,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide (3 mg). 1 H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.77 (s, 1H), 7.72 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 3.60 (s, 2H), 3.32 (s, 3H), 3.13 (t, J = 9.4 Hz, 2H), 2.93-2.83 (m, 2H), 2.55-2.48 (m, 1H), 2.38 (t, J = 10.2 Hz, 2H), 2.00 (t, J = 10.0 Hz, 1H), 1.77-1.56 (m, 5H), 1.17 (d, J = 6.4 Hz, 3H), 0.97-0.84 (m, 4H); MS:M / e 498 (M+H) + .

[0271] Compound A3: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0272] To a solution of 2-((1s,3s)-3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (30 mg, 91 μmol) in dioxane (3 mL), (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide (25 mg, 91 μmol), tBuXPhospd-G3 (7.9 mg, 9.1 μmol), tBuXPhos (3.8 mg, 9.1 μmol), and t-BuONa (18 mg, 182 μmol) were added under N at 15° C. The mixture was stirred at 80° C. for 12 h under N. The mixture was concentrated to give a residue which was purified by preparative HPLC (water (NH4HCO3)-ACN, C18 100 x 25 mm x 5 um) to give the title product (3.7 mg). 1 H NMR (400 MHz, CDCl3-d) δ 12.5 (s, 1H), 8.12 (s, 1H), 7.99-8.02 (m, 2H) 7.94 (s, 1H) 7.76 (s, 1H) 7.67-7.69 (d, J = 8 Hz, 1H) 7.37-7.41 (t, J = 8 Hz, 1H) 7.04-7.06 (d, J = 8 Hz, 1H) 4.27 (br s, 2H) 3.39 (s, 2H) 3.23-2.26 (m, 3H) 3.00-3.10 (m, 3H) 2.82-2.90 (m, 3H) 2.57-2.58 (m, 3H) 2.49 (m, 1H) 1.85-1.90 (m, 3H) 0.94-0.95 (m, 4H)ppm; MS:M / e 523 (M+H) + .

[0273] Compound A4: N-(3-((1r,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0274] To a solution of (1r,3r)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (10 mg, 0.04 mmol) and (S)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (12 mg, 0.04 mmol) in DMF (2 mL) was added HATU (23 mg, 0.06 mmol) and DIEA (26 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, then quenched with water (3 mL) and extracted with DCM (10 mL). The organic layer was dried, concentrated, and purified by preparative HPLC (mobile phase A: 0.1% FA-HO, mobile phase B: 0.1% FA-ACN) to give the product (5 mg, 24%). 1H NMR (400 MHz, CD3OD) δ 8.68 (s, 1H), 8.23 ​​(s, 1H), 8.16 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 3.85 (s, 2H), 3.42 (s, 2H), 3.23-3.15 (m, 1H), 3.10-3.05 (m, 1H), 3.01 (s, 3H), 2.99 (s, 2H), 2.81 (s, 3H), 2.29 (t, J=12.0 Hz, 1H), 2.00 (t, J=12.0 Hz, 1H), 1.79-1.62 (m, 4H), 1.05-0.96 (m, 1H), 0.91 (d, J=8.0 Hz, 3H) ppm.MS:M / e 523 (M+1) +

[0275] Compound A5: N-(3-((1s,3S)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((R)-2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0276] Step A: Methyl (R)-6-((2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0277] To a solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (100 mg, 0.49 mmol), (R)-2-methylmorpholine (98 mg, 0.97 mmol), and AcOH (40 μL) in DCM (10 mL) was added NaBH(OAc) (207 mg, 0.976 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction was quenched with aqueous NaHCO (20 mL), extracted with DCM / MeOH (10 / 1, 3 × 30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the title compound (85 mg, 63%). MS: M / e 290 (M+H) + .

[0278] Step B: (R)-6-((2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0279] To a solution of methyl (R)-6-((2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (20 mg, 0.069 mmol) in MeOH (5 mL) / HO (0.5 mL) was added LiOH HO (15 mg, 0.357 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the solvent was concentrated in vacuo. The residue was diluted with water, neutralized with 2N HCl, and freed dried to give the title compound (20 mg, crude). MS: M / e 276 (M+H) + .

[0280] Step C: N-(3-((1s,3S)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((R)-2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0281] To a solution of (R)-6-((2-methylmorpholino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (20 mg, crude), 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (19 mg, 0.071 mmol), and DIEA (18 mg, 0.139 mmol) in DMF (3 mL) was added HATU (40 mg, 0.105 mmol). The reaction mixture was stirred at 25 °C for 1 h. After completion, the reaction was quenched with aqueous NH4Cl (10 mL), extracted with DCM / MeOH (10 / 1, 3 × 30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (15 mg, 36%). 1 H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 7.96 (s, 2H), 7.72 (s, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 3.84 (d, J = 11.6 Hz, 1H), 3.72-3.64 (m, 2H), 3.63 (s, 2H), 3.34 (s, 3H), 3.09-3.00 (m, 2H), 3.00-2.90 (m, 1H), 2.90-2.72 (m, 4H), 2.67 (d, J = 5.8 Hz, 2H), 2.29-2.19 (m, 1H), 1.93 (t, J = 10.8 Hz, 1H), 1.11 (d, J = 6.4 Hz, 3H) ppm.MS:M / e 525 (M+H) + .

[0282] Compound A6: 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide [ka] Step 1: 6-Bromo-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0283] To a solution of methyl 6-bromoimidazo[1,2-a]pyridine-8-carboxylate (5 g, 18.622 mmol, 1 equiv.) in THF was added sodium hydride (60% in oil, 1.2 g) at 0° C. The mixture was stirred for 15 min. Selectfluor (20 g, 53.633 mmol, 2.88 equiv.) was added portionwise at 0° C., and the mixture was allowed to warm to room temperature and stirred for 10 min. The resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 40 h. The reaction mixture was quenched with water (40 mL) at 0° C. and extracted with EA (3×130 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (100:0-0:100) to give methyl 6-bromo-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (3.8 g). MS:M / e 273 (M+1) + .

[0284] Step 2: 6-ethenyl-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0285] To a solution of methyl 6-bromo-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (3.7 g, 12.710 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.2 g, 25.906 mmol, 2.04 equiv.) in dioxane (40 mL) and HO (4 mL) was added KCO (3.70 g, 25.420 mmol, 2.00 equiv.) and Pd(dppf)ClCHCl (1 g, 1.166 mmol, 0.09 equiv.). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (30 mL). The resulting mixture was filtered, and the filter cake was washed with DCM (4 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:9) to give methyl 6-ethenyl-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (1.9 g). MS: M / e 221 (M+1) + .

[0286] Step 3: Methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0287] To a stirred mixture of methyl 6-ethenyl-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (1.8 g, 7.823 mmol, 1 equiv.) in dioxane and HO (12 mL), KOsO.2HO (303 mg, 0.781 mmol, 0.10 equiv.) and NaIO (3.6 g, 15.99 mmol, 2.04 equiv.) were added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with room temperature water (8 mL). The precipitated solid was collected by filtration and washed with water (3 × 1 mL). The aqueous layer was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (1.2 g). MS: M / e 241 (M+1) +

[0288] Step 4: Methyl 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate [ka] To a stirred mixture of methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (800 mg, 3.266 mmol, 1 eq.) and (3S)-3-methylpiperidine hydrochloride (932 mg, 6.528 mmol, 2.00 eq., 95%) in DCE was added STAB (1.1 g, 4.931 mmol, 1.51 eq.) in small portions at room temperature. The mixture was stirred at 40°C for an additional 3 hours. The mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 30%-60% gradient in 30 min; detector, UV 220 nm. This gave methyl 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate and methyl (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (670 mg, 61.00%). MS: M / e 306 (M+1). + .

[0289] Step 5: 3-Fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0290] To a stirred solution of methyl 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate and methyl (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (630 mg, 1.873 mmol, 1 equiv., 90.8%) in THF and HO (1.5 mL, 99%), LiOH (142 mg, 5.633 mmol, 3.01 equiv., 95%) was added. The resulting mixture was stirred at room temperature for 15 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH = 3 with HCl (1 M). The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0%; detector, UV 220 nm. This gave 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (350 mg, 59.45%), MS: M / e 292 (M+1). + , and (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (170 mg, 26.94%), MS: M / e 292 (M+1) + .

[0291] Step 6: 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0292] A mixture of 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (39 mg, 0.124 mmol, 1.23 equiv.) and EDC.HCl (31 mg, 0.154 mmol, 1.52 equiv.) and HOBT (22 mg, 0.155 mmol, 1.53 equiv.) and EtN (44 mg, 0.413 mmol, 4.08 equiv.) in DMF was stirred for 5 minutes. 3-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]aniline (30 mg, 0.101 mmol, 1.00 equiv.) in DMF was added dropwise at room temperature. The resulting mixture was stirred at 40 °C for an additional 3 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 0%-80% gradient in 20 min; detector, UV 220 nm. The crude product (50 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (49% ACN, up to 79% in 8 min), to give 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide (22.1 mg, 41.56%). MS: M / e 516 (M+1). + ; 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.46 - 7.38 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 3.55 (s, 2H), 3.20 (s, 3H), 2.87 - 2.73 (m, 4H), 2.55 (d, J = 6.8 Hz, 3H), 1.98 - 1.88 (m, 1H), 1.68 - 1.56 (m, 4H), 1.47 (d, J = 12.3 Hz, 1H), 1.09 (d, J = 5.0 Hz, 3H), 0.82 (d, J = 5.9 Hz, 4H)ppm.

[0293] Compound A7: (S)-2-fluoro-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0294] To a stirred mixture of (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (42 mg, 0.125 mmol, 1.22 equiv.), HOBT (22 mg, 0.155 mmol, 1.51 equiv.), and EDC.HCl (31 mg, 0.154 mmol, 1.50 equiv.) in DMF, EtN (44 mg, 0.413 mmol, 4.04 equiv.) was added dropwise at room temperature. After 5 minutes, 3-{3-[(4-methyl-1,2,4-triazol-3-yl)methyl]oxetan-3-yl}aniline (25 mg, 0.102 mmol, 1.00 equiv.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 40 °C for an additional 3 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 0% to 95% gradient in 25 min; detector, UV 220 nm. The crude product (50 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (31% ACN, up to 61% in 8 min). This gave (S)-2-fluoro-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide (24 mg, 44.95%). MS: M / e 518 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.40 - 7.35 (m, 1H), 7.35 - 7.28 (m, 1H), 6.74 - 6.67 (m, 1H), 4.96 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 3.59 - 3.47 (m, 4H), 2.94 (s, 3H), 2.76 (t, J = 10.1 Hz, 2H), 1.97 - 1.87 (m, 1H), 1.70 - 1.55 (m, 4H), 1.54 - 1.40 (m, 1H), 0.92 - 0.78 (m, 4H)ppm.

[0295] Compound A8: 2-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka] Step 1: (S)-2-Fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0296] To a stirred solution of methyl 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate and methyl (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylate (630 mg, 1.873 mmol, 1 equiv., 90.8%) in THF and HO (1.5 mL, 99%), LiOH (142 mg, 5.633 mmol, 3.01 equiv., 95%) was added. The resulting mixture was stirred at room temperature for 15 hours. The resulting mixture was concentrated in vacuo. The residue was acidified to pH 3 with HCl (1 M). The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0%; detector, UV 220 nm. This gave 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (350 mg, 59.45%), MS: M / e 292 (M+H). + , and (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (170 mg, 26.94%), MS: M / e 292 (M+H) + .

[0297] Step 2: 2-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0298] To a stirred mixture of (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (38 mg, 0.113 mmol, 1.19 equiv.), HOBT (21 mg, 0.148 mmol, 1.56 equiv.), and EDC.HCl (29 mg, 0.144 mmol, 1.52 equiv.) in DMF, EtN (41 mg, 0.385 mmol, 4.07 equiv.) was added dropwise at room temperature. After 5 minutes, 3-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]aniline (28 mg, 0.095 mmol, 1.00 equiv.) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 40 °C for an additional 3 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 0%-95% gradient in 25 min; detector, UV 220 nm. The crude product (45 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (49% ACN, up to 79% in 8 min), to give 2-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide (18.9 mg). MS: M / e 516 (M+H). + . 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 2.0 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.19 - 7.12 (m, 1H), 3.52 (d, J = 3.1 Hz, 2H), 3.20 (s, 3H), 2.89 - 2.71 (m, 4H), 2.55 (d, J = 6.7 Hz, 3H), 1.92 (t, J = 10.9 Hz, 1H), 1.63 - 1.58 (m, 4H), 1.48 (d, J = 12.4 Hz, 1H), 1.09 (d, J = 4.7 Hz, 3H), 0.82 (d, J = 5.7 Hz, 4H)ppm.

[0299] Compound A9: 6-((cyclohexylamino)methyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0300] Step 1: N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-vinylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0301] To a solution of lithium 6-vinylimidazo[1,2-a]pyridine-8-carboxylate (2.12 g, 8.19 mmol) in DMF (20 mL) was added DIEA (2.12 g, 16.37 mmol) and HATU (3.74 g, 9.82 mmol). The mixture was stirred at room temperature for 5 minutes, and then 3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline (2 g, 8.19 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was poured into water (10 mL) and extracted with DCM (30 mL, 10 mL). The combined organic phase was filtered and concentrated to give a residue, which was purified by column chromatography (SiO, EA / MeOH=100 / 1-0 / 1) to give the product (2.1 mg, 61.89% yield). MS:M / e 415 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.31 (s, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.33 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.69 (dd, J = 4.0, 8.0 Hz, 1H), 7.38 (t, J = 4.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.0, 16.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.96 (d, J = 20.0 Hz, 1H), 5.43 (d, J = 8.0 Hz, 1H), 4.96 (d, J = 4.0 Hz, 2H), 4.88 (d, J = 4.0 Hz, 2H), 3.52 (s, 2H), 2.94 (s, 3H)ppm.

[0302] Step 2: 6-formyl-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0303] To a mixture of N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)-6-vinylimidazo[1,2-a]pyridine-8-carboxamide (2.10 g, 5.07 mmol) and KOsO·HO (186.68 mg, 506.67 μmol) in dioxane (40 mL) and HO (8 mL) was added NaIO (4.33 g, 20.27 mmol) in one portion under N at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by the addition of 30 mL of HO at 20 °C and then extracted with DCM (60 mL, 20 mL). The combined organic layers were washed with brine (60 mL, 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (1.7 g, crude) which was used in the next step without purification. MS: M / e 417 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.15 (s, 1H), 10.06 (s, 1H), 9.58 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.20 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.78 - 7.67 (m, 1H), 7.41 - 7.24 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 4.96 (d, J = 8.0 Hz, 2H), 4.88 (d, J = 4.0 Hz, 2H), 3.57 (s, 2H), 2.95 (s, 3H)ppm.

[0304] Step 3: 6-((cyclohexylamino)methyl)-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0305] To a solution of 6-formyl-N-(3-(3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (20 mg, 48.03 μmol) and cyclohexanamine (4.76 mg, 48.03 μmol) in DCM (1 mL), NaBH(OAc) (20.36 mg, 96.05 μmol) was added. The mixture was stirred at room temperature under N for 16 h. The mixture was poured into water (1 mL) and extracted with DCM (2 mL, 1 mL). The combined organic phase was washed with brine (1 mL), dried over Na2SO4, filtered, and concentrated to give a residue which was purified by preparative HPLC (column = Waters Xbridge BEH C18 (100 x 30 mm x 10 um); mobile phase = water (NH4HCO3)-ACN, B% = 20%-50%; 10 min) to give the product (4.42 mg, 34.6% yield). MS: M / e 500 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.40 (s, 1H), 8.74 (s, 1H), 8.24 - 8.10 (m, 3H), 7.78 (s, 1H), 7.75 - 7.67 (m, 1H), 7.40 - 7.27 (m, 2H), 6.69 (br d, J = 7.6 Hz, 1H), 4.96 (br d, J = 6.0 Hz, 2H), 4.87 (br d, J = 6.0 Hz, 2H), 3.82 (s, 2H), 3.52 (s, 3H), 2.94 (s, 3H), 2.40 (br s, 1H), 1.87 (br d, J = 11.6 Hz, 2H), 1.66 (br s, 2H), 1.61 - 1.39 (m, 1H), 1.28 - 0.98 (m, 5H)ppm.

[0306] Compound A10: 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0307] Step 1: 2-Bromopropanal [ka]

[0308] To a stirred solution of propionaldehyde (18 g, 294.421 mmol, 1 equiv.) in 1,4-dioxane and DCM (3 mL) was added Br (15.88 mL, 294.421 mmol, 1 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was quenched by the addition of saturated NaHCO (aq.) (50 mL) at 0 °C. The aqueous layer was extracted with CHCl (2 × 50 mL). The resulting mixture was concentrated under reduced pressure. This afforded 2-bromopropanal (30 g, 44.63%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0309] Step 2: Methyl 6-bromo-3-methylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0310] To a stirred solution of methyl 2-amino-5-bromopyridine-3-carboxylate (2 g, 8.223 mmol, 1 equiv.) in EtOH was added 2-bromopropanal (7.51 g, 32.892 mmol, 4 equiv.) at room temperature. The resulting mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (10:1) to give methyl 6-bromo-3-methylimidazo[1,2-a]pyridine-8-carboxylate (2 g). MS: M / e 269 (M+H). + .

[0311] Step 3: Methyl 6-ethenyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0312] To a stirred mixture of methyl 6-bromo-3-methylimidazo[1,2-a]pyridine-8-carboxylate (2 g, 6.927 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.25 g, 13.854 mmol, 2 equiv.) in 1,4-dioxane and HO (1 mL, 55.509 mmol, 8.01 equiv., 100%), KCO (2.02 g, 13.854 mmol, 2 equiv.) and Pd(dppf)ClCHCl (0.59 g, 0.693 mmol, 0.1 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give methyl 6-ethenyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate (1.3 g). MS: M / e 217 (M+H). + .

[0313] Step 4: Methyl 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0314] To a stirred solution of methyl 6-ethenyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate (1.3 g, 5.609 mmol, 1 equiv.) in dioxane and HO (5 mL, 277.546 mmol, 49.48 equiv.), KOsO.2HO (217.54 mg, 0.561 mmol, 0.1 equiv.) and NaIO (2525.72 g, 11218.075 mmol, 2000.00 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with MeOH (10 mL). The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give methyl 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate (400 mg, 31.24%). MS: M / e 219 (M+H) + .

[0315] Step 5: Methyl 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0316] To a stirred mixture of methyl 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate (400 mg, 1.752 mmol, 1 equiv.) and (3S)-3-methylpiperidine hydrochloride (500.42 mg, 3.505 mmol, 2.00 equiv.) in DCE was added STAB (586.43 mg, 2.628 mmol, 1.5 equiv.) in small portions at room temperature. The resulting mixture was stirred at 40° C. for an additional 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (9:1) to give methyl 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate (200 mg). MS: M / e 302 (M+H). + .

[0317] Step 6: 3-Methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0318] To a stirred solution of methyl 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylate (200 mg, 0.516 mmol, 1 equiv., 77.7%) in THF and HO (2 mL, 111.019 mmol, 215.31 equiv., 100%), LiOH (52.00 mg, 2.064 mmol, 4 equiv., 95%) was added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH (10 mmol / L NH4HCO3) in water, 30%-40% gradient in 10 min; detector, UV 254 nm. This gave 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (90 mg, 60.68%). MS: M / e 288 (M+H) + .

