Piperidine derivatives as METTL3 inhibitors

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, wherein m, n, R 1 , R 2 , R 3 , R 4 , R 5 , L, Ar 1 and Ar 2 as defined in the claims, which are useful as inhibitors of METTL3 (N6-adenosine methyltransferase subunit) activity, particularly for the treatment of proliferative diseases such as cancer. [Formula 1] TIFF2026504952000171.tif43159

Description

[Technical Field]

[0001] The present invention relates to piperidine derivatives, particularly compounds of formula (I) as detailed below, which are useful as inhibitors of METTL3 (N6-adenosine methyltransferase subunit) activity, particularly for the treatment of proliferative diseases such as cancer. [Background technology]

[0002] The most well-characterized and common post-transcriptional internal mRNA modification in eukaryotes is adenosine methylation at position 6, resulting in the formation of N6-methyladenosine (m6A). This modification was first analyzed transcriptome-wide using high-throughput sequencing techniques, and since then, significant progress has been made in elucidating its prevalence, distribution, and biological function. Approximately 0.1–0.4% of all mRNA adenosines are m6A methylated, corresponding to approximately 3–5 modifications per mRNA molecule. Its distribution is species- and tissue-specific, with the highest abundance found in brain, liver, kidney, and malignant tissues. The m6A modification has been shown to play an important role in regulating gene expression by exerting various biological functions, including RNA stability, maturation, export, decay, and translation (Roundtree et al., Cell, 2017, 169, 1187–1200).

[0003] Multiple m6A-regulating enzymes have been identified and classified as m6A "writers," "erasers," and "readers." Evidence suggests that the m6A modification is dynamic and its introduction requires a multicomponent system, including two methyltransferases, METTL3 and METTL14, that play key roles in the process (Liu et al., Nature Chemical Biology, 2014, 10, 93-95). METTL3 functions as the primary catalytic subunit, while METTL14 functions as the RNA-binding scaffold. m6A is also a reversible modification through the actions of two RNA demethylases, FTO and ALKBH5. Alterations in the m6A mechanism have been linked to several pathologies, including neuropathies, diabetes, obesity, cardiovascular disease, immune disorders, and infectious diseases (Yang et al., Cell Death & Disease, 2020, 11, 960). The importance of the m6A modification in cancer is emerging due to the important role played by the m6A enzyme in both solid tumors and hematological malignancies (Barbieri and Kouzarides, Nature Reviews Cancer, 2020, 20, 303-322).

[0004] The m6A methyltransferase METTL3 is the primary enzyme responsible for catalyzing the deposition of m6A onto nascent mRNA in nuclear speckles. Together with METTL14, METTL3 forms a heterodimeric catalytic complex that mediates the transfer of a methyl group from S-adenosylmethionine to mRNA molecules. The introduction of m6A is mediated by additional cofactors, including regulatory proteins such as Wilms' tumor 1-associated protein (WTAP), VIRMA, and RNA-binding motif protein (RBM15), which play roles in complex formation and substrate binding. In addition to its methyltransferase activity, METTL3 has been shown to promote the translation of specific mRNA targets.

[0005] The physiological role of METTL3-mediated m6A modification has been reported, namely, that this writer is involved in neurogenesis and nervous system cell reprogramming, immune response, stemness, cardiac homeostasis, and reproduction. METTL3 is also involved in several pathologies, especially neurodegenerative diseases, metabolic disorders, inflammatory responses, and cancer (Ibid., Yang et al., 2020).

[0006] The METTL3 enzyme is associated with all hallmarks of cancer and regulates key tumorigenic processes (cell cycle and proliferation, apoptosis, migration, stemness, metabolism, and immune surveillance). Oncogenic activity has been attributed to this methyltransferase in the majority of cancers (ibid., Barbieri and Kouzarides, 2020). The tumor-promoting activity of METTL3 relies primarily on its ability to regulate the stability and translation of key oncogene and tumor suppressor mRNA targets (MYC, SOX4, mTORC, PTEN, BCL2, SP1) in an m6A-dependent manner.

[0007] Several studies have implicated m6A-related enzymes in tumor growth, revealing that the m6A writer METTL3 is essential for the growth and maintenance of acute myeloid leukemia (AML) (Barbieri et al., Nature, 2017, 552, 126-131; Vu et al., Nature Medicine, 2017, 23, 1369-1376). Using CRISPR screens, in vitro, and in vivo models, we identified METTL3 as a gene required for AML growth and myeloid differentiation. Of all the identified RNA-modifying enzymes, METTL3 achieved the highest score in the CRISPR screen, which was confirmed by in vitro proliferation assays in a panel of 10 AML cell lines. Genetic ablation of METTL3 resulted in cell cycle arrest, differentiation of AML cells, and an inability to initiate leukemia in an in vivo model. Mechanistically, METTL3 exerts its leukemia-promoting activity by promoting the translation of oncogenic targets (SP1 / 2) in an m6A-dependent manner.

[0008] METTL3 has also been shown to be upregulated in AML compared with healthy human hematopoietic stem / progenitor cells and other tumor cell types (ibid., Vu et al., 2017). While depletion of METTL3 promotes leukemic cell differentiation and reduces tumor growth, overexpression of wild-type but not catalytic mutant forms sustains AML maintenance and proliferation. The same study reported that downregulation of METTL3 in an in vivo leukemia model favors AML cell differentiation and apoptosis. The tumor-promoting function of METTL3-mediated m6A modification in AML was attributed to increased translation of key leukemia mRNA targets c-MYC, BCL2, and PTEN, as well as activation of the AKT signaling pathway. Inhibition of METTL3 activity with a small molecule inhibitor has been shown to result in favorable anticancer responses in patient-derived leukemia models (Yankova et al., Nature, 2021, 593, 597-601).

[0009] Overall, these findings identify the catalytic activity of METTL3 as a promising therapeutic target in AML.

[0010] METTL3 has also been implicated in the development, progression, and metastasis of solid tumors. Aberrant expression of this reporter has been reported in several solid tumors, including glioblastoma (Visvanathan et al., Oncogene, 2018, 37, 522-533), hepatocellular carcinoma (Lin et al., Nature Communications, 2019, 10, 2065), cervical cancer (Wang et al., Cell Death & Disease, 2020, 11, 911), breast cancer (Wang et al., Gene, 2020, 722, 144076), bladder cancer (Cheng et al., Oncogene, 2019, 38, 3667-3680), colorectal cancer (Li et al., Molecular Cancer, 2019, 18, 112), and esophageal cancer (Wang et al., Nature Communications, 2021, 12, 3803). In these cancers, METTL3 promotes the translation of key oncogenic targets (SOX2, SNAIL, BCL2, MYC, IKBKB) and is associated with poor patient prognosis. Genetic targeting of METTL3 in cells and in vivo models has been shown to reduce tumor growth, invasion, metabolic reprogramming, and immune evasion (ibid., Barbieri and Kouzarides, 2020).

[0011] Overall, these findings suggest that pharmacological targeting of METTL3 offers a promising and powerful therapeutic opportunity for developing new anticancer epidrugs.

[0012] Recent studies have revealed that METTL3 depletion alters the replication of various viruses (Winkler et al., Nature Immunology, 2019, 20, 173-182). Following viral infection or cell stimulation with inactivated virus, METTL3 deletion resulted in increased induction of interferon-stimulated genes. As a result, the replication of various viruses was suppressed in an interferon signal-dependent manner. Importantly, IFNB mRNA was modified with m6A and stabilized after METTL3 suppression. m6A functions as a negative regulator of the interferon response by directing rapid turnover of interferon mRNA, thereby promoting viral replication.

[0013] METTL3-dependent m6A on the HBV and HCV viral genomes controls viral genome recognition by the RIG-I RNA sensor. Depletion of METTL3 promotes viral dsRNA recognition and induces antiviral immune responses (Kim et al., J. Biol. Chem., 2020, 295, 13123-131333).

[0014] Recent studies have shown that (i) METTL3 depletion promotes the expression of innate immune effector genes (suggesting that reducing m6A levels in SARS-CoV-2 RNA can enhance host cell immunity against viral infection) and (ii) METTL3 depletion reduces the mRNA expression and m6A levels of several proviral host genes during SARS-CoV-2 infection (Li et al., Cell Reports, 2021, 35, 109091). The synergistic effect of directly controlling viral m6A levels to promote a timely innate immune response and indirectly disrupting the viral life cycle by depleting / inhibiting METTL3 may be beneficial for the treatment of COVID-19 patients, especially those with mild or moderate disease who do not develop a cytokine storm (ibid., Li et al., 2021). The ability of a METTL3 small molecule inhibitor to restrict coronavirus replication in a cell line model has recently been demonstrated (U.S. Patent Application Publication No. 2022 / 125768).

[0015] Therefore, METTL3 inhibitors may also provide novel therapeutic approaches for treating various infectious and inflammatory diseases, in particular they offer potential therapeutic agents for viral diseases.

[0016] Thus, the present invention provides novel METTL3 (N6 adenosine-methyltransferase subunit) inhibitors that may be useful in the treatment of METTL3 / 14 complex-associated diseases, particularly cancer, infectious diseases and inflammatory diseases. Summary of the Invention

[0017] The present invention therefore provides compounds of formula (I): [ka] or a pharmaceutically acceptable salt and / or solvate thereof, wherein m, n, R 1 , R 2 , R 3 , R 4 , R 5 , L, Ar 1 and Ar 2 is as defined in the claims and below.

[0018] The present invention also relates to pharmaceutical compositions comprising a compound according to the invention or a pharmaceutically acceptable salt and / or solvate thereof and at least one pharmaceutically acceptable carrier.

[0019] Another aspect of the present invention relates to a compound according to the present invention or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicament.

[0020] The present invention also relates to a compound according to the present invention or a pharmaceutically acceptable salt and / or solvate thereof for use in treating a proliferative disorder, preferably cancer. In one embodiment, the cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, leukemia, lymphoma, multiple myeloma, non-Hodgkin's lymphoma (NHL), bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal / upper gastrointestinal cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, and thyroid cancer.

[0021] The present invention further relates to a compound according to the invention or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of an autoimmune disease, a neurological disease, an inflammatory disease or an infectious disease.

[0022] The present invention further relates to the compounds according to the invention or pharmaceutically acceptable salts and / or solvates thereof for use in inhibiting METTL3 activity.

[0023] definition The following definitions and explanations are for terms used throughout this application, including both the specification and the claims. Terms used in describing the compounds of the present invention shall be construed in accordance with the following definitions unless otherwise indicated.

[0024] When a chemical substituent is a combination of chemical groups, the point of attachment of the substituent to the molecule is through the last chemical group listed. For example, an arylalkyl substituent is attached to the rest of the molecule through the alkyl moiety and may be depicted as "alkyl-aryl."

[0025] In the present invention, the following terms have the following meanings:

[0026] "Alkyl" alone or as part of another substituent refers to a group of formula C n H 2n+1 (where n is a number equal to or greater than 1) refers to a hydrocarbyl radical of the formula: (where n is a number equal to or greater than 1). Generally, alkyl groups of the present invention contain 1 to 12 carbon atoms, 1 to 6 carbon atoms, and preferably 1 to 4 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as indicated in the present invention. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl and its isomers (e.g., n-pentyl, isopentyl), and hexyl and its isomers (e.g., n-hexyl, isohexyl). Preferred alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

[0027] As used herein, "alkylamino" refers to an amino group substituted with one alkyl group, as defined herein (i.e., -NH2). As used herein, "dialkylamino" refers to an amino group substituted with two alkyl groups, as defined herein.

[0028] "Alkylaminocarbonyl" and "dialkylaminocarbonyl" refer to any -(C=O)-alkylamino and -(C=O)-dialkylamino group, respectively, where alkylamino and dialkylamino are defined above.

[0029] As used herein, "alkoxy" refers to any -O-alkyl group, where alkyl is as defined above. Suitable alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, s-butoxy, and n-pentoxy.

[0030] As used herein, "alkynyl" refers to a monovalent unsaturated hydrocarbyl group, where the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Generally, an alkynyl group contains from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. Suitable alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, and 3-butynyl.

[0031] "Aryl," alone or as part of another substituent, refers to a polyvalent, unsaturated, aromatic hydrocarbyl group having a single ring (i.e., phenyl) or multiple aromatic rings fused (e.g., naphthyl) or covalently linked together, typically containing 5 to 12, preferably 6 to 10, atoms, in which at least one ring is aromatic. The aromatic ring may optionally contain one to two additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Non-limiting examples of aryl include phenyl, biphenylyl, biphenylenyl, 5-tetralinyl, 6-tetralinyl, naphthalen-1-yl, naphthalen-2-yl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-acenaphthylenyl, 2-acenaphthylenyl, 3-acenaphthylenyl, 4-acenaphthylenyl, 5-acenaphthylenyl, 3-acenaphthenyl, 4-acenaphthenyl, 5-acenaphthen ... naphthenyl, 5-acenaphthenyl, 1-pentalenyl, 2-pentalenyl, 4-indanyl, 5-indanyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 7-tetrahydronaphthyl, 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-pyrenyl, 2-pyrenyl, 3-pyrenyl, 4-pyrenyl or 5-pyrenyl.

[0032] "Cycloalkyl," alone or as part of another substituent, refers to a cyclic alkyl group, i.e., a monovalent saturated or unsaturated hydrocarbyl group having one or two ring structures. Cycloalkyl includes monocyclic and bicyclic hydrocarbyl groups. Cycloalkyl groups can contain three or more carbon atoms in the ring, and generally, according to the present invention, contain 3 to 10, more preferably 3 to 8, and even more preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] "Cycloalkyl-alkyl" refers to any -alkyl-cycloalkyl group, where alkyl and cycloalkyl are defined above.

[0034] "Cycloalkyloxy" refers to any -O-cycloalkyl group, where cycloalkyl is as defined above.

[0035] "Haloalkyl," by itself or as part of another substituent, refers to an alkyl radical having the meaning defined above in which one or more hydrogens have been replaced with a halogen, as defined above. Non-limiting examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.

[0036] "Haloalkoxy," by itself or as part of another substituent, refers to an alkoxy radical having the meaning defined above in which one or more hydrogens have been replaced with a halogen, as defined above. Suitable haloalkoxy groups include, for example, trifluoromethoxy.

[0037] "Heteroaryl," alone or as part of another substituent, refers to an aromatic ring or ring system of 5 to 12 carbon atoms containing one to two fused or covalently bonded rings, typically containing 5 or 6 atoms, at least one of which is aromatic, and in which one or more carbon atoms in one or more of the rings are replaced with oxygen, nitrogen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl ring. Non-limiting examples of such heteroaryls include furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, and isobenzothiophenyl. , indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3- Examples include benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 6-oxopyridazin-1(6H)-yl, 2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0038] As used herein, "heterocyclyl," alone or as part of another substituent, refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., a 3- to 7-membered monocyclic ring, a 7- to 11-membered bicyclic ring, or a total of 3 to 10 ring atoms) having at least one heteroatom in a ring containing at least one carbon atom. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Any of the carbon atoms of a heterocyclic group can be substituted with oxo (e.g., piperidone, pyrrolidinone). A heterocyclic group can be attached at any heteroatom or carbon atom of the ring or ring system, if valences permit. The rings of polycyclic heterocyclic compounds can be fused, bridged, and / or attached through one or more spiro atoms. Non-limiting exemplary heterocyclic groups include oxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl, isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolinyl, yl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, thiomorpholin-4-yl sulfoxide, thiomorpholin-4-yl sulfone, 1,3-dioxolanyl, 1,4-oxathianyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

[0039] "Heterocyclyl-alkyl" refers to any -alkyl-heterocyclyl group, where alkyl and heterocyclyl are as defined above.

[0040] "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent.

[0041] "Pharmaceutically acceptable" means that the component is not harmful to the subject to which it is administered, and is compatible with each of the other components with which it is administered.

[0042] A "pharmaceutically acceptable carrier" refers to an excipient that does not produce adverse, allergic, or other untoward reactions when administered to animals, preferably humans. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Formulations for human administration must meet sterility, pyrogenicity, general safety, and purity standards required by regulatory authorities, such as the FDA or EMA.

[0043] As used herein, "prodrug" refers to a pharmacologically acceptable derivative of a compound of the present invention whose biotransformation product is an active drug. Prodrugs are characterized by increased bioavailability and are easily metabolized in vivo to the active compound. Prodrugs suitable for the purposes of the present invention include carboxylic acid esters, particularly alkyl esters, aryl esters, acyloxyalkyl esters, dioxolene carboxylic acid esters, and ascorbic acid esters.

[0044] "Solvate" is used herein to describe a molecular complex comprising a compound of the invention and containing a stoichiometric or sub-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0045] "Administration" or variations thereof (e.g., "administering") means providing an active agent or ingredient, alone or as part of a pharmaceutically acceptable composition, to a subject in need thereof.

[0046] "Subject" refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from and / or susceptible to developing a target disease. In one embodiment, the subject is a "patient," i.e., a mammal, preferably a human, awaiting or receiving medical care, or has been, is currently, or will be the subject of medical treatment, or is being monitored for the development of a target disease.

[0047] As used herein, a "therapeutically effective amount" (or more simply, "effective amount") refers to an amount of an active agent or ingredient intended to prevent, alleviate, relieve or slow (slow progression of) one or more symptoms of a target disease without causing significant adverse or harmful side effects to the subject in need of treatment.

[0048] "Treating" or "treatment" refers to therapeutic or prophylactic treatment, or both, aimed at preventing, alleviating, alleviating, and / or slowing (slowing progression) one or more symptoms of the target disease in a subject in need thereof. Those in need of treatment include those already with the disease as well as those prone to have the disease, or those in whom the disease is to be prevented. DETAILED DESCRIPTION OF THE INVENTION

[0049] compound The present invention provides compounds of formula (I): [ka] or a pharmaceutically acceptable salt and / or solvate thereof, During the ceremony, R 1 is C 2~12 Alkyl, C 2~12 Haloalkyl, C3~8 Cycloalkyl-C 1~3 Alkyl, heterocyclyl-C 1~3 Alkyl, C 3~8 is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl moieties are C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 optionally substituted with one or more substituents selected from haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are C 3~6 Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 haloalkoxy; and / or said cycloalkyl and heterocyclyl moieties are optionally bridged ring systems; R 2 is H, or halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 C optionally substituted with one or more substituents selected from haloalkoxy 1~4 Alkyl, or C 3~6 is cycloalkyl, or Or R 1 and R 2 form a heterocyclic ring together with the nitrogen atom to which they are attached, Here, the heterocycle is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 optionally substituted with one or more substituents selected from haloalkoxy; and / or the heterocycle is C 3~6 Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 haloalkoxy; and / or the heterocyclyl ring is optionally a bridged ring system; Each R 3 is independently C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy, C 1~4 haloalkoxy, oxo, or thioxo; Two R's on the same carbon atom 3 The groups are spiro-fused together with the carbon atoms to which they are attached. 3~6 forming a cycloalkyl, or Two R's on two adjacent carbon atoms 3 The groups, together with the carbon atoms to which they are attached, form fused C 3~6 forming a cycloalkyl, or Two R's on two non-adjacent carbon atoms 3 The group is bonded to C 1~4 It forms an alkyl bridge, m is 0, 1, 2, 3, or 4; n is 1 or 2, R 4 and R 5 are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, halo, cyano, or hydroxy; R 4 and R 5 together with the carbon atom to which they are attached form a heterocyclyl ring or C 3~4forming a cycloalkyl ring, wherein the heterocyclyl and cycloalkyl moieties are C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 optionally substituted with one or more substituents selected from haloalkyl, halo, or cyano; R 4 and R 5 together with the carbon atom to which they are attached form an ethylenyl, Ar 1 (Ar 1a ), (Ar 1b ) and (Ar 1c ): [ka] an aryl or heteroaryl group selected from During the ceremony, p is 0, 1, 2, 3, or 4; R 6 is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 haloalkyl, halo, or cyano; Each X is independently N, NR 7 , C, C.R. 8 , C(O) and C(S), wherein at least one of X is N or NR 7 and R 7 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 is haloalkyl, R 8 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, Each Y is independently N, NR 9 ,S,O,C,CR 10, C(O) and C(S), wherein at least one of Y is N, NR 9 , S or O, R 9 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 is haloalkyl, R 10 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, [ka] represents a single or double bond depending on X or Y, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 represents the point of attachment to the - moiety, L is (L 1 ), (L 2 ) and five-membered heteroaryl (L 3 ): [ka] is selected from During the ceremony, X 1 is O or S, preferably X 1 is O, Each Z is independently N, NR 11 ,S,O,C,CR 12 , C(O) and C(S), wherein at least one of Z is N, NR 11 , S or O, R 11 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 is haloalkyl, R 12 is H, C 1~4 Alkyl, C 3~6Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, [ka] represents a single or double bond depending on Z, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 represents the point of attachment to Ar 2 is preferably halo, cyano, oxo, hydroxy, amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~6 Cycloalkyloxy, (C 1~4 alkyl)aminocarbonyl, (C 1~4 haloalkyl)aminocarbonyl, di(C 1~4 alkyl)aminocarbonyl, di(C 1~4 haloalkyl)aminocarbonyl, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)aminocarbonyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 2~4 Alkynyl, C 6~10 a 5-10 membered mono- or bicycloaryl or heteroaryl group optionally substituted with one or more substituents selected from aryl, heteroaryl and heterocyclyl, wherein the substituents are preferably halo, cyano, oxo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, or one or more C 3~6 The cycloalkyl or heterocyclyl group may be fused to the above heterocyclyl substituents, or may be one or more C optionally substituted with one or more halo. 3~6 A cycloalkyl or heterocyclyl group may be spiro-fused to said heterocyclyl substituent.

[0050] n, m, R 3 According to one embodiment, the compound of formula (I) comprises a piperidine group, i.e., n is 1. According to another embodiment, the compound of formula (I) comprises an azepane group, i.e., n is 2. According to a preferred embodiment, n is 1.

[0051] According to one embodiment, m is preferably 0, 1 or 2. In one preferred embodiment, m is 0.

[0052] According to one embodiment, if present, R 3 is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 is selected from alkoxy and oxo, preferably R 3 is C 1~2 alkyl or halo, more preferably R 3 is methyl or F.

[0053] According to another embodiment, m is at least equal to 2 and two R 3 The groups are bonded to each other. 3When the groups are on the same carbon atom, they can form a spiro-fused cycloalkyl with the carbon atoms to which they are attached. 3 If the groups are present on two adjacent carbon atoms, the fused cycloalkyls can be joined by the carbon atoms to which they are attached. 3 When the groups are present on two non-adjacent carbon atoms, they can form an alkyl bridge on the piperidine or azepane group to which they are attached.

[0054] NR 1 R 2 According to one embodiment, R 1 is C 2~12 Alkyl, C 2~12 Haloalkyl, C 3~8 Cycloalkyl-C 1~3 Alkyl, heterocyclyl-C 1~3 Alkyl, C 3~8 is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl moieties are C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 optionally substituted with one or more substituents selected from haloalkoxy; and / or the cycloalkyl and heterocyclyl moieties are C 3~6 Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 haloalkoxy; and / or said cycloalkyl and heterocyclyl moieties are optionally bridged ring systems.