[0319] Step 7: 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0320] To a stirred mixture of 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (20.66 mg, 0.072 mmol, 1.2 equiv, 99.9%) and EDCI (20.53 mg, 0.102 mmol, 1.7 equiv, 95%) and HOBT (13.62 mg, 0.096 mmol, 1.6 equiv, 95%) and TEA (27.41 mg, 0.258 mmol, 4.3 equiv, 95%) in DMF was stirred for 5 min. To the above mixture was added 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (20 mg, 0.060 mmol, 1.00 equiv., 80%) in DMF at room temperature. The resulting mixture was stirred at 40 °C for an additional 3 h. The mixture was allowed to cool to room temperature. The crude product was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (35% ACN, up to 65% in 8 min). This gave 3-methyl-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide (13.7 mg, 42.27%). MS: M / e 537 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.80 - 7.75 (m, 1H), 7.66 (d, J = 8.0, 2.0 Hz, 1H), 7.59 (s, 1H), 7.48 - 7.40 (m, 1H), 7.20 (d, J = 7.6, 1.9 Hz, 1H), 3.56 (s, 2H), 3.22 (s, 3H), 2.94 - 2.66 (m, 9H), 2.53 (s, 3H), 1.98 - 1.87 (m, 1H), 1.70 - 1.54 (m, 4H), 1.54 - 1.41 (m, 1H), 0.93 - 0.79 (m, 4H)ppm.

[0321] Compound A11: 5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0322] Step 1: 5-Ethenylpyrazolo[1,5-a]pyridine [ka]

[0323] To a solution of 5-bromopyrazolo[1,5-a]pyridine (4 g, 19.286 mmol, 1 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.64 g, 23.143 mmol, 1.20 equiv.) in dioxane (40 mL) and HO (4 mL) was added KCO (5.61 g, 38.572 mmol, 2.00 equiv.) and Pd(dppf)Cl.CHCl (1.98 g, 2.314 mmol, 0.12 equiv.). After stirring at 100 °C under a nitrogen atmosphere for 5 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / PE (1:3) to give 5-ethenylpyrazolo[1,5-a]pyridine (1.6 g, 35.45%). MS: M / e 145 (M+H) + .

[0324] Step 2: 7-Bromo-5-ethenylpyrazolo[1,5-a]pyridine [ka]

[0325] To a stirred solution of 5-ethenylpyrazolo[1,5-a]pyridine (150 mg, 0.678 mmol, 1 equiv.) in THF was added dropwise a (1 M) solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (0.81 mL, 0.814 mmol, 1.2 equiv.) in THF at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere. To the mixture was added dropwise 1,2-dibromo-1,1,2,2-tetrachloroethane (349 mg, 1.018 mmol, 1.50 equiv.) in 20 mL of THF at −78° C. The resulting mixture was stirred at room temperature for an additional 4 hours. The reaction was quenched by the addition of saturated NH4Cl (aq.) (20 mL) at 0° C. Water (100 mL) was added to the resulting mixture. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (4:1) to give 7-bromo-5-ethenylpyrazolo[1,5-a]pyridine (1.5 g, 89.71%). MS: M / e 223 (M+H) + .

[0326] Step 3: 5-Ethenylpyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0327] A solution of 7-bromo-5-ethenylpyrazolo[1,5-a]pyridine (1.5 g, 6.133 mmol, 1 equiv, 91.2%), Zn (42 mg, 0.610 mmol, 0.10 equiv, 95%), Zn(CN) (1.21 g, 9.813 mmol, 1.6 equiv, 95%), XantPhos (1.49 g, 2.453 mmol, 0.40 equiv, 95%), and Pd(OAc) (290 mg, 1.227 mmol, 0.20 equiv, 95%) in DMA was stirred at 110 °C under a nitrogen atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to give 5-ethenylpyrazolo[1,5-a]pyridine-7-carbonitrile (650 mg, 61.90%). MS: M / e 170 (M+H) + .

[0328] Step 4: 5-Formylpyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0329] To a stirred solution of 5-ethenylpyrazolo[1,5-a]pyridine-7-carbonitrile (650 mg, 3.796 mmol, 1 equiv.) in dioxane (6 mL, 69.407 mmol, 18.29 equiv.) and HO (6 mL, 326.395 mmol, 85.99 equiv.), KOsO.2HO (147 mg, 0.379 mmol, 0.10 equiv.) and NaIO (1.70 g, 7.551 mmol, 1.99 equiv.) were added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 3 h. HO (20 mL) was added to the mixture. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. This gave 5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (600 mg, 85.70%). MS: M / e 172 (M+H) + .

[0330] Step 5: 5-{[(3S)-3-Methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0331] A solution of 5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (600 mg, 3.253 mmol, 1 equiv., 92.8%) and (3S)-3-methylpiperidine hydrochloride (687 mg, 4.812 mmol, 1.48 equiv.) in DCE was stirred at 70° C. for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. STAB (1.08 g, 4.847 mmol, 1.49 equiv., 95%) was added to the reaction mixture in small portions at room temperature. The resulting mixture was stirred at 40° C. for an additional 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 40%-50% gradient in 5 minutes; detector, UV 220 nm. This gave 5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (600 mg, 64.98%). MS: M / e 255 (M+H) + .

[0332] Step 6: 5-{[(3S)-3-Methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid [ka]

[0333] To a stirred solution of 5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (600 mg, 2.114 mmol, 1 equiv, 89.6%) in EtOH (5 mL, 84.345 mmol, 39.90 equiv, 98%) and HO (5 mL, 271.996 mmol, 128.68 equiv, 98%), NaOH (359 mg, 8.527 mmol, 4.03 equiv, 95%) was added portionwise at 0 °C. The resulting mixture was stirred at 85 °C overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% HCl) in water, 15%-30% gradient in 5 min; detector, UV 220 nm. This gave 5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (400 mg, 67.36%). MS: M / e 274 (M+H). + .

[0334] Step 7: 5-{[(3S)-3-Methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0335] A solution of 5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (28 mg, 0.100 mmol, 1.11 equiv., 97.3%), EDCI (27 mg, 0.134 mmol, 1.49 equiv., 95%), HOBT (19 mg, 0.134 mmol, 1.49 equiv., 95%), and TEA (0.06 mL, 0.450 mmol, 5 equiv., 98%) in DMF was stirred at room temperature for 5 minutes. 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (30 mg, 0.090 mmol, 1.00 equiv., 80%) in DMF was added dropwise at room temperature. The resulting mixture was further stirred at 40° C. overnight. The mixture was allowed to cool to room temperature and purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 45%-50% gradient in 2 min; detector, UV 220 nm. The crude product was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (42% ACN, up to 72% in 8 min), to give 5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide (12.9 mg, 27.16%). MS: M / e 523 (M+H). + ; 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.86 (s, 1H), 7.81 - 7.73 (m, 2H), 7.73 - 7.65 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 3.55 (s, 2H), 3.22 (s, 3H), 2.94 - 2.68 (m, 9H), 1.94 (t, J = 11.0 Hz, 1H), 1.75 - 1.39 (m, 5H), 1.73-1.41 (m, 4H)ppm.

[0336] Compound A12: 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0337] A mixture of 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}imidazo[1,2-a]pyridine-8-carboxylic acid (23 mg, 0.073 mmol, 1.11 equivalents) and HOBT (15 mg, 0.105 mmol, 1.60 equivalents), EDCI (20 mg, 0.099 mmol, 1.51 equivalents), and EtN (29 mg, 0.272 mmol, 4.14 equivalents) in DMF was stirred for 5 minutes, and 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (22 mg, 0.066 mmol, 1.00 equivalents) was added dropwise at room temperature. The resulting mixture was stirred at 40 ° C. for 14 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 0%-95% gradient in 15 min; detector, UV 254 nm. The crude product (55 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (40% ACN, up to 70% in 68 min), to give 3-fluoro-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}imidazo[1,2-a]pyridine-8-carboxamide (21.6 mg, 58.56%). MS: M / e 541 (M+H). + ; 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.50 - 7.39 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.52 (s, 2H), 3.22 (s, 3H), 2.95 - 2.66 (m, 9H), 1.98 - 1.85 (m, 1H), 1.72 - 1.41 (m, 5H), 0.94 - 0.77 (m, 4H)ppm.

[0338] Compound A13: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-fluoro-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0339] A mixture of (S)-2-fluoro-6-((3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (22 mg, 0.065 mmol, 1.09 equiv., 86.5%) and HOBT (13 mg, 0.091 mmol, 1.53 equiv., 95%), EDCI (19 mg, 0.094 mmol, 1.57 equiv., 95%), and EtN (26 mg, 0.244 mmol, 4.08 equiv., 95%) in DMF was stirred for 5 minutes, and 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (20 mg, 0.060 mmol, 1.00 equiv., 80%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 0%-95% gradient in 15 min; detector, UV 254 nm. The crude product (30 mg) was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (42% ACN, up to 72% in 8 min), to give N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-fluoro-6-(((S)-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide (7.6 mg, 23.30%). MS: M / e 541 (M+H). + ; 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.50 - 7.39 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.52 (s, 2H), 3.22 (s, 3H), 2.95 - 2.66 (m, 9H), 1.98 - 1.85 (m, 1H), 1.72 - 1.41 (m, 5H), 0.94 - 0.77 (m, 4H)ppm.

[0340] Compound A14: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka]

[0341] Step A: Methyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate [ka]

[0342] To a solution of methyl 6-amino-4-bromopicolinate (200 mg, 0.87 mmol) in MeOH (4 mL) was added DMF-DMA (0.23 mL, 1.73 mmol). The reaction mixture was stirred at 70° C. for 12 hours. The reaction was cooled to room temperature, and hydroxylamine hydrochloride (120 mg, 1.73 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in THF (5 mL), and TFAA (0.36 mL, 2.60 mmol) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. After completion, the reaction was quenched with aqueous NaHCO (30 mL), extracted with DCM / MeOH (10 / 1, 3×50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (130 mg, 58%). 1 H NMR (400 MHz, CDCl3-d) δ 8.48 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 4.10 (s, 3H).MS:M / e 256, 258 (M+H) + .

[0343] Step B: 7-Bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid [ka]

[0344] To a solution of methyl 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylate (50 mg, 0.195 mmol) in MeOH (5 mL) / HO (0.5 mL) was added LiOH HO (41 mg, 0.976 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the solvent was concentrated in vacuo. The residue was diluted with water, neutralized with 2N HCl, and free-dried to give the title compound (50 mg, crude). MS: M / e 242, 244 (M+H) + .

[0345] Step C: 7-Bromo-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka]

[0346] To a solution of 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid (50 mg, crude), 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (52 mg, 0.195 mmol), and DIEA (50 mg, 0.387 mmol) in DMF (2 mL) was added HATU (110 mg, 0.289 mmol). The reaction mixture was stirred at 25 °C for 1 h. After completion, the reaction was quenched with aqueous NH4Cl (10 mL), extracted with DCM (3 × 30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give the title compound (80 mg, 83%). MS: M / e 491, 493 (M+H) + .

[0347] Step D: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-(((S)-3-methylpiperidin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka]

[0348] To a solution of 7-bromo-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide (80 mg, 0.163 mmol), potassium (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate (55 mg, 0.252 mmol) in THF / HO (2 mL) / HO (0.2 mL) was added Pd(OAc) (4 mg, 0.017 mmol), Xphos (16 mg, 0.034 mmol), and CsCO (106 mg, 0.325 mmol) under N. The reaction mixture was stirred at 100 °C for 12 h. After completion, the reaction was quenched with water (10 mL), extracted with EtOAc (3×20 mL), dried over Na SO and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (25 mg, 29%). 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 6.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 3.72 (s, 2H), 3.34 (s, 3H), 3.08-3.00 (m, 2H), 2.99-2.78 (m, 5H), 2.67 (d, J = 5.7 Hz, 2H), 2.05 (t, J = 9.6 Hz, 1H), 1.80-1.57 (m, 5H), 1.00-0.90 (m, 1H), 0.88 (d, J = 5.2 Hz, 3H)ppm.MS:M / e 524 (M+H) + .

[0349] Compound A15: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0350] Step 1: Methyl 6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0351] To a mixture of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (227.38 mg, 1.11 mmol) and (1-methylcyclopentyl)methanamine hydrochloride (250 mg, 1.67 mmol) in DCM (3 mL) was added TEA (169.04 mg, 1.67 mmol) and NaBH(OAc) (472.04 mg, 2.23 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (5 mL) and extracted with DCM (15 mL). The combined organic phase was washed with brine (5 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 - 0 / 1) to give the product (245 mg, 73% yield). MS: M / e 302 (M +1). +

[0352] Step 2: Methyl 6-(((tert-butoxycarbonyl)((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0353] To a solution of methyl 6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (245 mg, 812.90 μmol) and (Boc)O (354.83 mg, 1.63 mmol) in DCM (3 mL) was added TEA (246.78 mg, 2.44 mmol). The mixture was stirred at room temperature for 2 h. The mixture was poured into water (5 mL) and extracted with DCM (10 mL, 5 mL). The combined organic phases were washed with brine (5 mL), dried over NaSO, filtered, and concentrated to give a residue which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 1-0 / 1) to give the product (290 mg, 88.85% yield). MS: M / e 402 (M +1) + .

[0354] Step 3: 6-(((tert-butoxycarbonyl)((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0355] To a solution of methyl 6-(((tert-butoxycarbonyl)((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (290 mg, 722 μmol) in MeOH / THF / HO (1 mL / 1 mL / 1 mL) was added LiOH.HO (36.37 mg, 867 μmol). The mixture was stirred at room temperature for 12 hours. The mixture was filtered and concentrated to give the crude product (280 mg, crude), which was used in the next step without purification. MS: M / e 388 (M +1) + .

[0356] Step 4: tert-butyl ((8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl)((1-methylcyclopentyl)methyl)carbamate [ka]

[0357] To a solution of 6-(((tert-butoxycarbonyl)((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (200 mg, 438.74 μmol) in DMF (2 mL) was added DIEA (113.41 mg, 877.48 μmol) and HATU (200.19 mg, 526.49 μmol). The mixture was stirred at room temperature for 5 minutes, after which 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (117.29 mg, 438.74 μmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was poured into water (2 mL) and extracted with DCM (4 mL, 2 mL). The combined organic phase was filtered and concentrated to give a residue which was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); mobile phase = water (NH4HCO3)-ACN, B% = 25%-55%; 8 min) to give the product (150 mg, 53.69% yield). MS: M / e 637 (M +1) + .

[0358] Step 5: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0359] To a solution of tert-butyl ((8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl)((1-methylcyclopentyl)methyl)carbamate (70 mg, 109.9 μmol) in DCM (1 mL) was added TMSI (109.98 mg, 549.63 μmol) at 0° C. The mixture was poured into water (2 mL) and extracted with DCM (6 mL). The combined organic phase was filtered and concentrated to give a residue which was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); mobile phase = water (NH4HCO3)-ACN, B% = 25%-55%; 8 min) to give the product (15.73 mg, 26.7% yield). MS: M / e 537 (M +1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.43 (s, 1H), 8.71 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.16 - 8.13 (m, 1H), 7.79 (s, 1H), 7.76 - 7.73 (m, 1H), 7.72 - 7.67 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.20 (br d, J = 7.6 Hz, 1H), 3.79 (s, 2H), 3.22 (s, 3H), 2.89 (br s, 2H), 2.76 (d, J = 6.4 Hz, 3H), 2.73 - 2.69 (m, 2H), 2.35 (s, 2H), 2.17 (br s, 1H), 1.60 - 1.43 (m, 6H), 1.28 - 1.19 (m, 2H), 0.96 (s, 3H).

[0360] Compound A16: N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0361] Step 1: Methyl 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0362] To a solution of 1-methylcyclopropan-1-amine hydrochloride (1.58 g, 14.69 mmol) in DCE (6 mL) was added TEA (743.37 mg, 7.35 mmol), AcOH (882.33 mg, 14.69 mmol), and methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (1 g, 4.90 mmol). The mixture was stirred at 25 °C for 5 min. Then, NaBH(OAc) (3.11 g, 14.69 mmol) was added at 25 °C, and the resulting mixture was stirred at 25 °C for 16 h. The aqueous phase was adjusted to pH 9–10 with saturated aqueous NaCO and then extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1-0 / 1) to give the product (520 mg, yield 37.67%). MS: M / e 260 (M +1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.68 (s, 1H), 8.01 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 3.89 (s, 3H), 3.76 (s, 2H), 1.25 (s, 3H), 0.50 (br s, 2H), 0.31 (br s, 2H) ppm.

[0363] Step 2: Lithium 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0364] To a solution of methyl 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (280 mg, 1.08 mmol) in HO (1 mL), THF (1 mL), MeOH (1 mL) was added LiOH.HO (54.38 mg, 1.30 mmol). The mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the product (150 mg, crude). MS: M / e 246 (M +1) + .

[0365] Step 3: N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0366] To a stirred solution of 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (151.93 mg, 626.97 μmol) and lithium 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (210 mg, 626.97 μmol) in pyridine (5 mL) was added T3P (1.20 g, 1.88 mmol, 50 wt % in ethyl acetate) at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by the addition of 10 mL of HO at 20 °C and then extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the product (182.57 mg, 31.01% yield). MS: M / e 470 (M +1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 12.40 (br s, 1H), 8.70 (br s, 1H), 8.30 (br s, 1H), 8.11 (br d, J = 8.0 Hz, 2H), 7.75 (br d, J = 8.0 Hz, 2H), 7.66 (br d, J = 4.0 Hz, 1H), 7.41 (br s, 1H), 7.15 (br s, 1H), 3.81 (br s, 2H), 3.19 (br s, 3H), 2.83 (br s, 2H), 2.54 (br s, 3H), 1.26 (br s, 3H), 1.08 (br s, 3H), 0.51 (br s, 2H), 0.32 (br s, 2H) ppm. Compound A17: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0367] Step 1: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0368] A mixture of lithium 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (0.2 g, 740.42 μmol), 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (197.93 mg, 740.42 μmol), HATU (337.84 mg, 888.50 μmol), and DIEA (287.08 mg, 2.22 mmol) in DMF (4 mL) was stirred at 25° C. for 2 hours. The mixture was poured into 50 mL of HO, extracted with dichloromethane (30 mL x 2), washed with brine (20 mL x 2), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NHHCO)-ACN]; B%: 20%-50%, 8 min) to give the product (0.045 g, 13.23% yield). MS: M / e 460 (M +1) + . 1H NMR (400 MHz, DMSO-d6) δ = 11.94 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H), 8.32 (s, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.69 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.22 (br d, J = 8.0 Hz, 1H), 5.59 (t, J = 4.0 Hz, 1H), 4.63 (d, J = 4.0 Hz, 2H), 3.22 (s, 3H), 2.91 - 2.85 (m, 2H), 2.80 -2.65(m, 6H).

[0369] Step 2: 6-(chloromethyl)-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxamide & (8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate [ka]

[0370] To a mixture of N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxamide (60 mg, 130.58 μmol) and TEA (105.71 mg, 1.04 mmol) in DMF (2 mL) was added MsCl (74.79 mg, 652.92 μmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 h. The mixture was poured into 5 mL of HO, extracted with dichloromethane (5 mL × 5), washed with brine (5 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 6-(chloromethyl)-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxamide and (8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (60 mg, crude), which was used in the next step without purification. MS:M / e 478 (M +1) +

[0371] Step 3: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0372] To a solution of 1-methylcyclopropan-1-amine hydrochloride (54.02 mg, 502.18 μmol) in DMF (2 mL) was added TEA (76.22 mg, 753.26 μmol). The mixture was stirred at 25° C. for 5 minutes. Then, pyridine, the product of Step 2 (60 mg), and CsCO (81.81 mg, 251.09 μmol) were added at 25° C. The resulting mixture was stirred at 25° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. This was purified by preparative HPLC (Column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; Mobile phase: [water (NHHCO)-ACN]; B%: 30%-50%, 8 min) to give the product (13.53 mg, 21.03% yield). MS: M / e 513 (M +1). + . 1 H NMR (400 MHz, DMSO-d6) δ = 11.94 (s, 1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.73 (s, 1H), 7.68 (br d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.20 (br d, J = 8.0 Hz, 1H), 3.85 (s, 2H), 3.21 (s, 3H), 2.94 - 2.82 (m, 2H), 2.82 - 2.66 (m, 5H), 2.55 (br d, J = 4.0 Hz, 1H), 1.27 (s, 3H), 0.59 - 0.46 (m, 2H), 0.38 - 0.27 (m, 2H) ppm.

[0373] Compound A18: 6-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0374] Step 1: Methyl 6-((isobutylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0375] To a solution of 2-methylpropan-1-amine (214.92 mg, 2.94 mmol) and methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (200 mg, 979.52 mmol) in DCE (3 mL) was added NaBH(OAc) (622.80 mg, 2.94 mmol) and CHCOOH (176.46 mg, 2.94 mmol). The mixture was stirred at 25 °C for 16 h. Then, NaBH(OAc) (415.20 mg, 1.96 mmol) and CHCOOH (58.82 mg, 979.52 mmol) were added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 12 h. The aqueous phase was adjusted to pH 9–10 with saturated aqueous NaCO solution and then extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (SiO2, ethyl acetate:methanol = 4:1, Rf = 0.5) to give the product (110 mg, 42.97% yield). MS: M / e 262 (M +1) + .

[0376] Step 2: Lithium 6-((isobutylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0377] To a solution of methyl 6-((isobutylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (110 mg, 420.94 umol) in HO (1 mL), MeOH (1 mL), and THF (1 mL) was added LiOH.HO (21.20 mg, 505.13 umol). The mixture was stirred at 25 °C for 2 h. The mixture was filtered and concentrated to give the crude product (120 mg, crude), which was used in the next step without purification. MS: M / e 248 (M +1) + .

[0378] Step 3: 6-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0379] To a stirred solution of 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (91.87 mg, 379.11 μmol) and lithium 6-((isobutylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (120 mg, 379.11 μmol) in pyridine (5 mL) was added T3P (723.75 mg, 1.14 mmol, 50% purity) at 25 °C. The resulting mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by the addition of 10 mL of HO at 20 °C and then extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 25 mm x 5 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give the product (34.13 mg, 19.09% yield). MS: M / e 472 (M +1) + . 1H NMR (400 MHz, DMSO-d6) δ = 12.41 (s, 1H), 8.72 (d, J = 1.2 Hz, 1H), 8.30 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.74 (t, J = 1.6 Hz, 1H), 7.67 (dd, J = 1.2, 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.19 - 7.12 (m, 1H), 3.76 (s, 2H), 3.20 (s, 3H), 2.84 (br d, J = 4.0 Hz, 2H), 2.55 (br d, J = 8.0 Hz, 3H), 2.32 (d, J = 8.0 Hz, 2H), 1.69 (quind, J = 8.0, 12.0 Hz, 1H), 1.09 (d, J = 4.0 Hz, 3H), 0.87 (d, J = 8.0 Hz, 6H);

[0380] Compound A19: 6-((((S)-1-cyclopropylethyl)amino)methyl)-3-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0381] Step 1: Methyl 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0382] To a solution of methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (2 g, 9.00 mmol) in EtOH (20 mL) was added NaBH (374.62 mg, 9.90 mmol) at 0 °C. The mixture was stirred at 0-20 °C for 2 h. The reaction mixture was quenched by adding 20 mL of HO at 25 °C and extracted with 60 mL of EA (20 mL × 3). The combined organic layers were washed with 10 mL of aqueous NaCl solution (5 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate / dichloromethane = 5 / 1 / 1 to 1 / 1 / 1) to give the product (800 mg, 33.69% yield). MS: M / e 225 (M +1). + .

[0383] Step 2: Lithium 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0384] To a solution of methyl 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (800 mg, 3.57 mmol) in THF (3 mL), MeOH (3 mL), and HO (3 mL) was added LiOH.HO (179.69 mg, 4.28 mmol). The mixture was stirred at 20 °C for 2 h. The yellow solid was recrystallized from water and dried by lyophilization to give a yellow solid (800 mg, crude), which was used in the next step without purification. MS: M / e 211 (M +1). + .

[0385] Step 3: 3-Fluoro-6-(hydroxymethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0386] To a solution of lithium 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (1.2 g, 5.00 mmol, 90% purity) and 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (1.21 g, 5.00 mmol) in DMF (15 mL) was added HATU (2.09 g, 5.50 mmol) and DIEA (1.29 g, 10.00 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by the addition of 10 mL of HO at 25 °C, then diluted with 20 mL of EtOAc and extracted with 30 mL of EtOAc. The combined organic layers were washed with 2 mL of saturated brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Column: Waters Xbridge BEH C18 250 x 70 mm x 10 um; Mobile phase: [water (NHHCO)-ACN]; B%: 25%-55%, 18 min) to give the product (0.333 g, 15.34% yield). MS: M / e 435 (M +1) + .

[0387] Step 4: (3-fluoro-8-((3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate and 6-(chloromethyl)-3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0388] To a mixture of the product of Step 3 (333 mg, 766.46 μmol), DMF (3 mL), and TEA (620.46 mg, 6.13 mmol) was added MsCl (438.99 mg, 3.83 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The mixture was poured into 20 mL of HO, extracted with dichloromethane (20 mL × 2), washed with brine (10 mL × 2), and the combined organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 6-(chloromethyl)-3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (300 mg, crude). MS:M / e 453 (M +1) + .

[0389] Step 5: 6-((((S)-1-cyclopropylethyl)amino)methyl)-3-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0390] To a solution of (S)-1-cyclopropylethan-1-amine hydrochloride (107.40 mg, 883.16 μmol) in DMF (1 mL) was added TEA (134.05 mg, 1.32 mmol). The mixture was stirred at 25° C. for 5 minutes. Then, 6-(chloromethyl)-3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (100 mg, 220.79 μmol) and CsCO (143.88 mg, 441.58 μmol) were added at 25° C. The resulting mixture was stirred at 25° C. for 2 hours. The mixture was filtered, and the filtrate was concentrated in vacuo, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-50%, 8 min) to give the product (21.25 mg, 19.19% yield). MS: M / e 502 (M +1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 11.94 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), 7.66 (br d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.16 (br d, J = 8.0 Hz, 1H), 3.97 - 3.79 (m, 2H), 3.19 (s, 3H), 2.84 (br d, J = 4.0Hz, 2H), 2.55 (br d, J = 8.0 Hz, 3H), 1.91 (br dd, J = 4.0, 8.0 Hz, 1H), 1.17 - 1.03 (m, 6H), 0.78 - 0.59 (m, 1H), 0.50 - 0.40 (m, 1H), 0.34 (tt, J = 4.0, 8.7 Hz, 1H), 0.20 (qd, J = 4.0, 8.0 Hz, 1H), 0.02 (qd, J = 4.0, 8.0 Hz, 1H).

[0391] Compound A20: 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0392] Step 1: 7-Bromo-5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine [ka]

[0393] To a stirred solution of 7-bromo-5-ethenylpyrazolo[1,5-a]pyridine (700 mg, 3.078 mmol, 1 equiv., 98.1%) in MeCN was added Selectfluor (2.4 g, 6.436 mmol, 2.09 equiv., 95%) in small portions at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.2 h. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (12:1) to give 7-bromo-5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine (290 mg, 38.10%). MS: M / e 241 (M+1) + . Step 2: 5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0394] To a 10 mL sealed tube was added 7-bromo-5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine (280 mg, 1.132 mmol, 1 equiv., 97.5%), Zn(CN) (224 mg, 1.812 mmol, 1.60 equiv., 95%), Zn (8 mg, 0.116 mmol, 0.10 equiv., 95%), XantPhos (276 mg, 0.453 mmol, 0.40 equiv., 95%), Pd(OAc) (54 mg, 0.228 mmol, 0.20 equiv., 95%), and DMA (2 mL, 99%) at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE / EA (9:1) to give 5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (185 mg, 87.19%). MS: M / e 188 (M+1) + .

[0395] Step 3: 3-Fluoro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0396] To a stirred solution of 5-ethenyl-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (180 mg, 0.961 mmol, 1 equiv, 99.9%) in dioxane (3 mL, 99%) and HO (3 mL, 99%), KOsO.2HO (38 mg, 0.098 mmol, 0.10 equiv, 95%) and NaIO (433 mg, 1.923 mmol, 2.00 equiv, 95%) were added. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (1 × 15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 3-fluoro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (170 mg, 90.09%). MS: M / e 190 (M+1) + .

[0397] Step 4: 3-Fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0398] To a 20 mL sealed tube, 3-fluoro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (160 mg, 0.815 mmol, 1 equiv, 96.3%), (3S)-3-methylpiperidine hydrochloride (233 mg, 1.632 mmol, 2.00 equiv, 95%), and DCE (5 mL, 99%) were added at room temperature. The resulting mixture was stirred at 70° C. for 4 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. To the above mixture, STAB (275 mg, 1.233 mmol, 1.51 equiv, 95%) was added in small portions at room temperature. The resulting mixture was stirred at 40° C. for an additional 3 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (97:3) to give 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (145 mg, 63.79%). MS: M / e 273 (M+1). + .

[0399] Step 5: 3-Fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid [ka]

[0400] To a stirred solution of 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (130 mg, 0.466 mmol, 1 equiv., 97.6%) in EtOH and HO was added NaOH (60 mg, 1.425 mmol, 3.06 equiv., 95%) in small portions. The resulting mixture was stirred at 80 °C for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The mixture was acidified to pH 3 with HCl (1 M). The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 10%-40% gradient in 20 min; detector, UV 220 nm. This gave 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (115 mg, 83.88%). MS: M / e 292 (M+1) + .

[0401] Step 6: 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0402] To a stirred mixture of 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (35 mg, 0.119 mmol, 1 equivalent, 99.0%) and HOBT (26 mg, 0.183 mmol, 1.54 equivalent, 95%), EDCI (36.00 mg, 0.178 mmol, 1.5 equivalent, 95%), EtN (38 mg, 0.357 mmol, 3.00 equivalent, 95%) in DMF, 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (22 mg, 0.081 mmol, 0.68 equivalent, 98.3%) was added. The resulting mixture was stirred at 40 ° C. for 8 hours. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.H2O) in water, 10%-95% gradient in 15 min; detector, UV 254 nm. The crude product (45 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (45% ACN, up to 75% in 8 min), to give 3-fluoro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide (20.6 mg, 30.63%). MS: M / e 541 (M+1). + . 1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.37 - 8.29 (m, 2H), 7.81 (s, 1H), 7.74 - 7.62 (m, 3H), 7.48 - 7.41 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.55 (s, 2H), 3.22 (s, 3H), 2.95 - 2.65 (m, 9H), 2.02 - 1.87 (m, 1H), 1.75 - 1.39 (m, 5H), 0.98 - 0.70 (m, 4H).

[0403] Compound A21: 3-chloro-N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0404] Step 1: 7-Bromo-3-chloro-5-vinylpyrazolo[1,5-a]pyridine [ka]

[0405] A solution of 7-bromo-5-ethenylpyrazolo[1,5-a]pyridine (900 mg, 3.833 mmol, 1 equiv., 95%) and NCS (1077.47 mg, 7.666 mmol, 2 equiv., 95%) in DMF was stirred at 50° C. under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to give 7-bromo-3-chloro-5-ethenylpyrazolo[1,5-a]pyridine (820 mg, 78.92%). MS: M / e 257 (M+1). + .

[0406] Step 2: 3-Chloro-5-vinylpyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0407] To a stirred solution of 7-bromo-3-chloro-5-ethenylpyrazolo[1,5-a]pyridine (800 mg, 2.951 mmol, 1 equiv., 95%) and Zn(CN) (583.63 mg, 4.722 mmol, 1.6 equiv., 95%) in 1,4-dioxane, Zn (223.42 mg, 3.246 mmol, 1.1 equiv., 95%), XantPhos (719.02 mg, 1.180 mmol, 0.4 equiv., 95%), and Pd(OAc) (139.49 mg, 0.590 mmol, 0.2 equiv., 95%) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 110 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (5:1) to give 3-chloro-5-ethenylpyrazolo[1,5-a]pyridine-7-carbonitrile (490 mg, 77.46%). MS: M / e 204 (M+1) + . Step 3: 3-Chloro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0408] To a stirred solution of 3-chloro-5-ethenylpyrazolo[1,5-a]pyridine-7-carbonitrile (440 mg, 2.053 mmol, 1 equiv., 95%) and KOsO.2HO (79.61 mg, 0.205 mmol, 0.1 equiv., 95%) in 1,4-dioxane / HO was added NaIO (924.34 mg, 4.106 mmol, 2 equiv., 95%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 h. The aqueous layer was extracted with EtOAc (2 × 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (3:1) to give 3-chloro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (330 mg, 74.28%). MS:M / e 206 (M+1) + .

[0409] Step 4: (S)-3-chloro-5-((3-methylpiperidin-1-yl)methyl)pyrazolo[1,5-a]pyridine-7-carbonitrile [ka]

[0410] A solution of 3-chloro-5-formylpyrazolo[1,5-a]pyridine-7-carbonitrile (310 mg, 1.432 mmol, 1 equiv., 95%) and (3S)-3-methylpiperidine (299.07 mg, 2.864 mmol, 2 equiv., 95%) in DCE was stirred at 70° C. for 2 hours under a nitrogen atmosphere. To the above mixture, STAB (479.34 mg, 2.148 mmol, 1.5 equiv., 95%) was added at room temperature. The resulting mixture was stirred at 40° C. for an additional 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-chloro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (280 mg, 64.31%). MS:M / e 289 (M+1) + .

[0411] Step 5: (S)-3-chloro-5-((3-methylpiperidin-1-yl)methyl)pyrazolo[1,5-a]pyridine-7-carboxylic acid [ka]

[0412] A solution of 3-chloro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carbonitrile (260 mg, 0.855 mmol, 1 equiv., 95%) and NaOH (108.03 mg, 2.565 mmol, 3 equiv., 95%) in EtOH / HO was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This afforded 3-chloro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (170 mg, 58.12%). MS:M / e 308 (M+1) + .

[0413] Step 6: 3-chloro-N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(((S)-3-methylpiperidin-1-yl)methyl)pyrazolo[1,5-a]pyridine-7-carboxamide [ka]

[0414] To a stirred solution of 3-chloro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}pyrazolo[1,5-a]pyridine-7-carboxylic acid (34.54 mg, 0.106 mmol, 1.5 equiv, 95%) and EtN (22.71 mg, 0.213 mmol, 3 equiv, 95%) in DMF, EDCI (21.51 mg, 0.106 mmol, 1.5 equiv, 95%) and HOBT (15.16 mg, 0.106 mmol, 1.5 equiv, 95%) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 20 minutes. To the above mixture, 2-[(1s,3s)-3-(3-aminophenyl)-3-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]acetonitrile (20 mg, 0.071 mmol, 1.00 equiv., 95%) was added at room temperature. The resulting mixture was stirred at 40 °C for an additional 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (55% ACN, up to 70% in 8 min). This gave 3-chloro-5-{[(3S)-3-methylpiperidin-1-yl]methyl}-N-{3-[(1s,3s)-3-(cyanomethyl)-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl}pyrazolo[1,5-a]pyridine-7-carboxamide (7 mg, 17.22%). MS: M / e 557 (M+1) + .. 1 H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.34 (m, 2H), 7.76 - 7.64 (m, 4H), 7.43 (m, 1H), 7.26 - 7.16 (m, 1H), 3.57 (s, 2H), 3.20 (s, 3H), 2.90 - 2.66 (m, 9H), 1.94 (m, 1H), 1.70 - 1.39 (m, 5H), 0.81 (m, 4H).

[0415] Compound A22: 6-(((cyclobutylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0416] Step 1: 6-Formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0417] To a solution of 6-formylimidazo[1,2-a]pyridine-8-carboxylic acid (250 mg, 1.31 mmol) in DMF (1 mL) was added HATU (599.87 mg, 1.58 mmol) and DIEA (339.84 mg, 2.63 mmol). After the addition, the mixture was stirred at this temperature for 5 minutes, and then 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (318.58 mg, 1.31 mmol) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched by adding 5 mL of HO at 20 °C and then extracted with 30 mL of DCM (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give the product (350 mg, 64.23% yield). MS: M / e 415 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ = 12.15 (s, 1H), 10.05 (s, 1H), 9.56 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.75 - 7.70 (m, 1H), 7.68 (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.20 (s, 3H), 2.84 (br d, J = 4.0 Hz, 2H), 2.55 (br d, J = 8.0 Hz, 3H), 1.09 (br d, J = 8.0 Hz, 3H).

[0418] Step 2: 6-(((cyclobutylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0419] To a solution of cyclobutylmethanamine hydrochloride (88.02 mg, 723.84 μmol) in DCE (2 mL) was added TEA (73.24 mg, 723.84 μmol). After the addition, the mixture was stirred at this temperature for 5 minutes, after which 6-formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (150 mg, 361.92 μmol) and NaBH(OAc) (191.76 mg, 904.79 μmol) were added dropwise at 25° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min) to give the product (85.53 mg, 48.87% yield). MS: M / e 484 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 12.41 (s, 1H), 8.71 (s, 1H), 8.30 (s, 1H), 8.14 (dd, J = 1.2, 4.0 Hz, 2H), 7.78 (d, J = 1.2 Hz, 1H), 7.73 (s, 1H), 7.70 - 7.62 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.15 (br d, J = 8.0 Hz, 1H), 3.76 (s, 2H), 3.25 - 3.15 (m, 4H), 2.84 (br d, J = 4.0 Hz, 2H), 2.61 - 2.52 (m, 5H), 2.41 (td, J = 8.0, 16.0 Hz, 1H), 2.05 - 1.91 (m, 2H), 1.86 - 1.72 (m, 2H), 1.71 - 1.58 (m, 2H), 1.09 (br d, J = 8.0 Hz, 3H).

[0420] Compound A23: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-3,3-difluorocyclopentyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0421] Step 1: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0422] To a solution of 6-formylimidazo[1,2-a]pyridine-8-carboxylic acid (88.91 mg, 467.59 μmol) in DMF (2 mL) was added HATU (213.35 mg, 561.11 μmol), DIEA (120.86 mg, 935.18 μmol), and 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (100 mg, 374.07 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of HO (5 mL) at 20 °C and then extracted with 30 mL of DCM (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give the product (50 mg, 24.33% yield). MS: M / e 440 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ = 12.16 (s, 1H), 10.06 (s, 1H), 9.57 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.32 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 3.22 (s, 3H), 2.90 (br d, J = 4.0 Hz, 2H), 2.76 (br d, J = 8.0 Hz, 3H), 2.71 (br s, 2H).