[0055] R1 The phrase "wherein the cycloalkyl and heterocyclyl moieties are optionally ..." in the above definition of 3~8 Cycloalkyl and heterocyclyl and moieties that are part of a constituent group, i.e., C 3~8 Cycloalkyl-C 1~3 Alkyl or heterocyclyl-C 1~3 It refers to both cycloalkyl or heterocyclyl groups within an alkyl group.

[0056] According to one embodiment, R 2 is H, or halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 C optionally substituted with one or more substituents selected from haloalkoxy 1~4 Alkyl, or C 3~6 cycloalkyl, preferably R 2 is H or methyl, more preferably R 2 is H.

[0057] According to another embodiment, R 1 and R 2 form a heterocyclic ring together with the nitrogen atom to which they are attached, Here, the heterocycle is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 optionally substituted with one or more substituents selected from haloalkoxy; and / or the heterocycle is C 3~6 Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy and C 1~4 haloalkoxy; and / or the heterocyclyl ring is optionally a bridged ring system.

[0058] R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle, the heterocycle may contain one or more additional heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.

[0059] According to one embodiment, NR 1 R 2 teeth, [ka] is selected from During the ceremony, [ka] represents the point of attachment to the remainder of the compound.

[0060] According to one embodiment, NR 1 R 2 teeth, [ka] is selected from During the ceremony, [ka] represents the point of attachment to the remainder of the compound.

[0061] According to one embodiment, NR 1 R 2 teeth, [ka] is selected from During the ceremony, [ka] represents the point of attachment to the remainder of the compound.

[0062] According to one embodiment, NR 1 R 2 teeth, [ka] is selected from During the ceremony, [ka] represents the point of attachment to the remainder of the compound.

[0063] Ar 1 In the compounds of the present invention, Ar 1 is defined hereinabove (Ar 1a ), (Ar 1b ) and (Ar 1c is a 6-membered aryl or 5- or 6-membered heteroaryl group selected from

[0064] According to one embodiment, Ar 1 is a six-membered aryl group (Ar 1a ): [ka] and During the ceremony, p is 0, 1, 2, 3 or 4, preferably p is 0 or 1, more preferably p is 0; R 6 is C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 haloalkyl, halo, or cyano, preferably R 6 is methyl, F, Cl or cyano, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0065] According to one embodiment, Ar 1 is a six-membered heteroaryl group (Ar 1b ): [ka] and During the ceremony, Each X is independently N, NR 7 , C, C.R. 8 , C(O) and C(S), wherein at least one of X is N or NR 7 and R 7 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 7 is H, R 8 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 8 is H, methyl, halo, more preferably R 8 is H, [ka] represents a single or double bond depending on X, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0066] In one embodiment, Ar 1b is preferably [ka] is selected from During the ceremony, R 7 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C1~4 haloalkyl, preferably R 7 is H, R 8 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 8 is H, methyl, halo, more preferably R 8 is H, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0067] According to one embodiment, Ar 1 is a five-membered heteroaryl group (Ar 1c ): [ka] and During the ceremony, Each Y is independently N, NR 9 ,S,O,C,CR 10 , C(O) and C(S), wherein at least one of Y is N, NR 9 , S or O, R 9 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 9 is H, R 10 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 10 is H, [ka] represents a single or double bond depending on Y, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0068] According to another embodiment, Ar 1c teeth, [ka] is selected from During the ceremony, R 9 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 9 is H, R 10 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 10 is H, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0069] According to one embodiment, Ar 1 teeth, [ka] is selected from During the ceremony, R 7 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 7 is H, R 8 is H, C 1~4 Alkyl, C3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 8 is H, methyl, halo, more preferably R 8 is H, R 9 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 9 is H, R 10 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 10 is H, * represents the point of attachment to the piperidine ring, and ** is -CR 4 R 5 - represents the point of attachment to the moiety.

[0070] R 4 , R 5 According to one embodiment, R 4 and R 5 are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, halo, cyano, or hydroxy, preferably R 4 and R 5 are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, more preferably R 4 and R 5 are each independently H, methyl, ethyl, CF, or cyclopropyl. 4 and R 5are both H, or one is H and the other is methyl.

[0071] According to another embodiment, R 4 and R 5 together with the carbon atoms to which they are attached, The heterocyclyl and cycloalkyl moieties are C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 a heterocyclyl ring or C optionally substituted with one or more substituents selected from haloalkyl, halo, or cyano 3~4 a cycloalkyl ring, or Ethylene group is formed.

[0072] In one embodiment, R 4 and R 5 are oxetane, cyclopropyl, cyclobutyl, C optionally substituted together with the carbon atom to which they are attached with one or two halo substituents (preferably fluoro); 1~4 In one preferred embodiment, R 4 and R 5 together with the carbon atom to which they are attached form a group selected from oxetane, cyclopropyl, and ethylenyl. 4 and R 5 together with the carbon atom to which they are attached form an oxetane group.

[0073] In another preferred embodiment, R 4 and R 5 are both H, or one is H and the other is methyl, or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane group.

[0074] Linker L According to one embodiment, L is an amide or thioamide (L) as defined hereinabove. 1 ), retroamide or retrothioamide (L 2 ) and five-membered heteroaryl (L 3 ) is selected.

[0075] According to one embodiment, L is X 1 is O 1 The corresponding amide bond (L 1a ): [ka] and During the ceremony, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0076] According to one embodiment, L is X 1 is O 2 The retroamide bond (L 2a ): [ka] and During the ceremony, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, ●● is Ar 2 Represents the attachment point to

[0077] According to one embodiment, L is a 5-membered heteroaryl bond (L 3 ): [ka] and During the ceremony, Each Z is independently N, NR 11 ,S,O,C,CR 12 , C(O) and C(S), wherein at least one of Z is N, NR 11, S or O, R 11 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 is haloalkyl, R 12 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, [ka] represents a single or double bond depending on Z, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0078] According to one embodiment, L 3 teeth, [ka] is selected from During the ceremony, Each R 11 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 11 is H or methyl, more preferably R 11 is H, Each R 12 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 12 is H, methyl, halo, cyano or methoxy, more preferably R 12 is H, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0079] According to a preferred embodiment, L 3 teeth, [ka] is selected from During the ceremony, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0080] According to a preferred embodiment, L 3 teeth, [ka] is selected from During the ceremony, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0081] According to one embodiment, L is [ka] is selected from During the ceremony, Each R 11 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 11 is H or methyl, more preferably R 11 is H, Each R 12 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 12 is H, methyl, halo, cyano or methoxy, more preferably R 12 is H, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0082] According to one embodiment, L is preferably [ka] is selected from Each R 11 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 11 is H or methyl, more preferably R 11 is H, Each R 12 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 12 is H, methyl, halo, cyano or methoxy, more preferably R 12 is H, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0083] According to one embodiment, L is preferably [ka] is selected from Each R11 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl or C 1~4 haloalkyl, preferably R 11 is H or methyl, more preferably R 11 is H, Each R 12 are independently H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Haloalkyl, halo, cyano, hydroxy, C 1~4 Alkoxy or C 1~4 haloalkoxy, preferably R 12 is H, methyl, halo, cyano or methoxy, more preferably R 12 is H, ●Ha-CR 4 R 5 represents the point of attachment to the - moiety, and ●● is Ar 2 Represents the attachment point to

[0084] Ar 2 In the compounds of the present invention, Ar 2 is preferably halo, cyano, oxo, hydroxy, amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~6 Cycloalkyloxy, (C 1~4 alkyl)aminocarbonyl, (C 1~4 haloalkyl)aminocarbonyl, di(C 1~4 alkyl)aminocarbonyl, di(C 1~4 haloalkyl)aminocarbonyl, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)aminocarbonyl, C 1~4Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 2~4 Alkynyl, C 6~10 a 5-10 membered mono- or bicycloaryl or heteroaryl group optionally substituted with one or more substituents selected from aryl, heteroaryl and heterocyclyl, wherein the substituents are preferably halo, cyano, oxo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, or one or more C 3~6 The cycloalkyl or heterocyclyl group may be fused to the above heterocyclyl substituents, or may be one or more C optionally substituted with one or more halo. 3~6 A cycloalkyl or heterocyclyl group may be spiro-fused to said heterocyclyl substituent.

[0085] In the compounds of the present invention, Ar 2 is preferably halo, cyano, oxo, hydroxy, amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, C 1~4 Alkoxy, C 1~4 Haloalkoxy, (C 1~4 alkyl)aminocarbonyl, (C 1~4 haloalkyl)aminocarbonyl, di(C 1~4alkyl)aminocarbonyl, di(C 1~4 haloalkyl)aminocarbonyl, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)aminocarbonyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 6~10 a 5-10 membered mono- or bicycloaryl or heteroaryl group optionally substituted with one or more substituents selected from aryl, heteroaryl and heterocyclyl, wherein the substituents are preferably halo, cyano, oxo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, or one or more C 3~6 The cycloalkyl or heterocyclyl group may be fused to the above heterocyclyl substituents, or may be one or more C optionally substituted with one or more halo. 3~6 A cycloalkyl or heterocyclyl group may be spiro-fused to said heterocyclyl substituent.

[0086] According to one embodiment, Ar 2 teeth, [ka] is selected from In the formula, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21are each independently H, halo, cyano, oxo, hydroxy, amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~6 Cycloalkyloxy, (C 1~4 alkyl)aminocarbonyl, (C 1~4 haloalkyl)aminocarbonyl, di(C 1~4 alkyl)aminocarbonyl, di(C 1~4 haloalkyl)aminocarbonyl, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)aminocarbonyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 2~4 Alkynyl, C 6~10 aryl, heteroaryl and heterocyclyl, where these substituents are preferably halo, cyano, oxo, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, or one or more C 3~6 The cycloalkyl or heterocyclyl group may be fused to the above heterocyclyl substituents, or may be one or more C optionally substituted with one or more halo. 3~6a cycloalkyl or heterocyclyl group optionally spiro-fused to said heterocyclyl substituent; and [ka] represents the point of attachment to the remainder of the compound.

[0087] According to one embodiment, Ar 2 teeth, [ka] is selected from In the formula, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 are each independently H, halo, cyano, oxo, hydroxy, amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, C 1~4 Alkoxy, C 1~4 Haloalkoxy, (C 1~4 alkyl)aminocarbonyl, (C 1~4 haloalkyl)aminocarbonyl, di(C 1~4 alkyl)aminocarbonyl, di(C 1~4 haloalkyl)aminocarbonyl, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)aminocarbonyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 6~10 aryl, heteroaryl and heterocyclyl, where these substituents are preferably halo, cyano, oxo, hydroxy, C 1~4 Alkyl, C1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, C 1~4 Alkylamino, C 1~4 Haloalkylamino, di(C 1~4 alkyl)amino, di(C 1~4 haloalkyl)amino, N-(C 1~4 alkyl)-N-(C 1~4 haloalkyl)amino, or one or more C 3~6 The cycloalkyl or heterocyclyl group may be fused to the above heterocyclyl substituents, or may be one or more C optionally substituted with one or more halo. 3~6 a cycloalkyl or heterocyclyl group optionally spiro-fused to said heterocyclyl substituent; and [ka] represents the point of attachment to the remainder of the compound.

[0088] In one embodiment, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21are preferably each independently H, F, Cl, Br, cyano, hydroxy, methylamino, isopropylamino, 2-hydroxyethylamino, dimethylamino, N-methyl-N-ethylamino, N-methyl-N-(2,2,2-trifluoroethyl)amino, N-methyl-N-(trifluoromethyl)amino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, cyclobutoxy, methyl, cyclopropylmethyl, cyclopropyl, cyclopentyl, 1-propynyl, pyrazolyl, imidazolyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 3-methyl-2-oxoimidazolidin-1-yl, 2-oxopyrrolidin-1-yl, 4-methylpiperazin-1-yl, 2-methyl-2-oxoimidazolidin-1-yl, 2-methyl-2-oxopyrrolidin-1-yl, 4-methylpiperazin-1-yl, 2-methyl-2-oxoimidazolidin-1-yl, 2-methyl-2-oxo-2-oxopyrrolidin-1-yl, 4-methyl-2-oxo ... ethylpyrrolidin-1-yl, 3-methylazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-(difluoromethyl)azetidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, azabicyclo[3.1.0]hexan-3-yl, 2-oxa-6-azaspiro[3.3]heptan-2-yl, 2-azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.3]hexan-5-yl, 1,1-difluoro-5-azaspiro[2.3]hexan-5-yl, and 5-azaspiro[2.4]heptan-5-yl.

[0089] In one embodiment, R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and R 21are preferably each independently H, F, Cl, Br, cyano, hydroxy, methylamino, isopropylamino, 2-hydroxyethylamino, dimethylamino, N-methyl-N-ethylamino, N-methyl-N-(2,2,2-trifluoroethyl)amino, N-methyl-N-(trifluoromethyl)amino, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methyl, cyclopropyl, cyclopentyl, pyrazolyl, imidazolyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 3-methyl-2-oxoimidazolidin-1-yl, 2-oxopyrrolidin-1-yl, 4-methylpiperazin-1-yl, 2-methylpyrrolidin-1-yl, 3-methylazetidin-1-yl, 3,3-difluoroazetidin-1-yl, 3-methoxyazetidin-1-yl, 3-(difluoromethyl)azetidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, azabicyclo[3.1.0]hexan-3-yl, 2-oxa-6-azaspiro[3.3]heptan-2-yl, 2-azaspiro[3.3]heptan-2-yl, 5-azaspiro[2.3]hexan-5-yl, 1,1-difluoro-5-azaspiro[2.3]hexan-5-yl, and 5-azaspiro[2.4]heptan-5-yl.

[0090] According to one embodiment, Ar 2 teeth, [ka] Selected from TIFF2026504952000039.tif221159.

[0091] In one embodiment, the compound of the present invention is a compound of formula (Ia): [ka] and In the formula, m, R 1 , R 2 , R 3 , R 4 , R5 , L, Ar 1 and Ar 2 is as defined above.

[0092] In one embodiment, the compound of the present invention is a compound of formula (Ia'): [ka] and In the formula, m, R 1 , R 2 , R 3 , R 4 , R 5 , L, Ar 1 and Ar 2 is as defined above.

[0093] In one embodiment, the compound of the present invention is a compound of formula (Ib): [ka] and In the formula, m, R 1 , R 2 , R 3 , R 4 , R 5 , L, Ar 1 and Ar 2 is as defined above.

[0094] In one embodiment, the compound of the present invention is a compound of formula (I-1): [ka] and In the formula, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , Ar 1 and Ar 2 is as defined above.

[0095] In one embodiment, the compound of the present invention is a compound of formula (I-2): [ka] and In the formula, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , Ar 1 and Ar 2 is as defined above.

[0096] In one embodiment, the compound of the present invention is a compound of formula (I-3): [ka] and In the formula, m, n, R 1 , R 2 , R 3 , R 4 , R 5 , L 3 , Ar 1 and Ar 2 is as defined above.

[0097] In one embodiment, in formula (I-3), L 3 is preferably [ka] is selected from In the formula, ● is -CR 4 R 5 represents the point of attachment to the - moiety, and ●● represents Ar 2 Represents the attachment point to

[0098] In one embodiment, in formula (I-3), L 3 is preferably [ka] is selected from In the formula, ● is -CR 4 R 5 represents the point of attachment to the - moiety, and ●● represents Ar 2 Represents the attachment point to

[0099] Unless otherwise specified, when formula (I) is mentioned it also includes any of the above subformulas thereof.

[0100] According to one embodiment, the compounds of the present invention are those listed in Table 1 below: [Table 1] TIFF2026504952000049.tif218159TIFF2026504952000050.tif229159TIFF2026504952000051.tif220159 TIFF2026504952000052.tif243159TIFF2026504952000053.tif219159TIFF2026504952000054.tif236159 TIFF2026504952000055.tif221159TIFF2026504952000056.tif231159TIFF2026504952000057.tif217159 TIFF2026504952000058.tif222159TIFF2026504952000059.tif209159TIFF2026504952000060.tif215159 TIFF2026504952000061.tif217159TIFF2026504952000062.tif233159TIFF2026504952000063.tif221159TIFF2026504952000064.tif221159TIFF2026504952000065.tif214159TIFF2026504952000066.tif220159TIFF2026504952000067.tif209159TIFF2026504952000068.tif227159TIFF2026504952000069.tif227159TIFF2026504952000070.tif225159TIFF2026504952000071.tif221159TIFF2026504952000072.tif234159JPEG2026504952000073.jpg232159TIFF2026504952000074.tif220159TIFF2026504952000075.tif222159TIFF2026504952000076.tif234159TIFF2026504952000077.tif223159TIFF2026504952000078.tif229159TIFF2026504952000079.tif228159TIFF2026504952000080.tif237159TIFF2026504952000081.tif228159TIFF2026504952000082.tif234159TIFF2026504952000083.tif209159TIFF2026504952000084.tif201159TIFF2026504952000085.tif231159TIFF2026504952000086.tif234159TIFF2026504952000087.tif195159TIFF2026504952000088.tif236159TIFF2026504952000089.tif235159TIFF2026504952000090.tif229159TIFF2026504952000091.tif230159TIFF2026504952000092.tif215159TIFF2026504952000093.tif217159TIFF2026504952000094.tif232159TIFF2026504952000095.tif228159 TIFF2026504952000096.tif227159TIFF2026504952000097.tif212159TIFF20265 04952000098.tif233159TIFF2026504952000099.tif234159TIFF20265049520001 00.tif208159TIFF2026504952000101.tif231159TIFF2026504952000102.tif222 159TIFF2026504952000103.tif229159TIFF2026504952000104.tif207159TIFF2026504952000105.tif231159TIFF2026504952000106.tif240159TIFF2026504952000107.tif233159TIFF2026504952000108.tif241159TIFF2026504952000109.tif236159TIFF2026504952000110.tif43159 and pharmaceutically acceptable salts and / or solvates thereof.

[0101] The compounds in Table 1 were named using ChemDraw21®, purchased from CambridgeSoft, Inc. (Cambridge, Massachusetts, USA).

[0102] All references to compounds of formula (I) include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to compounds of formula (I) include references to polymorphs and / or crystal habits thereof. All references to compounds of formula (I) include references to pharmaceutically acceptable prodrugs thereof.

[0103] The compounds of formula (I) and its subformulas contain at least one asymmetric center and may therefore exist as different stereoisomers. Accordingly, all references to compounds of formula (I) include references to all possible stereoisomers and include not only racemates but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, such a single enantiomer may be obtained by stereospecific synthesis, resolution of the final product or any convenient intermediate, or chiral chromatographic methods, each of which are known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method known in the art.

[0104] The bond from the asymmetric carbon in a compound is generally represented by a solid line. [ka] Solid wedge [ka] or dashed wedge [ka] The use of either a solid line or a dashed wedge to depict bonds from asymmetric carbon atoms is intended to indicate that only the stereoisomer shown is intended to be included. The use of a solid line to depict bonds from asymmetric carbon atoms is intended to indicate that all possible stereoisomers are intended, unless it is clear from the context that a specific stereoisomer is intended.

[0105] All references to compounds of formula (I) include references to isotopically labeled compounds of formula (I), including deuterated compounds of formula (I).

[0106] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.

[0107] Suitable acid addition salts are formed from acids which form non-toxic salts, examples of which include acetate, adipate, ammonium salt, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, bitartrate / tartrate, borate, bromide, calcium edetate, camsylate, chloride, citrate, clavulanate, cyclamate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hybenzate, hydrochloride / chloride, hydrabamine, hydrobromide / bromide, hydroiodide / iodide, and hydroxynaphthoate. Salts include, isethionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, methyl bromide, N-methylglucamine, methyl nitrate, methyl sulfate, mucate, naphthylate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate, pantothenate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, pyroglutamate, saccharate, salicylate, stearate, succinate, sulfate, subacetate, tannate, teoclate, tosylate, triethiodide, trifluoroacetate, valerate, and xinofoate.

[0108] Suitable base salts are formed from bases which form non-toxic salts, examples of which include aluminum, ammonia, arginine, benzathine, N-benzylphenethylamine, calcium, choline, chloroprocaine, N,N'-dibenzylethylenediamine, diethanolamine, diethylamine, 2-(diethylamino)ethanol, diolamine, ethylenediamine, ethanolamine, glycine, 4-(2-hydroxyethyl)morpholine, lithium, lysine, magnesium, meglumine, N-methylglutamine, morpholine, olamine, ornithine, potassium, piperazine, procaine, sodium, tetramethylammonium hydroxide, tris(hydroxymethyl)aminomethane, tromethamine, and zinc salts.

[0109] Hemi-salts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts.

[0110] When the compounds of formula (I) contain an acidic group and a basic group, the compounds of the present invention may form internal salts, and such compounds are within the scope of the present invention. When the compounds of the present invention contain a hydrogen-donating heteroatom (e.g., NH), the present invention also encompasses salts and / or isomers formed by migration of said hydrogen atom to a basic group or atom within the molecule.

[0111] Pharmaceutically acceptable salts of the compounds of formula (I) include (i) reacting a compound of formula (I) with a desired acid; (ii) reacting a compound of formula (I) with a desired base; (iii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I) or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; and / or (iv) converting one salt of a compound of formula (I) to another salt by reaction with an appropriate acid or using a suitable ion exchange column; It may be prepared by one or more of the following methods.

[0112] All of these reactions are typically carried out in solution. The salts may precipitate from solution and be recovered by filtration, or may be recovered by evaporation of the solvent. The degree of ionization in the salts may vary from fully ionized to nearly non-ionized.

[0113] Generally, pharmaceutically acceptable salts are preferred with respect to salts of the compounds of the present invention, although it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which may be used, for example, for the isolation and / or purification of the compounds of the present invention. For example, salts formed with optically active acids or bases may be used to form diastereomeric salts which may facilitate the separation of optically active isomers of the compounds of formula (I) above.

[0114] Manufacturing Process The compounds of the present invention can be synthesized by methods known in the art, in particular by the methods detailed in the experimental section below.

[0115] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising the compounds according to the invention described hereinabove and at least one pharmaceutically acceptable carrier.

[0116] According to a first embodiment, the pharmaceutical composition comprises a compound according to the invention as the only therapeutic agent.

[0117] According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent, which in one embodiment is selected from those therapeutic agents detailed below with respect to combination therapy.

[0118] The pharmaceutical compositions of the present invention may further comprise therapeutically active compounds other than those listed herein that are normally applied in the treatment of the target condition.

[0119] Medical Uses and Treatment Methods The present invention also relates to the compounds according to the invention described herein above for use as a medicine.

[0120] The present invention also relates to the compounds according to the invention described herein above for use as inhibitors of METTL3 activity.

[0121] The present invention also relates to the compounds according to the present invention as described herein above for use in treating diseases or disorders in which METTL3 activity is involved, such as proliferative diseases, including cancer, autoimmune diseases, inflammatory diseases, neurological diseases, and infectious diseases, including viral infections.

[0122] The present invention also relates to the compounds according to the present invention described herein above for use in treating a disease or disorder in which the activity of the METTL3 / 14 complex is involved, such as proliferative diseases, autoimmune diseases, inflammatory diseases, neurological diseases, and infectious diseases, such as viral infections.

[0123] In one embodiment, the present invention provides a compound according to the invention as described hereinabove for use in the treatment of a proliferative disorder.