[0423] Step 2: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-3,3-difluorocyclopentyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0424] A solution of N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (60 mg, 0.14 mmol), (S)-3,3-difluorocyclopentan-1-amine hydrochloride (43 mg, 0.28 mmol), and TEA (28 mg, 0.28 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. Then, it was cooled in an ice bath, and NaBH(OAc) (57 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, after which additional NaBH(OAc) (57 mg, 0.28 mmol) was added, and it was continued stirring overnight. The reaction mixture was added with water (3 mL), basified with NaHCO3 solution to pH = 7-8, and extracted with DCM (6 mL). The organic layer was dried, concentrated, and purified by preparative TLC (DCM:MeOH = 8:1) to give the product (25 mg, 34%). 1 H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.33 (s, 1H), 8.23 ​​(s, 1H), 7.96 (d, J=8.0 Hz, 2H), 7.72 (s, 1H), 7.71 (d, J=4.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 3.90 (s, 2H), 3.40-3.35 (m, 1H), 3.34 (s, 3H), 3.05-3.02 (m, 2H), 2.96-2.86 (m, 3H), 2.67 (d, J=8.0 Hz, 2H), 2.53-2.42 (m, 1H), 2.26-2.16 (m, 2H), 2.06-1.92 (m, 2H), 1.75-1.68 (m, 1H). ppm.MS:M / e 545 (M+1) +

[0425] Compound A24: N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0426] Step A: 6-Formylimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0427] To a solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (300 mg, 1.47 mmol) in MeOH (10 mL) / HO (1 mL) was added LiOH HO (312 mg, 7.43 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the mixture was filtered and the solid was collected, washed with MeOH (10 mL), and dried to give the title compound (240 mg, 86%). MS: M / e 191 (M+H) + .

[0428] Step B: N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0429] To a solution of 6-formylimidazo[1,2-a]pyridine-8-carboxylic acid (240 mg, 1.26 mmol), (1r,3r)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutane-1-carbonitrile (330 mg, 1.23 mmol), and DIEA (320 mg, 2.48 mmol) in DMF (5 mL) was added HATU (720 mg, 1.89 mmol). The reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction was quenched with aqueous NH4Cl (20 mL), extracted with DCM (3 × 30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol (5%) in dichloromethane to give the title compound (300 mg, 54%). MS: M / e 440. (M+H) + .

[0430] Step C: N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0431] To a solution of (1-methylcyclopentyl)methanamine hydrochloride (51.08 mg, 341.31 μmol) in DCE (2 mL) was added TEA (34.54 mg, 341.31 μmol). After the addition, the mixture was stirred at this temperature for 5 minutes, and then N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (100 mg, 227.54 μmol) and NaBH(OAc) (144.68 mg, 682.63 μmol) were added dropwise at 25° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); mobile phase: water (NH4HCO3)-ACN, B% = 40%-70%; 8 min) to give the product (32.13 mg, 26.31% yield). MS: M / e 537 (M+1) +; 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.72 (d, J = 1.2 Hz, 1H), 8.21 - 8.16 (m, 2H), 8.15 (d, J = 1.2 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.69 (dd, J = 1.2, 8.1 Hz, 1H), 7.41 (t, J = 2.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 3.80 (s, 2H), 3.31 (s, 2H), 3.29 - 3.21 (m, 1H), 2.93 - 2.83 (m, 4H), 2.80 (s, 3H), 2.36 (s, 2H), 2.30 - 2.14 (m, 1H), 1.63 - 1.41 (m, 6H), 1.31 - 1.18 (m, 2H), 0.97 (s, 3H) ppm.

[0432] Compound A25: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0433] To a solution of N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (30 mg, 68.26 μmol), 1-methylcyclopropan-1-amine hydrochloride (10.36 mg, 102.39 μmol), and trimethylamine (7.28 mg, 102.39 μmol) in DCM (1 mL) was added NaBH(OAc) (43.40 mg, 204.79 μmol). The mixture was stirred at room temperature under N for 16 hours. The mixture was poured into water (1 mL) and extracted with DCM (2 mL, 1 mL). The combined organic phase was washed with brine (1 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by preparative HPLC (water (NH4HCO3)-CAN, Waters Xbridge BEH C18 100 x 30 mm x 10 um, B% = 50%-80%; 8 min) to give the product (14.55 mg). MS: M / e 495 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 8.13 (m, 2H), 7.78 (d, J = 1.6 Hz, 1H), 7.76 - 7.75 (m, 1H), 7.69 (d, J = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.20 (d, J = 8 Hz, 1H), 3.83 (s, 2H), 3.23 (s, 3H), 2.96 - 2.82 (m, 2H), 2.80 - 2.69 (m, 5H), 1.28 (s, 3H), 0.55 - 0.49 (m, 2H), 0.36 - 0.31 (m, 2H) ppm.

[0434] Compound A26: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((cyclopentylmethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0435] Compound A26 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (14.68 mg). MS: M / e 523 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 4 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.79 (s, 2H), 3.40 - 3.35 (m, 1H), 3.30 - 3.25 (m, 1H), 3.23 (s, 3H), 2.96 - 2.82 (m, 2H), 2.80 - 2.69 (m, 5H), 2.45 - 2.43 (m, 1H), 2.05 - 1.94 (m, 1H), 1.76 - 1.65 (m, 2H), 1.59 - 1.43 (m, 4H), 1.23 - 1.12 (m, 2H) ppm.

[0436] Compound A27: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-1-cyclopropylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0437] Compound A27 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (2.79 mg, 12.05% yield). MS: M / e 509 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.74 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 8.16 - 8.13 (m, 1H), 7.79 - 7.78 (m, 1H), 7.75 (s, 1H), 7.72 - 7.67 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 3.92 - 3.81 (m, 2H), 3.22 (s, 3H), 2.93 - 2.85 (m, 2H), 2.82 - 2.67 (m, 5H), 2.40 - 2.25 (m, 1H), 1.96 - 1.86 (m, 1H), 1.13 - 1.08 (m, 3H), 0.75 - 0.64 (m, 1H), 0.53 - 0.39 (m, 1H), 0.39 - 0.30 (m, 1H), 0.25 - 0.19 (m, 1H), 0.08 - -0.03 (m, 1H) ppm.

[0438] Compound A28: 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0439] Step A: Methyl 3-chloro-6-formylimidazo[1,2-a]pyridine-8-carboxylate [ka] To a solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (500 mg, 2.45 mmol) in DMF (5 mL) was added NCS (330 mg, 2.48 mmol). The reaction mixture was stirred at 80° C. for 4 h. After completion, the reaction was quenched with water (10 mL), extracted with DCM (3×30 mL), dried over NaSO, and concentrated in vacuo. The crude product (600 mg) was obtained and used in the next step without purification. MS: M / e 239. 241 (M+H) + .

[0440] Step B: 3-Chloro-6-formylimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0441] To a solution of methyl 3-chloro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (600 mg, crude) in MeOH (20 mL) was added LiOH HO (510 mg, 12.14 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, the reaction mixture was filtered, and the solid was collected and concentrated in vacuo. The product (480 mg) was obtained and used in the next step without purification. MS: M / e 225, 227 (M+H) + .

[0442] Step C: 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0443] To a solution of 3-chloro-6-formylimidazo[1,2-a]pyridine-8-carboxylic acid (480 mg, 2.14 mmol) and 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (570 mg, 2.13 mmol) in DMF (5 mL) was added HATU (1.2 g, 3.15 mmol) and DIEA (550 mg, 4.26 mmol). The reaction mixture was stirred at 25 °C for 1 h. After completion, the reaction was quenched with aqueous NH4Cl (20 mL), extracted with DCM (3 × 30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol (10%) in dichloromethane to give the title compound (600 mg, 59%). MS: M / e 474, 476 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.78 - 11.72 (m, 1H), 10.18 (s, 1H), 9.47 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.74 - 7.68 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.22 (s, 3H), 2.93 - 2.86 (m, 2H), 2.76 (d, J = 6.8 Hz, 3H), 2.70 (s, 2H) ppm.

[0444] Step D: 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0445] To a mixture of 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (15 mg, 31.65 μmol), (1-methylcyclopentyl)methanamine hydrochloride (7.11 mg, 48.48 μmol), and TEA (4.8 mg, 47.48 μmol) in DCM (1 mL) was added NaBH(OAc) (16.77 mg, 79.13 μmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was poured into water (2 mL) and extracted with DCM (9 mL, 3 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to give a residue which was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); mobile phase = water (NH4HCO3)-ACN, B% = 25%-55%; 8 min) to give the product (5.19 mg, 28.71% yield). MS: M / e 571 (M+1) +; 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 2.76 (d, J = 6.8 Hz, 2H), 2.70 (s, 2H), 2.36 (s, 2H), 1.62 - 1.43 (m, 6H), 1.29 - 1.20 (m, 2H), 0.97 (s, 3H) ppm.

[0446] Compound A29: 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0447] Step 1: Methyl 6-bromo-3-chloroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0448] To a solution of methyl 6-bromoimidazo[1,2-a]pyridine-8-carboxylate (10 g, 39.21 mmol) in CHCN (100 mL) was added NCS (6.28 g, 47.05 mmol). The resulting mixture was stirred at 60 °C for 16 h, then quenched with HO and extracted with DCM (300 mL, 100 mL). The combined organic layers were washed with brine (100 mL) and dried over NaSO. After filtration and concentration, the resulting residue was purified by column chromatography (SiO, PE:EA = 50 / 1, 1 / 1) to give the product (11 g, 96.91% yield). MS: M / e 291 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 1.6 Hz, 1H), 8.12 - 8.08 (m, 1H), 7.99 (s, 1H), 3.94 (s, 3H) ppm.

[0449] Step 2: Methyl 3-chloro-6-vinylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0450] A mixture of methyl 6-bromo-3-chloroimidazo[1,2-a]pyridine-8-carboxylate (11 g, 37.99 mmol), potassium trifluoro(vinyl)borate (15.27 g, 113.98 mmol), Pd(dppf)Cl (2.78 g, 3.8 mmol), and KCO (15.75 g, 113.98 mmol) in dioxane (90 mL) and HO (30 mL) was degassed and purged with N three times, then the mixture was stirred under a N atmosphere at 100 °C for 12 h. HO (50 mL) was added to the reaction mixture at 20 °C, followed by extraction with DCM (120 mL, 40 mL). The combined organic layers were washed with brine (60 mL, 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=100 / 1-0 / 1) to give the product (5.5 g, yield 61.18%). MS: M / e 237 (M+1) + ;1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 6.99 - 6.85 (m, 1H), 6.00 (d, J = 17.6 Hz, 1H), 5.43 (d, J = 10.8 Hz, 1H), 4.01 - 3.87 (m, 3H) ppm.

[0451] Step 3: Lithium 3-chloro-6-vinylimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0452] To a solution of methyl 3-chloro-6-vinylimidazo[1,2-a]pyridine-8-carboxylate (1 g, 4.23 mmol) in MeOH / THF / HO (5 mL / 5 mL / 5 mL) was added LiOH.HO (212.78 mg, 5.07 mmol). The mixture was stirred at 30 °C for 1 h. The mixture was filtered and concentrated to give the crude product (1 g, crude), which was used in the next step without purification. MS: M / e 223 (M+1) +; 1 H NMR (400 MHz, DMSO-d6) δ 8.48 - 8.44 (m, 1H), 8.23 ​​- 8.16 (m, 1H), 7.68 (s, 1H), 6.98 - 6.87 (m, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H) ppm

[0453] Step 4: 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-vinylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0454] To a solution of lithium 3-chloro-6-vinylimidazo[1,2-a]pyridine-8-carboxylate (250 mg, 929.73 μmol) in DMF (3 mL) was added DIEA (240.23 mg, 1.86 mmol) and HATU (424.21 mg, 1.12 mmol). The mixture was stirred at room temperature for 5 minutes, and then (1r,3r)-3-(3-aminophenyl)-3-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutanecarbonitrile (248.54 mg, 929.73 μmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was poured into water (1 mL) and extracted with DCM (2 mL, 1 mL). The combined organic phase was filtered and concentrated to give a residue, and the resulting residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=100 / 1-0 / 1) to give the product (230 mg, yield 52.41%). MS: M / e 472 (M+1) + 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.70 - 7.63 (m, 1H), 7.47 - 7.42 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.05 - 6.93 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.07 (d, J = 17.6 Hz, 1H), 5.49 (d, J = 11.2 Hz, 1H), 3.30 - 3.20 (m, 2H), 2.93 - 2.82 (m, 4H), 2.81 (s, 3H), 1.75 (s, 1H) ppm.

[0455] Step 5: 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0456] To a mixture of 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-vinylimidazo[1,2-a]pyridine-8-carboxamide (230 mg, 478.35 μmol) and KOsO·HO (17.96 mg, 48.73 μmol) in dioxane (10 mL) and HO (2 mL) was added NaIO (416.96 mg, 1.95 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by the addition of HO (10 mL) at 20 °C and then extracted with DCM (30 mL, 10 mL). The combined organic layers were washed with brine (30 mL, 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The combined organic phases were filtered and concentrated to give a residue which was purified by preparative HPLC (Column = Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); Mobile phase = Water (NH4HCO3)-ACN, B% = 25%-55%; 8 min) to give the product (20 mg, 8.65% yield). MS: M / e 474 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ 11.79 - 11.73 (m, 1H), 10.18 (s, 1H), 9.49 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.75 - 7.68 (m, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.31 (s, 2H), 3.29 - 3.24 (m, 1H), 2.92 - 2.79 (m, 7H) ppm.

[0457] Step 6: 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((((1-methylcyclopentyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0458] To a mixture of 3-chloro-N-(3-((1r,3r)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (20 mg, 42.2 μmol), (1-methylcyclopentyl)methanamine hydrochloride (9.47 mg, 63.3 μmol), and TEA (6.41 mg, 63.3 μmol) in DCM (1 mL) was added NaBH(OAc) (22.36 mg, 105.5 μmol) in one portion at 20° C. The mixture was stirred at 20° C. for 12 h. The mixture was poured into water (2 mL) and extracted with DCM (9 mL, 3 mL). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated to give a residue which was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 (150 x 40 mm x 10 um); mobile phase = water (NH4HCO3)-ACN, B% = 25%-55%; 8 min) to give the product (4.45 mg, 18.46% yield). MS: M / e 571 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.54 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.78 - 6.72 (m, 1H), 3.88 (s, 2H), 3.29 (s, 2H), 3.27 - 3.22 (m, 1H), 2.93 - 2.83 (m, 4H), 2.81 (s, 3H), 2.36 (s, 2H), 1.63 - 1.45 (m, 6H), 1.30 - 1.20 (m, 3H), 0.98 (s, 3H) ppm.

[0459] Compound A30: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclobutyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0460] Compound A30 was synthesized starting from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (23 mg, 26%). 1H NMR (400 MHz, CD3OD) δ 8.82 (s, 1H), 8.33 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.79 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 4.27 (s, 2H), 3.33 (s, 3H), 3.07-3.01 (m, 2H), 3.00 (s, 2H), 2.97-2.84 (m, 3H), 2.67 (d, J=8.0 Hz, 2H), 2.00-1.95 (m, 3H), 1.91-1.76 (m, 3H), 1.26 (s, 3H) ppm.MS:M / e 523 (M+1) +

[0461] Compound A31: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-1-cyclopentylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0462] Compound A31 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (20.50 mg, 33.57% yield). MS: M / e 537 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.75 (s, 1H), 7.72 - 7.65 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 3.93 - 3.80 (m, 1H), 3.78 - 3.68 (m, 1H), 3.22 (s, 3H), 2.89 (br d, J = 2.8 Hz, 2H), 2.81 - 2.67 (m, 5H), 2.44 - 2.36 (m, 1H), 2.04 (br d, J = 1.8 Hz, 1H), 1.87 - 1.70 (m, 2H), 1.69 - 1.36 (m, 5H), 1.30 - 1.11 (m, 2H), 1.01 (d, J = 6.1 Hz, 3H) ppm.

[0463] Compound A32: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((neopentylamino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0464] Compound A32 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (6.13 mg). MS: M / e 511 (M+1) +;H NMR (400 MHz, DMSO-d6) δ = 12.44 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 8.20 (d, J =4 Hz, 1H), 8.15 (d, J = 4 Hz, 1H), 7.79 (d, J = 4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 3.80 (s, 2H), 3.23 (s, 3H), 2.90 (m, 2H), 2.81 - 2.69 (m, 5H), 2.54 - 2.53 (m, 1H), 2.27 (s, 2H), 0.88 (s, 9H) ppm.

[0465] Compound A33: N-(3-((1r,3S)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-((((S)-1-cyclopentylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0466] Compound A33 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A24 to give the product (7.12 mg, 23.32% yield). MS: M / e 537 (M+1) +; H NMR (400 MHz, DMSO-d6) δ = 12.43 - 12.38 (m, 1H), 8.73 (s, 1H), 8.20 - 8.15 (m, 2H), 8.15 - 8.14 (m, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.73 (d, J = 8.2 Hz, 1H), 3.92 - 3.84 (m, 1H), 3.78 - 3.69 (m, 1H), 3.32 - 3.23 (m, 4H), 2.94 - 2.83 (m, 4H), 2.80 (s, 3H), 2.44 - 2.36 (m, 1H), 1.84 - 1.73 (m, 2H), 1.67 - 1.58 (m, 1H), 1.56 - 1.42 (m, 4H), 1.27 - 1.13 (m, 2H), 1.04 - 0.98 (m, 3H) ppm.

[0467] Compound A34: 3-chloro-N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-1-cyclopentylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0468] Compound A34 was synthesized starting from the corresponding starting material following a procedure similar to that described for compound A28 to give the title compound (45 mg, 54%). 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.99-7.92 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.79 (d, J = 13.8 Hz, 1H), 3.34 (s, 3H), 3.08-2.82 (m, 5H), 2.67 (d, J = 6.0 Hz, 2H), 2.53-2.42 (m, 1H), 1.92-1.68 (m, 3H), 1.65-1.48 (m, 4H), 1.29-1.14 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H) ppm.MS:M / e 571 / 573 (M+H) + .

[0469] Compound A35: 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-methylcyclobutyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0470] Compound A35 was synthesized starting from the corresponding starting material according to a procedure similar to that described for compound A28 to give the title compound (35 mg, 59%). 1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.34 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.98-7.90 (m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 2.0 Hz, 2H), 3.34 (s, 3H), 3.08-2.82 (m, 5H), 2.67 (d, J = 6.0 Hz, 2H), 2.56 (s, 2H), 1.97-1.76 (m, 4H), 1.76-1.64 (m, 2H), 1.17 (s, 3H) ppm.MS:M / e 557, 559 (M+H) + .

[0471] Compound A36: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide and N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (1:1) [ka]

[0472] Compound A36 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (59.62 mg, 117.22 umol, 51.51% yield). MS: M / e 509 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (s, 1 H), 8.75 (d, J=1.38 Hz, 1 H), 8.32 (s, 1 H), 8.15 (dd, J=6.50, 1.38 Hz, 2 H), 7.73 - 7.80 (m, 2 H), 7.69 (dd, J=8.07, 1.19 Hz, 1 H), 7.44 (t, J=7.88 Hz, 1 H), 7.20 (d, J=8.50 Hz, 1 H), 3.71 (s, 2 H), 3.22 (s, 3 H), 2.84 - 2.98 (m, 2 H), 2.62 - 2.83 (m, 5 H), 2.35 - 2.46 (m, 1 H), 1.92 - 2.05 (m, 2 H), 1.59 - 1.79 (m, 4 H), 1.25 (s, 3 H) ppm.

[0473] Compound A37: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((1-fluorocyclobutyl)methyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0474] Compound A37 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (26.58 mg, yield: 31.4%). MS: M / e 527 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1 H), 8.73 (s, 1 H), 8.32 (s, 1 H), 8.19 (s, 1 H), 8.15 (s, 1 H), 7.79 (s, 1 H), 7.75 (s, 1 H), 7.70 (br d, J = 8.0 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 3.85 (br s, 2 H), 3.22 (s, 3 H), 2.94 - 2.84 (m, 2 H), 2.84 - 2.72 (m, 5H), 2.71 (br s, 2 H), 2.23 - 2.09 (m, 4 H), 1.80 - 1.66 (m, 1 H), 1.50 - 1.35 (m, 1 H) ppm.

[0475] Compound A38: N-(3-((1s,3R)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((((S)-1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0476] Compound A38 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (88.6 mg, yield: 62.1%). MS: M / e 523 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1 H), 8.72 (s, 1 H), 8.32 (s, 1 H), 8.16 (dd, J = 1.4, 11.8 Hz, 2 H), 7.78 (d, J = 1.2 Hz, 1 H), 7.74 (s, 1 H), 7.70 (br d, J = 8.0 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.20 (br d, J = 7.8 Hz, 1 H), 3.81 (s, 1 H), 3.77 - 3.69 (m, 1 H), 3.22 (s, 3H), 2.89 (br d. 1.82 - 1.60 (m, 4 H), 0.91 (d, J = 6.0 Hz, 3 H) ppm.

[0477] Compound A39: N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0478] Compound A39 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A22 to give the product (11.36 mg, 24.34% yield). MS: M / e 484 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ = 12.44 - 12.36 (m, 1H), 8.77 - 8.69 (m, 1H), 8.29 (s, 1H), 8.17 - 8.10 (m, 2H), 7.81 - 7.73 (m, 2H), 7.69 - 7.62 (m, 1H), 7.48 - 7.36 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 3.73 - 3.67 (m, 2H), 3.20 (s, 3H), 2.91 - 2.78 (m, 2H), 2.54 (d, J = 6.4Hz, 3H), 2.06 - 1.93 (m, 2H), 1.78 - 1.63 (m, 4H), 1.29 - 1.21 (m, 3H), 1.12 - 1.05 (m, 3H) ppm.

[0479] Compound A40: 6-((((S)-1-cyclopentylethyl)amino)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0480] Compound A40 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A22 to give the product (2.58 mg, 5.22% yield). MS: M / e 512 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ = 12.41 (s, 1H), 8.72 (s, 1H), 8.30 (s, 1H), 8.17 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.39 - 7.38 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.90 - 3.82 (m, 1H), 3.77 - 3.69 (m, 1H), 3.20 (s, 3H), 2.84 (d, J = 3.2 Hz, 2H), 2.60 - 2.52 (m, 3H), 2.45 - 2.35 (m, 1H), 1.82 - 1.72 (m, 2H), 1.69 - 1.56 (m, 1H), 1.56 - 1.41 (m, 4H), 1.29 - 1.13 (m, 2H), 1.11 - 1.06 (m, 3H), 1.00 (d, J = 6.4 Hz, 3H) ppm.

[0481] Compound A41: 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0482] To a solution of 1-methylcyclopropan-1-amine hydrochloride (17.03 mg, 158.26 μmol) in DCE (4 mL) was added TEA (16.01 mg, 158.26 μmol), 3-chloro-N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formylimidazo[1,2-a]pyridine-8-carboxamide (50 mg, 105.50 μmol), and NaBH(OAc) (67.08 mg, 316.51 μmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with HO (1 mL), filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; Mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-55%, 8 min) to give the product (7.13 mg, 12.77% yield). MS: M / e 529 (M+1) + ; H NMR (400 MHz, DMSO-d6) δ = 11.96 (s, 1H), 8.51 (d, J = 1.2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 7.70 - 7.62 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.90 (s, 2H), 3.21 (s, 3H), 2.95 - 2.82 (m, 2H), 2.76 (br d, J = 8.0 Hz, 3H), 2.70 (br s, 2H), 2.61 (br s, 1H), 1.27 (s, 3H), 0.60 - 0.47 (m, 2H), 0.38 - 0.27 (m, 2H) ppm.

[0483] Compound A42: 6-(((cyclopentylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0484] Compound A42 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A22 to give the product (13.91 mg, 28.96% yield). MS: M / e 498 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 12.44 - 12.39 (m, 1H), 8.71 (d, J = 0.4 Hz, 1H), 8.33 - 8.27 (m, 1H), 8.18 - 8.11 (m, 2H), 7.79 - 7.76 (m, 1H), 7.75 - 7.72 (m, 1H), 7.69 - 7.65 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.77 (s, 2H), 3.20 (s, 3H), 2.90 - 2.78 (m, 2H), 2.55 (d, J = 6.4 Hz, 3H), 2.43 (d, J = 7.2 Hz, 2H), 2.03 - 1.93 (m, 1H), 1.75 - 1.64 (m, 2H), 1.59 - 1.41 (m, 4H), 1.23 - 1.12 (m, 2H), 1.12 - 1.06 (m, 3H) ppm.

[0485] Compound A43: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((cyclobutylmethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0486] Compound A43 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A23 to give the product (30.83 mg). MS: M / e 509 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.42 (s, 1H), 8.71 (s, 1H), 8.32 (s, 1H), 8.14 (d, J = 1.4, 4.0 Hz, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 3.76 (s, 2H), 3.22 (s, 3H), 2.91 - 2.86 (m, 2H), 2.76 (d, J = 8.0 Hz, 3H), 2.73 - 2.68 (m, 2H), 2.54 (d, J = 8.0 Hz, 2H), 2.46 - 2.37 (m, 1H), 2.03 - 1.93 (m, 2H), 1.87 - 1.75 (m, 2H), 1.70 - 1.57 (m, 2H) ppm.

[0487] Compound A44: 3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0488] Compound A44 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A19 to give (5.23 mg, 10.43 umol, 23.61% yield). MS: M / e 502 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (s, 1 H), 8.49 (s, 1 H), 8.29 (s, 1 H), 8.17 (d, J=0.88 Hz, 1 H), 7.71 (s, 1 H), 7.59 - 7.68 (m, 2 H), 7.42 (t, J=7.88 Hz, 1 H), 7.16 (d, J=7.88 Hz, 1 H), 3.75 (s, 2 H), 3.19 (s, 3 H), 2.78 - 2.91 (m, 2 H), 2.54 - 2.54 (m, 1 H), 2.54 (d, J=6.50Hz, 3H), 1.92 - 2.05 (m, 2 H), 1.63 - 1.79 (m, 4 H), 1.26 (s, 3 H), 1.08 (d, J=5.12 Hz, 3 H) ppm.

[0489] Compound A45: 3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0490] Compound A45 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A19 to give (4.10 mg, 8.41 μmol, 19.04% yield). MS: M / e 488 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (s, 1 H), 8.46 (s, 1 H), 8.29 (s, 1 H), 8.12 (d, J=1.38 Hz, 1 H), 7.67 - 7.74 (m, 1 H), 7.59 - 7.67 (m, 2 H), 7.42 (t, J=7.94 Hz, 1 H), 7.16 (d, J=8.38 Hz, 1 H), 3.86 (s, 2 H), 3.19 (s, 3 H), 2.75 - 2.91 (m, 2 H), 2.50 - 2.61 (m, 3 H), 1.27 (s, 3H), 1.09 (d, J=5.38 Hz, 3 H), 0.53 (s, 2 H), 0.29 - 0.40 (m, 2 H) ppm.

[0491] Compound A46: 6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methyl-N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0492] Step 1: 6-Formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0493] A solution of methyl 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylate (100 mg, 0.435 mmol, 1 equiv., 95%) in HCl (5.00 mL, 59.195 mmol, 136.08 equiv., 36%) and HO (5.00 mL, 277.321 mmol, 637.52 equiv., 100%) was stirred at 90 °C for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0%-10% gradient in 10 min; detector, UV 254 nm. This afforded 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylic acid (50 mg, 50.57%). MS:M / e 205 (M+1) + .

[0494] Step 2: 6-Formyl-3-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0495] To a solution of 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylic acid (279 mg, 1.37 mmol) in DMF (3 mL) was added HATU (623.47 mg, 1.64 mmol), DIEA (353.19 mg, 2.73 mmol), and 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (298.00 mg, 1.23 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give the product (230 mg, 39.28% yield). MS: M / e 429 (M+1) + .

[0496] Step 3: 6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methyl-N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0497] To a mixture of 6-formyl-3-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.02 g, 46.68 μmol, 1 equiv.), (3R,4S)-4-fluoro-3-methyl-piperidine (14.34 mg, 93.35 μmol, 2 equiv., HCl), TEA (9.45 mg, 93.35 μmol, 12.99 μL, 2 equiv.), and DCE (2 mL) was added NaBH(OAc) (39.57 mg, 186.70 μmol, 4 equiv.) at 20° C. The mixture was stirred at 20° C. for 12 hours. The mixture was diluted with DCM (30 mL), adjusted to pH = 8 with saturated aqueous NaHCO3, extracted with DCM (50 mL × 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min). The compound 6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methyl-N-(3-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (9.89 mg, 18.67 μmol, 40.00% yield) was obtained. MS: M / e 530 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (s, 1 H), 8.45 (s, 1 H), 8.30 (s, 1 H), 8.12 (d, J=1.14 Hz, 1 H), 7.77 (s, 1 H), 7.61 - 7.66 (m, 1 H), 7.59 (s, 1 H), 7.41 (t, J=7.88 Hz, 1 H), 7.15 (d, J=7.88 Hz, 1 H), 4.71 (s, 1 H), 3.60 (s, 2 H), 3.19 (s, 3 H), 2.78 - 2.90 (m, 2 H), 2.52 - 2.69 (m, 8 H), 2.20 - 2.35 (m, 1 H), 2.04 (t, J=11.32 Hz, 1 H), 1.65 - 1.93 (m, 3 H), 1.09 (d, J=5.24Hz, 3 H), 0.90 (d, J=6.88 Hz, 3 H) ppm.

[0498] Compound A47: N-(3-((1s,3S)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0499] Step 1: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0500] A mixture of 6-formyl-3-methyl-imidazo[1,2-a]pyridine-8-carboxylic acid (0.2 g, 979.52 μmol, 1 equiv.), 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (237.36 mg, 979.52 μmol, 1 equiv.), HATU (484.18 mg, 1.27 mmol, 1.3 equiv.), DIEA (253.19 mg, 1.96 mmol, 341.22 μL, 2 equiv.), and DMF (2 mL) was stirred at 30° C. for 2 hours. The mixture was poured into 60 mL of HO, extracted with dichloromethane (60 mL × 2), washed with brine (30 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1-1 / 1). The compound N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxamide (0.08 g, 186.70 μmol, 19.06% yield) was obtained.

[0501] Step 2: N-(3-((1s,3S)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methylimidazo[1,2-a]pyridine-8-carboxamide [ka]

[0502] To a mixture of N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxamide (0.02 g, 44.10 μmol, 1 equiv.), (3R,4S)-4-fluoro-3-methyl-piperidine (13.55 mg, 88.20 μmol, 2 equiv., HCl), TEA (8.93 mg, 88.20 μmol, 12.28 μL, 2 equiv.) in DCE (1 mL) was added NaBH(OAc) (37.39 mg, 176.41 μmol, 4 equiv.) at 20° C. The mixture was stirred at 20° C. for 12 h. The mixture was diluted with DCM (30 mL), adjusted to pH = 8 with saturated aqueous NaHCO3, extracted with DCM (50 mL × 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8 min). The compound N-(3-((1s,3S)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-3-methylimidazo[1,2-a]pyridine-8-carboxamide (10.50 mg, 18.93 μmol, 42.92% yield) was obtained. MS: M / e 555 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.45 (s, 1 H), 8.46 (s, 1 H), 8.32 (s, 1 H), 8.12 (d, J=1.38 Hz, 1 H), 7.76 - 7.79 (m, 1 H), 7.65 (dd, J=1.24 Hz, 1 H), 7.59 (d, J=0.88 Hz, 1 H), 7.44 (t, J=7.94 Hz, 1 H), 7.17 - 7.25 (m, 1 H), 4.52 - 4.74 (m, 1 H), 3.60 (s, 2 H), 3.22 (s, 3 H), 2.84 - 2.93 (m, 2 H), 2.68 - 2.81 (m, 5 H), 2.54 - 2.66 (m, 5 H), 2.22 - 2.35 (m, 1 H), 2.00 - 2.11 (m, 1 H), 1.65 - 1.96 (m, 3 H), 0.90 (d, J=6.88 Hz, 3H)ppm.

[0503] Compound A48: N-(3-((1r,3R)-3-cyano-1-((4-methyl-4H-1,2,4-triazol-3-yl)methyl)cyclobutyl)phenyl)-6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0504] Compound A48 was synthesized starting from the corresponding starting material following a procedure similar to that described for compound A5 to give the product (11 mg, 31%). 1H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.23 ​​(s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.34 (t, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 4.70 - 4.57 (m, 1H), 3.71 (s, 2H), 3.42 (s, 2H), 3.21-3.17 (m, 1H), 3.00 (d, J=8.0 Hz, 4H), 2.81 (s, 3H), 2.77-2.70 (m, 2H), 2.46 (t, J=12.0 Hz, 1H), 2.24 (t, J=12.0 Hz, 1H), 2.02-1.81 (m, 3H), 0.98 (d, J=4.0 Hz, 3H) ppm.MS:M / e 541 (M+1) +

[0505] Compound A49: 6-((((S)-sec-butyl)amino)methyl)-N-(5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0506] Step 1: Methyl (S)-6-((sec-butylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0507] A mixture of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (0.2 g, 489.76 μmol), (2S)-butan-2-amine (107.35 mg, 979.52 μmol), CHCOOH (44.12 mg, 734.64 μmol), NaBHCN (92.33 mg, 1.47 mmol), and TEA (99.12 mg, 979.52 μmol) in MeOH (2 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 20 °C for 16 h. The reaction mixture was quenched by the addition of 10 mL of HO at 20 °C and then extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with 30 mL of brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The resulting residue was purified by preparative TLC (SiO2, DCM:MeOH=3:1) to give the product (0.06 g, 46.88% yield). MS: M / e 262 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.71 (s, 1H), 8.10 - 7.96 (m, 1H), 7.90 (s, 1H), 7.61 (s, 1H), 3.89 (s, 3H), 3.83 - 3.65 (m, 2H), 1.47 (d, J = 4.32 Hz, 1H), 1.36 - 1.17 (m, 2H), 1.06 - 0.96 (m, 3H), 0.84 (t, J = 7.52 Hz, 3H) ppm.

[0508] Step 2: (S)-6-((sec-butylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0509] A mixture of methyl (S)-6-((sec-butylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (0.06 g, 229.60 μmol, 1 equiv.), LiOH.HO (9.64 mg, 229.60 μmol, 1 equiv.) in THF (1 mL), MeOH (1 mL), and HO (1 mL) was degassed and purged with N three times, after which the mixture was stirred under N atmosphere at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification to give the product (47 mg, 80.84% ​​yield). MS: M / e 248 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.48 (s, 1H), 7.94 (d, J = 1.0 Hz, 1H), 7.87 (s, 1H), 7.48 (s, 1H), 3.78 - 3.63 (m, 2H), 1.97 - 1.90 (m, 1H), 1.55 - 1.40 (m, 1H), 1.34 - 1.22 (m, 1H), 1.00 (d, J = 6.32 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H) ppm.

[0510] Step 3: 6-((((S)-sec-butyl)amino)methyl)-N-(5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0511] To a stirred solution of (S)-6-((sec-butylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (47 mg, 148.48 μmol) and 5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (36.13 mg, 148.48 μmol) in pyridine (1 mL) was added T3P (283.47 mg, 445.45 μmol) at 20° C. The resulting mixture was stirred at 20° C. for 3 hours. The reaction mixture was quenched by the addition of 10 mL of HO at 20° C., and then extracted with 30 mL of EtOAc (10 mL×3). The combined organic layers were washed with 30 mL of brine (10 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; Mobile phase: [HO (10 mM NH4HCO3)-ACN], Gradient: 20%-50% B over 8.0 min) to give the product (11.19 mg, 23.68 μmol, 15.95% yield). MS: M / e 472 (M+1) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 12.63 - 12.36 (m, 1H), 8.86 (d, J = 2.32 Hz, 1H), 8.76 (s, 1H), 8.41 (d, J = 1.92 Hz, 1H), 8.34 (s, 1H), 8.19 - 8.12 (m, 3H), 7.81 - 7.78 (m, 1H), 3.85 - 3.73 (m, 2H), 3.24 (s, 3H), 2.94 - 2.88 (m, 2H), 2.62 - 2.56 (m, 4H), 1.53 - 1.41 (m, 1H), 1.36 - 1.20 (m, 1H), 1.12 - 1.06 (m, 3H), 1.01 (d, J = 6.32 Hz, 3H), 0.88 - 0.82 (m, 3H) ppm.

[0512] Compound A50: 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0513] Step 1: Methyl 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0514] To a stirred mixture of methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (150 mg, 0.596 mmol, 1 equiv, 88.3%) and (1S)-1-cyclobutylethanamine hydrochloride (128 mg, 0.896 mmol, 1.50 equiv, 95%) in MeOH (5 mL, 99%), tetrakis(propan-2-yloxy)titanium (714 mg, 2.387 mmol, 4.00 equiv, 95%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. To the above mixture, NaBHCN (79 mg, 1.194 mmol, 2.00 equiv, 95%) was added in small portions at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (7:1) to give methyl 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (110 mg, 50.64%). MS: M / e 306 (M+1) + . Step 2: 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0515] To a stirred solution of methyl 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (110 mg, 0.302 mmol, 1 equiv., 83.8%) in THF (2 mL, 99%) and HO (1 mL, 99%), LiOH (16 mg, 0.635 mmol, 2.10 equiv., 95%) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH = 4 with HCl (1 M). The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0%; detector, UV 254 nm. This gave 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (33 mg, 31.74%). MS: M / e 292 (M+1) + .

[0516] Step 3: 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0517] To a stirred mixture of 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (30 mg, 0.087 mmol, 1 equivalent, 84.6%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (23 mg, 0.090 mmol, 1.03 equivalent, 95.0%) in pyridine (1.5 mL, 95%), T3P (555 mg, 0.872 mmol, 10.01 equivalent, 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (12% ACN, maximum 42% in 8 min), to give 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (9.8 mg, 21.43%). MS: M / e 517 (M+1). + ; 1H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.49 (s, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.14 - 8.07 (m, 1H), 7.62 (d, J = 6.9 Hz, 1H), 3.91 - 3.72 (m, 2H), 3.24 (s, 3H), 2.91 (d, J = 3.6 Hz, 2H), 2.59 (d, J = 6.8 Hz, 3H), 2.51 - 2.40 (m, 1H), 2.23 - 2.12 (m, 1H), 2.06 - 1.94 (m, 1H), 1.93 - 1.82 (m, 1H), 1.82 - 1.56 (m, 4H), 1.10 (d, J = 4.8 Hz, 3H), 0.91 (d, J = 6.1 Hz, 3H) ppm.