[0124] The terms "proliferative disease" and "proliferative disorder" are used interchangeably herein and refer to unwanted or uncontrolled cell proliferation, such as excessive or abnormal cell proliferation, whether in vitro or in vivo, including neoplastic or hyperplastic growth. Examples of proliferative diseases include, but are not limited to, premalignant and malignant cell proliferation, including malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative diseases (e.g., connective tissue fibroproliferative diseases), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin. The effect of the compounds of the present invention on cell viability of cancer cells is particularly applicable to the treatment of human cancer (by their inhibition of METTL3 activity). Anti-cancer effects may occur through one or more mechanisms, including, but not limited to, modulation of cell proliferation, modulation of cell viability, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of a tumor from its source), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

[0125] In one embodiment, the proliferative disease is cancer. Accordingly, the present invention provides a compound according to the present invention as described hereinabove for use in treating cancer. In a particular embodiment, the cancer is a human cancer. In one embodiment, the cancer is a solid tumor. In another embodiment, the cancer is a non-solid tumor.

[0126] Examples of cancer include, but are not limited to, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia, leukemia, lymphoma, multiple myeloma, non-Hodgkin's lymphoma (NHL), bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal / upper gastrointestinal cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, and thyroid cancer.

[0127] The present invention also provides a compound according to the invention as described hereinabove for use in treating autoimmune diseases, including but not limited to colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis of the liver, and dermatitis.

[0128] The present invention also provides a compound according to the invention as described hereinabove for use in treating an inflammatory disease.

[0129] The present invention also provides a compound according to the invention as described hereinabove for use in treating a neurological disorder.

[0130] The present invention also provides a compound according to the present invention described hereinabove for use in treating an infectious disease. Infectious diseases include viral infections. Viral infections include RNA virus infections. Examples of viral infections include infections caused by human papillomavirus (HPV), hepatitis viruses such as hepatitis B virus (HBV) or hepatitis C virus (HCV), and SARS-CoV-2.

[0131] The present invention also relates to the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for inhibiting METTL3 activity.

[0132] The present invention also relates to the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of a disease or disorder in which METTL3 activity is implicated as defined above.

[0133] In one embodiment, the present invention provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of a proliferative disorder as defined above.

[0134] Accordingly, the present invention provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of cancer as defined above.

[0135] The present invention also provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of an autoimmune disease as defined above.

[0136] The present invention also provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of an inflammatory disease.

[0137] The present invention also provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of a neurological disorder.

[0138] The present invention also provides the use of a compound according to the invention as described hereinabove in the manufacture of a medicament for the treatment of an infection as defined above.

[0139] The present invention also relates to a method of inhibiting METTL3 activity in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to the invention as described herein above.

[0140] The present invention also relates to a method for the treatment of a disease or disorder involving METTL3 activity in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to the invention as described herein above.

[0141] The present invention also relates to a method for the treatment of a proliferative disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to the present invention as described herein above.

[0142] The present invention also relates to a method for the treatment of cancer in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to the present invention as described herein above.

[0143] The present invention also relates to a method for the treatment of an autoimmune disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to the present invention as described herein above.

[0144] The present invention also relates to a method for the treatment of an inflammatory disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to the present invention.

[0145] The present invention also relates to a method for the treatment of a neurological disorder in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to the present invention.

[0146] The present invention also relates to a method for the treatment of an infectious disease in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a compound according to the invention as described herein above.

[0147] Combination therapy According to one embodiment, a compound of the present invention is administered to a subject as the only therapeutic agent.

[0148] According to another embodiment, the compounds of the present invention are administered to a subject in combination with at least another therapeutic agent.

[0149] In one embodiment, the other therapeutic agent may be selected from a second anti-cancer therapeutic agent, such as a chemotherapeutic agent, an immunotherapeutic agent, a cell therapy agent, and / or any anti-cancer agent currently in clinical use or in clinical trials.

[0150] According to one embodiment, the compounds according to the invention may be administered in combination with conventional surgery, radiotherapy or transplantation and / or at least another therapeutic agent as mentioned above.

[0151] Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the therapeutic agents. Such combination products employ the compounds of this invention within the dosage ranges described herein and the other therapeutic agent within its approved dosage range.

[0152] The term "combination" in the context of the present invention preferably refers to the combination of a compound of the present invention with an additional therapeutic agent. The combination may thus be in the form of a single composition, with all components in one and the same mixture (e.g., a pharmaceutical composition), or in the form of a kit-of-parts, with different components forming different parts of such a kit-of-parts. The administration of the compound of the present invention and the additional therapeutic agent may be simultaneous or chronologically staggered, in similar or different dosage forms, at the same or different administration sites, with similar or different administration timings (i.e., similar or different administration times for each component).

[0153] Administration method The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation spray, intranasal, intravaginal, rectal, sublingual or topical routes of administration and may be formulated into suitable dosage unit formulations containing non-toxic conventional pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

[0154] Pharmaceutical compositions for administering the compounds of the present invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. The active ingredient in the pharmaceutical composition is present in an amount sufficient to produce the desired effect upon the process or condition of a disease. As used herein, the term "composition" is intended to encompass products containing specified amounts of the specified ingredients, as well as any product resulting directly or indirectly from combining the specified amounts of the specified ingredients.

[0155] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable formulation. Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may include inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binders (e.g., starch, gelatin, or acacia), and lubricants (e.g., magnesium stearate, stearic acid, or talc). Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, may be used. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for controlled release. Oral formulations may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0156] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending agents. Any non-irritating, fixed oil, including synthetic mono- or diglycerides, may be used for this purpose. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0157] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts in the rectum and releases the drug. Such materials include cocoa butter and polyethylene glycol.

[0158] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.

[0159] In the treatment or prevention of METTL3-related disorders, appropriate dosage levels generally range from about 0.01 to 250 mg per kilogram of patient body weight per day (mg / kg / day), which can be administered in single or multiple doses. Preferably, dosage levels range from about 0.1 to about 100 mg / kg / day, such as 0.1 to 50 mg / kg / day. For oral administration, the composition is provided in tablet form, preferably containing 1.0 to 1000 mg of active ingredient, for symptomatic adjustment of dosage to the patient being treated. The compound may be administered as a single daily dose or may be divided into one or more daily doses, e.g., on a 1-4 times per day regimen. However, it will be understood that the specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode of administration, time of administration, excretion rate, drug combination, the severity of the particular disease, and the host being treated. [Example]

[0160] The present invention is further illustrated by the following examples. Chemical Examples material and method

[0161] All reported temperatures are in degrees Celsius (°C) and all reactions were conducted at room temperature (rt) unless otherwise noted.

[0162] Analysis method Analytical thin-layer chromatography (TLC) was used to monitor reactions, establish flash chromatography conditions, and confirm the purity of intermediates or final products. The TLC plates used were Merck TLC aluminum sheets silica gel 60 F254. The TLC plates were developed using KMnO4 color developer by UV irradiation (wavelength = 254 nm) at room temperature or by heating at 160 °C. KMnO4 TLC color developer was prepared by dissolving 1.5 g of KMnO4, 10 g of K2CO3, and 1.25 mL of 10% NaOH in 200 mL of water. Vanillin TLC color developer was prepared by dissolving 15 g of vanillin and 2.5 mL of concentrated sulfuric acid in 250 mL of 96% ethanol. Phosphomolybdic acid color developer was prepared by dissolving 10 g of phosphomolybdic acid in 100 mL of 96% ethanol.

[0163] 1 H and 13 C NMR spectra were recorded on a Bruker ARX 300 MHz. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are expressed in hertz (Hz). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), sex (sexlet), sept (septet), m (multiplet), or br (broad).

[0164] HPLC-MS spectra were obtained: Gradient A: An Agilent LCMS with electrospray ionization (ESI) was used. The instrument was equipped with an autosampler 1200, a binary pump 1100, a multi-wavelength detector 1100, and a 6100 single quadrupole mass spectrometer detector. The column used was a Sunfire C18 (3.5 μm, 3.0 × 50 mm). The eluent was a mixture of solution "A" (0.1% TFA / HO) and solution "B" (0.1% TFA / MeCN). The gradient used was as follows: an initial condition of 5% solution "B" was maintained for 0.2 minutes, linearly increased to 95% solution "B" over 1.8 minutes, maintained at 95% for 1.75 minutes, and returned to the initial condition over 0.25 minutes. Flow rate: 1.0 mL / min. Gradient B: An Agilent LCMS with electrospray ionization (ESI) was used. The instrument was equipped with an autosampler 1200, a binary pump 1100, a multi-wavelength detector 1100, and a 6100 single quadrupole mass spectrometer detector. The column used was a Sunfire C18 (3.5 μm, 3.0 × 50 mm). The eluent was a mixture of solution "A" (0.1% TFA / HO) and solution "B" (0.1% TFA / MeCN). The gradient used was as follows: an initial condition of 5% solution B was maintained for 0.2 minutes, linearly increased to 95% over 5.3 minutes, maintained at 95% for 2.25 minutes, and returned to the initial condition over 0.25 minutes. Flow rate: 1.0 mL / min. Gradient C: Waters Acquity UPLC was used. UV detection: Waters Acquity PDA (198-360 nm). MS detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu). The column used was a Waters Acquity UPLC CSH C18 (1.8 μm, 2.1 × 30 mm, 40 °C). The eluent was a mixture of solution "A" (Milli-Q H2O + 10 mM ammonium bicarbonate (pH: 10)) and solution "B" (ACN). The gradient used was as follows: linear increase from 5% to 100% "B" over 2.0 min, maintained at 100% for 0.7 min. Flow rate: 0.9 mL / min. Gradient D: Waters Alliance 2695. UV detection: Waters Acquity PDA (198-360 nm). MS detection: Waters ZD 2000, ESI (ES+, 100-1200 amu). The column used was a Waters Acquity UPLC CSH C18 (3.5 μm, 4.6 × 30 mm). The eluent was a mixture of solution "A" (Milli-Q HO + 10 mM ammonium bicarbonate (pH: 10)) and solution "B" (ACN). The gradient used was as follows: 5% "B" held for 0.2 min, increased linearly to 100% "B" over 1.8 min, and held at 100% for 1.0 min. Flow rate: 3.0 mL / min. Gradient E: Waters Acquity UPLC. UV detection: Waters Acquity PDA (198-360 nm). MS detection: Waters SQD, ESI (ES+ / ES-, 120-1200 amu). The column used was a Waters Acquity UPLC CSH C18 (1.8 μm, 2.1 × 30 mm, 40 °C). The eluent was a mixture of solution "A" (Milli-Q H2O + 10 mM ammonium bicarbonate (pH: 10)) and solution "B" (ACN). The gradient used was as follows: linear increase from 5% to 100% "B" over 5.2 minutes, maintained at 100% for 1.8 minutes. Flow rate: 0.9 mL / min. Gradient F: Waters Acquity UPLC was used. UV detection: Waters Acquity PDA (198-360 nm). MS detection: Waters 3100, ESI (ES+ / ES-, 120-1200 amu). The column used was a Waters Acquity UPLC CSH C18 (1.8 μm, 2.1 × 30 mm, 40 °C). The eluent was a mixture of solution "A" (Milli-Q HO + 10 mM ammonium formate (pH: 3.8)) and solution "B" (ACN). The gradient used was as follows: linear increase from 5% to 100% "B" over 2.0 min, maintained at 100% for 0.7 min. Flow rate: 0.9 mL / min.

[0165] The determination of chiral purity was carried out on an Agilent 1100 HPLC instrument, equipped with an autosampler 1100, a binary pump 1100 and a multi-wavelength detector 1100. The columns used were Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralpak ID and Chiralpak IE, each packed with 5 μm particles and measuring 4.6 × 250 mm. The mixture of eluents was selected individually depending on the separation of enantiomers or diastereomers obtained.

[0166] Preparative HPLC purification was performed using an Agilent 1200 preparative HPLC instrument, consisting of a gradient pump 1200, a multi-wavelength detector 1200 and a Rheodyne manual injector.

[0167] The columns used for reversed-phase preparative HPLC purification were Waters XBridge C18 (5 μm, 19 × 100 mm) or Phenomenex Luna C18(2) (5 μm, 21.2 × 100 mm). The gradient was adapted depending on the nature of the compound to be purified and the impurities to allow sufficient separation of the impurities from the target compound. Unless otherwise stated, the eluent was a mixture of solution "A" (0.02 M ammonium bicarbonate) and solution "B" (MeCN).

[0168] The columns used for chiral preparative HPLC purification were Chiralpak IA, Chiralpak IB, Chiralpak ID, and Chiralpak IE, each packed with 5 μm particles and measuring 10 or 20 × 250 mm. The eluent mixture was selected depending on the enantiomeric or diastereomeric separation to be achieved by the analytical method. Typically, the eluent mixture was the same as that used for the determination of ee or de. Unless otherwise specified, the wavelength used was 280 nm.

[0169] Unless otherwise specified, solvents, reagents and starting materials were purchased from commercial vendors and used as received.

[0170] Abbreviation The following abbreviations are used: ACN or MeCN: acetonitrile Ar: Argon BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl dba: dibenzylidene acetone Boc: tert-butoxycarbonyl DCE: 1,2-dichloroethane DCM: dichloromethane DIEA or DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DPPA: Diphenylphosphoryl azide ee: enantiomeric excess eq: equivalent EtOAc or AcOEt: ethyl acetate EtOH: ethanol g: grams h: time HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High-performance liquid chromatography IM: Intermediate L: Liter LDA: lithium diisopropylamide LiHMDS: Lithium hexamethyldisilazane MeOH: Methanol min:minutes mg: milligram mL: milliliter mmol: millimolar mol: mole MS: Mass spectrometry MW: molecular weight NMP: N-methylpyrrolidinone NMR: nuclear magnetic resonance P: UV purity at 254 nm determined by HPLC-MS PMB: paramethoxybenzyl rt: room temperature RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl T3P: Tripropylphosphonic anhydride TBAF: Tetrabutylammonium fluoride TBME: tert-butyl methyl ether TFA: Trifluoroacetic acid THF: tetrahydrofuran THP: tetrahydropyran TLC: Thin Layer Chromatography TMS: trimethylsilyl Vol: Volume (L of solvent in g of starting material) Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Y: Yield μL: microliter

[0171] All compounds disclosed in this application were named using ChemDraw21®, purchased from CambridgeSoft, Inc. (Cambridge, Massachusetts, USA).

[0172] General synthetic scheme The compounds of the present invention can be synthesized using the general routes depicted in Schemes 1-6 below, which represent either synthesis of the product as a racemic mixture or mixture of diastereomers (using chiral starting materials with an uncontrolled second stereocenter) or chiral synthesis using enantiomerically pure starting materials. Enantiomerically impure products can then be subjected to chiral HPLC for chiral separation. Scheme 1: General scheme for accessing compounds of the present invention where L is a triazole [ka] Scheme 2: General scheme for accessing compounds of the invention where L is an amide or thioamide bond [ka] Scheme 3: General scheme for accessing compounds of the invention where L is 1,3,4-thiadiazole or thiazole [ka] Scheme 4: General scheme for accessing compounds of the present invention where L is imidazole [ka] Scheme 5: General scheme for accessing compounds of the present invention where L is pyrazole [ka] Scheme 6: General scheme for accessing compounds of the invention where L is a retroamide bond [ka]

[0173] General Procedure General Procedure A1: HCl Deprotection To a solution of the protected substrate (THP, Boc) (1.0 equiv.) in methanol (0.05–1.2 mol / L, typically 0.10–0.20 mol / L) under an argon atmosphere (ice bath) at 0 °C, hydrogen chloride solution (4 N in 1,4-dioxane, 10–110 equiv., typically 30 equiv.) was added. The resulting solution was stirred at room temperature. The reaction progress was monitored by HPLC-MS. After completion (0.25–20 h, typically 1–4 h), the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM and saturated aqueous K2CO3. The layers were separated, and the aqueous layer was extracted with DCM (2×). The organic layer was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude residue could be purified using an SCX-2 cartridge (eluent: MeOH, eluted with [7 N MeOH / NH3] / MeOH (2 / 1)) or by reverse-phase preparative HPLC.

[0174] General Procedure A2: TFA Deprotection To a solution of the protected substrate (THP, Boc, PMB) (1.0 equiv.) in anhydrous DCM (0.05–0.20 mol / L) was added TFA (10–140 equiv., typically 25–40 equiv.) under argon at room temperature, and the resulting solution was stirred at room temperature. The reaction progress was monitored by HPLC-MS (if the reaction proceeded slowly, the reaction was heated to 50 °C). Upon completion (typically less than 2 h), the reaction mixture was concentrated to dryness under reduced pressure. The residue may be purified by reverse-phase flash chromatography (Biotage, C18 cartridge) using a gradient of MeCN / 10 mM ammonium bicarbonate buffer or reverse-phase preparative HPLC on an SCX-2 cartridge (eluted with MeOH, [7N MeOH / NH3] / MeOH (2 / 1)).

[0175] General Procedure B: Click Chemistry A solution of the azide substrate (1.0 equiv.) and alkyne substrate (1.00–1.25 equiv., typically 1.05 equiv.) in anhydrous DMF (0.1–0.3 mol / L, typically 0.25 mol / L) was degassed by bubbling argon through it with stirring for 15 min. Copper iodide (0.05–0.2 equiv.) was added, and the resulting suspension was stirred at room temperature in the dark (the flask was covered with aluminum foil). The reaction progress was monitored by HPLC-MS. After completion (typically less than 4 h), the reaction mixture was diluted with EtOAc (10–100 × DMF volume). The resulting solution was washed with water (5 × 5–50 × DMF volume), then brine (5 × 5–50 × DMF volume), dried over MgSO4, and then filtered. The solvent mixture was concentrated to dryness under reduced pressure to afford the highly pure product, typically as a solid, which was used crude in the following step or purified by silica gel flash chromatography.

[0176] General Procedure C:S N Ar To a solution of electrophile (1.0 equiv.) in anhydrous NMP (0.1–1.3 mol / L, typically 0.3–0.9 mol / L) under an argon atmosphere at room temperature, either triethylamine (2.0–4.3 equiv., typically 3.0 equiv.) or diisopropylethylamine (2.0–3.6 equiv., typically 3.0 equiv.) and nucleophile (1.05–2.00 equiv., typically 1.1 equiv.) were added. The resulting mixture was stirred at 120 °C and monitored by HPLC-MS. When the conversion did not increase further (typically 20 h), the reaction was allowed to cool to room temperature. The mixture was diluted with EtOAc (20 NMP volumes), washed with brine (5 × 50 NMP volumes), dried over MgSO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel flash chromatography.

[0177] General Procedure D1: Alkyne-TMS Deprotection with K2CO3 The intermediate was deprotected (1 equiv.) by adding potassium bicarbonate (0.30-2.00 equiv., typically 0.37 equiv.) to a solution of anhydrous methanol (0.1-0.5 mol / L, typically 0.3 mol / L). The mixture was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After complete conversion (typically 30 min), the reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel flash chromatography.

[0178] General Procedure D2: Alkyne-TMS deprotection with TBAF To a suspension of the crude ethynyltrimethylsilane substrate (1.0 equiv.) in anhydrous THF (0.1 mol / L) under an argon atmosphere at room temperature, TBAF (1.5 equiv.) was added in one portion. The resulting solution was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After complete conversion (typically 30 min), the reaction mixture was diluted with water (6 THF volumes) and EtOAc (25 THF volumes), and the layers were separated. The organic layer was washed with water (3 × 6 THF volumes), dried over MgSO4, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product may be purified by silica gel flash chromatography.

[0179] General Procedure E1: Sonogashira Coupling Ethynyltrimethylsilane (1.1–1.4 equiv, typically 1.2 equiv), triethylamine (2.5–11.0 equiv, typically 2.5–3.0 equiv), and haloaromatic substrate (1.0 equiv) in anhydrous DMF (0.15–0.40 mol / L, typically 0.15 mol / L) were added to a Schlenk tube under argon. The mixture was degassed with argon (sparging for 5 min). Dichlorobis(triphenylphosphine)palladium(II) (0.05 equiv) and copper(I) iodide (0.05 equiv) were then added, and the mixture was degassed with argon (3 × vacuum / argon cycles). The reaction mixture was stirred at temperatures between room temperature and 70 °C, and the reaction progress was monitored by HPLC-MS. After complete conversion (typically 16–21 h), the reaction was cooled to room temperature. EtOAc was added (60 volumes relative to the haloaromatic substrate) and washed with water (3 x 30 volumes) and then brine (2 x 12 volumes). The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography.

[0180] Another common procedure E2: Ethynyltrimethylsilane (1.4–3.0 equiv, typically 1.5 equiv), triethylamine (4.4–5.0 equiv), and haloaromatic substrate (1.0 equiv) in anhydrous DMF (0.2–1.0 mol / L) were added to a Schlenk tube under argon. The mixture was degassed with argon (sparging for 5 min). Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.04–0.10 equiv) and copper(I) iodide (0.05–0.10 equiv) were added, and the mixture was degassed with argon (3 × vacuum / argon cycles). The reaction mixture was stirred at temperatures between room temperature and 120 °C (typically 100 °C), and the reaction progress was monitored by HPLC-MS. After complete conversion (typically 2 h), the reaction was cooled to room temperature, diluted with EtOAc (5 × DMF volume), and filtered through Celite. The filtrate was concentrated in vacuo and the crude product was purified by silica gel flash chromatography.

[0181] Another common procedure E3: To a Schlenk tube under argon, the haloaromatic substrate (1.0 equiv.), tetrakis(triphenylphosphine)palladium (0.05 equiv.), copper(I) iodide (0.1 equiv.), and DIEA (1.5 equiv.) in anhydrous DMF (0.25 mol / L) were added. The mixture was degassed with argon (sparging for 5 min). Ethynyltrimethylsilane (1.2 equiv.) was added slowly, and the reaction mixture was stirred at 60 °C. The reaction progress was monitored by HPLC-MS. After complete conversion (typically 16 h), the reaction was cooled to room temperature, and water (10 DMF volumes) was added. The mixture was extracted with EtOAc (2 × 7 DMF volumes). The combined organic layers were washed with water (5 × 3 DMF volumes), brine (2 × DMF volumes), dried over MgSO4, filtered, and concentrated in vacuo. The crude product may be purified by silica gel flash chromatography.

[0182] General Procedure F: T3P Coupling Reaction The acid (1.0–1.5 equiv, typically 1.2 equiv) was dissolved in anhydrous DMF (0.15 mol / L) at room temperature under argon, and DIEA (1.75–4.6 equiv, typically 2.4 equiv) was added, followed by T3P (50% w / w in AcOEt) (1.3 equiv). After stirring at room temperature for 15 min, a solution of the amine (1.0–1.5 equiv, typically 1.0 equiv) in anhydrous DMF (0.15 mol / L) was added dropwise to the suspension. The reaction progress was monitored by HPLC-MS. After complete conversion (typically less than 1 h), the reaction mixture was diluted with water (8 DMF volumes) and extracted with EtOAc (3 × 12 DMF volumes). The organic layers were combined, washed with brine (8 DMF volumes), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product may be purified by silica gel flash chromatography.

[0183] General Procedure G: One-pot debenzylation-Boc protection A solution of benzylamine (1.0 equiv.) in absolute ethanol (0.18 mol / L) was degassed by bubbling argon through it while stirring under an argon atmosphere for 15 minutes. Dry palladium on carbon (10 wt%) (0.2 equiv.) was then added at room temperature, followed by di-tert-butyl dicarbonate (1.5 equiv.). The resulting solution was placed in a pressure vessel and charged with 10 bar of hydrogen. The suspension was vigorously stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After complete conversion (up to 3.5 days), the pressure was released, and the reaction mixture was degassed with argon. The solvent was then removed under reduced pressure, and the resulting black mixture was purified by silica gel flash chromatography.

[0184] General Procedure H1: Reductive Amination Titanium(IV) isopropoxide (2.0 equiv.) was added dropwise to a mixture of an aldehyde (or ketone) (1.0–6.5 equiv., typically 1.1 equiv.) in anhydrous methanol (0.07–0.7 mol / L) at 0 °C (ice bath) under argon. After 45 min at 0 °C, an ice-cold solution of an amine (1.0–15.0 equiv., typically 1.0 equiv.) in anhydrous methanol (0.02–0.25 mol / L) was added to the reaction mixture at 0 °C, yielding a light brown suspension. This suspension was stirred at room temperature (the ice bath was removed) for 0.5–2.5 h, cooled to 0 °C (ice bath), and sodium borohydride (1.2–2.2 equiv., typically 2.0 equiv.) was carefully added in several portions over 30 min (vigorous bubbling with air bubbles was observed). The resulting foamy suspension was stirred at 0 °C for 25 min, then at room temperature to yield a yellow solution. After approximately 1 hour, the reaction was quenched with aqueous NHOH (2.5% aqueous solution) with vigorous stirring to give a white suspension, which was stirred for an additional 10 minutes. The suspension was then filtered and rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (10 MeOH vol) and water (3 MeOH vol). The layers were separated. The organic layer was washed with brine (3 MeOH vol), dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give the desired product.

[0185] Alternative general procedure H2: reductive amination from amine salts Titanium(IV) isopropoxide (2.6 equiv.) was added dropwise to a mixture of aldehyde or ketone (1.0–3.0 equiv., typically 1.0 equiv.) in anhydrous methanol (0.1–1.0 mol / L, typically 0.7 mol / L) under argon at room temperature. After 30–55 min at room temperature, an amine (1.05 equiv.) was added (followed by DIEA (1.5–3.6 equiv., typically 2.5 equiv.) if an amine hydrochloride was used). The suspension was stirred at room temperature for 0.5–2 h and then cooled to 0 °C (ice bath). Sodium borohydride (1.2–2.7 equiv., typically 2.0 equiv.) was carefully added in several portions over 30 min (vigorous bubbling with air bubbles was observed). The resulting foamy suspension was stirred at 0 °C for 15 min (complete conversion confirmed by HPLC-MS). The reaction mixture was poured into NH4OH solution (1.5 N, 2-3 MeOH volumes) at room temperature with vigorous stirring. The mixture was stirred at room temperature for 10 minutes, filtered, and the residue on the filter was rinsed with DCM (3 x 15-20 MeOH volumes). The layers of the filtrate were separated, and the organic layer was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the desired crude product.

[0186] General Procedure I: N-Debenzylation To a solution of the N-benzylated substrate (1.0 equiv.) in absolute ethanol (0.12–0.25 mol / L, typically 0.15 mol / L) under argon, hydrazine monohydrate (2.0–4.0 equiv., typically 2.2 equiv.) was added. The mixture was degassed by bubbling argon through it (5 min). Palladium on activated carbon (10 wt%) (0.08–0.20 equiv.) was then added, and the reaction mixture was stirred at reflux. After complete N-debenzylation was monitored by HPLC-MS, the reaction was cooled to room temperature, filtered through Celite, and rinsed with EtOH and DCM. The filtrate was concentrated to dryness under reduced pressure to give the desired product.

[0187] General Procedure J: Amine Protection To a solution of amine (1.0 equiv.) in anhydrous DCM (0.15–0.40 mol / L, typically 0.15 mol / L) under argon and ice bath at 0°C, triethylamine (2.0–6.0 equiv., typically 2.0 equiv.) was added. A solution of di-tert-butyl dicarbonate (1.1–6.0 equiv., typically 1.2 equiv.) in anhydrous DCM (0.1–0.2 mol / L, typically 0.15 mol / L) was added over 15 min at 0°C. Five min after the addition was complete, the ice bath was removed, and the reaction was stirred at room temperature. After 16 h, water was added, and the layers were separated. The organic layer was washed with 1 M NaOH, water, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel flash chromatography.

[0188] General Procedure K: Phthalimide Removal To a solution of the protected amine (1.0 equiv.) in ethanol (0.09 mol / L) was added hydrazine monohydrate (6.5 equiv.). The reaction mixture was stirred at 80°C, where a white suspension usually formed within a few minutes at 80°C. After complete conversion (typically less than 1 h), as monitored by HPLC-MS, the reaction was concentrated in vacuo. To the residue was added EtO (2 EtOH volumes), and the reaction mixture was sonicated (2 min) and filtered. The solid was rinsed with EtO (1.5 EtOH volumes), and the filtrate was collected and concentrated in vacuo to give the crude product.

[0189] General Procedure L: Hydrodebenzylation or Azide Reduction A solution of the benzyl-protected amine (1.0 equiv.) in absolute ethanol (0.05–0.02 mol / L) was degassed by bubbling argon through it while stirring under an argon atmosphere for 15 min. Palladium on activated carbon (10 wt.% on dry carbon, 0.1–0.2 equiv.) was then added, and the resulting solution was bubbled with H2 for 5 min with stirring. A hydrogen balloon (approximately 3 bar) was then placed and the mixture was vigorously stirred at room temperature. After complete disappearance of the starting material (monitored by HPLC-MS, typically 14 h), the H2 balloon was removed, and the reaction mixture was bubbled with argon for 5 min. The mixture was then filtered through a short Celite pad, which was then rinsed with MeOH (3 × EtOH vol / 6). The filtrate was concentrated to dryness under reduced pressure to afford the desired amine, which was used crude in the next step.

[0190] General Procedure M:DPPA To a sealed tube equipped with a magnetic stir bar under argon, a solution of the alcohol substrate (1.0 equiv.) and diphenylphosphoryl azide (1.3–3.3 equiv., typically 1.3 equiv.) in anhydrous toluene (0.2 mol / L) was added. The solution was cooled to 0°C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3–3.3 equiv., typically 1.3 equiv.) was added dropwise. The reaction was allowed to warm to room temperature overnight. Water was added (10 toluene volumes), and the mixture was stirred vigorously. EtOAc was added (30 toluene volumes), and the layers were separated. The organic layer was washed with water (20 toluene volumes), aqueous HCl (0.1 N, 10 toluene volumes), and brine (10 toluene volumes), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography.

[0191] General Procedure N: Azide Introduction To a stirred solution of electrophile (1.0 equiv.) in anhydrous DMF (0.1–0.9 mol / L, typically 0.5 mol / L) under an argon atmosphere at room temperature, NaN3 (1.0–3.0 equiv., typically 1.4 equiv.) was added, and the reaction mixture was stirred at room temperature or heated at 70 °C. The reaction progress was monitored by HPLC-MS. Upon completion (HPLC-MS monitoring), the reaction mixture was diluted with EtOAc (50 vol.), washed with water (5 × 3.7 vol.) and brine (2 × 0.5 vol.), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give the crude product.

[0192] General Procedure O1: N-Alkylation with CMCF The N-nucleophile (1.0 equiv.) was suspended in anhydrous DCM (0.2 mol / L). Chloromethyl chloroformate (1.2 equiv.) was added, followed by DMF (0.2 mol / L). The mixture was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. When the conversion no longer proceeded (typically after 10-16 h), ethyl acetate (10 DCM volumes) was added, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 DCM volumes) and brine (8 DCM volumes), dried over MgSO4, filtered, and evaporated in vacuo to give the crude product, which was used directly in the next step.

[0193] Another general procedure O2: N-alkylation with CECF To a slurry of N-nucleophile (1.0 equiv.) in anhydrous DCE (0.3 mol / L) and DMF (0.3 mol / L) was added 1,4-diazabicyclo[2.2.2]octane (0.5 equiv.) at room temperature. 1-Chloroethyl chloroformate (1.5 equiv.) was added dropwise to the slurry at room temperature. The resulting mixture was stirred under argon at 60 °C (typically overnight), and the reaction progress was monitored by HPLC-MS. The reaction mixture was cooled to room temperature, and the suspension was filtered and rinsed with DCM (2 volumes of DCE). The filtrate was washed with water (2 volumes of DCE), saturated aqueous NaHCO3 (2 volumes of DCE), brine (2 volumes of DMF), dried over MgSO4, filtered, and concentrated to dryness in vacuo to give the crude product.

[0194] General Procedure P: Mesylate Formation The alcohol substrate (1.0 equiv.) was treated with triethylamine (1.3-2.0 equiv., typically 1.3 equiv.) and a DCM solution (0.2-0.5 mol / L, typically 0.25 mol / L) of methanesulfonyl chloride (1.1-1.6 equiv., typically 1.2 equiv.) at 0°C, then stirred at room temperature for 1 h (reaction progress was monitored by TLC). The resulting mixture was quenched with saturated aqueous NH4Cl (25 volumes of DCM), extracted with DCM (3 × NH4Cl volumes), then dried over MgSO4 and concentrated under reduced pressure to give the crude product, which was used directly in the next step.

[0195] General Procedure Q: Aldehyde Methylation To a solution of the aldehyde substrate (1.0 equiv.) in anhydrous THF (0.25 mol / L) at −78°C was added dropwise methylmagnesium bromide solution (3N in EtO, 1.2 equiv.). The reaction was stirred at −78°C, and the progress of the reaction was monitored by HPLC-MS. After 1.5 h, the reaction was quenched with 0.1 N HCl (THF volume) and stirred at room temperature for 5 min. Water (4 THF volumes) was added, and the reaction mixture was then extracted with EtOAc (2 × 8 THF volumes). The combined organic layers were washed with water (6 THF volumes), brine (4 THF volumes), dried over MgSO, filtered, and concentrated under reduced pressure. The crude product may be purified by silica gel flash chromatography.

[0196] General Procedure R: Azide Reduction with TPP A mixture of the azide substrate (1.0 equiv.) and resin-supported triphenylphosphine (1.6 equiv., 3 mmol / g) in anhydrous methanol (0.06 mol / L) was stirred at reflux under an argon atmosphere, and the reaction progress was monitored by HPLC-MS. After typically 5 h, the mixture was allowed to reach room temperature and then filtered. The solids were rinsed with MeOH (4 × half reaction volume), and the filtrate was concentrated to dryness under reduced pressure to give the crude product, which was used directly in the next step.

[0197] General procedure for S:N-C coupling reactions The amino substrate (1.0 equiv.), haloaromatic substrate (1.0 equiv.), and cesium carbonate (1.5 equiv.) were added to anhydrous toluene (0.15 mol / L) under argon at room temperature. The reaction mixture was degassed with argon for 5 minutes, and rac-BINAP (0.1 equiv.) and palladium(II) acetate (0.1 equiv.) were added. The reaction mixture was stirred at 95–110 °C for 5–16 hours (reaction progress was monitored by HPLC-MS). The reaction mixture was then cooled to room temperature, filtered through Celite, rinsed with toluene (6 reaction volumes), and concentrated to dryness under reduced pressure. The crude product was purified by silica gel flash chromatography.

[0198] General Procedure T: Mitsunobu Reaction To a solution of the alcohol substrate (1.15 equiv.) and pyridone substrate (1.00 equiv.) in anhydrous THF (0.1 mol / L) cooled to 0 °C, triphenylphosphine (1.20 equiv.) and diisopropyl azodicarboxylate (1.20 equiv.) were added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by reverse-phase flash chromatography (Biotage, C18 cartridge) using a gradient of MeCN (0-100%) in 10 mM ammonium bicarbonate buffer.

[0199] General Procedure U: Suzuki Reaction To a microwave vial under nitrogen, the haloaromatic substrate (1.0 equiv.), 5-methoxy-3-pyridineboronic acid pinacol ester (1.1–1.6 equiv., typically 1.1 equiv.), potassium carbonate (2.5 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.06–0.10 equiv.), and dioxane / water (0.13 mol / L, 5 / 1) were sequentially added. The mixture was degassed with nitrogen for 15 min and then heated to 100 °C for 1–48 h. After cooling to room temperature, the mixture was purified by reverse-phase flash chromatography (Biotage, C18 cartridge, loaded in dioxane) using a gradient of MeCN (0–100%) / 10 mM ammonium bicarbonate buffer.

[0200] General Procedure V: Azide Formation A solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (1.2-1.5 equiv, typically 1.5 equiv) in anhydrous MeCN (0.35 mol / L) was added dropwise (over 5 min) to a mixture of the amino substrate (1.0 equiv) and diethylamine (5.0 equiv) in anhydrous MeCN (0.15 mol / L) under an argon atmosphere at room temperature. The reaction mixture was stirred at 30 °C, and the reaction progress was monitored by HPLC-MS. After 1 h, a solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (0.5-0.8 equiv, typically 0.7 equiv) in anhydrous MeCN (0.35 mol / L) was added, and complete conversion was achieved after 15 min. The reaction mixture was allowed to cool to room temperature (oil bath removed), diluted with EtOAc (12 vol. MeCN), then washed with saturated NaHCO3 solution (2 x 12 vol. MeCN), dried over MgSO4, filtered, and the filtrate concentrated to dryness under reduced pressure.

[0201] General Procedure W: Reductive Amination with Ammonia To a solution of ketone (1.0 equiv.) in anhydrous methanol (0.1–0.3 mol / L, typically 0.3 mol / L) was added ammonium acetate salt (5.0–10.0 equiv., typically 10 equiv.) and sodium cyanoborohydride (5.0 equiv.). The mixture was stirred at 90 °C, and the reaction progress was monitored by HPLC-MS. After 1 h, the reaction mixture was quenched with water (5 mL) and extracted with DCM (3 × 20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure.

[0202] General Procedure X: One-pot alkyne deprotection / click reaction To a solution of trimethylsilyl alkyne substrate-181-02 (1.0–1.7 equiv., typically 1.1 equiv.) in DMF (0.15–0.19 mol / L, typically 0.15 mol / L) was added the azide substrate (1.0 equiv.) and CuF (1.8–2.0 equiv., typically 2.0 equiv.). The reaction mixture was purged with N for 5 min and then stirred at 60 °C for 18 h. The mixture was diluted with water (15 DMF volumes) and extracted with DCM (3 × 5 DMF volumes). The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on a C18 cartridge.

[0203] General Procedure Y: RuPhos C-N Cross Coupling To a mixture of amino substrate (1.05 equiv.), halo-(hetero)aromatic substrate (1.00 equiv.), RuPhos Pd G4 (0.06-0.20 equiv., typically 0.06 equiv.), RuPhos (0.08-0.15 equiv., typically 0.08 equiv.), and cesium carbonate (3.00 equiv.) under an argon atmosphere, anhydrous, degassed tert-amyl alcohol (0.3 mol / L) was added. The reaction mixture was stirred at 80 °C for 19 h. The reaction was cooled to room temperature, diluted with DCM (10 vol.), and filtered through Celite. The Celite was rinsed with DCM (30 vol.), and the filtrate was concentrated under reduced pressure and purified to give the desired product.

[0204] General Procedure Z: Hydrogen Dehydroxylation A solution of the hydroxyl(hetero)benzyl substrate (1.0 equiv.) in anhydrous methanol (0.05 mol / L) was degassed and backfilled with argon (3x). 4-Methylbenzenesulfonic acid hydrate (1.5–2.5 equiv., preferably 1.6 equiv.) and palladium on activated carbon (10 wt.%, 0.3 equiv.) were added, and the reaction mixture was degassed and backfilled with hydrogen and vigorously stirred at room temperature for 22–40 h. The reaction mixture was then degassed and backfilled with argon, filtered through Celite, rinsed with MeOH (6 reaction volumes), and concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO3 (4 reaction volumes) and extracted with DCM (3x4 reaction volumes). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was typically purified on an automated flash chromatography system (dry loaded in Celite, 0-100% EtOAc / heptane) to give the desired dehydroxylated product.

[0205] General Procedure AA: Ullmann Cross Coupling A mixture of bromoaryl (1 equiv.), L(-)-proline (0.2 equiv.), amino substrate (1.3–6.0 equiv., typically 1.5 equiv. added up to four times if volatile), potassium carbonate (1.5–7.0 equiv., typically 1.6 equiv.), and copper(I) iodide (0.1 equiv.) in anhydrous, degassed DMSO (1 mol / L) was stirred in a sealed tube and heated at 90 °C for typically 18 h. If the reaction had not gone to completion, the amino substrate was added and the reaction mixture was stirred at 90 °C for an additional 16 h. Additional reagent additions could be made up to four times. The cooled mixture was then partitioned between water (10 vol. DMSO) and ethyl acetate (10 vol. DMSO). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 vol. DMSO). The combined organic layers were washed with water (10 vol. DMSO), brine (10 vol. DMSO), dried over MgSO, filtered, and concentrated in vacuo to give the crude product as a brown foam, which was purified by automated flash chromatography to give the desired product.

[0206] General Procedure AB: Buchwald Cross-Coupling with Xantphos To a mixture of Pd(dba) (0.5–0.13 equiv., typically 1.0 equiv.), Xantphos (0.15–0.25 equiv., typically 0.2 equiv.), cesium carbonate (2.0–2.6 equiv., typically 2.0 equiv.), and halo substrate (0.8–1.5 equiv., typically 1.5 equiv.), a solution of the carboxamide substrate (1.0 equiv.) in anhydrous 1,4-dioxane (0.10–0.13 mol / L, typically 0.12 mol / L) (previously degassed with argon) was added at room temperature. The reaction mixture was sonicated for 15 s and stirred at 80–100 °C (typically 100 °C, preheated oil bath) for 1.5–21.0 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (5 vol.), and filtered through Celite. The Celite was rinsed with EtOAc (10 vol.). The filtrate was concentrated in vacuo to give the crude product, which was purified on an automated normal-phase or reverse-phase flash chromatography system to give the desired product.

[0207] General Procedure AC: Carboxamide Formation To a mixture of carboxylic acid substrate (potentially as the hydrochloride salt) (1.0 equiv.), ammonium chloride (4.0–6.0 equiv.), and HATU (1.0–1.4 equiv.) in anhydrous DMF (4 vol.) under an argon atmosphere, DIEA (1.0–2.5 equiv.) was added at room temperature to give a suspension, which was stirred for 0.33–2.25 h at room temperature. Additional HATU (based on LC conversion) and additional DIEA (same as above) could then be added, and the reaction mixture stirred for up to an additional 3 h. The reaction mixture was diluted with EtOAc (15–100 vol.), washed with saturated aqueous NaHCO3 (2 × 40 vol.), brine (40 vol.), dried over MgSO4, and filtered. The filtrate was concentrated to dryness under reduced pressure to give a crude oil, which was purified using an automated normal-phase or reverse-phase flash chromatography system to give the desired product.

[0208] General Procedure AD: Cyanohydrolysis to Acid To a solution of the cyano intermediate (1 equiv) in ethanol (9 vol) was added a solution of sodium hydroxide (4.0–4.6 equiv) in water (4 vol) at room temperature, and the reaction mixture was stirred at 80°C for 1.0–3 h. The reaction mixture was cooled to room temperature and then concentrated to dryness under reduced pressure. The residue was solubilized in water (50 vol) and acidified to a pH of approximately 2 by the addition of 1 M HCl (some precipitation was observed), and the mixture was extracted with DCM (3 × 50 vol). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated to dryness under reduced pressure to give the crude acid, potentially as the HCl salt.

[0209] General Procedure AE: Reductive Amination with Alkyl Aldehydes To a solution of an aldehyde or ketone (1.04–4.80 equiv, typically 1.30 equiv) and an amine substrate (1.00 equiv) in anhydrous methanol (0.1 mol / L) under argon was added acetic acid (1.00 equiv). After stirring at room temperature for 1.5 h, sodium cyanoborohydride (5.6–8.2 equiv) was added in one portion, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was then quenched with saturated aqueous NaHCO3 (20 vol) and extracted with DCM (3 × 20 vol). The organic layers were combined, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure.

[0210] Synthesis of Compounds of the Invention Compound 1: General Scheme 1 Route B was used to obtain (3R)-N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0211] Synthesis of tert-butyl (R)-(cyclobutylmethyl)(piperidin-3-yl)carbamate IM3: Step 1: From cyclobutanecarboxaldehyde and (R)-1-benzylpiperidin-3-amine, general procedure H1 was used to give (R)-1-benzyl-N-(cyclobutylmethyl)piperidin-3-amine IM1: 27.05 g, 72% yield, P=71% (gradient A), retention time=1.9 min, (M+H) +:259. Step 2: Using general procedure J from IM1, (R)-tert-butyl(1-benzylpiperidin-3-yl)(cyclobutylmethyl)carbamate IM2 was obtained as a colorless oil: 25.76 g, 96% yield, P=100%, retention time=2.5 min (gradient A), (M+H). + :359. Step 3: Using general procedure L from IM2, (R)-(cyclobutylmethyl)(piperidin-3-yl)tert-butylcarbamate IM3 was obtained as a colorless oil: 3.5 g, 99% yield.

[0212] Synthesis of 3-(azidomethyl)-6-chloropyridazine IM5: Step 1: To a stirred solution (dark brown) of 3-chloro-6-methylpyridazine (25 g, 190.57 mmol) in chloroform (953 mL) at 60 °C under an argon atmosphere was added trichloroisocyanuric acid (22.17 g, 95.39 mmol) at 60 °C. The resulting mixture was stirred at this temperature, and the reaction was monitored by HPLC-MS. After completion (18 h), the reaction mixture was allowed to reach room temperature and then stirred at 0 °C (ice bath) for 10 min. The suspension was then filtered through a short pad of Celite, which was rinsed with DCM (800 mL). The resulting yellow filtrate was concentrated to dryness under reduced pressure to give 21.7 g of a crude dark brown solid, which was purified by silica gel flash chromatography (n-heptane / EtOAc: 8 / 2) to give 3-chloro-6-(chloromethyl)pyridazine IM4 (R f 0.3, n-heptane / EtOAC: 1 / 1) was obtained as a pinkish crystalline solid: 14.58 g, 47% yield, P>95%, retention time = 2.5 min (gradient A), (M+H) + :163. Step 2: Using general procedure N from IM4, 3-(azidomethyl)-6-chloropyridazine IM5 was obtained as an off-white solid: 9.19 g, 99% yield, P=97%, retention time=2.2 min (gradient A), (M+H). + :170.

[0213] Synthesis of 4-ethynyl-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM8: Step 1: To a stirred solution of 4-bromo-6-methoxy-1H-indazole (2.60 g, 10.53 mmol) in anhydrous THF (105 mL) was added 4-methylbenzenesulfonic acid hydrate (102 mg, 0.53 mmol) and 3,4-dihydro-2H-pyran (3.66 g, 42.2 mmol) at room temperature. The reaction mixture was degassed by bubbling argon through it and refluxed. The progress of the reaction was monitored by HPLC-MS for 18 h, and then the solvent was removed under reduced pressure. The residue (6.2 g) was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 1 / 1) to give 4-bromo-6-methoxy-1-tetrahydropyran-2-yl-indazole IM6 (R f 0.7, n-heptane / EtOAc: 1 / 1) was obtained as a white solid: 1.6 g, 46% yield, P=95%, retention time=3.3 min (gradient A), (M+H) + : 311 / 313. ​​Step 2: Using general procedure E1 from IM6, 6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-4-((trimethylsilyl)ethynyl)-1H-indazole IM7 was obtained as an orange-yellow oil: 1.60 g, 91% yield, P=92%, retention time=3.4 min (gradient A), (M+H) + :329. Step 3: Using general procedure D1 from IM7, 4-ethynyl-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM8 was obtained as a yellow oil: 0.79 g, 63% yield, P=90%, retention time=3.1 min (gradient A), (M+H) + :257.