[0518] Compound A51: 6-(((cyclopentylmethyl)amino)methyl)-3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0519] Compound A51 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A19 to give (12.97 mg, 25.15 μmol, 11.39% yield). MS: M / e 516 (M+1) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (s, 1 H), 8.45 (s, 1 H), 8.30 (s, 1 H), 8.16 (s, 1 H), 7.71 (s, 1 H), 7.66 (d, J=8.00 Hz, 1 H), 7.61 (d, J=6.88 Hz, 1 H), 7.42 (t, J=7.94 Hz, 1 H), 7.16 (d, J=7.74 Hz, 1 H), 3.80 (s, 2 H), 3.19 (s, 3 H), 2.78 - 2.89 (m, 2 H), 2.55 (q, J=6.74 Hz, 3H), 2.42 (d, J=7.12 Hz, 2 H), 1.98 (d, J=14.88 Hz, 1 H), 1.62 - 1.76 (m, 2 H), 1.39 - 1.56 (m, 4 H), 1.13 - 1.24 (m, 2 H), 1.09 (d, J=5.12 Hz, 3 H)ppm.

[0520] Compound A52: 6-(((cyclobutylmethyl)amino)methyl)-3-fluoro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0521] Compound A52 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A19 to give the title product (16.94 mg, 33.77 umol, 15.30% yield). MS: M / e 502 (M+1) +; H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (s, 1 H), 8.46 (s, 1 H), 8.29 (s, 1 H), 8.16 (d, J=1.00 Hz, 1 H), 7.71 (s, 1 H), 7.66 (d, J=8.00 Hz, 1 H), 7.62 (d, J=6.88 Hz, 1 H), 7.42 (t, J=7.88 Hz, 1 H), 7.16 (d, J=7.63 Hz, 1 H), 3.79 (s, 2 H), 3.19 (s, 3 H), 2.84 (d, J=3.25 Hz, 2 H), 2.48 - 2.59 (m, 6 H), 2.41 (dt, J=14.82, 7.47 Hz, 1 H), 1.93 - 2.05 (m, 2 H), 1.74 - 1.89 (m, 2 H), 1.56 - 1.69 (m, 2 H), 1.09 (d, J=5.00 Hz, 3 H) ppm.

[0522] Compound A53: 6-(((cyclobutylmethyl)amino)methyl)-3-methyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0523] Compound A53 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A46 to give the product (85.32 mg, 48.98% yield). MS: M / e 498 (M+1) +; H NMR (400 MHz, DMSO-d6) δ = 12.45 (s, 1H), 8.43 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 7.65 (br d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.79 (s, 2H), 3.20 (s, 3H), 2.84 (br d, J = 4.0 Hz, 2H), 2.65 - 2.51 (m, 7H), 2.48 - 2.22 (m, 2H), 2.04 - 1.93 (m, 2H), 1.88 - 1.72 (m, 2H), 1.70 - 1.57 (m, 2H), 1.09 (br d, J = 4.0 Hz, 3H) ppm.

[0524] Compound A54: 6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-N-(5-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0525] Step 1: 6-Formyl-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0526] To a stirred solution of 6-formylimidazo[1,2-a]pyridine-8-carboxylic acid (40 mg, 0.200 mmol, 1 equiv., 95%) and DIEA (108.75 mg, 0.800 mmol, 4 equiv., 95%) in DMF (3 mL) was added HATU (119.97 mg, 0.300 mmol, 1.5 equiv., 95%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (51.18 mg, 0.200 mmol, 1 equiv., 95%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 6-formyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (71 mg, 85.52%). MS: M / e 416 (M+1). + .

[0527] Step 2: 6-(((3R,4S)-4-fluoro-3-methylpiperidin-1-yl)methyl)-N-(5-((1s,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0528] To a stirred solution of 6-formyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (25 mg, 0.057 mmol, 1 equiv., 95%) and (3R,4S)-4-fluoro-3-methylpiperidine hydrochloride (18.49 mg, 0.114 mmol, 2 equiv., 95%) in MeOH (2 mL), tetrakis(propan-2-yloxy)titanium (68.41 mg, 0.228 mmol, 4 equiv., 95%) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 hour. To the above mixture, NaBHCN (7.56 mg, 0.114 mmol, 2 equiv., 95%) was added. The resulting mixture was stirred at room temperature for an additional hour. The crude product was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (25% ACN, up to 55% in 8 min), to give 6-{[(3R,4S)-4-fluoro-3-methylpiperidin-1-yl]methyl}-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (9.0 mg, 29.62%). MS: M / e 517 (M+1). + . 1 H NMR (300 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.81 (m, 2H), 8.45 - 8.33 (m, 2H), 8.18 - 8.08 (m, 3H), 7.81 (m, 1H), 4.65 (m, 1H), 3.65 - 3.49 (m, 2H), 3.24 (s, 3H), 2.92 (s, 2H), 2.59 (m, 5H), 2.25 (m, 1H), 2.03 (m, 1H), 1.93 - 1.66 (m, 3H), 1.10 (m, 3H), 0.90 (m, 3H) ppm.

[0529] Compound A55: 6-{[(3R,4S)-4-fluoro-3-methylpiperidin-1-yl]methyl}-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0530] Step 1: 6-Formyl-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0531] To a stirred solution of 6-formyl-3-methylimidazo[1,2-a]pyridine-8-carboxylic acid (45 mg, 0.198 mmol, 1 equiv., 89.9%) in DMF (3 mL, 100%), HATU (118.95 mg, 0.297 mmol, 1.5 equiv., 95%) and DIEA (8.99 mg, 0.066 mmol, 3 equiv., 95%) were added at room temperature. The resulting mixture was stirred at room temperature for 10 minutes. To the above mixture, 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (50.74 mg, 0.198 mmol, 1 equiv., 95%) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% NH3.HO) in water, 20%-50% gradient in 10 min; detector, UV 254 nm. This gave 6-formyl-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (30 mg, 33.49%). MS: M / e 430 (M+1). + .

[0532] Step 2: 6-{[(3R,4S)-4-fluoro-3-methylpiperidin-1-yl]methyl}-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0533] To a stirred solution of 6-formyl-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (10 mg, 0.022 mmol, 1 equiv., 95%) and (3R,4S)-4-fluoro-3-methylpiperidine hydrochloride (7.15 mg, 0.044 mmol, 2 equiv., 95%) in MeOH (2 mL, 100%), tetrakis(propan-2-yloxy)titanium (26.47 mg, 0.088 mmol, 4 equiv., 95%) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. To the above mixture, NaBHCN (2.93 mg, 0.044 mmol, 2 equiv., 95%) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by chiral preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (30% ACN, up to 60% in 8 min), to give 6-{[(3R,4S)-4-fluoro-3-methylpiperidin-1-yl]methyl}-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (2 mg, 16.58%). MS:M / e 531 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.84 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.18 - 8.11 (m, 2H), 7.60 (d, J = 1.2 Hz, 1H), 4.65 (d, J = 50.1 Hz, 1H), 3.61 (s, 2H), 3.24 (s, 3H), 2.91 (d, J = 3.8 Hz, 2H), 2.62 - 2.52 (m, 8H), 2.32 - 2.21 (m, 1H), 2.10 - 1.99 (m, 1H), 1.92 - 1.80 (m, 3H), 1.10 (d, J = 4.7 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H) ppm.

[0534] Compound A56: 6-{[(cyclobutylmethyl)amino]methyl}-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide

[0535] [ka]

[0536] Compound A56 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A55 to give the product (12.3 mg, 35.54%). MS: M / e 499 (M+1) + ; 1H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.84 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.34 (s, 1H), 8.20 - 8.10 (m, 2H), 7.59 (d, J = 1.1 Hz, 1H), 3.80 (s, 2H), 3.24 (s, 3H), 2.91 (d, J = 3.9 Hz, 2H), 2.64 - 2.55 (m, 4H), 2.53 (d, J = 1.2 Hz, 4H), 2.49 - 2.33 (m, 2H), 2.07 - 1.92 (m, 2H), 1.91 - 1.75 (m, 2H), 1.75 - 1.54 (m, 2H), 1.10 (d, J = 4.9 Hz, 3H) ppm.

[0537] Compound A57: 3-chloro-6-(((cyclobutylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0538] Step 1: 3-chloro-6-formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0539] A mixture of 3-chloro-6-formyl-imidazo[1,2-a]pyridine-8-carboxylic acid (72.10 mg, 320.99 μmol), 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (77.78 mg, 320.99 μmol), HATU (146.46 mg, 385.19 μmol), DIEA (124.46 mg, 962.98 μmol, 167.73 μL), and DMF (1 mL) was stirred at 25° C. for 2 hours. The mixture was poured into 20 mL of HO, the solid was filtered, and the solid was concentrated in vacuo. The compound 3-chloro-6-formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.08 g, 178.21 μmol, yield 55.52%) was obtained. MS: M / e 449 (M+1) + .

[0540] Step 2: 3-chloro-6-(((cyclobutylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0541] A mixture of 3-chloro-6-formyl-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.04 g, 89.11 μmol, 1 equiv.), cyclobutylmethanamine (43.34 mg, 356.42 μmol, HCl), TEA (36.07 mg, 356.42 μmol, 49.61 μL), NaBH(OAc) (56.66 mg, 267.32 μmol), and DCE (2 mL) was stirred at 20 °C for 12 h. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 min). The compound 3-chloro-6-(((cyclobutylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (11.37 mg, 21.95 μmol, 24.63% yield) was obtained. MS: M / e 518 (M+1). + . 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1 H), 8.51 (s, 1 H), 8.30 (s, 1 H), 8.22 (s, 1 H), 7.95 (s, 1 H), 7.72 (s, 1 H), 7.66 (d, J=8.00 Hz, 1 H), 7.42 (t, J=7.94 Hz, 1 H), 7.17 (d, J=7.88 Hz, 1 H), 3.83 (s, 2 H), 3.19 (s, 3 H), 2.83 (s, 2 H), 2.54 (d, J=7.00 Hz, 5 H), 2.41 (d, J=14.88Hz, 2H), 1.93 - 2.05 (m, 2H), 1.74 - 1.88 (m, 2H), 1.57 - 1.69 (m, 2H), 1.09 (d, J=4.88 Hz, 3H) ppm.

[0542] Compound A58: 3-chloro-6-((((S)-1-cyclopropylethyl)amino)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0543] Compound A58 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A57 to give (14.59 mg, 28.16 umol, 31.61% yield). MS: M / e 518 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (s, 1 H), 8.52 (s, 1 H), 8.30 (s, 1 H), 8.24 (s, 1 H), 7.94 (s, 1 H), 7.73 (s, 1 H), 7.66 (d, J=8.12 Hz, 1 H), 7.42 (t, J=7.88 Hz, 1 H), 7.16 (d, J=7.74 Hz, 1 H), 3.84 - 4.03 (m, 2 H), 3.20 (s, 3 H), 2.84 (d, J=3.38 Hz, 2 H), 2.52 - 2.61 (m, 3 H), 2.33 - 2.43 (m, 1 H), 1.91 (dd, J=8.00, 6.50 Hz, 1 H), 1.05 - 1.12 (m, 6 H), 0.64 - 0.74 (m, 1 H), 0.40 - 0.50 (m, 1 H), 0.29 - 0.37 (m, 1 H), 0.20 (d, J=9.20, 4.73 Hz, 1 H), 0.03 (m, 1 H) ppm.

[0544] Compound A59: 6-((((S)-1-cyclopropylethyl)amino)methyl)-3-methyl-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0545] Compound A59 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A46 to give the product (33.69 mg, 29.01% yield). MS: M / e 484 (M+1) + ; H NMR (400 MHz, DMSO-d6) δ = 12.45 (s, 1H), 8.46 (s, 1H), 8.33 - 8.28 (m, 1H), 8.22 - 8.14 (m, 1H), 7.77 - 7.73 (m, 1H), 7.70 - 7.62 (m, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.18 - 7.10 (m, 1H), 3.98 - 3.79 (m, 2H), 3.20 (s, 3H), 2.90 - 2.77 (m, 2H), 2.55 (br d, J = 8.0 Hz, 3H), 2.53 (s, 3H), 1.98 - 1.85 (m, 1H), 1.13 - 1.08 (m, 6H), 0.77 - 0.65 (m, 1H), 0.51 - 0.41 (m, 1H), 0.39 - 0.29 (m, 1H), 0.26 - 0.16 (m, 1H), 0.08 - 0.01 (m, 1H) ppm.

[0546] Compound A60: 6-((((S)-1-cyclobutylethyl)amino)methyl)-3-methyl-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0547] Compound A60 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A46 to give the product (2.40 mg, 13.40% yield). MS: M / e 512 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 12.46 (s, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 0.8 Hz, 1H), 7.75 (s, 1H), 7.65 (br d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 4.03 - 3.66 (m, 2H), 3.20 (s, 3H), 2.84 (br d, J = 4.0 Hz, 2H), 2.62 - 2.51 (m, 6H), 2.48 - 2.39 (m, 1H), 2.27 - 2.12 (m, 1H), 2.10 - 1.57 (m, 7H), 1.09 (br d, J = 8.0 Hz, 3H), 0.92 (d, J = 8.0 Hz, 3H) ppm.

[0548] Compound A61: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0549] Step 1: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0550] A mixture of [3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carbonyl]oxylithium (0.2 g, 740.42 μmol, 80% purity, 1 equiv.), 2-((1s,3s)-3-(3-aminophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)acetonitrile (197.93 mg, 740.42 μmol, 1 equiv.), HATU (337.84 mg, 888.50 μmol, 1.2 equiv.), DIEA (287.08 mg, 2.22 mmol, 386.89 μL, 3 equiv.), and DMF (4 mL) was stirred at 25° C. for 2 hours. The mixture was poured into 50 mL of H2O, extracted with dichloromethane (30 mL x 2), washed with brine (20 mL x 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min). The compound N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxamide (0.045 g, 97.94 umol, 13.23% yield) was obtained. MS:M / e 460 (M+1) +

[0551] Step 2: (8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate [ka]

[0552] To a mixture of N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxamide (0.045 g, 97.94 μmol, 1 equiv), TEA (99.10 mg, 979.38 μmol, 136.32 μL, 10 equiv), and DMF (2 mL) was added MsCl (53.85 mg, 470.10 μmol, 36.39 μL, 4.8 equiv) at 0° C., and the mixture was then warmed to 25° C. for 2 hours. The mixture was diluted with dichloromethane (20 mL) and washed with HO (15 mL × 3), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Compound (8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (0.045 g, crude) was obtained. MS: M / e 538 (M+1) +

[0553] Step 3: N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0554] To a mixture of 1-methylcyclobutanamine (57.25 mg, 470.79 μmol, 5 equiv., HCl), DMF (2 mL), and TEA (47.64 mg, 470.79 μmol, 65.53 μL, 5 equiv.), (8-((3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)-3-fluoroimidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (0.045 g, 94.16 μmol, 1 equiv.), and CsCO (61.36 mg, 188.32 μmol, 2 equiv.) were added. The mixture was stirred at 25 °C for 2 h. The solution was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 min). The compound N-(3-((1s,3s)-3-(cyanomethyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide (14.18 mg, 26.93 μmol, 28.60% yield) was obtained. MS: M / e 527 (M+1). + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (s, 1 H), 8.49 (d, J=0.88 Hz, 1 H), 8.32 (s, 1 H), 8.17 (d, J=1.50 Hz, 1 H), 7.72 (d, J=1.63 Hz, 1 H), 7.66 - 7.71 (m, 1 H), 7.62 (d, J=6.88 Hz, 1 H), 7.44 (t, J=7.94 Hz, 1 H), 7.21 (d, J=7.75 Hz, 1 H), 3.74 (s, 2 H), 3.22 (s, 3 H), 2.84 - 2.94 (m, 2H), 2.66 - 2.81 (m, 5 H), 2.44 (s, 1 H), 1.94 - 2.05 (m, 2 H), 1.63 - 1.80 (m, 4 H), 1.26 (s, 3 H) ppm.

[0555] Compound A62: 3-fluoro-6-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0556] Step 1: (3-fluoro-8-((3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate [ka]

[0557] To a solution of 3-fluoro-6-(hydroxymethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide (0.077 g, 177.23 μmol) and TEA (143.47 mg, 1.42 mmol) in DMF (3 mL) was added MsCl (101.51 mg, 886.15 μmol) at 0° C. The mixture was stirred at 0° C. to 25° C. for 2 h. LCMS showed that 3-fluoro-6-(hydroxymethyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide remained. TEA (143.47 mg, 1.42 mmol) and MsCl (101.51 mg, 886.15 mmol) were then added to the reaction at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was diluted with DCM (5 mL), then poured into HO (2 mL), extracted with DCM (5 mL × 3), dried over NaSO, filtered, and concentrated to give the crude product. The compound (3-fluoro-8-((3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (90 mg, crude) was used directly in the next step. MS: M / e 453 (M+1) + .

[0558] Step 2: 3-fluoro-6-((isobutylamino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0559] To a solution of (3-fluoro-8-((3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)carbamoyl)imidazo[1,2-a]pyridin-6-yl)methyl methanesulfonate (0.09 g, 175.59 umol) and 2-methylpropan-1-amine (64.21 mg, 877.95 umol) in DMF (2 mL) was added CsCO (114.42 mg, 351.18 umol). The mixture was stirred at 25 °C for 12 h. The mixture was filtered and purified by preparative HPLC (column: Waters Xbridge Prep OBD C). 18 Purification by HPLC (150 x 40 mm x 10 um; mobile phase = water (NH4HCO3)-ACN, B% = 35%-65%; 8 min) gave the product (13.47 mg, 15.4% yield). MS: M / e 490 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ = 11.95 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.71 (s, 1H), 7.68 - 7.64 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 3.80 (s, 2H), 3.19 (s, 3H), 2.87 - 2.80 (m, 2H), 2.55 (br d, J = 6.4 Hz, 3H), 2.32 (d, J = 6.8 Hz, 2H), 1.68 (td, J = 6.4, 13.3 Hz, 1H), 1.09 (d, J = 5.2 Hz, 3H), 0.87 (d, J = 6.4 Hz, 6H) ppm.

[0560] Compound A63: 6-({[(1S)-1-cyclobutylethyl]amino}methyl)-3-methyl-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0561] Compound A63 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A55 to give the product (4.6 mg, 18.51%). MS: M / e 513 (M+1) + .. 1 H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.17 - 8.12 (m, 1H), 7.59 (d, J = 1.2 Hz, 1H), 3.93 - 3.73 (m, 2H), 3.24 (s, 3H), 2.91 (d, J = 3.5 Hz, 2H), 2.59 (d, J = 6.6 Hz, 3H), 2.56 - 2.51 (m, 4H), 2.48 (d, J = 5.9 Hz, 1H), 2.21 (s, 1H), 2.07 - 1.95 (m, 1H), 1.95 - 1.82 (m, 1H), 1.82 - 1.61 (m, 4H), 1.10 (d, J = 5.0 Hz, 3H), 0.93 (d, J = 6.2 Hz, 3H) ppm.