[0214] Synthesis of 4-(1-((6-chloropyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM9: Using general procedure B between IM5 and IM8, 4-(1-((6-chloropyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM9 was obtained as an off-white solid: 9.64 g, 92% yield, P=96%, retention time=4.2 min (gradient A), (M+H). + :426.

[0215] Synthesis of (3R)—N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine (Compound 1): Step 1: Using general procedure C between IM3 and IM9, (cyclobutylmethyl)((3R)-1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM10 was obtained as a beige solid: 10.01 g, 68% yield, P=97%, retention time=4.6 min (gradient B), (M+H). + :658. Step 2: Compound 1 was obtained from IM10 using general procedure A1 as a white powder: 5.17 g, 73% yield, P=100%, retention time=2.8 min (gradient B), (M+H) + :474. Chiral HPLC (IB, TBME / MEOH / DEA: 85 / 15 / 0.1%, flow rate: 1 mL / min): P=100%. 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 8.40 (s, 1H), 7.43 (d, J = 9.4 Hz, 1H), 7.32-7.18 (m, 2H), 6.95 (s, 1H), 5.80 (s, 2H), 4.38 (dd, J = 13.0, 3.7 Hz, 1H), 4.08 (d, J = 13.6 Hz, 1H), 3.89 (s, 3H), 3.17-3.02 (m, 1H), 3.02-2.87 (m, 1H), 2.75-2.59 (m, 3H), 2.52-2.37 (m, 1H), 2.14-1.97 (m, 4H), 1.97-1.38 (m, 6H), 2H was exchanged with CD3OD. 13 C-NMR(CD3OD):δ161.0,160.7,149.1,147.5,143.6,134.8,129.1,125.0,124.0,116.0,115.4,111.5,92 .0,56.1,54.6,54.2,53.4,50.3,49.9,49.6,19.3,48.7,48.4,48.2,46.5,36.1,31.2,23.3,24.2,19.5.

[0216] Compound 2: General Scheme 2, Route A was used to provide (R)—N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[0217] Step 1: 4-Oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride (130 mg, 0.57 mmol) was dissolved in anhydrous DMF (4 mL) at room temperature under argon. DIEA (250 μL, 1.43 mmol) was then added, followed by HATU (220 mg, 0.58 mmol). After 30 min at room temperature, a solution of (6-chloropyridazin-3-yl)methanamine (102 mg, 0.71 mmol) in anhydrous DMF (2 mL) was added dropwise to the solution. The reaction progress was monitored by HPLC-MS, and the conversion was stopped after 1 h. HATU (115 mg, 0.30 mmol) was added to the reaction mixture, and complete conversion was achieved after 30 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined and washed with water (2 × 20 mL) and brine (2 × 10 mL). The resulting organic layer was dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 352 mg of a crude yellow solid. The residue was purified by silica gel flash chromatography (DCM / MeOH: 1 / 0 to 98 / 2) to give N-((6-chloropyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide IM11 (R f 0.25, DCM / MeOH:98 / 2) was obtained as an off-white solid: 71 mg, 37% yield, P=98%, retention time=2.9 min (gradient B), (M+H) + :316 / 318.

[0218] Step 2: Using general procedure C between IM3 and IM11, (R)-(cyclobutylmethyl)(1-(6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM12 was obtained as a pale yellow solid: 78 mg, 66% yield, P = 98%, retention time = 3.9 min (gradient B), (M+H). + :548.

[0219] Step 3: The dihydrochloride salt of compound 2 was obtained from IM12 using general procedure A1 as a greenish powder: 80 mg, 100% yield, P=98%, retention time=2.5 min (gradient B), (M+H)+ :448.

[0220] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Solution "A" was adjusted to pH = 9 with NH4OH. The gradient used was: linear increase from 15% to 50% solution "B" over 5.0 min, then linear increase from 50% to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. Chiral HPLC (IA, TBME / MEOH / DEA: 85 / 15 / 0.1%, flow rate: 1 mL / min): 99.7% purity at 254 nm. 1 H NMR(300MHz,CDCl3)δ9.05(d,J=8.1Hz,1H),8.81(bs,1H),7.82-7.74(m,1H),7.69(d,J=8.1Hz,1H),7.27(d,J=1 0.8Hz,1H),7.26(s,1H),7.18(td,J=6.8,1.5Hz,1H),6.90(d,J=10.8Hz,1H),4.77(d,J=5.9Hz,2H),4.34(dd,J= 12.8, 3.9 Hz, 1H), 4.05 (d, J = 13.2 Hz, 1H), 3.13-3.01 (m, 1H), 2.86 (dd, J = 12.7, 9.2 Hz, 1H), 2.77-2.60 (m, 3H), 2.49-2.33 (m, 1H), 2.11-1.94 (m, 2H), 1.93-1.74 (m, 2H), 1.60 (q, J = 9.4 Hz, 5H), 1.48-1.30 (m, 1H). 1H had exchanged with solvent.

[0221] Compound 3: General Scheme 1 Route B was used to obtain (R)—N-(cyclobutylmethyl)-1-(6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0222] Step 1: 8-Bromoimidazo[1,5-a]pyridine was used to obtain 8-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine IM13 as a yellow oil using general procedure E2: 105 mg, 66% yield, P = 95%, retention time = 1.4 min (gradient A), (M+H) + :215.

[0223] Step 2: 8-ethynylimidazo[1,5-a]pyridine IM14 was obtained from IM13 using general procedure D1 as a brown solid: 70 mg, 95% yield, P=90%, retention time=1.6 min (gradient A), (M+H) + :143.

[0224] Step 3: Using general procedure B between IM5 and IM14, 8-(1-((6-chloropyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)imidazo[1,5-a]pyridine IM15 was obtained as a brown solid: 208 mg, 99% yield, P=68%, retention time=2.0 min (gradient A), (M+H). + :311 / 313.

[0225] Step 4: Using general procedure C between IM3 and IM15, (R)-(cyclobutylmethyl)(1-(6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM16 was obtained as a yellow solid: 124 mg, 40% yield, P=90%, retention time=2.4 min (gradient A), (M+H). + :544.

[0226] Step 5: Using general procedure A1 from IM16, crude compound 3 was obtained as a brown oil: 109 mg, 99% yield, P=87%, retention time=2.4 min (gradient B), (M+H) + :444.

[0227] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Solution "A" was 0.04 M ammonium bicarbonate. The gradient used was: linear increase from 10% to 45% solution "B" over 5.5 min, then linear increase to 90% solution "B" over 0.5 min, hold at 90% for 0.2 min, and return to initial conditions over 0.3 min. Flow rate: 20 mL / min. P = 100%. Chiral HPLC (IA, TBME / MeOH / DEA: 85 / 15 / 0.1%, flow rate: 1 mL / min): 99.7% purity at 254 nm. 1 H NMR(300MHz,DMSO-d6)δ8.88(s,1H),8.46(s,1H),8.36(d,J=6.9Hz,1H),7.89(s,1H),7.42(d,J=9.5 Hz,1H),7.38(d,J=6.9Hz,1H),7.27(d,J=9.5Hz,1H),6.77(t,J=6.9Hz,1H),5.80(s,2H),4.29(d,J= 13.0 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1H), 3.11-2.94 (m, 1H), 2.77 (dd, J = 12.9, 9.3 Hz, 1H), 2.64-2.44 (m, 3H), 2.39-2.23 (m, 1H), 2.03-1.86 (m, 4H), 1.87-1.53 ​​(m, 4H), 1.49-1.20 (m, 2H), 1H was exchanged with CD3OD.

[0228] Compound 4: General Scheme 2, Route A was used to provide (R)—N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-5-methoxynicotinamide.

[0229] Step 1: Using general procedure F between 5-methoxy-nicotinic acid and (6-chloropyridazin-3-yl)methanamine, N-[(6-chloropyridazin-3-yl)methyl]-5-methoxypyridine-3-carboxamide IM17 was obtained as a yellow solid: 56 mg, 59% yield, P = 96%, retention time = 2.0 min (gradient A), (M+H). + :279 / 281.

[0230] Step 2: Using general procedure C between IM3 and IM17, (R)-(cyclobutylmethyl)(1-(6-((5-methoxynicotinamido)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM18 was obtained as a pale yellow solid: 65 mg, 59% yield, P = 89%, retention time = 2.4 min (gradient A), (M+H). + :511.

[0231] Step 3: Using general procedure A1 from IM18, crude compound 4 was obtained as a brown oil: 60 mg, 84% yield, P=82%, retention time=2.3 min (gradient B), (M+H) + :411.

[0232] The product was further purified by reversed-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Solution "A" was adjusted to pH = 9 with NH4OH. The gradient used was: linear increase from 15% to 50% solution "B" over 5.0 min, then linear increase from 50% to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%, 1 H NMR(300MHz,CD3OD)δ8.61(s,1H),8.38(s,1H),7.83(s,1H),7.44(d,J=9.5Hz,1H),7.2 4(d,J=9.5Hz,1H),4.71(s,2H),4.38(d,J=12.0Hz,1H),4.09(d,J=13.3Hz,1H),3.93(s ,3H), 3.07 (t,J=11.9Hz,1H), 2.89 (dd,J=12.7,9.6Hz,1H), 2.80-2.58 (m,3H), 2.56-2.37 (m,1H), 2.17-1.99 (m,3H), 2.00-1.76 (m,3H), 1.75-1.37 (m,4H), 2H was exchanged with CD3OD.

[0233] Compound 5: General Scheme 2, Route A was used to provide (R)—N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-6-methoxy-1H-indazole-4-carboxamide.

[0234] Step 1: To a mixture of IM8 (100 mg, 0.38 mmol) and FeCl3 (3.2 mg, 0.02 mmol) was added tert-butyl hydroperoxide (70% aqueous solution, 0.32 mL, 2.31 mmol) and water (0.2 mL). After 1 h, sodium hydroxide (62 mg, 1.55 mmol) was added. The reaction mixture was then heated at 80 °C, and the reaction progress was monitored by HPLC-MS. After 5 h, the conversion had not progressed further (approximately 50%), so the reaction mixture was cooled to room temperature, diluted with water (5 mL), and acidified with 1 N HCl to a pH of approximately 3–4. EtOAc (20 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give 130 mg of a yellow oil. The residue was purified by silica gel flash chromatography (EtOAc / MeOH: 1 / 0 to 95 / 5) to give 6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxylic acid IM19 (R f 0.7, EtOAc / MeOH: 9 / 1) was obtained as a yellow oil: 70 mg, 31% yield, P=47%, retention time=2.5 min (gradient A), (M+H) + :277.

[0235] Step 2: Using general procedure F between IM19 and IM5, N-((6-chloropyridazin-3-yl)methyl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxamide IM20 was obtained as a yellow oil: 34 mg, 60% yield, P = 80%, retention time = 3.8 min (gradient A), (M+H). + :402 / 404.

[0236] Step 3: Using general procedure C between IM3 and IM20, tert-butyl (cyclobutylmethyl)((3R)-1-(6-((6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carboxamido)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM21 was obtained as a light brown foam: 26 mg, 41% yield, P=85%, retention time=2.6 min (gradient A), (M+H). + :634.

[0237] Step 4: From IM21, crude compound 5 was obtained using general procedure A2 as a brown oil: 25 mg, 65% yield, P=72%, retention time=2.5 min (gradient B), (M+H) + :450.

[0238] The product was purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 25% to 35% solution "B" over 4.0 min, then linear increase to 40% solution "B" over 1.0 min, then linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 98%. 1 H NMR (300MHz, CDCl3): δ8.37(s,1H),7.69(bs,1H),7.34-7.20(m,2H),7.00-6 .91(m,2H),4.82(d,J=5.0Hz,2H),4.33(d,J=12.9Hz,1H),4.05(d,J=13.3Hz ,1H),3.86(s,3H),3.19-3.06(m,1H),3.03-2.92(m,1H),2.79-2.65(m,2H), 2.54-2.38 (m, 1H), 2.13-1.96 (m, 2H), 1.95-1.75 (m, 3H), 1.73-1.41 (m, 5H).

[0239] Compound 6: General Scheme 1 Route B was used to provide 4-(1-((6-(4,4-dimethyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1H-indazole.

[0240] Step 1: Using general procedure H2 between 1-benzylpiperidin-3-one and 4,4-dimethylpiperidine hydrochloride, 1-(1-benzyl-3-piperidyl)-4,4-dimethylpiperidine IM22 was obtained as an orange-yellow oil: 128 mg, 47% yield, P = 80%, retention time = 2.0 min (gradient A), (M+H). + :287.

[0241] Step 2: Using general procedure G from IM22, tert-butyl 4,4-dimethyl-[1,3'-bipiperidine]-1'-carboxylate IM23 was obtained as a yellow oil: 68 mg, 73% yield, retention time = 2.3 min (gradient A), (M+H). + :297.

[0242] Step 3: General procedure A1 was used from IM23 to give crude 4,4-dimethyl-1,3'-bipiperidine dihydrochloride IM24 (no workup) as a yellow oil: 62 mg, 100% yield.

[0243] Step 4: Using general procedure C between IM24 and IM9, 4-(1-((6-(4,4-dimethyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM25 was obtained as a brown oil: 89 mg, 58% yield, P = 63%, retention time = 2.4 min (gradient A), (M+H). + :586.

[0244] Step 5: Using general procedure A2 from IM25, crude compound 6 was obtained as a brown oil: 25 mg, 100% yield, P=75%, retention time=2.2 min (gradient A), (M+H). + :502.

[0245] The product was purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 25% to 35% solution "B" over 4.0 min, then linear increase to 85% solution "B" over 2.2 min, hold at 85% for 0.3 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 98%. 1 H NMR(300MHz,CD3OD)δ8.58(s,1H),8.40(s,1H),7.44(d,J=9.6Hz,1H),7.27(d,J=1.9Hz,1H), 7.23(d,J=9.6Hz,1H),6.96(s,1H),5.81(s,2H),4.63(d,J=13.0Hz,1H),4.25(d,J=13.0Hz,1 H), 3.89 (s, 3H), 3.03-2.84 (m, 2H), 2.74-2.56 (m, 4H), 2.49-2.37 (m, 1H), 2.14-2.03 (m, 1H), 1.90-1.79 (m, 1H), 1.67-1.50 (m, 2H), 1.42 (t, J=5.6 Hz, 4H), 0.93 (s, 6H). 1H was exchanged with CD3OD.

[0246] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IB column (5 μm, 10 × 250 mm). Eluent used: MTBE / MeOH / DEA: 85 / 15 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 95%, retention time = 5.1 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 98%, retention time = 8.1 min, chiral HPLC: P = 100%.

[0247] Compound 7: General Scheme 1 Route B was used to provide 6-methoxy-4-(1-((6-(4-methyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-indazole.

[0248] Step 1: Using general procedure H1 between 1-benzylpiperidin-3-one and 4-methylpiperidine, 1-benzyl-3-(4-methyl-1-piperidyl)piperidine IM26 was obtained as an orange-yellow oil: 55 mg, 13% yield, P=50%, retention time=1.9 min (gradient A), (M+H). + :273.

[0249] Step 2: Using general procedure G from IM26, tert-butyl 3-(4-methyl-1-piperidyl)piperidine-1-carboxylate IM27 was obtained as a yellow oil: 14 mg, 49% yield, retention time = 2.2 min (gradient A), (M+H). + :285.

[0250] Step 3: General procedure A1 was used from IM27 to give crude 4-methyl-1,3'-bipiperidine dihydrochloride IM28 (no workup) as a yellow oil: 12 mg, 95% yield.

[0251] Step 4: Using general procedure C between IM27 and IM9, 6-methoxy-4-(1-((6-(4-methyl-[1,3'-bipiperidin]-1'-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM28 was obtained as an orange-yellow oil: 42 mg, 65% yield, P = 40%, retention time = 2.3 min (gradient A), (M+H). + :572.

[0252] Step 5: Using general procedure A2 from IM28, crude compound 7 was obtained as an orange-yellow oil: 30 mg, 68% yield, P=40%, retention time=2.1 min (gradient A), (M+H) + :488.

[0253] The product was purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 30% to 35% solution "B" over 3.5 min, then linear increase to 60% solution "B" over 1.5 min, then linear increase to 85% solution "B" over 1.2 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 97%. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.44(d,J=9.6Hz,1H),7.28(d,J=1.7Hz,1 H),7.24(d,J=9.6Hz,1H),6.97(s,1H),5.81(s,2H),4.62(d,J=12.2Hz,2H),4.26(d,J=12. 2Hz, 1H), 3.90(s, 3H), 3.10-2.85(m, 4H), 2.51-2.24(m, 3H), 2.12-2.03(m, 1H), 1.92-1.79(m, 1H), 1.77-1.50(m, 4H), 1.44-1.16(m, 3H), 0.93(d, J=6.3Hz, 3H), 1H was exchanged with CD3OD.

[0254] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IB column (5 μm, 10 × 250 mm). Eluent used: MTBE / MeOH / DEA: 85 / 15 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 97%, retention time = 5.5 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 98%, retention time = 9.6 min, chiral HPLC: P = 100%.

[0255] Compound 8: General Scheme 1 Route B was used to provide 4-(1-((6-(3-(6-azaspiro[3.4]octan-6-yl)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1H-indazole.

[0256] Step 1: Using general procedure H1 between 1-benzylpiperidin-3-one and 6-azaspiro[3.4]octane, 6-(1-benzylpiperidin-3-yl)-6-azaspiro[3.4]octane was obtained as a green oil: 158 mg, 41% yield, P = 56%, retention time = 2.0 min (gradient A), (M+H). + :285.

[0257] Step 2: General procedure G was used from IM29 to give tert-butyl 3-(6-azaspiro[3.4]octan-6-yl)piperidine-1-carboxylate IM30 as a yellow oil: 38 mg, 47% yield, retention time = 2.2 min (gradient A), (M+H). + :295.

[0258] Step 3: General procedure A1 was used from IM30 to give crude 6-(3-piperidyl)-6-azaspiro[3.4]octane dihydrochloride IM31 (no workup) as a light brown solid: 29 mg, 67% yield.

[0259] Step 4: General procedure C was used between IM31 and IM9 to give crude 4-(1-((6-(3-(6-azaspiro[3.4]octan-6-yl)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM32 as a brown oil: 50 mg, 44% yield, P=46%, retention time=2.4 min (gradient A), (M+H). + :585.

[0260] Step 5: From IM32, crude compound 8 was obtained using general procedure A2 as a brown oil: 60 mg, 85% yield, P=35%, retention time=2.2 min (gradient A), (M+H) + :500.

[0261] The product was purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 15% to 40% solution "B" over 5.0 min, then linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 98%. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.46(d,J=9.4Hz,1H),7.31-7.22(m,2H),6.97(s,1H),5.82(s,2H),4.58(d,J=14.1Hz,1H),4.12( d,J=11.4Hz,1H),3.90(s,3H),3.12-2.97(m,2H),2.93-2.76(m,4H),2.4 5-2.32(m,1H),2.18-1.74(m,10H),1.68-1.52(m,1H),1.39-1.25(m,1H).

[0262] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IB column (5 μm, 10 × 250 mm). Eluent used: MTBE / MeOH / DEA: 85 / 15 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 98%, retention time = 6.1 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 98%, retention time = 9.6 min, chiral HPLC: P = 99%.

[0263] Compound 9: General Scheme 1 Route B was used to obtain (3R)—N-(cyclobutylmethyl)-1-(6-((4-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0264] Step 1: From 5-bromo-7-azaindole, trimethyl-[2-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethynyl]silane IM33 was obtained using general procedure E3 as a yellow solid: 920 mg, 76% yield, P=60% ( 1H-NMR), retention time = 2.9 min (gradient A), (M+H) + :215.

[0265] Step 2: 5-ethynyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine IM34 was obtained from IM33 using general procedure D1 as a brown solid: 73 mg, 18% yield, P=90% ( 1 H-NMR), retention time = 2.3 min (gradient A), (M+H) + :143.

[0266] Step 3: Using general procedure B between IM5 and IM34, 5-(1-((6-chloropyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine IM35 was obtained as a beige solid: 88 mg, 43% yield, P = 71%, retention time = 2.1 min (gradient A), (M+H). + :311 / 313.

[0267] Step 4: Using general procedure C between IM3 and IM35, tert-butyl (cyclobutylmethyl)((3R)-1-(6-((4-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM36 was obtained as a brown foam: 103 mg, 76% yield, P=80%, retention time=2.5 min (gradient A), (M+H). + :544.

[0268] Step 5: Using general procedure A1 from IM36, crude compound 9 was obtained as a brown foam: 78 mg, 100% yield, P=87%, retention time=2.1 min (gradient A), (M+H) + :444.

[0269] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 25% to 50% solution "B" over 4.5 min, then linear increase to 85% solution "B" over 2.0 min, hold at 90% for 0.4 min, and return to initial conditions over 1.1 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR(300MHz,CD3OD)δ8.65(s,1H),8.44-8.36(m,2H),7.48-7.38(m,2H),7.25(d,J=9. 7Hz,1H),6.54(d,J=3.4Hz,1H),5.78(s,2H),4.40(d,J=12.3Hz,1H),4.11(d,J=14.1H) z, 1H), 3.17-3.03 (m, 1H), 2.93 (dd, J = 12.6, 9.6 Hz, 1H), 2.74-2.59 (m, 3H), 2.54-2.38 (m, 1H), 2.14-1.99 (m, 3H), 1.95-1.56 (m, 5H), 1.56-1.38 (m, 2H), 2H was exchanged with CD3OD.

[0270] Compound 10: General Scheme 2 Route B was used to provide (R)—N-((6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-carboxamide.

[0271] Step 1: To a solution of 3-chloro-6-(chloromethyl)pyridazine (250 mg, 1.53 mmol) in anhydrous DMF (6.2 mL) was added potassium phthalimide (305 mg, 1.61 mmol) in small portions. The mixture was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After complete conversion (2 h), water (20 mL) was added. The mixture was cooled to 0 °C and filtered. The solid was rinsed with water (10 mL) and then triturated with EtOH (6 mL) to give the desired 2-((6-chloropyridazin-3-yl)methyl)isoindoline-1,3-dione IM37 as a gray solid after drying: 300 mg, 71% yield, P = 100%, retention time = 2.5 min (gradient A), (M+H). + :274 / 276.

[0272] Step 2: Using general procedure C between IM3 and IM37, tert-butyl ((R)-(cyclobutylmethyl)(1-(6-((1,3-dioxoisoindolin-2-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM38 was obtained as a white foam: 335 mg, 73% yield, P=100%, retention time=2.6 min (gradient A), (M+H). + :506.

[0273] Step 3: Using general procedure K from IM38, (R)-tert-butyl(1-(6-(aminomethyl)pyridazin-3-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM39 was obtained as a yellow gum: 186 mg, 85% yield, P=100%, retention time=2.3 min (gradient A), (M+H). + :376.

[0274] Step 4: General procedure F was used between IM39 and 5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-carboxylic acid to give crude (R)-(cyclobutylmethyl)(1-(6-((5-oxo-5H-thiazolo[3,2-a]pyrimidine-7-carboxamido)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM40 as a yellow foam: 38 mg, 78% yield, P=100%, retention time=2.5 min (gradient A), (M+H). + :554.

[0275] Step 5: Compound 10 was obtained from IM40 using general procedure A1 as an off-white powder: 18 mg, 62% yield, P=98%, retention time=2.4 min (gradient B), (M+H) + :454. 1H NMR(300MHz,CD3OD)δ8.10(d,J=4.9Hz,1H),7.54(d,J=4.9Hz,1H),7.42(d,J=9.5Hz,1H) ,7.24(d,J=9.5Hz,1H),6.98(s,1H),4.70(s,2H),4.37(d,J=12.9Hz,1H),4.08(d,J=13. 3Hz, 1H), 3.14-3.00(m, 1H), 2.91(dd, J=12.9, 9.4Hz, 1H), 2.78-2.59(m, 3H), 2.57-2.40(m, 1H), 2.09(d, J=9.3Hz, 3H), 1.94-1.65(m, 5H), 1.55-1.37(m, 2H), 2H was exchanged with CD3OD.

[0276] Compound 11: General Scheme 2 Route A was used to provide (R)—N-((6-(3-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[0277] Step 1: Using general procedure H2 between 1-benzylpiperidin-3-one hydrochloride and 1-{3-fluorobicyclo[1.1.1]pentan-1-ylmethanamine hydrochloride, 1-benzyl-N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)piperidin-3-amine IM41 was obtained as a yellow oil: 264 mg, 79% yield, P = 73%, retention time = 2.0 min (gradient A), (M+H). + :289.

[0278] Step 2: Using general procedure J from IM41, tert-butyl (1-benzylpiperidin-3-yl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)carbamate IM42 was obtained as a colorless oil: 309 mg, 85% yield.

[0279] Step 3: A solution of IM41 (309 mg, 0.76 mmol) in absolute ethanol (15.1 mL) was degassed by bubbling argon through it while stirring under an argon atmosphere for 15 minutes. Palladium on activated carbon (10 wt % on dry carbon, 157 mg, 0.15 mmol) was then added, and hydrogen was bubbled through the resulting solution with stirring for 5 minutes. A hydrogen balloon (approximately 3 bar) was then placed, and the mixture was vigorously stirred at room temperature. The reaction progress was monitored by HPLC-MS. After 16 hours, argon was bubbled through the reaction mixture for 5 minutes. The mixture was then filtered through a short Celite pad, which was then rinsed with MeOH (5 mL, then 4 × 10 mL). The filtrate was concentrated to dryness under reduced pressure to give tert-butyl ((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)(piperidin-3-yl)carbamate IM43 as a colorless oil: 275 mg, 98% yield.

[0280] Step 4: General procedure C was used between IM11 and IM43 to give crude compound 11 (in situ partial Boc deprotection) as an orange-yellow oil: 30 mg, 11% yield, P=50%, retention time=1.8 min (gradient A), (M+H). + :478.

[0281] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Solution "A" was water + 0.1% TFA. The gradient used was: linear increase from 23% to 35% solution "B" over 5.0 min, then linear increase to 85% solution "B" over 1.0 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1H NMR(300MHz,CD3OD)δ9.08(d,J=7.1Hz,1H),8.07-7.95(m,1H),7.84(d,J=8.9Hz,1H),7.49-7. 36(m,2H),7.24(d,J=9.5Hz,1H),7.10(s,1H),4.37(d,J=12.8Hz,1H),4.09(d,J=13.3Hz,1H), 3.17-3.01 (m, 1H), 3.00-2.85 (m, 3H), 2.75-2.61 (m, 1H), 2.11-2.00 (m, 1H), 1.95 (d, J=2.6 Hz, 6H), 1.87-1.76 (m, 1H), 1.64-1.36 (m, 2H). The benzyl CH2 was shielded by the water signal, and the 1H was exchanged with CD3OD. 19 F NMR (H decoupling) (282 MHz, CD3OD) δ -144.08.

[0282] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: EtOAc / EtOH / TFA: 75 / 25 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: retention time = 3.7 min. Second eluting enantiomer: retention time = 4.4 min.

[0283] Residual TFA was removed by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 5% to 40% solution "B" over 6.0 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. First eluting enantiomer: P = 100%, Chiral HPLC: P = 100%. Second eluting enantiomer: P = 100%, Chiral HPLC: P = 99.3%.

[0284] Compound 12: General Scheme 1 Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0285] Synthesis of 3-ethynyl-5-methoxypyridine IM44: A mixture of 3-bromo-5-methoxypyridine (379 mg, 2.02 mmol), tetrakis(triphenylphosphine)palladium (76 mg, 0.06 mmol), and copper(I) iodide (15 mg, 0.08 mmol) was degassed by bubbling argon under an argon atmosphere at room temperature for 15 minutes. Triethylamine (1.2 mL, 8.8 mmol) followed by ethynyltrimethylsilane (450 μL, 3.09 mmol) were added in one portion at room temperature, and the reaction mixture (yellow suspension) was stirred at 55 °C. The reaction progress was monitored by HPLC-MS. After 3 h (complete conversion), the reaction mixture was allowed to cool to room temperature, diluted with EtO (15 mL), and washed with water (4 × 30 mL). The organic layer was dried over MgSO4 and filtered through a short Celite pad, which was rinsed with Et2O (2 x 10 mL). TBAF (3.0 mL, 3.0 mmol) was added once to the brown filtrate with stirring at room temperature for 30 min. The reaction mixture was then washed with water (3 x 30 mL), the organic phase was dried over MgSO4, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 294 mg of a crude brown oil containing some white needles. The residue was purified by silica gel flash chromatography (n-heptane / EtOAc: 9 / 1) to give 3-ethynyl-5-methoxypyridine IM44 (R f 0.2, n-heptane / EtOAc: 4 / 1) was obtained as a white solid: 154 mg, 56% yield, P=98%, retention time=1.7 min (gradient A), (M+H) + :134.

[0286] Synthesis of tert-butyl (R)-(1-(6-(azidomethyl)pyridazin-3-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM45: General procedure V was used from IM39 to afford crude tert-butyl (R)-(1-(6-(azidomethyl)pyridazin-3-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM45 as a yellow oil: 66 mg, 96% yield, P = 78% (215 nm), retention time = 2.6 min (gradient A), (M+H). + :402.

[0287] Synthesis of (3R)—N-(cyclobutylmethyl)-1-(6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine (compound 12): Step 1: Using general procedure B between IM44 and IM45, tert-butyl (cyclobutylmethyl)((3R)-1-(6-((4-(5-methoxypyridin-3-yl)-1,212,312-triazolidin-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM46 was obtained as a yellow oil: 24 mg, 32% yield, P=90%, retention time=2.4 min (gradient A), (M+H). + :535. Step 2: Compound 12 was obtained from IM46 using general procedure A1 as a pale yellow solid: 18 mg, 94% yield, P=92%, retention time=2.4 min (gradient B), (M+H) + :435. 1 H NMR(300MHz,CD3OD)δ8.58(s,1H),8.54(s,1H),8.19(s,1H),7.86-7.79(m,1H),7.43 (d,J=9.5Hz,1H),7.24(d,J=9.5Hz,1H),5.78(s,2H),4.39(d,J=13.6Hz,1H),4.17-4 0.04 (m, 1H), 3.93 (d, J = 0.9 Hz, 3H), 3.16-3.01 (m, 1H), 2.99-2.85 (m, 1H), 2.78-2.55 (m, 3H), 2.54-2.37 (m, 1H), 2.13-1.99 (m, 3H), 1.96-1.35 (m, 7H), 1H was exchanged with CD3OD.

[0288] Compound 13: General Scheme 1, Route A was used to obtain (R)—N-(cyclobutylmethyl)-1-(6-((4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0289] Step 1: From 8-bromo-6-methoxyimidazo[1,5-a]pyridine using general procedure E3, crude 6-methoxy-8-((trimethylsilyl)ethynyl)imidazo[1,5-a]pyridine IM47 was obtained as a brown solid: 112 mg, 99% yield, P=30%, retention time=2.4 min (gradient A), (M+H). + :245.

[0290] Step 2: Using general procedure D from IM47, 8-ethynyl-6-methoxy-imidazo[1,5-a]pyridine IM48 was obtained as an orange-yellow solid: 8 mg, 30% yield, P=89%, retention time=2.0 min (gradient A), (M+H). + :173.

[0291] Step 3: Using general procedure B between IM45 and IM48, (R)-(cyclobutylmethyl)(1-(6-((4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM49 was obtained as a yellow film: 8 mg, 39% yield, P=98%, retention time=2.4 min (gradient A), (M+H). + :574.

[0292] Step 4: From IM49, crude compound 13 was obtained using general procedure A1 as a yellow solid: 7 mg, 100% yield, P=97%, retention time=2.5 min (gradient B), (M+H) + :474. 1H NMR(300MHz,CD3OD)δ8.63(s,1H),8.27(s,1H),7.91(s,1H),7.80(s,1H),7.45(d,J=9.5Hz,1 H),7.25(d,J=9.5Hz,1H),7.17(d,J=1.9Hz,1H),5.81(s,2H),4.40(d,J=13.0Hz,1H),4.14-4. 03 (m, 1H), 3.85 (s, 3H), 3.19-3.04 (m, 1H), 2.98 (dd, J = 12.9, 9.4 Hz, 1H), 2.81-2.62 (m, 3H), 2.55-2.37 (m, 1H), 2.16-2.00 (m, 3H), 2.00-1.77 (m, 3H), 1.77-1.39 (m, 4H), 1H was replaced with CD3OD.

[0293] Compound 14: General Scheme 2 Route A was used to provide N-((6-(3-(6-azaspiro[2.5]octan-6-yl)piperidin-1-yl)pyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[0294] Step 1: Using general procedure H2 between 1-benzylpiperidin-3-one hydrochloride and 6-azaspiro[2.5]octane hydrochloride, crude 6-(1-benzyl-3-piperidyl)-6-azaspiro[2.5]octane IM50 was obtained as a yellow oil: 198 mg, 82% yield, P = 82%, retention time = 1.9 min (gradient A), (M+H). + :285.

[0295] Step 2: General procedure I was used from IM50 to give crude 6-(piperidin-3-yl)-6-azaspiro[2.5]octane IM51 as a colorless oil: 105 mg, 78% yield.

[0296] Step 3: Using general procedure C between IM51 and IM11, compound 14 was obtained as a pale yellow oil: 20 mg, 27% yield, P=96%, retention time=2.5 min (gradient B), (M+H) + :474. 1H NMR(300MHz,CD3OD)δ9.08(d,J=7.0Hz,1H),8.07-7.95(m,1H),7.84(d,J=8.8Hz,1H),7.49-7.36 (m,2H),7.24(d,J=9.5Hz,1H),7.09(s,1H),4.63(d,J=12.8Hz,1H),4.25(d,J=13.4Hz,1H),3.05 -2.85(m,2H), 2.87-2.65(m,4H), 2.65-2.48(m,1H), 2.17-2.06(m,1H), 1.93-1.82(m,1H), 1.71-1.53(m,2H), 1.52-1.42(m,4H), 0.31(s,4H). The benzyl CH2 was shielded by the water signal and the 1H was exchanged with CD3OD.

[0297] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). The eluent used was TBME / EtOH / DCM / DEA: 80 / 20 / 10 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 100%, retention time = 15.1 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 100%, retention time = 17.2 min, chiral HPLC: P = 98%.

[0298] Compound 15: General Scheme 1 Route B was used to provide (3R)—N-(cyclopropylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0299] Step 1: (R)-1-benzyl-N-(cyclopropylmethyl)piperidin-3-amine IM52 was obtained from cyclopropanecarboxaldehyde and (R)-1-benzylpiperidin-3-amine using general procedure H1: 333 mg, 92% yield, P = 90% (215 nm), retention time = 1.8 min (gradient A), (M+H) + :245.

[0300] Step 2: Using general procedure J from IM52, (R)-tert-butyl(1-benzylpiperidin-3-yl)(cyclopropylmethyl)carbamate IM53 was obtained as a colorless oil: 406 mg, 94% yield, P = 98% (215 nm), retention time = 2.4 min (gradient A), (M+H). + :345.

[0301] Step 3: General procedure I was used from IM53 to give tert-butyl (R)-(cyclopropylmethyl)(piperidin-3-yl)carbamate IM54 as a colorless oil: 287 mg, 98% yield.

[0302] Step 4: Using general procedure C between IM9 and IM54, (cyclopropylmethyl)((3R)-1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM55 was obtained as a yellow film: 84 mg, 70% yield, P=98%, retention time=2.7 min (gradient A), (M+H). + :644.

[0303] Step 5: Compound 15 was obtained from IM55 using general procedure A1 as an off-white solid: 54 mg, 90% yield, P=98%, retention time=2.7 min (gradient B), (M+H) + :460. 1H NMR(300MHz,CD3OD)δ8.55(s,1H),8.39(d,J=1.1Hz,1H),7.38(d,J=9.5Hz,1H),7.21(d,J=2.0Hz,1H),7.15(d,J =9.5Hz,1H),6.91(dd,J=2.0,1.0Hz,1H),5.77(s,2H),4.41-4.28(m,1H),4.03(d,J=13.4Hz,1H),3.85(s,3H),3 1H-2.94 (m, 1H), 2.87 (dd, J = 12.9, 9.4 Hz, 1H), 2.71-2.55 (m, 1H), 2.46 (d, J = 6.9 Hz, 2H), 2.04-1.91 (m, 1H), 1.82-1.68 (m, 1H), 1.62-1.22 (m, 2H), 0.97-0.77 (m, 1H), 0.52-0.37 (m, 2H), 0.18-0.04 (m, 2H). 1H was replaced with CD3OD. Chiral HPLC (ID, TBME / EtOH / DEA: 80 / 20 / 0.1%, flow rate: 1 mL / min): 98.3% purity at 280 nm.

[0304] Compound 16: General Scheme 2, Route A was used to provide (R)—N-((6-(3-((cyclopropylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[0305] Step 1: Using general procedure C between IM3 and IM11, (R)-(cyclopropylmethyl)(1-(6-((4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamido)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM56 was obtained as a yellow film: 23 mg, 47% yield, P=98%, retention time=2.4 min (gradient A), (M+H). + :534.

[0306] Step 2: Compound 16 was obtained from IM56 using general procedure A1 as a pale yellow solid: 17 mg, 90% yield, P=97%, retention time=2.3 min (gradient B), (M+H) + :434. 1H NMR(300MHz,CD3OD)δ9.06(s,1H),7.98(dd,J=6.7,1.6Hz,1H),7.81(d,J=8.9Hz,1H),7.47-7.33(m,2H),7.2 2(d,J=9.5Hz,1H),7.06(s,1H),4.45-4.31(m,1H),4.14-4.03(m,1H),3.14-2.98(m,1H),2.89(dd,J=12.8,9 0.4Hz, 1H), 2.79-2.62(m, 1H), 2.53(d, J=6.9Hz, 2H), 2.11-1.97(m, 1H), 1.87-1.75(m, 1H), 1.67-1.35(m, 2H), 1.01-0.80(m, 1H), 0.55-0.45(m, 2H), 0.22-0.12(m, 2H). The benzyl CH2 was shielded by the water signal and the 1H was exchanged with CD3OD.

[0307] Compound 17: General Scheme 1 Route A was used to provide 2-(1-((6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-4H-pyrido[1,2-a]pyrimidin-4-one.

[0308] Step 1: General procedure E2 was used from 2-chloro-4H-pyrido[1,2-a]pyrimidin-4-one to give crude 2-((trimethylsilyl)ethynyl)-4H-pyrido[1,2-a]pyrimidin-4-one IM57 as a black solid: 468 mg, 99% yield, P=78%, retention time=2.8 min (gradient A), (M+H). + :243.

[0309] Step 2: 2-ethynylpyrido[1,2-a]pyrimidin-4-one IM58 was obtained from IM57 using general procedure D1 as an off-white solid: 156 mg, 51% yield, P=96%, retention time=2.1 min (gradient A), (M+H) + :171.

[0310] Step 3: Using general procedure B between IM45 and IM58, crude (cyclobutylmethyl)((3R)-1-(6-((4-(4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)tert-butylcarbamate IM59 was obtained as a brown solid: 28 mg, 42% yield, P=44%, retention time=2.5 min (gradient A), (M+H). + :572.

[0311] Step 4: From IM59, crude compound 17 was obtained using general procedure A1 as a brown solid: 7 mg, 100% yield, P=35%, retention time=2.0 min (gradient A), (M+H). + :472.

[0312] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 10% to 30% solution "B" over 3.0 min, then linear increase to 50% solution "B" over 2.5 min, then linear increase to 55% solution "B" over 1.0 min, then linear increase to 85% solution "B" over 1.0 min, hold at 85% for 0.3 min, and return to initial conditions over 0.2 min. Flow rate: 15 mL / min. P = 99%. 1 H NMR(300MHz,CDCl3)δ9.07(d,J=6.8Hz,1H),8.36(s,1H),7.72(t,J=8.0Hz,1H),7.61(d,J=8.9Hz ,1H),7.35-7.22(m,2H),7.10(t,J=7.0Hz,1H),6.89(d,J=9.4Hz,1H),5.76(s,2H),4.38(d,J=13. 2Hz, 1H), 4.09 (d, J = 13.6 Hz, 1H), 3.12 (t, J = 12.0 Hz, 1H), 2.93 (t, J = 11.1 Hz, 1H), 2.71 (t, J = 10.3 Hz, 3H), 2.49-2.37 (m, 1H), 2.05 (s, 3H), 1.87 (d, J = 8.4 Hz, 3H), 1.73-1.35 (m, 4H). 1H was in solvent exchange.

[0313] Compound 18: General Scheme 1 Route B was used to provide (3R)—N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0314] Step 1: (3R)-1-benzyl-N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]piperidin-3-amine IM60 was obtained from 3-fluorobicyclo[1.1.1]pentane-1-carbaldehyde and (R)-1-benzylpiperidin-3-amine using general procedure H1: 553 mg, 64% yield, P = 63% (215 nm), retention time = 2.0 min (gradient A), (M+H) + :289.

[0315] Step 2: Using general procedure J from IM60, (R)-(1-benzylpiperidin-3-yl)((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)tert-butylcarbamate IM61 was obtained as a colorless oil: 510 mg, 74% yield, P=68%, retention time=2.5 min (gradient A), (M+H). + :389.

[0316] Step 3: Using general procedure L from IM61, (R)-tert-butyl((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)(piperidin-3-yl)carbamate IM62 was obtained as a colorless oil: 350 mg, 89% yield.

[0317] Step 4: Using general procedure C between IM9 and IM62, tert-butyl ((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)((3R)-1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM63 was obtained as an off-white solid: 201 mg, 56% yield, P=100%, retention time=2.7 min (gradient A), (M+H). + :688.

[0318] Step 5: Compound 18 was obtained from IM63 using general procedure A1 as a white solid: 140 mg, 96% yield, P=100%, retention time=2.9 min (gradient B), (M+H) + :504. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.40(d,J=1.0Hz,1H),7.45(d,J=9.5Hz,1H),7.30-7.2 0(m,2H),6.96(s,1H),5.81(s,2H),4.42(dd,J=12.6,3.8Hz,1H),4.16-4.02(m,1H),3.89 (s, 3H), 3.17-3.02 (m, 1H), 3.00 (s, 2H), 3.00-2.89 (m, 1H), 2.79-2.66 (m, 1H), 2.12-2.00 (m, 1H), 1.96 (d, J = 2.6 Hz, 6H), 1.88-1.76 (m, 1H), 1.65-1.39 (m, 2H), 2H was exchanged with CD3OD. 19 F NMR (282 MHz, CD3OD) δ -144.17. Chiral HPLC (IB, MeCN / MeOH / DEA: 95 / 5 / 0.1%, flow rate: 1 mL / min): 97.8% purity at 280 nm.

[0319] Compound 19: General Scheme 1 Route A was used to provide 3-(1-((6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-methoxypicolinonitrile.

[0320] Step 1: 3-Bromo-5-methoxypicolinonitrile was used to obtain 5-methoxy-3-((trimethylsilyl)ethynyl)picolinonitrile IM64 as a yellow oil using general procedure E2: 9 mg, 15% yield, P = 90%, retention time = 2.6 min (gradient A), (M+H) + :281.

[0321] Step 2: A solution of TBAF (60 μL, 0.06 mmol) was added to a solution of IM45 (14 mg, 0.03 mmol), IM64 (9 mg, 0.04 mmol), copper(I) iodide (1.1 mg, 0.01 mmol), and DIEA (4 μL, 0.02 mmol) in anhydrous tert-butanol (360 μL) under an argon atmosphere. The reaction mixture was heated to 130 °C, and the progress of the reaction was monitored by HPLC-MS. After 15 min, the reaction mixture was allowed to cool to room temperature, diluted with EtOAc (20 mL), and washed with water (5 mL). The layers were separated, and the organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give 30 mg of a brown oil. The residue was purified by silica gel flash chromatography (EtOAc / n-heptane: 7 / 3 to 9 / 1) to give tert-butyl ((3R)-1-(6-((4-(2-cyano-5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM65 (R f 0.7, EtOAc / MeOH: 9 / 1) was obtained as a brown solid: 7 mg, 34% yield, P=96%, retention time=2.7 min (gradient A), (M+H) + :560.

[0322] Step 3: From IM65, crude compound 19 was obtained using general procedure A2 as a light brown oil: 25 mg, 96% yield (+TFA), P = 98%, retention time = 2.2 min (gradient A), (M+H) + :460.

[0323] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 10% to 40% solution "B" over 4.5 min, then linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR(300MHz,CDCl3)δ8.58(s,1H),8.31(d,J=2.8Hz,1H),8.08(d,J=2.8Hz,1H),7.23( d,J=9.5Hz,1H),6.90(d,J=9.5Hz,1H),5.80(s,2H),4.38(d,J=13.0Hz,1H),4.09(d,J = 13.3 Hz, 1H), 3.99 (s, 3H), 3.19-3.04 (m, 1H), 2.91 (dd, J = 12.8, 9.2 Hz, 1H), 2.77-2.60 (m, 3H), 2.51-2.35 (m, 1H), 2.12-1.96 (m, 3H), 1.94-1.73 (m, 3H), 1.73-1.51 (m, 4H). One NH was exchanged with the solvent.

[0324] Compound 20: General Scheme 1 Route B was used to provide ((3R)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)-N-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)piperidin-3-amine.

[0325] Step 1: To a solution of 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid (143 mg, 1.1 mmol) in anhydrous DMF (6.8 mL) was added DIEA (390 μL, 2.23 mmol), 1-benzylpiperidin-3-amine (200 mg, 1.05 mmol), and then T3P (50% w / w tripropylphosphonic anhydride in AcOEt) (800 μL, 1.34 mmol). The reaction was stirred at room temperature for 30 min, and saturated NaHCO3 solution (20 mL) was added. The mixture was extracted with EtOAc (50 mL), and the organic layer was further washed with saturated NaHCO solution (3 × 20 mL), dried over MgSO, filtered, and concentrated to dryness in vacuo to give N-(1-benzylpiperidin-3-yl)-3-methylbicyclo[1.1.1]pentane-1-carboxamide IM66 as an off-white solid: 276 mg, 88% yield, P = 100% (215 nm), retention time = 2.2 min (gradient A), (M+H). + :299.