[0562] Compound A64: 6-((((S)-1-cyclopropylethyl)amino)methyl)-3-methyl-N-(5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0563] Compound A64 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A55 to give the product (3.0 mg, 8.72%). MS: M / e 499 (M+1) + . 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.85 (m, 1H), 8.49 (m, 1H), 8.41 (m, 1H), 8.34 (s, 1H), 8.19 (m, 1H), 8.15 (m, 1H), 7.59 (s, 1H), 3.90 (m, 2H), 3.24 (s, 3H), 2.92 (m, 2H), 2.59 (m, 3H), 2.54 (s, 3H), 2.48 - 2.32 (m, 1H), 1.92 (m, 1H), 1.11 (m, 6H), 0.71 (m, 1H), 0.46 (m, 1H), 0.35 (m, 1H), 0.21 (m, 1H), 0.04 (m, 1H) ppm.

[0564] Compound A65: 6-((((S)-1-cyclobutylethyl)amino)methyl)-3-fluoro-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0565] Compound A65 was synthesized starting from the corresponding starting material according to a procedure similar to that described for compound A19 to give (6.04 mg, 11.71 umol, 15.01% yield). MS(ESI) m / e [M+1] 516; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.84 - 11.94 (m, 1 H) 8.50 (s, 1 H) 8.26 (s, 1 H) 8.15 - 8.19 (m, 1 H) 7.58 - 7.67 (m, 3 H) 7.35 - 7.41 (m, 1 H) 7.14 (d, J=7.74 Hz, 1 H) 3.74 - 3.95 (m, 2 H) 3.15 (s, 3 H) 2.80 (d, J=3.00 Hz, 2 H) 2.56 - 2.50 (m, 4 H), 2.20 (d, J=2.50 Hz, 1 H) 1.93 - 2.02 (m, 1 H) 1.81 - 1.89 (m, 1 H) 1.59 - 1.79 (m, 5 H) 1.05 (d, J=5.00 Hz, 3 H) 0.92 (s, 3 H) ppm.

[0566] Compound A66: 3-chloro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0567] Compound A66 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A57 to give the product (6.82 mg, 13.16 μmol, 14.77% yield). MS: M / e 518 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (s, 1 H), 8.55 (d, J=1.13 Hz, 1 H), 8.30 (s, 1 H), 8.25 (d, J=1.50 Hz, 1 H), 7.96 (s, 1 H), 7.73 (s, 1 H), 7.67 (d. H), 1.61 - 1.81 (m, 4 H), 1.26 (s, 3 H), 1.09 (d, J=5.38 Hz, 3 H) ppm.

[0568] Compound A67: 3-chloro-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0569] Compound A67 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A57 to give the product (17.27 mg, 34.26 umol, 38.45% yield). MS: M / e 504 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1 H), 8.48 - 8.61 (m, 1 H), 8.29 (s, 1 H), 8.19 (d, J=0.88 Hz, 1 H), 7.96 (s, 1 H), 7.57 - 7.77 (m, 2 H), 7.34 - 7.48 (m, 1 H), 7.11 - 7.21 (m, 1 H), 3.90 (s, 2 H), 3.19 (s, 3 H), 2.80 - 2.87 (m, 2 H), 2.55 (d, J=6.00 Hz, 3 H), 1.28 (s, 3 H), 1.09 (d, J=5.00 Hz, 3H), 0.53 (s, 2H), 0.33 (d, J=1.74 Hz, 2H) ppm.

[0570] Compound A68: 3-chloro-6-(((cyclopentylmethyl)amino)methyl)-N-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0571] Compound A68 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A57 to give the product (10.14 mg, 19.06 umol, 14.26% yield). MS: M / e 532 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ = 11.96 (s, 1H), 8.52 (s, 1H), 8.30 (s, 1H), 8.27 - 8.19 (m, 1H), 8.03 (s, 1H), 7.77 - 7.69 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.22 - 7.13 (m, 1H), 3.92 - 3.82 (m, 2H), 3.19 (s, 3H), 2.84 (d, J = 3.2 Hz, 2H), 2.55 (d, J = 6.4 Hz, 3H), 2.45 (d, J = 7.2 Hz, 2H), 2.05 - 1.88 (m, 1H), 1.77 - 1.64 (m, 2H), 1.59 - 1.49 (m, 2H), 1.49 - 1.40 (m, 2H), 1.27 - 1.12 (m, 2H), 1.09 (d, J = 5.2 Hz, 3H) ppm.

[0572] Compound A69: 3-chloro-6-((((S)-1-cyclobutylethyl)amino)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0573] Compound A69 was synthesized from the corresponding starting material according to a procedure similar to that described for compound A57 to give the product (12.7 mg, 23.87 umol, 17.86% yield). MS: M / e 532 (M+1) +; 1H NMR (400 MHz, DMSO-d6) δ = 12.01 - 11.92 (m, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.24 (d, J = 0.9 Hz, 1H), 8.03 (s, 1H), 7.75 - 7.69 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.47 - 7.35 (m, 1H), 7.22 - 7.12 (m, 1H), 3.94 - 3.78 (m, 2H), 3.19 (s, 3H), 2.84 (d, J = 3.2 Hz, 2H), 2.60 - 2.52 (m, 3H), 2.49 - 2.44 (m, 1H), 2.25 - 2.12 (m, 1H), 2.06 - 1.93 (m, 1H), 1.92 - 1.82 (m, 2H), 1.81 - 1.71 (m, 2H), 1.71 - 1.59 (m, 2H), 1.09 (d, J = 4.8 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H) ppm.

[0574] Compound A70: 6-((((S)-1-cyclobutylethyl)amino)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0575] Step A: Methyl (S)-6-(((1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0576] A solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (50 mg, 0.25 mmol), (S)-1-cyclobutylethan-1-amine hydrochloride (51 mg, 0.38 mmol), and TEA (38 mg, 0.38 mmol) in DCM (2 mL) was stirred at room temperature for 30 minutes. After cooling in an ice bath, NaBH(OAc) (81 mg, 0.38 mmol) was added, followed by AcOH (0.1 mL). The mixture was stirred at room temperature overnight. Water (2 mL) was added, the mixture was basified with NaHCO solution, and extracted with DCM (8 mL). The organic layer was dried, concentrated, and purified by preparative TLC (DCM:MeOH = 10:1) to give the product (34 mg, 49%). MS: M / e 288 (M+1). +

[0577] Step B: Methyl (S)-6-(((tert-butoxycarbonyl)(1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0578] To a solution of methyl (S)-6-(((1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (34 mg, 0.12 mmol) in DCM (2 mL) was added (Boc)2O (39 mg, 0.18 mmol), followed by TEA (19 mg, 0.18 mmol) and DMAP (2 mg, 0.01 mmol). The solution was stirred overnight at room temperature. It was concentrated and purified by preparative TLC (EA) to give the product (11 mg, 24%). MS: M / e 388 (M+1). +

[0579] Step C: (S)-6-(((tert-butoxycarbonyl)(1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0580] A solution of LiOH.HO (5 mg, 0.1 mmol, in 1 mL of water) was added to a solution of methyl (S)-6-(((tert-butoxycarbonyl)(1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (11 mg, 0.03 mmol) in MeOH (2 mL), which was stirred at room temperature for 4 hours. The reaction mixture was evaporated, dissolved in water (2 mL), and lyophilized to give the product (11 mg, crude). MS: M / e 374 (M+1). +

[0581] Step D: 6-((((S)-1-cyclobutylethyl)amino)methyl)-N-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0582] To a solution of (S)-6-(((tert-butoxycarbonyl)(1-cyclobutylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (11 mg, 0.03 mmol) and 3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (8 mg, 0.03 mmol) in DMF (1 mL) was added HATU (19 mg, 0.05 mmol) and DIEA (8 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which water (3 mL) was added, extracted with DCM (5 mL), and washed with brine (5 mL). The organic layer was dried and concentrated to give the intermediate. This was dissolved in DCM (3 mL) and HCl / dioxane (2 M, 0.5 mL) was added. After stirring for 2 h, the solution was concentrated and purified by preparative HPLC (mobile phase A: 0.1% FA-H2O, mobile phase B: 0.1% FA-ACN) to give the product (7 mg, 48%). 1H NMR (400 MHz, CD3OD) δ 8.70 (s, 1H), 8.29 (s, 1H), 8.23 ​​(s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.74 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 4.11-3.98 (m, 2H), 3.32 (s, 3H), 2.96-2.92 (m, 3H), 2.67-2.64 (m, 1H), 2.61-2.56 (m, 2H), 2.44-2.38 (m, 1H), 2.16-2.13 (m, 1H), 2.05-2.01 (m, 1H), 1.94-1.77 (m, 4H), 1.14 (t, J=4.0 Hz, 6H) ppm.MS:M / e 498 (M+1) +

[0583] Compound A71: 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0584] Step 1: Methyl 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0585] To a stirred mixture of methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (250 mg, 0.994 mmol, 1 equiv, 88.3%) and 1-cyclobutylmethanamine hydrochloride (255 mg, 1.992 mmol, 2.00 equiv, 95%) in MeOH (10 mL, 99%), titanium(IV) isopropoxide (1.2 g, 4.011 mmol, 4.04 equiv, 95%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 3 hours. To the above mixture, NaBHCN (132 mg, 1.996 mmol, 2.01 equiv, 95%) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (8:1) to give methyl 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (160 mg, 44.00%). MS: M / e 292 (M+1). + . Step 2: 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0586] To a stirred solution of methyl 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (145 mg, 0.396 mmol, 1 equiv., 79.6%) in THF (3 mL, 99%) and HO (1.5 mL, 99%), LiOH (20 mg, 0.793 mmol, 2.00 equiv., 95%) was added portionwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH = 3 with HCl (1 M). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0%; detector, UV 254 nm. This gave 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (40 mg, 36.05%). MS: M / e 278 (M+1) + .

[0587] Step 3: 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0588] To a stirred mixture of 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (25 mg, 0.089 mmol, 1 equivalent, 99.0%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (23 mg, 0.090 mmol, 1.01 equivalent, 95.0%) in pyridine (1.5 mL, 95%), T3P (568 mg, 0.893 mmol, 10.00 equivalent, 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, YMC-Actus Triart C18 ExRS, 30 × 150 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (15% ACN, up to 45% in 8 min), to give 6-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (12.4 mg, 26.45%). MS: M / e 503 (M+1). + . 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.16 (d. 3H), 2.54 (d, J = 7.2 Hz, 2H), 2.48 - 2.36 (m, 1H), 2.05 - 1.93 (m, 2H), 1.91 - 1.71 (m, 2H), 1.70 - 1.56 (m, 2H), 1.10 (d, J = 5.0 Hz, 3H) ppm.

[0589] Compound A72: 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0590] Step 1: Methyl 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0591] To a stirred mixture of methyl 3-fluoro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (220 mg, 0.874 mmol, 1 equiv, 88.3%) and (1S)-1-cyclopropylethanamine hydrochloride (224 mg, 1.750 mmol, 2.00 equiv, 95%) in MeOH (10 mL, 99%), tetrakis(propan-2-yloxy)titanium (1.1 g, 3.677 mmol, 4.21 equiv, 95%) was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. To the above mixture, NaBHCN (116 mg, 1.754 mmol, 2.01 equiv, 95%) was added in small portions. The resulting mixture was stirred at room temperature for an additional 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (8:1) to give methyl 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (150 mg, 45.52%). MS: M / e 292 (M+1) + .

[0592] Step 2: 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0593] To a stirred solution of methyl 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (145 mg, 0.385 mmol, 1 equiv., 77.3%) in THF (2 mL, 99%) and HO (1 mL, 99%), LiOH (20 mg, 0.793 mmol, 2.06 equiv., 95%) was added portionwise. The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH = 4 with HCl (1 M). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 0%; detector, UV 254 nm. This gave 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (45 mg, 37.75%). MS: M / e 278 (M+1) + .

[0594] Step 3: 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0595] To a stirred mixture of 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylic acid (20 mg, 0.065 mmol, 1 equivalent, 89.5%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (17 mg, 0.066 mmol, 1.03 equivalent, 95.0%) in pyridine (1.5 mL, 95%), T3P (411 mg, 0.646 mmol, 10.01 equivalent, 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (25% ACN, up to 55% in 8 min), to give 6-({[(1S)-1-cyclopropylethyl]amino}methyl)-3-fluoro-N-{5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-yl}imidazo[1,2-a]pyridine-8-carboxamide (7.6 mg, 22.86%). MS: M / e 503 (M+1). + . 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.50 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.34 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 8.14 - 8.08 (m, 1H), 7.62 (d, J = 6.9 Hz, 1H), 3.96 - 3.82 (m, 2H), 3.24 (s, 3H), 2.95 - 2.85 (m, 2H), 2.64 - 2.53 (m, 3H), 1.96 - 1.85 (m, 1H), 1.15 - 1.07 (m, 6H), 0.76 - 0.63 (m, 1H), 0.50 - 0.39 (m, 1H), 0.39 - 0.29 (m, 1H), 0.25 - 0.15 (m, 1H), 0.06 - 0.00 (m, 1H) ppm.

[0596] Compound A73: 3-chloro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0597] Step 1: Methyl 3-chloro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0598] A solution of methyl 6-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine-8-carboxylate (200 mg, 0.652 mmol, 1 equiv, 98.9%), 1-methylcyclopropan-1-amine hydrochloride (150 mg, 1.325 mmol, 2.03 equiv, 95%), NaI (100 mg, 0.634 mmol, 0.97 equiv, 95%), and KCO (190 mg, 1.306 mmol, 2.00 equiv, 95%) in MeCN (10 mL, 95%) was stirred at 70 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (10:1) to give methyl 3-chloro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylate) (106 mg, 43.69%). MS: M / e 294 (M+1). +

[0599] Step 2: 3-chloro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0600] To a stirred solution of methyl 3-chloro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylate (106 mg, 0.285 mmol, 1 equiv, 78.9%) in THF (1.5 mL, 95%) and HO (0.5 mL, 26.367 mmol, 92.61 equiv, 95%), LiOH (14 mg, 0.555 mmol, 1.95 equiv, 95%) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 4 with HCl (3 N). The resulting mixture was concentrated under reduced pressure. The residue was purified under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 5%-10% gradient in 4 min; detector, UV Purification by reverse-phase flash chromatography using HPLC at 220 nm gave 3-chloro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylic acid (75 mg, 94.08%).

[0601] Step 3: 3-chloro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0602] To a stirred solution of 3-chloro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylic acid (75 mg, 0.268 mmol, 1 equiv., 99.9%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (69 mg, 0.269 mmol, 1.01 equiv., 95%) in pyridine (2 mL, 95%), T3P (1.70 g, 2.680 mmol, 10 equiv., 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions: column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, 10 mmol Purification by preparative HPLC using NH4HCO3 + 0.05% NH3.HO and ACN (56% ACN, maximum 86% in 9 min); detector at 254 nm. This gave 3-chloro-6-([(1-methylcyclopropyl)amino]methyl-N-(5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-ylimidazo[1,2-a]pyridine-8-carboxamide (53.3 mg, 37.5 l). 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.85 (s, 1H), 8.53 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 3.90 (s, 2H), 3.24 (s, 3H), 2.96-2.86 (m, 2H), 2.64-2.56 (m, 3H), 1.28 (s, 3H), 1.15-1.05 (m, 3H), 0.58-0.50 (m, 2H), 0.37-0.30 (m, 2H) ppm.MS:M / e 505 (M+1) +

[0603] Compound A74: 3-fluoro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0604] Step 1: Methyl 6-(bromomethyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0605] To a stirred solution of methyl 3-fluoro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (200 mg) in CHCl (5 mL, 99%) was added PBr (64 mg) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (7:1) to give the product (140 mg). MS: M / e 287 (M+1) + .

[0606] Step 2: Methyl 3-fluoro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0607] To a 10 mL sealed tube was added methyl 6-(bromomethyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (30 mg, 0.103 mmol, 1 equiv, 98.6%), 1-methylcyclopropan-1-amine hydrochloride (24 mg, 0.212 mmol, 2.06 equiv, 95%), NaI (17 mg, 0.108 mmol, 1.05 equiv, 95%), KCO (30 mg, 0.206 mmol, 2.00 equiv, 95%), and CHCN (1 mL, 99%). The resulting mixture was stirred at 70 °C for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (7:1) to give methyl 3-fluoro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylate) (28 mg, 85.75%). MS: M / e 278 (M+1). + .

[0608] Step 3: 3-Fluoro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0609] To a stirred solution of methyl 3-fluoro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylate (28 mg, 0.088 mmol, 1 equiv., 87.5%) in THF (1.5 mg, 99%) and HO (0.5 mL, 99%), LiOH (5 mg, 0.198 mmol, 2.24 equiv., 95%) was added portionwise. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 3 with HCl (1 M). The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 0%, which gave 3-fluoro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylic acid (22 mg, 82.28%). MS: M / e 264 (M+1) + .

[0610] Step 4: 3-fluoro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0611] To a stirred mixture of 3-fluoro-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (19 mg, 0.063 mmol, 1 equivalent, 87.0%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (16 mg, 0.062 mmol, 0.99 equivalent, 95.0%) in pyridine (2 mL, 95%), T3P (400 mg, 0.629 mmol, 10.01 equivalent, 50%) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated in vacuo. The crude product (200 mg) was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (5% ACN, maximum 35% in 8 min), which gave 3-fluoro-6-([(1-methylcyclopropyl)amino]methyl-N-(5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-ylimidazo[1,2-a]pyridine-8-carboxamide) (9.7 mg, 31.05%). MS: M / e 489 (M+1). + . 1 H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.53 (s, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 8.15 - 8.08 (m, 2H), 7.63 (d, J = 6.9 Hz, 1H), 3.91 (s, 2H), 3.24 (s, 3H), 2.91 (d, J = 3.8 Hz, 2H), 2.59 (d, J = 6.6 Hz, 3H), 1.44 (s, 3H), 1.13 (m, 3H), 0.62 - 0.54 (m, 2H), 0.41 - 0.33 (m, 2H) ppm.

[0612] Compound A75: N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0613] Step 1: 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0614] To a stirred solution of methyl 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (90 mg, 0.330 mmol, 1 equiv, 95%) in THF (1.5 mL, 95%) and HO (0.5 mL, 26.367 mmol, 79.97 equiv, 95%), LiOH (17 mg, 0.674 mmol, 2.05 equiv, 95%) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 0% gradient in 4 min to give the product (80 mg, 71.12%). MS: M / e 246 (M+1) + .

[0615] Step 2: N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0616] To a stirred solution of methyl 6-(((1-methylcyclopropyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (88 mg, 0.258 mmol, 1 equiv., 71.9%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (65 mg, 0.254 mmol, 0.98 equiv., 95.0%) in pyridine (3 mL, 95%), T3P (1.64 g, 2.580 mmol, 10 equiv., 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase, 10 mmol NH4HCO3 + 0.05% NH3H2O ​​and ACN (25% ACN, up to 50% in 8 min), which gave 6-([(1-methylcyclopropyl)amino]methyl-N-(5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-ylimidazo[1,2-a]pyridine-8-carboxamide) (45.6 mg, 36.63%). MS: M / e 471 (M+1). + . 1 H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.85 (d, J = 2.3 Hz, 1H), 8.77 - 8.70 (m, 1H), 8.43 - 8.31 (m, 2H), 8.17 - 8.08 (m, 3H), 7.78 (d, J = 1.4 Hz, 1H), 3.82 (s, 2H), 3.24 (s, 3H), 2.97 - 2.85 (m, 2H), 2.65 - 2.54 (m, 3H), 1.27 (s, 3H), 1.10 (d, J = 5.1 Hz, 3H), 0.56 - 0.47 (m, 2H), 0.37 - 0.28 (m, 2H) ppm.