[0326] Step 2: A solution of IM66 (276 mg, 0.92 mmol) in anhydrous THF (2 mL) was cooled to 0 °C under an argon atmosphere, and borane (THF complex, 1 M in THF, 10 mL, 10 mmol) was added. The reaction mixture was then stirred at 80 °C. The reaction progress was monitored by HPLC-MS, and additional borane (THF complex, 1 M in THF) was added after 3 h (2 mL, 2 mmol). After 5 h, the reaction mixture was quenched by the addition of water / MeOH (1 / 1, 20 mL) and concentrated under reduced pressure to give a white paste. The latter was solubilized with MeOH (30 mL), and aqueous hydrogen chloride solution (1 N, 30 mL, 30 mmol) was added. The solution was heated to 70 °C for 1 h and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure to give a white paste. To the paste (pH ∼9–10) was added 1 N NaOH (10 mL) and EtOAc (30 mL). The layers were separated and the basic aqueous layer was extracted with additional EtOAc (3 x 30 mL). The organic layers were combined, dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 1-benzyl-N-((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)piperidin-3-amine IM67 as a colorless oil: 250 mg, 94% yield, P = 99% (215 nm), retention time = 2.1 min (gradient A), (M+H). + :285.

[0327] Step 3: Using general procedure J from IM67, tert-butyl (1-benzylpiperidin-3-yl)((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)carbamate IM68 was obtained as a colorless oil: 266 mg, 79% yield, P=100%, retention time=2.6 min (gradient A), (M+H). + :385.

[0328] Step 4: Using general procedure I from IM68, tert-butyl ((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)(piperidin-3-yl)carbamate IM69 was obtained as a colorless oil: 170 mg, 83% yield.

[0329] Step 5: Using general procedure C between IM9 and IM69, tert-butyl (1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)((3-methylbicyclo[1.1.1]pentan-1-yl)methyl)carbamate IM70 was obtained as a yellow solid: 47 mg, 71% yield, P=94%, retention time=2.8 min (gradient A), (M+H). + :684.

[0330] Step 6: Compound 20 was obtained from IM70 using general procedure A1 as a white solid: 27 mg, 76% yield, P=97%, retention time=3.1 min (gradient B), (M+H) + :500. 1 H NMR(300MHz,CD3OD)δ8.58(s,1H),8.40(s,1H),7.44(d,J=9.8Hz,1H),7.27(s,1H) ),7.24(d,J=9.8Hz,1H),6.96(s,1H),5.81(s,2H),4.37(d,J=12.7Hz,1H),4.11(d , J = 14.2 Hz, 1H), 3.90 (s, 3H), 3.17-3.04 (m, 1H), 3.01-2.88 (m, 1H), 2.78-2.61 (m, 2H), 2.12-1.97 (m, 1H), 1.78 (s, 2H), 1.55 (s, 6H), 1.52-1.39 (m, 1H), 1.11 (s, 3H). 2H was exchanged with CD3OD.

[0331] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IB column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 88 / 12 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 100%, retention time = 7.1 min, chiral HPLC: P = 98.0%. Second eluting enantiomer: P = 98%, retention time = 8.0 min, chiral HPLC: P = 98.7%.

[0332] Compound 21: General Scheme 1 Route A was used to provide 5-(1-((6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)nicotinonitrile.

[0333] Step 1: From 5-bromonicotinonitrile, general procedure E2 (in THF instead of DMF) was used to give 5-((trimethylsilyl)ethynyl)nicotinonitrile IM71 as a yellow solid: 187 mg, 84% yield, P=98%, retention time=3.0 min (gradient A), (M+H). + :201.

[0334] Step 2: 5-ethynylnicotinonitrile IM72 was obtained from IM71 using general procedure D2 as a yellow solid: 61 mg, 52% yield, P=100%, retention time=2.3 min (gradient A), (M+H) + :129.

[0335] Step 3: Using general procedure B between IM45 and IM72, tert-butyl ((3R)-1-(6-((4-(5-cyanopyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM73 was obtained as a yellow oil: 30 mg, 45% yield, P=50%, retention time=2.6 min (gradient A), (M+H). + :530.

[0336] Step 4: From IM73, crude compound 21 was obtained using general procedure A2 as a yellow oil: 30 mg, 99% yield, P=57%, retention time=2.1 min (gradient A), (M+H) + :430.

[0337] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 20% to 40% solution "B" over 3.5 min, then linear increase to 85% solution "B" over 2.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 99%. 1 H NMR(300MHz,CDCl3)δ9.16(d,J=2.0Hz,1H),8.81(d,J=1.8Hz,1H),8.43(dd,J=2.0,1.8Hz ,1H),8.13(s,1H),7.29(d,J=9.5Hz,1H),6.90(d,J=9.5Hz,1H),5.75(s,2H),4.36(d,J=9 0.7 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.21-3.06 (m, 1H), 2.93 (dd, J = 12.8, 9.4 Hz, 1H), 2.76-2.59 (m, 3H), 2.50-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.95-1.80 (m, 3H), 1.71-1.48 (m, 5H). (One NH was exchanged with solvent.)

[0338] Compound 22: Reductive amination afforded (3R)—N-(cyclobutylmethyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)-N-methylpiperidin-3-amine: To a solution of compound 1 (23 mg, 0.05 mmol) and formaldehyde (6 μL, 0.08 mmol) in MeCN (0.5 mL) was added acetic acid (3 μL, 0.05 mmol) and sodium cyanoborohydride (6 mg, 0.10 mmol) in one go. The suspension was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After 3 h (complete conversion), the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 5 mL). The aqueous layer was basified to pH = 9 with 1 N NaOH and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give crude compound 22 as a colorless oil: 16 mg, 23% yield, P=32%, retention time=2.9 min (gradient B), (M+H). + :488.

[0339] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 10% to 70% solution "B" over 6.0 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), 8.41 (s, 1H), 7.44 (d, J = 9.5 Hz, 1H), 7.27 (s, 1H), 7.23 (d, J = 9.5 Hz, 1H), 6.96 (s, 1H), 5.81 (s, 2H), 4.57 (d, J = 12.1 Hz, 1H), 4.24 (d, J = 12.4 Hz, 1H), 3.90 (s, 3H), 2.99-2.84 (m, 2H), 2.68-2.43 (m, 4H), 2.30 (s, 3H), 2.14-1.95 (m, 3H), 1.95-1.65 (m, 5H), 1.65-1.49 (m, 2H). One NH was exchanged with CD3OD.

[0340] Compound 23: General Scheme 1 Route B was used to provide (3R)-N-cyclopentyl-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0341] Step 1: Using general procedure C between IM9 and tert-butyl (R)-piperidin-3-ylcarbamate, ((3R)-1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate tert-butyl IM74 was obtained as a white solid: 670 mg, 100% yield, P=100%, retention time=2.5 min (gradient A), (M+H). + :590.

[0342] Step 2: General procedure A1 was used from IM74 to obtain crude (3R)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine as a white solid: 450 mg, 96% yield, P=100%, retention time=1.9 min (gradient A), (M+H). + :406.

[0343] Step 3: Using general procedure H1 between cyclopentanone and IM74, compound 23 was obtained as a white solid: 30 mg, 48% yield, P=94%, retention time=2.9 min (gradient B), (M+H). + :474. 1 H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), 8.40 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.24 (d, J = 12.9 Hz, 2H), 6.96 (s, 1H), 5.81 (s, 2H), 4.46 (d, J = 12.8 Hz, 1H), 4.12 (d, J = 13.3 Hz, 1H), 3.89 (s, 3H), 3.29-3.20 (m, 1H), 3.15-2.98 (m, 1H), 2.94-2.79 (m, 1H), 2.77-2.64 (m, 1H), 2.14-1.21 (m, 12H). Two NH groups had been exchanged with CD3OD. Chiral HPLC (ID, TBME / EtOH / DEA: 80 / 20 / 0.1%, flow rate: 1 mL / min): 97.5% purity at 280 nm.

[0344] Compound 24: General Scheme 1 Route B was used to provide (3R)—N-(3,3-dimethylbutyl)-1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-amine.

[0345] Using general procedure H1 between 3,3-dimethylbutyraldehyde and IM74, compound 24 was obtained as a white solid: 17 mg, 45% yield, P=97%, retention time=3.1 min (gradient B), (M+H). + :490. 1H NMR (300 MHz, CD3OD) δ 8.57 (s, 1H), 8.40 (s, 1H), 7.48-7.38 (m, 1H), 7.30-7.17 (m, 2H), 6.95 (s, 1H), 5.80 (s, 2H), 4.41 (d, J = 13.0 Hz, 1H), 4.07 (d, J = 13.2 Hz, 1H), 3.88 (s, 3H), 3.16-3.01 (m, 1H), 3.00-2.85 (m, 1H), 2.76-2.55 (m, 3H), 2.09-1.99 (m, 1H), 1.86-1.73 (m, 1H), 1.65-1.33 (m, 4H), 0.90 (s, 9H). Two NH groups had been exchanged with CD3OD. Chiral HPLC (ID, TBME / EtOH / DEA: 80 / 20 / 0.1%, flow rate: 1 mL / min): 98.5% purity at 280 nm.

[0346] Compound 25: General Scheme 1 Route B was used to provide 1-(6-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)-N-(spiro[2.3]hexan-1-yl)piperidin-3-amine.

[0347] Step 1: General procedure H2 was used from spiro[2.3]hexan-1-amine hydrochloride and 1-benzylpiperidin-3-one hydrochloride to give 1-benzyl-N-(spiro[2.3]hexan-1-yl)piperidin-3-amine IM75: 230 mg, 25% yield, P = 38% (215 nm), retention time = 2.0 min (gradient A), (M+H) + :271.

[0348] Step 2: Using general procedure J from IM75, tert-butyl (1-benzylpiperidin-3-yl)(spiro[2.3]hexan-1-yl)carbamate IM76 was obtained as a yellow oil: 115 mg, 29% yield, P = 95% (215 nm), retention time = 2.6 min (gradient A), (M+H). + :371.

[0349] Step 3: General procedure L was used from IM76 to give tert-butyl piperidin-3-yl(spiro[2.3]hexan-1-yl)carbamate IM77 as a white solid: 86 mg, 100% yield.

[0350] Step 4: Using general procedure C between IM9 and IM77, tert-butyl (1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3-yl)piperidin-3-yl)(spiro[2.3]hexan-1-yl)carbamate IM78 was obtained as a colorless oil: 44 mg, 35% yield, P=98%, retention time=2.8 min (gradient A), (M+H). + :670.

[0351] Step 5: Compound 25 was obtained from IM78 using general procedure A1 as a white solid: 21 mg, 61% yield, P=93%, retention time=2.9 min (gradient B), (M+H) + :486.

[0352] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IB column (5 μm, 10 × 250 mm). The eluent used was ACN / MeOH / DEA: 95 / 5 / 0.1% at a flow rate of 7 mL / min. The first eluting fraction was a mixture of two stereoisomers: P = 100%, retention time = 6.4 min. The second eluting fraction: P = 97%, retention time = 7.0 min, chiral HPLC: P = 97.1%. 1H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.45(d,J=9.5Hz,1H),7.28(d,J=2.0Hz,1H),7.2 5(d,J=9.6Hz,1H),6.96(s,1H),5.81(s,2H),4.52-4.42(m,1H),4.19-4.09(m,1H),3.90(s,3H),3 .16-3.02 (m, 1H), 2.97 (dd, J = 12.8, 9.6 Hz, 1H), 2.83-2.69 (m, 1H), 2.26-2.12 (m, 1H), 2.15-1.96 (m, 7H), 1.91-1.76 (m, 1H), 1.70-1.37 (m, 2H), 0.63 (dd, J = 7.4, 5.3 Hz, 1H), 0.30 (t, J = 4.8 Hz, 1H). Both NH groups had been exchanged with CD3OD. The third eluting fraction: P = 95%, retention time = 8.1 min. Chiral HPLC: P = 98.1%. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.45(d,J=9.5Hz,1H),7.28(d,J=2.0Hz,1H),7.2 5(d,J=9.6Hz,1H),6.96(s,1H),5.81(s,2H),4.52-4.42(m,1H),4.19-4.09(m,1H),3.90(s,3H),3 .16-3.02 (m, 1H), 2.97 (dd, J = 12.8, 9.6 Hz, 1H), 2.83-2.69 (m, 1H), 2.26-2.12 (m, 1H), 2.15-1.96 (m, 7H), 1.91-1.76 (m, 1H), 1.70-1.37 (m, 2H), 0.63 (dd, J = 7.4, 5.3 Hz, 1H), 0.30 (t, J = 4.8 Hz, 1H). Two NH groups had been exchanged with CD3OD.

[0353] The first fraction was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). The eluent used was EtOAc / EtOH / DEA: 93 / 7 / 0.1% at a flow rate of 6 mL / min. The first eluted stereoisomer: P = 92%, retention time = 25.7 min. Chiral HPLC: P = 98.1%, 1H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.46(d,J=9.4Hz,1H),7.31-7.21( m,2H),6.97(s,1H),5.82(s,2H),4.48(d,J=10.7Hz,1H),4.13(d,J=13.3Hz,1H),3 0.90 (s, 3H), 3.17-2.93 (m, 2H), 2.88-2.72 (m, 1H), 2.26-2.17 (m, 1H), 2.16-2.00 (m, 7H), 1.89-1.70 (m, 1H), 1.64-1.45 (m, 2H), 0.70-0.62 (m, 1H), 0.35-0.27 (m, 1H). Two NH groups were exchanged with CD3OD. First-eluting stereoisomer: P = 92%, retention time = 26.1 min. Chiral HPLC: P = 96.9%. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.46(d,J=9.4Hz,1H),7.31-7.21(m,2H) ,6.97(s,1H),5.82(s,2H),4.48(d,J=10.7Hz,1H),4.13(d,J=13.3Hz,1H),3.90(s,3H), 3.17-2.93(m,2H), 2.88-2.72(m,1H), 2.26-2.17(m,1H), 2.16-2.00(m,7H), 1.89-1.70(m,1H), 1.64-1.45(m,2H), 0.70-0.62(m,1H), 0.35-0.27(m,1H), two NHs were exchanged with CD3OD.

[0354] Compound 26: General Scheme 1, Route A was used to provide N-(cyclobutylmethyl)-1-(5-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)thiazol-2-yl)piperidin-3-amine.

[0355] Step 1: A mixture of (cyclobutylmethyl)(piperidin-3-yl)butylcarbamate IM79 (68 mg, 0.25 mmol), 2-bromothiazole-5-methanol (50 mg, 0.25 mmol), and dipotassium carbonate (70 mg, 0.51 mmol) in anhydrous DMF (250 μL) was stirred at 110 °C, and the reaction progress was monitored by HPLC-MS. When the conversion did not increase further, the reaction was allowed to reach room temperature. Water (10 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 100 / 0 to 50 / 50) to give tert-butyl (cyclobutylmethyl)(1-(5-(hydroxymethyl)thiazol-2-yl)piperidin-3-yl)carbamate IM80 (R f 0.2, nHept / EtOAc:1 / 1) was obtained as a yellow oil: 68 mg, 67% yield, P=95%, retention time=2.4 min (gradient A), (M+H) + :382.

[0356] Step 2: Using general procedure M from IM80, tert-butyl (1-(5-(azidomethyl)thiazol-2-yl)piperidin-3-yl)(cyclobutylmethyl)carbamate IM81 was obtained as a colorless oil: 27 mg, 37% yield, P = 74%, retention time = 2.8 min (gradient A), (M+H). + :407.

[0357] Step 3: Using general procedure B between IM8 and IM81, tert-butyl (cyclobutylmethyl)(1-(5-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)thiazol-2-yl)piperidin-3-yl)carbamate IM82 was obtained as a white solid: 32 mg, 69% yield, P = 95% (215 nm), retention time = 2.9 min (gradient A), (M + H-THP). + :579.

[0358] Step 4: Compound 26 was obtained from IM82 using general procedure A1 as a white solid: 21 mg, 88% yield, P=92%, retention time=2.2 min (gradient A), (M+H) + :479. 1 H NMR(300MHz,CD3OD)δ8.51(s,1H),8.39(s,1H),7.28(s,1H),7.26(d,J=2.0Hz, 1H),6.96(s,1H),5.74(s,2H),3.99-3.93(m,1H),3.90(s,3H),3.78-3.67(m,1H) ),3.17-3.07(m,1H),2.92(dd,J=12.6,9.4Hz,1H),2.72-2.58(m,3H),2.51-2.3 9(m,1H),2.11-2.01(m,2H),1.94-1.73(m,4H),1.67(s,3H),1.43-1.35(m,1H). Two NHs were exchanged for CD3OD.

[0359] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 93 / 7 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 98%, retention time = 12.2 min, chiral HPLC: P = 98.0%. Second eluting enantiomer: P = 93%, retention time = 13.1 min, chiral HPLC: P = 91.0%.

[0360] Compound 27: General Scheme 1 Route B was used to provide 4-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-1-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one.

[0361] Step 1: 4-chloro-1-(chloromethyl)pyridin-2-one IM83 was obtained from 4-chloro-2-hydroxypyridine using general procedure O1 as a white solid: 113 mg, 78% yield, P=92%, retention time=2.3 min (gradient A), (M+H) + :178 / 180.

[0362] Step 2: General procedure N was used from IM83 to give 1-(azidomethyl)-4-chloropyridin-2(1H)-one IM84 as a white solid: 80 mg, 68% yield, P=100% ( 1 H-NMR), retention time = 2.3 min (gradient A), (M+H) + :185.

[0363] Step 3: Using general procedure B between IM8 and IM84, 5-chloro-2-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3(2H)-one IM85 was obtained as a white foam: 207 mg, 100% yield, P = 98% (215 nm), retention time = 2.7 min (gradient A), (M+H). + :441 / 443.

[0364] Step 4: Using general procedure C between IM79 and IM85, tert-butyl (cyclobutylmethyl)(1-(1-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-2-oxo-1,2-dihydropyridin-4-yl)piperidin-3-yl)carbamate IM86 was obtained as an orange-yellow foam: 260 mg, 95% yield, P=98%, retention time=3.1 min (gradient A), (M+H). + :673.

[0365] Step 5: From IM86 using general procedure A1 crude compound 27 was obtained as a brown oil: 203 mg, 100% yield, P=96%, retention time=2.2 min (gradient A), (M+H) + :489. 1H NMR(300MHz,CD3OD)δ8.64(s,1H),8.40(s,1H),7.70(d,J=8.0Hz,1H),7.27(d,J=2.0Hz,1H),6.97(s,1H) ),6.46(s,2H),6.32(dd,J=8.0,2.7Hz,1H),5.69(d,J=2.7Hz,1H),3.90(s,3H),3.92-3.84(m,1H),3.75( d, J = 13.6 Hz, 1H), 3.06-2.93 (m, 1H), 2.82 (dd, J = 13.1, 9.6 Hz, 1H), 2.66 (d, J = 7.3 Hz, 2H), 2.62-2.53 (m, 1H), 2.51-2.37 (m, 1H), 2.11-1.98 (m, 3H), 1.94-1.64 (m, 6H), 1.44-1.30 (m, 1H). Two NH groups had been exchanged with CD3OD.

[0366] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 60 / 40 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 98%, retention time = 7.8 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 98%, retention time = 9.8 min, chiral HPLC: P = 100%.

[0367] Compound 28: General Scheme 1 Route B was used to provide 5-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-2-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-3(2H)-one.

[0368] Step 1: 5-Chloro-2-(chloromethyl)pyridazin-3-one IM87 was obtained from 5-chloropyridazin-3(2H)-one using general procedure O1 as a yellow liquid: 263 mg, 93% yield, P=95% ( 1 H-NMR), retention time = 2.3 min (gradient A), (M+H) + :179 / 181.

[0369] Step 2: 2-(azidomethyl)-5-chloropyridazin-3-one IM88 was obtained from IM87 using general procedure N as a yellow liquid: 118 mg, 46% yield, P=100%, retention time=2.4 min (gradient A), (M+H) + :186.

[0370] Step 3: Using general procedure B between IM8 and IM88, 5-chloro-2-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-one IM89 was obtained as a white foam: 218 mg, 72% yield, P=93%, retention time=2.7 min (gradient A), (M+H). + :441 / 443.

[0371] Step 4: Using general procedure C between IM79 and IM89, tert-butyl N-(cyclobutylmethyl)-N-[1-[1-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-6-oxopyridazin-4-yl]-3-piperidyl]carbamate IM90 was obtained as a yellow foam: 215 mg, 92% yield, P=79% ( 1 H-NMR), retention time = 3.2 min (gradient A), (M+H) + :674.

[0372] Step 5: From IM90, crude compound 28 was obtained using general procedure A1 as a beige foam: 109 mg, 82% yield, P=90%, retention time=2.2 min (gradient A), (M+H) + :490. 1H NMR(300MHz,CD3OD)δ8.61(s,1H),8.40(s,1H),8.03(d,J=2.8Hz,1H),7.26(d,J=2.0Hz,1 H),6.97(s,1H),6.60(s,2H),5.89(d,J=2.8Hz,1H),3.94-3.87(m,1H),3.85(s,3H),3.81- 3.70 (m, 1H), 3.13-2.99 (m, 1H), 2.90 (dd, J = 13.1, 9.3 Hz, 1H), 2.70-2.57 (m, 3H), 2.51-2.34 (m, 1H), 2.10-1.97 (m, 3H), 1.96-1.62 (m, 6H), 1.47-1.25 (m, 1H), two NH groups had been exchanged with CD3OD.

[0373] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). The eluent used was TBME / MeOH / DEA: 70 / 30 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 100%, retention time = 6.5 min, chiral HPLC: P = 97.1%. Second eluting enantiomer: P = 97%, retention time = 7.0 min, chiral HPLC: P = 96.6%.

[0374] Compound 29: General Scheme 1 Route A was used to provide 2-(1-((6-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)quinazolin-4(3H)-one.

[0375] Step 1: 2-Chloroquinazolin-4(3H)-one (300 mg, 1.58 mmol) was dissolved in anhydrous DMF (3.2 mL) and potassium carbonate (480 mg, 3.47 mmol) was added, followed by 4-methoxybenzyl bromide (441 mg, 2.19 mmol). The reaction mixture was heated to 80 °C for 1 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (3 × 10 mL) followed by brine (10 mL). The resulting organic layer was dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 9 / 1) to give 2-chloro-3-[(4-methoxyphenyl)methyl]quinazolin-4-one IM91 (R f 0.6, nHept / EtOAc:1 / 1) was obtained as a white solid: 295 mg, 62% yield, P=95%, retention time=3.0 min (gradient A), (M+H) + :301 / 303.

[0376] Step 2: Using general procedure E2 from IM91 (in THF instead of DMF), 3-(4-methoxybenzyl)-2-((trimethylsilyl)ethynyl)quinazolin-4(3H)-one IM92 was obtained as a colorless oil: 120 mg, 33% yield, P=90%, retention time=3.2 min (gradient A), (M+H). + :363.