[0617] Compound A76: 3-fluoro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0618] Step A: Methyl 3-fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0619] A solution of methyl 6-(bromomethyl)-3-fluoroimidazo[1,2-a]pyridine-8-carboxylate (100 mg, 0.350 mmol), 1-methylcyclobutan-1-amine hydrochloride (64 mg, 0.524 mmol), KCO (145 mg, 1.050 mmol), and NaI (53 mg, 0.350 mmol) in CHCN (3 mL) was stirred at room temperature for 6 h. After completion, the reaction was quenched with aqueous NHCl (3 mL), extracted with EA (2 × 15 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound (80 mg, 79%). MS: M / e 292 (M+1). +.

[0620] Step B: 3-Fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0621] To a solution of methyl 3-fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (80 mg, 0.275 mmol) in MeOH (3 mL) and HO (1 mL) was added LiOH HO (35 mg, 0.825 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The pH was adjusted to about 6 by adding HCl (2N) and the mixture was allowed to dry to give the crude product (80 mg, crude). MS: M / e 278 (M+1). +.

[0622] Step C: 3-Fluoro-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0623] To a solution of 3-fluoro-6-(((1-methylcyclobutyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (60 mg, 0.217 mmol), 5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-amine (53 mg, 0.217 mmol) in pyridine (3 mL) was added T3P (414 mg, 0.651 mmol, 50% in EA). The mixture was stirred at room temperature for 2 hours. Then, the reaction solution was quenched with aqueous NH4Cl (2 mL), extracted with EA (2 x 10 mL), dried over Na2SO4, and concentrated in vacuo. This was purified by preparative HPLC to give the title compound (48 mg, 44%). MS: M / e 503 (M+1) + . 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.63 (d, J = 6.9 Hz, 1H), 3.78 (s, 2H), 3.23 (s, 3H), 2.90 (d, J = 3.1 Hz, 2H), 2.57 (t, J = 9.7 Hz, 3H), 2.07 - 1.96 (m, 2H), 1.70 (dt, J = 8.7, 5.0 Hz, 4H), 1.28 (s, 3H), 1.09 (d, J = 4.8 Hz, 3H) ppm.

[0624] Compound A77: 3-chloro-6-((((S)-1-cyclopropylethyl)amino)methyl)-N-(5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0625] Step 1: Methyl 3-chloro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0626] To a stirred solution of methyl 3-chloro-6-formylimidazo[1,2-a]pyridine-8-carboxylate (800 mg, 3.282 mmol, 1 equiv, 97.9%) in MeOH was added NaBH (261 mg, 6.554 mmol, 2.00 equiv, 95%) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (10:1) to give methyl 3-chloro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (550 mg, 55.71%). MS: M / e 241 (M+1) + .

[0627] Step 2: Methyl 6-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine-8-carboxylate [ka]

[0628] To a stirred solution of methyl 3-chloro-6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (550 mg, 1.828 mmol, 1 equiv., 80.0%) in CHCl3 (10 mL, 95%) was added PBr3 (0.27 mL, 2.742 mmol, 1.5 equiv., 95%) dropwise at room temperature. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CHCl2 / MeOH (10:1) to give methyl 6-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine-8-carboxylate (550 mg, 98.01%). MS: M / e 303 (M+1). + .

[0629] Step 3: Methyl (S)-3-chloro-6-(((1-cyclopropylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0630] A solution of methyl 6-(bromomethyl)-3-chloroimidazo[1,2-a]pyridine-8-carboxylate (200 mg, 0.652 mmol, 1 equiv, 98.9%), (1S)-1-cyclopropylethanamine hydrochloride (170 mg, 1.328 mmol, 2.04 equiv, 95%), NaI (100 mg, 0.634 mmol, 0.97 equiv, 95%), and KCO (190 mg, 1.306 mmol, 2.00 equiv, 95%) in MeCN (10 mL, 95%) was stirred under a nitrogen atmosphere at 70 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (19:1) to give methyl (S)-3-chloro-6-(((1-cyclopropylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylate (150 mg, 61.93%). MS: M / e 308 (M+1) + .

[0631] Step 4: (S)-3-chloro-6-(((1-cyclopropylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid [ka]

[0632] To a stirred solution of methyl 3-chloro-6-(([(1S)-1-cyclopropylethyl]aminomethyl)imidazo[1,2-a]pyridine-8-carboxylate (150 mg, 0.404 mmol, 1 equiv, 82.8%) in THF (3 mL, 95%) and HO (1 mL, 52.734 mmol, 130.68 equiv, 95%), LiOH (20 mg, 0.793 mmol, 1.97 equiv, 95%) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 4 with HCl (aq). The resulting mixture was concentrated under reduced pressure. The residue was purified under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 5%-10% gradient in 4 min; detector, UV Purification by reverse-phase flash chromatography using HPLC at 220 nm gave (S)-3-chloro-6-(((1-cyclopropylethyl)amino)methyl)imidazo[1,2-a]pyridine-8-carboxylic acid (100 mg, 83.10%). MS: M / e 294 (M+1). + .

[0633] Step 5: 3-chloro-6-((((S)-1-cyclopropylethyl)amino)methyl)-N-(5-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0634] To a stirred solution of 3-chloro-6-([(1-methylcyclopropyl)amino]methylimidazo[1,2-a]pyridine-8-carboxylic acid (75 mg, 0.268 mmol, 1 equiv., 99.9%) and 5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-amine (43 mg, 0.168 mmol, 1.00 equiv., 95%) in pyridine (2 mL, 95%), T3P (1.07 g, 1.680 mmol, 10 equiv., 50%) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was purified using the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase, 10 mmol Purification by preparative HPLC using NH4HCO3 + 0.05% NH3H2O ​​and ACN (56% ACN, max. 86% in 9 min) gave 3-chloro-6-(([(1S)-1-cyclopropylethyl]aminomethyl)-N-(5-[(1r,3s)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]pyridin-3-ylimidazo[1,2-a]pyridine-8-carboxamide (14.2 mg, 15.88%). MS: M / e 294 (M+1). + . 1 H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 8.15 - 8.08 (m, 1H), 7.96 (s, 1H), 4.04 - 3.86 (m, 2H), 3.24 (s, 3H), 2.97 - 2.83 (m, 2H), 2.69 - 2.52 (m, 4H), 2.00 - 1.85 (m, 1H), 1.15 - 1.06 (m, 6H), 0.77 - 0.61 (m, 1H), 0.52 - 0.16 (m, 3H) ppm.

[0635] Compound A78: 6-((isobutylamino)methyl)-N-(5-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-3-yl)imidazo[1,2-a]pyridine-8-carboxamide [ka]

[0636] Step 1: Methyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0637] To a stirred solution of methyl 6-formylimidazo[1,2-a]pyridine-8-carboxylate (2.4 g, 7.099 mmol, 1 equiv, 60.4%) in MeOH was added NaBH (566 mg, 14.214 mmol, 2.00 equiv, 95%) in small portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl / MeOH (8:1) to give methyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (575 mg, 37.31%). MS: M / e 207 (M+1) + .

[0638] Step 2: Methyl 6-(bromomethyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0639] To a stirred solution of methyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-8-carboxylate (550 mg, 2.534 mmol, 1 equiv., 95.0%) in CHCl3 (3 mL, 99%) was added PBr3 (722.00 mg, 2.534 mmol, 1 equiv., 95%) dropwise at 0 °C. The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with CHCl2 / MeOH (8:1) to give methyl 6-(bromomethyl)imidazo[1,2-a]pyridine-8-carboxylate (410 mg, 57.18%). MS: M / e 269 (M+1). + .

[0640] Step 3: Methyl 6-((isobutylamino)methyl)imidazo[1,2-a]pyridine-8-carboxylate [ka]

[0641] To a stirred solution of methyl 6-(bromomethyl)imidazo[1,2-a]pyridine-8-carboxylate (65 mg, 0.229 mmol, 1 equiv., 95%) and isobutylamine (35.33 mg, 0.458 mmol, 2 equiv., 95%) in acetonitrile, KCO (66.77 mg, 0.458 mmol, 2 equiv., 95%) and NaI (36.21 mg, 0.229 mmol, 1 equiv., 95%) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for an additional 3 h. The resulting mixture was concentrated ...

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, V, W, X, Y, and Z are each independently CH or N; R １ and R ２ are each independently hydrogen, substituted or unsubstituted C １－８ alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted saturated cycloalkylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, or R １ and R ２ But, R １ and R ２ together with the atom to which it is attached form a substituted or unsubstituted cycloalkyl or non-aromatic heterocyclyl; R ３ is hydrogen, halogen, -CN, hydroxyl, substituted or unsubstituted C １－８ alkyl, or substituted or unsubstituted saturated cycloalkyl; R ４ is hydrogen, halogen, substituted or unsubstituted C １－８ alkyl, or substituted or unsubstituted saturated cycloalkyl; R ５ is hydrogen, halogen, substituted or unsubstituted C １－８ alkyl, or substituted or unsubstituted saturated cycloalkyl; R ６ is hydrogen, or a substituted or unsubstituted C １－８ is alkyl, R ７ is hydrogen, deuterium, a halogen, or a substituted or unsubstituted C １－８ alkyl, or substituted or unsubstituted saturated cycloalkyl; Ring A is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; the moiety B is a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted saturated spiro bicyclic ring, or a substituted or unsubstituted non-aromatic heterocyclyl; The compound, or a pharma- ceutically acceptable salt, tautomer, stereoisomer, isotopic substitution, or enantiomer thereof, wherein m, n, and p are each independently 0, 1, or 2.

2. R ７ is hydrogen, halogen, or substituted or unsubstituted C １－８ The compound of claim 1 which is alkyl, or substituted or unsubstituted saturated cycloalkyl.

3. The compound has the formula (IIa): 【Chemistry 2】 The compound of claim 1 ,

4. The compound has the formula (IIb): 【Chemistry 3】 The compound of claim 1 ,

5. R １ is a substituted or unsubstituted C １－８ The compound of any one of claims 1 to 4, which is alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl.

6. R １ is 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 3,3-difluorocyclopentyl, cyclohexyl, 3,3-difluoro-cyclohexyl, 3-trifluoromethylcyclohexyl, or 1-methylbicyclo[1.1.1]pentyl, preferably 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, 3,3-difluoro-cyclopentyl, cyclohexyl, 3,3-difluoro-cyclohexyl, 3-trifluoromethylcyclohexyl, or 1-methylbicyclo[1.1.1]pentyl.

7. R １ is a substituted or unsubstituted C ２－８ alkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted cyclopropylmethyl, substituted or unsubstituted cyclobutylmethyl, substituted or unsubstituted cyclopentylmethyl, substituted or unsubstituted cyclohexylmethyl; More preferably, 2-methylpropyl, neopentyl, (R)-(sec-butyl), 1-methylcyclopropyl, 1-methylcyclobutyl, (1S,3S)-3-methylcyclobutyl, 3-methylcyclobutyl, (R)-3,3-difluorocyclopentyl, cyclopropylmethyl, (S)-3,3-difluorocyclopentyl, (S)-1-cyclopropylethyl, (1-methylcyclopropyl)methyl, (1-fluorocyclopropyl)methyl, cyclobutylmethyl, 1-cyclobutylethyl, (S)-1-cyclobutylethyl, (1-methylcyclobutyl)methyl, (1- 6. The compound according to any one of claims 1 to 5, wherein the aryl group is 1-fluorocyclobutyl, cyclopentylmethyl, (1-methylcyclopentyl)methyl, (1-fluorocyclopentyl)methyl, 1-cyclopentylethyl, (S)-1-cyclopentylethyl, (1-methylcyclopentyl)methyl, cyclohexylmethyl, 1-cyclohexylethyl, (1-methylcyclohexyl)methyl, (4,4-difluorocyclohexyl)methyl, (3,3-difluorocyclohexyl)methyl, (3,3-difluorocyclopentyl)methyl, cyclohexyl, or cycloheptyl.

8. R ２ The compound according to any one of claims 3 to 7, wherein is hydrogen.

9. The compound is of formula (IIIa) 【Chemistry 4】 wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R ８ is hydrogen, halogen, substituted or unsubstituted C １－８ Alkyl, substituted or unsubstituted C １－８ alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R ８ together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3; Other variables R ３ , R ４ , R ５ , R ６ , R ７ 2. The compound of claim 1, wherein ring A, moiety B, p, and n are as defined in formula (I).

10. The compound is of formula (IIIb), 【Chemistry 5】 wherein the moiety C is a substituted or unsubstituted saturated spiro bicyclic ring, a substituted or unsubstituted non-aromatic heterocyclyl, or a substituted or unsubstituted amino; R ８ is hydrogen, halogen, substituted or unsubstituted C １－８ Alkyl, substituted or unsubstituted C １－８ alkoxyl, substituted or unsubstituted saturated cycloalkyl, or substituted or unsubstituted saturated cycloalkylalkyl, or two R ８ together with the atom(s) to which they are attached form a substituted or unsubstituted saturated cycloalkyl or a substituted or unsubstituted saturated spirocyclic ring; q is 0, 1, 2, or 3; Other variables R ３ , R ４ , R ５ , R ６ , R ７ 2. The compound of claim 1, wherein ring A, moiety B, p, and n are as defined in formula (I).

11. The compound of any one of claims 1 to 10, wherein Ring A is a substituted or unsubstituted bicyclic heteroaryl.

12. Ring A is 【Chemistry 6】 The compound according to any one of claims 1 to 11,

13. Ring A is 【Chemistry 7】 The compound according to any one of claims 1 to 12,

14. R ３ is hydrogen, halogen, or substituted or unsubstituted C １－８ A compound according to any one of claims 1 to 13, wherein R is alkyl, preferably hydrogen, F, Cl or methyl.

15. 【Chemical 8】 The compound according to any one of claims 1 to 14,

16. Part B is 【Chemistry 9】 The compound according to any one of claims 1 to 15,

17. Part B is 【Chemistry 10】 and preferably 【Chemistry 11】 The compound according to any one of claims 1 to 15,

18. 18. The compound according to any one of claims 9 to 17, wherein the moiety C is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, or a substituted or unsubstituted saturated spiro-bicyclic ring, wherein one ring of the spiro-bicyclic ring is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, and the other ring of the spiro-bicyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

19. 18. The compound according to any one of claims 9 to 17, wherein the moiety C is substituted or unsubstituted aminoalkyl, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino. 【Request 20】 【Chemical 12-1】 【Chemistry 12-2】 The compound according to any one of claims 9 to 19,

21. 【Chemical 13】 The compound according to any one of claims 9 to 19,

22. Ring A is 【Chemistry 14】 The compound according to any one of claims 1 to 10,

23. Ring A is 【Chemistry 15】 The compound according to any one of claims 1 to 10,

24. R ３ is hydrogen, halogen, -CN, -CF ３ , substituted or unsubstituted C １－４ The compound of any one of claims 22 to 23, which is alkyl, or substituted or unsubstituted cycloalkyl.

25. R ３ The compound according to any one of claims 20 to 21, wherein is H, F, Cl, Br, or methyl.

26. 【Catalog 16】 The compound according to any one of claims 22 to 25,

27. 【Catalogue 17】 The compound according to any one of claims 22 to 25,

28. Part B is 【Chemistry 18】 and preferably 【Chemistry 19】 The compound according to any one of claims 22 to 27,

29. Part B is 【Chemistry 20】 and preferably 【Chemistry 21】 The compound according to any one of claims 22 to 27,

30. 30. The compound of any one of claims 22 to 29, wherein the moiety C is substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl, substituted or unsubstituted azetidyl, or substituted or unsubstituted 5-azaspiro[2.4]heptyl.

31. 30. The compound according to any one of claims 22 to 29, wherein the moiety C is substituted or unsubstituted alkylamino, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl.

32. 【Chemical 22】 The compound according to any one of claims 22 to 31, 【Request 33】 【Chemical 23】 The compound according to any one of claims 22 to 31,

34. Ring A is 【Chemistry 24】 and preferably 【Chemistry 25】 The compound according to any one of claims 1 to 10,

35. R ３ is hydrogen, halogen, hydroxyl, or substituted or unsubstituted C １－４ The compound of claim 34, wherein is alkyl, preferably methyl, F, or spiro-cyclopropyl.

36. A compound according to any one of claims 34 to 35, wherein p is 0, 1 or 2, or preferably 2.

37. 【Catalogue 26】 The compound according to any one of claims 34 to 36,

38. Part B is 【Chemistry 27】 The compound according to any one of claims 34 to 37,

39. Part B is 【Chemistry 28】 and preferably 【Chemical 29】 The compound according to any one of claims 34 to 37,

40. Compounds according to any one of claims 34 to 39, wherein the moiety C is substituted or unsubstituted alkylamino, substituted or unsubstituted cyclohexylmethylamino, substituted or unsubstituted cyclopentylmethylamino, substituted or unsubstituted cyclobutylmethylamino, or substituted or unsubstituted saturated cyclopropylmethylamino, substituted or unsubstituted azetidyl, substituted or unsubstituted azepanyl, substituted or unsubstituted piperidyl, substituted or unsubstituted pyrrolidyl.

41. 【Chemical 30】 The compound according to any one of claims 34 to 40,

42. 【Chemical 31】 The compound according to any one of claims 34 to 40,

43. R ５ is hydrogen, substituted or unsubstituted C １－８ A compound according to any one of claims 1 to 42, which is alkyl, or substituted or unsubstituted saturated cycloalkyl, preferably hydrogen or methyl.

44. R ６ The compound according to any one of claims 1 to 43, wherein is methyl or ethyl.

45. R ６ The compound according to any one of claims 1 to 43, wherein is methyl-d3.

46. The compound of any one of claims 1 to 45, wherein n and p are each independently 0 or 1.

47. The compound according to any one of claims 1 to 46, wherein m is 1.

48. R ７ is hydrogen, substituted or unsubstituted C １－４ The compound of any one of claims 1 to 47, which is alkyl, or substituted or unsubstituted cycloalkyl.

49. R ７ is hydrogen, deuterium, methyl, ethyl, isopropyl, or 2-hydroxyethyl, preferably R ７ The compound according to any one of claims 1 to 48, wherein is hydrogen or methyl.

50. 50. The compound of any one of claims 1 to 49, wherein the compound is selected from Table 1, Table 2, and Table 3.

51. 51. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 50, or a pharma- ceutically acceptable salt, tautomer, isotopic substitute, stereoisomer, or prodrug thereof, and a pharma- ceutically acceptable carrier, excipient, or vehicle.

52. 51. A method of modulating the activity of an immune cell, comprising contacting said cell with an effective amount of a compound of any one of claims 1 to 50, or a pharma- ceutically acceptable salt, tautomer, isotopic substitution, stereoisomer, or prodrug thereof.

53. A method for treating or preventing a cancer responsive to Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 50.

54. 54. The method of claim 53, wherein the cancer is a hematological cancer.

55. 55. The method of claim 54, wherein the hematological cancer is lymphoma, leukemia, myeloma, or glioblastoma.

Images