[0377] Step 3: IM92 (84 mg, 0.21 mmol) was suspended in anhydrous methanol (1.6 mL), and the reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give 2-ethynyl-3-[(4-methoxyphenyl)methyl]quinazolin-4-one IM93 as a brown solid: 60 mg, 90% yield, P=92%, retention time=2.8 min (gradient A), (M+H). + :291.

[0378] Step 4: Using general procedure B between IM45 and IM93, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-quinazolin-2-yl]triazol-1-yl]methyl]pyridazin-3-yl]-3-piperidyl]carbamate IM94 was obtained as a light brown solid: 80 mg, 95% yield, P=100%, retention time=2.8 min (gradient A), (M+H). + :692.

[0379] Step 5: Using general procedure A2 from IM94, crude compound 29 was obtained as an off-white powder: 33 mg, 59% yield, P=99%, retention time=2.9 min (gradient B), (M+H). + :472. 1 H NMR(300MHz,CD3OD)δ8.73(s,1H),8.23(d,J=8.3Hz,1H),7.81(dd,J=7.6,7.6Hz,1H),7.72(d,J=8.1Hz,1H ),7.51(t,J=7.7Hz,1H),7.46(d,J=9.5Hz,1H),7.26(d,J=9.5Hz,1H),5.84(s,2H),4.41(d,J=13.0Hz,1H) , 4.11 (d, J = 13.2 Hz, 1H), 3.17-3.05 (m, 1H), 2.95 (dd, J = 12.9, 9.5 Hz, 1H), 2.77-2.59 (m, 3H), 2.53-2.41 (m, 1H), 2.15-2.00 (m, 3H), 1.99-1.76 (m, 4H), 1.75-1.62 (m, 2H), 1.52-1.37 (m, 1H). Two NH groups were exchanged with CD3OD.

[0380] Compound 30: General Scheme 1 Route B was used to provide (3R)-N-cyclobutyl-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0381] Using general procedure H1 between cyclobutanone and IM74, compound 30 was obtained as a white solid: 22 mg, 63% yield, P=97%, retention time=2.1 min (gradient A), (M+H). + :460. 1 H NMR(300MHz,CD3OD)δ8.59(s,1H),8.41(s,1H),7.44(d,J=9.5Hz,1H),7.27(d,J=2.0Hz,1H),7.2 3(d,J=9.5Hz,1H),6.96(s,1H),5.81(s,2H),4.37(d,J=12.7Hz,1H),4.12(d,J=13.5Hz,1H),3.90 (s, 3H), 3.49-3.34(m, 1H), 3.11-2.98(m, 1H), 2.84(dd, J=12.8, 9.7Hz, 1H), 2.71-2.58(m, 1H), 2.29-2.15(m, 2H), 2.07-1.93(m, 1H), 1.87-1.62(m, 6H), 1.59-1.33(m, 1H), two NH groups were exchanged with CD3OD.

[0382] Compound 31: General Scheme 1, Route B was used to provide (3R)-N-isobutyl-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0383] Using general procedure H1 between isobutyraldehyde and IM74, compound 31 was obtained as a white solid: 8 mg, 24% yield, P=90%, retention time=2.1 min (gradient A), (M+H). + :462. 1H NMR(300MHz,CD3OD)δ8.59(s,1H),8.40(s,1H),7.44(d,J=9.5Hz,1H),7.27(s,1H),7.25(d,J=9.5 Hz,1H),6.97(s,1H),5.81(s,2H),4.41(d,J=13.2Hz,1H),4.11(d,J=13.7Hz,1H),3.90(s,3H),3.1 9-3.03(m,1H), 2.96(dd,J=12.9,9.4Hz,1H), 2.74-2.58(m,1H), 2.50(d,J=7.4Hz,2H), 2.13-1.99(m,1H), 1.89-1.66(m,2H), 1.68-1.39(m,2H), 0.91(dd,J=6.7,3.9Hz,6H). Two NH groups were exchanged with CD3OD.

[0384] Compound 32: General Scheme 1 Route B was used to provide (3R)—N-(2,2-dimethylpropyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0385] Using general procedure H1 between trimethylacetaldehyde and IM74, compound 32 was obtained as a white solid: 20 mg, 60% yield, P=91%, retention time=2.1 min (gradient A), (M+H). + :476. 1 H NMR(300MHz,CD3OD)δ8.58(s,1H),8.40(s,1H),7.43(d,J=9.5Hz,1H),7.27(d,J=2.0Hz,1H),7.2 4(d,J=9.5Hz,1H),6.96(d,J=2.0Hz,1H),5.80(s,2H),4.43-4.30(m,1H),4.17-4.00(m,1H),3.9 0(s,3H), 3.19-3.04(m,1H), 2.97(dd,J=13.0,9.2Hz,1H), 2.64-2.51(m,1H), 2.43(d,J=3.4Hz,2H), 2.10-1.93(m,1H), 1.86-1.76(m,1H), 1.66-1.38(m,2H), 0.89(s,9H). Two NH groups had been exchanged with CD3OD.

[0386] Chiral HPLC (ID, TBME / EtOH / DEA: 80 / 20 / 0.1%, flow rate: 1 mL / min): 100% purity at 280 nm.

[0387] Compound 33: General Scheme 1 Route B was used to provide (3R)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]-N-tetrahydrofuran-3-yl-piperidin-3-amine.

[0388] General procedure H1 was used between 3-oxotetrahydrofuran and IM74 to give crude compound 33 as a white solid: 30 mg, 79% yield, P=93%, retention time=2.0 min (gradient A), (M+H). + :476.

[0389] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: DCM / EtOH / DEA: 85 / 15 / 0.1% at a flow rate of 5 mL / min. First eluting diastereomer: P = 100%, retention time = 16.1 min. Chiral HPLC: P = 100%, 1 H NMR(300MHz,CD3OD)δ8.61(s,1H),8.40(s,1H),7.52(d,J=9.5Hz,1H),7.33(d,J=9.5Hz,1H),7 .26(d,J=2.1Hz,1H),6.97(s,1H),5.84(s,2H),4.54(d,J=12.6Hz,1H),4.08-3.94(m,4H),3.8 9 (s, 3H), 3.86 (d, J = 5.5 Hz, 1H), 3.43-3.33 (m, 1H), 3.31-3.18 (m, 3H), 2.46-2.29 (m, 1H), 2.27-2.15 (m, 1H), 2.07-1.91 (m, 1H), 1.95-1.83 (m, 1H), 1.83-1.60 (m, 2H). Two NH groups had been exchanged with CD3OD. Second-eluting diastereomer: P = 100%, retention time = 28.7 min. Chiral HPLC: P = 99.3%. 1H NMR(300MHz,MeOH)δ8.60(s,1H),8.40(s,1H),7.49(d,J=9.5Hz,1H),7.35-7.24(m,2H) ,6.97(s,1H),5.83(s,2H),4.49(d,J=13.1Hz,1zH),4.06-3.93(m,2H),3.90(s,3H),3. 89-3.80(m,2H), 3.80-3.60(m,2H), 3.21-3.12(m,2H), 3.01-2.96(m,1H), 2.31-2.16(m,1H), 2.16-2.08(m,1H), 1.91-1.80(m,2H), 1.68-1.53(m,2H), two NHs were exchanged with CD3OD.

[0390] Compound 34: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[(4-imidazo[5,1-b]thiazol-3-yltriazol-1-yl)methyl]pyridazin-3-yl]piperidin-3-amine.

[0391] Step 1: 2-Imidazo[5,1-b]thiazol-3-ylethynyl(trimethyl)silane IM95 was obtained from 3-bromoimidazo[5,1-b]thiazole using general procedure E2 as a pink oil: 35 mg, 31% yield, P = 95%, retention time = 2.3 min (gradient A), (M+H) + :221.

[0392] Step 2: 3-ethynylimidazo[5,1-b]thiazole IM96 was obtained from IM95 using general procedure D1 as a yellow solid: 22 mg, 92% yield, P=93%, retention time=0.8 min (gradient A), (M+H) + :149.

[0393] Step 3: Using general procedure B between IM45 and IM96, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[(4-imidazo[5,1-b]thiazol-3-yltriazol-1-yl)methyl]pyridazin-3-yl]-3-piperidyl]carbamate IM97 was obtained as a yellow oil: 26 mg, 35% yield, P = 92%, retention time = 2.4 min (gradient A), (M+H). + :550.

[0394] Step 4: From IM97, crude compound 34 was obtained using general procedure A1 as a yellow solid: 18 mg, 100% yield, P=94%, retention time=1.9 min (gradient A), (M+H). + :450.

[0395] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 5% to 40% solution "B" over 5.0 min, then linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR (300 MHz, CD3OD) δ 8.77 (s, 1H), 8.62 (s, 1H), 7.44 (d, J = 10.0 Hz, 2H), 7.24 (d, J = 9.5 Hz, 1H), 7.13 (s, 1H), 5.81 (s, 2H), 4.45-4.35 (m, 1H), 4.16-4.05 (m, 1H), 3.31 (s, 2H), 3.10 (s, 1H), 2.91 (dd, J = 12.8, 9.5 Hz, 1H), 2.78-2.55 (m, 3H), 2.45 (hept, J = 7.6 Hz, 1H), 2.06 (dt, J = 10.9, 5.5 Hz, 2H), 1.95-1.39 (m, 8H). 1H was exchanged with CD3OD.

[0396] Compound 35: General Scheme 1 Route B was used to provide 4-[1-[[6-[3-(2-azaspiro[3.3]heptan-2-yl)-1-piperidyl]pyridazin-3-yl]methyl]triazol-4-yl]-6-methoxy-1H-indazole.

[0397] Step 1: Using general procedure H2 between 1-benzylpiperidin-3-one hydrochloride and 2-azaspiro[3.3]heptane hemioxalate, 2-(1-benzyl-3-piperidyl)-2-azaspiro[3.3]heptane IM98 was obtained as a yellow oil: 214 mg, 93% yield, P = 95%, retention time = 1.9 min (gradient A), (M+H). + :271.

[0398] Step 2: Using general procedure L from IM98, crude 2-(3-piperidyl)-2-azaspiro[3.3]heptane IM99 was obtained as a pale yellow oil: 103 mg, 92% yield, P=95% ( 1 H-NMR).

[0399] Step 3: Using general procedure C between IM9 and IM99, 4-[1-[[6-[3-(2-azaspiro[3.3]heptan-2-yl)-1-piperidyl]pyridazin-3-yl]methyl]triazol-4-yl]-6-methoxy-1-tetrahydropyran-2-yl-indazole IM100 was obtained as a yellow solid: 19 mg, 28% yield, P=95%, retention time=2.8 min (gradient A), (M+H) + :684.

[0400] Step 4: Using general procedure A1 from IM100, crude compound 35 was obtained as an off-white solid: 14 mg, 86% yield, P=96%, retention time=2.9 min (gradient B), (M+H). + :486. 1 H NMR (300 MHz, CD3OD) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.49 (d, J = 9.5 Hz, 1H), 7.33-7.24 (m, 2H), 6.97 (s, 1H), 5.83 (s, 2H), 4.25-4.13 (m, 1H), 3.90 (s, 4H), 3.70 (s, 4H), 3.31-3.21 (m, 2H), 2.77 (s, 1H), 2.18 (t, J = 7.7 Hz, 4H), 1.99-1.36 (m, 6H). 1H was exchanged with CD3OD.

[0401] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). The eluent used was ACN / MeOH / DEA: 95 / 5 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 100%, retention time = 6.8 min, chiral HPLC: P = 99.8%. Second eluting enantiomer: P = 93%, retention time = 8.9 min, chiral HPLC: P = 97.6%.

[0402] Compound 36: General Scheme 1, Route A was used to provide N-(cyclobutylmethyl)-1-[5-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]-1,3,4-thiadiazol-2-yl]piperidin-3-amine.

[0403] Step 1: Ethyl 5-bromo-1,3,4-thiadiazole-2-carboxylate (50 mg, 0.20 mmol) was diluted with anhydrous DMSO (0.25 mL) and tert-butyl N-(cyclobutylmethyl)-N-[3-piperidyl]carbamate (80 mg, 0.30 mmol) was added, followed by triethylamine (83 μL, 0.60 mmol). The vial was sealed and the mixture was heated to 90 °C for 15 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with NH Cl (20 mL). The resulting organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give a colorless oil. The latter was purified by silica gel flash chromatography (30% ethyl acetate / heptane) to give ethyl 5-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]-1,3,4-thiadiazole-2-carboxylate IM101 as a colorless oil: 66 mg, 78% yield, P=100% ( 1 H-NMR), retention time = 3.2 min (gradient A), (M+H) + :425.

[0404] Step 2: IM101 (62 mg, 0.15 mmol) in methanol (2 mL) was cooled to 0 °C and sodium borohydride (16 mg, 0.42 mmol) was added slowly. The reaction mixture was stirred at room temperature for 16 h. Because the reaction was not complete as monitored by HPLC-MS, additional amounts of sodium borohydride were added every 3 h at room temperature (4 × 16 mg, 0.42 mmol). The reaction mixture was then quenched with acetic acid (1 mL), treated with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (2 × 50 mL), and washed with brine (10 mL). The organic layer was separated, dried over MgSO, filtered, and evaporated under reduced pressure to give crude tert-butyl N-(cyclobutylmethyl)-N-[1-[5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl]-3-piperidyl]carbamate IM102 as a colorless oil: 64 mg, 97% yield, P=96%, retention time=3.2 min (gradient A), (M+H). + :425.

[0405] Steps 3 and 4: General procedure P was used from IM102 to give the desired crude mesylate, which was used directly in general procedure N (assuming 100% yield) to give crude tert-butyl N-[1-[5-(azidomethyl)-1,3,4-thiadiazol-2-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM103 as a brown oil: 70 mg, 99% yield, P = 86%, retention time = 3.2 min (gradient A), (M+H). + :408.

[0406] Step 5: Using general procedure B between IM8 and IM103, tert-butyl N-(cyclobutylmethyl)-N-[1-[5-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-1,3,4-thiadiazol-2-yl]-3-piperidyl]carbamate IM104 was obtained as a yellowish oil: 84 mg, 62% yield, P = 84%, retention time = 3.2 min (gradient A), (M+H). + :664.

[0407] Step 6: Compound 36 was obtained from IM104 using general procedure A1 as an off-white powder: 45 mg, 80% yield, P=91%, retention time=3.0 min (gradient B), (M+H) + :480. 1 H NMR (300 MHz, CD3OD) δ 8.62 (s, 1H), 8.41 (d, J = 1.0 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.01-6.93 (m, 1H), 5.97 (s, 2H), 4.02-3.91 (m, 1H), 3.90 (s, 3H), 3.74-3.62 (m, 1H), 3.28-3.15 (m, 1H), 3.07 (dd, J = 12.7, 9.2 Hz, 1H), 2.84-2.67 (m, 3H), 2.46 (hept, J = 7.6 Hz, 1H), 2.07 (qt, J = 7.8, 4.0 Hz, 2H), 1.94-1.39 (m, 8H). 2H was exchanged with CD3OD.

[0408] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: EtOAc / EtOH / DEA: 95 / 5 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 100%, retention time = 10.3 min, chiral HPLC: P = 99.4%. Second eluting enantiomer: P = 95%, retention time = 11.8 min, chiral HPLC: P = 98.4%.

[0409] Compound 37: General Scheme 1 Route B was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[1-[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]ethyl]pyridazin-3-yl]piperidin-3-amine.

[0410] Step 1: 1-(6-chloropyridazin-3-yl)ethanol IM105 was obtained from 6-chloropyridazine-3-carbaldehyde using general procedure Q as a brownish oil: 60 mg, 54% yield, P = 95% (215 nm), retention time = 1.4 min (gradient A), (M+H) + :159 / 161.

[0411] Step 2: Using general procedure M from IM105, 3-(1-azidoethyl)-6-chloropyridazine IM106 was obtained as a yellowish liquid: 42 mg, 59% yield, P = 93% (215 nm), retention time = 2.5 min (gradient A), (M+H) + :184 / 186.

[0412] Step 3: Using general procedure B between IM8 and IM106, 4-[1-[1-(6-chloropyridazin-3-yl)ethyl]triazol-4-yl]-6-methoxy-1-tetrahydropyran-2-yl-indazole IM107 was obtained as a white gum: 73 mg, 68% yield, P=87%, retention time=2.8 min (gradient A), (M+H) + :440 / 442.

[0413] Step 4: Using general procedure C between IM3 and IM107, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[1-[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]ethyl]pyridazin-3-yl]-3-piperidyl]carbamate IM108 was obtained as a brownish gum: 80 mg, 66% yield, P=93%, retention time=4.7 min (gradient B), (M+H). + :672.

[0414] Step 5: From IM108 using general procedure A1 crude compound 37 was obtained as a brownish foam: 48 mg, 94% yield, P=93%, retention time=2.2 min (gradient A), (M+H) + :488.

[0415] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 85 / 15 / 0.1% at a flow rate of 6 mL / min. First eluting diastereomer: P = 99%, retention time = 7.3 min. Chiral HPLC: P = 98.3%, 1H NMR(300MHz,CD3OD)δ8.61(s,1H),8.42(d,J=1.0Hz,1H),7.42(d,J=9.6Hz,1H),7.26(d, J=2.0Hz,1H),7.23(d,J=9.6Hz,1H),6.95(d,J=1.9Hz,1H),6.13(q,J=7.1Hz,1H),4.43-4 .32 (m, 1H), 4.14-4.03 (m, 1H), 3.89 (s, 3H), 3.16-3.01 (m, 1H), 2.93 (dd, J = 12.9, 9.3 Hz, 1H), 2.77-2.55 (m, 3H), 2.45 (hept, J = 7.6 Hz, 1H), 2.14-1.24 (m, 13H). 1H had been exchanged with CD3OD. Second-eluting enantiomer: P = 100%, retention time = 10.8 min. Chiral HPLC: P = 99.3%. 1 H NMR(300MHz,CD3OD)δ8.61(s,1H),8.42(d,J=1.0Hz,1H),7.43(d,J=9.6Hz,1H),7.27(d, J=2.1Hz,1H),7.24(d,J=9.6Hz,1H),7.00-6.92(m,1H),6.13(q,J=7.1Hz,1H),4.44-4.33 (m, 1H), 4.13-4.02 (m, 1H), 3.89 (s, 3H), 3.17-3.04 (m, 1H), 2.95 (dd, J = 12.9, 9.4 Hz, 1H), 2.80-2.58 (m, 3H), 2.46 (dt, J = 15.3, 7.6 Hz, 1H), 2.14-1.24 (m, 13H), 2H was exchanged with CD3OD.

[0416] Compound 38: General Scheme 1 Route B was used to provide (3R,6S)—N-(cyclobutylmethyl)-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-6-methylpiperidin-3-amine.

[0417] Synthesis of tert-butyl N-(cyclobutylmethyl)-N-[(3R,6S)-6-methyl-3-piperidyl]carbamate IM111: Step 1: General procedure H1 was used between cyclobutanecarboxaldehyde and (2S,5R)-5-amino-2-methylpiperidine-1-carboxylic acid benzyl ester to give crude benzyl (2S,5R)-5-(cyclobutylmethylamino)-2-methylpiperidine-1-carboxylate IM109 as a yellow oil: 349 mg, 34% yield, P = 37% (215 nm), retention time = 2.4 min (gradient A), (M+H) + :317. Step 2: Using general procedure J from IM109, benzyl (2S,5R)-5-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-2-methylpiperidine-1-carboxylate IM110 was obtained as a colorless oil: 160 mg, 85% yield, P=90% (215 nm), retention time=3.6 min (gradient A), (M+H) + :417. Step 3: From IM110 using general procedure L, tert-butyl N-(cyclobutylmethyl)-N-[(3R,6S)-6-methyl-3-piperidyl]carbamate IM111 was obtained as a colorless oil: 106 mg, 98% yield.

[0418] Synthesis of 3-chloro-6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazine IM112: Step 4: Using general procedure B between IM5 and IM44, crude 3-chloro-6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazine IM112 was obtained as a yellow solid: 1.53 g, 80% yield, P=92%, retention time=2.4 min (gradient B), (M+H). + :303.

[0419] Step 5: Using general procedure C between IM111 and IM112, tert-butyl N-(cyclobutylmethyl)-N-[(3R,6S)-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-6-methyl-3-piperidyl]carbamate IM113 was obtained as a dark yellow oil: 36 mg, 37% yield, P=81%, retention time=2.5 min (gradient A), (M+H). + :549.

[0420] Step 6: From IM113 using general procedure A1, crude compound 38 dihydrochloride was obtained as a dark yellow oil: 42 mg, 99% yield, P=83%, retention time=2.0 min (gradient B), (M+H). + :449.

[0421] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 10% to 40% solution "B" over 5.5 min, linear increase to 85% solution "B" over 1.0 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 98%. 1 H NMR (300 MHz, CD3OD) δ 8.62-8.50 (m, 2H), 8.20 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 2.8, 1.7 Hz, 1H), 7.43 (d, J = 9.5 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 5.79 (s, 2H), 4.68-4.57 (m, 1H), 4.56-4.44 (m, 1H), 3.93 (s, 3H), 2.82-2.67 (m, 3H), 2.67-2.39 (m, 2H), 2.11 (tt, J = 7.8, 5.8 Hz, 2H), 1.99-1.42 (m, 8H), 1.20 (d, J = 6.8 Hz, 3H). 1H was exchanged with CD3OD.

[0422] Compound 39: General Scheme 1 Route B was used to provide (R)-6-(3-((cyclobutylmethyl)amino)piperidin-1-yl)-3-((4-(6-methoxy-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridazin-4(1H)-one.

[0423] Step 1: To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (207 mg, 980 μmol) and 4-methoxybenzyl alcohol (167 mg, 1.19 mmol) in MeCN (25 mL) was added cesium carbonate (387 mg, 1.18 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and purified directly on a C18 column (40 g column, 0-100% MeCN / AmB) to give methyl 6-chloro-4-((4-methoxybenzyl)oxy)pyridazine-3-carboxylate IM114 as a brown solid: 136 mg, 38% yield, P = 84%, retention time = 2.1 min (gradient C), (M + Na). + :331.

[0424] Step 2: To a solution of IM114 (130 mg, 421 μmol) in THF (1.1 mL) / MeOH (217 μL) at 0 °C, lithium borohydride (2N in THF, 526 μL, 1.05 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was directly purified on a C18 column (30 g, 0-100% MeCN / AmB, product eluted at 35% MeCN) to give (6-chloro-4-((4-methoxybenzyl)oxy)pyridazin-3-yl)methanol as a white solid: 58 mg, 47% yield, P = 95%, retention time = 0.8 min (gradient C), (M+H). + :281.

[0425] Step 3: Using general procedure M from IM114, 3-(azidomethyl)-6-chloro-4-((4-methoxybenzyl)oxy)pyridazine IM115 was obtained as a white solid: 30 mg, 50% yield, P=100%, retention time=1.6 min (gradient D), (M+H) + :306.

[0426] Step 4: Using general procedure B between IM8 and IM115, 3 4-(1-((6-chloro-4-((4-methoxybenzyl)oxy)pyridazin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole IM116 was obtained as a brown solid: 43 mg, 89% yield, P=100%, retention time=1.3 min (gradient C), (M+H). + :562 / 564.

[0427] Step 5: Using general procedure C between IM116 and IM3, tert-butyl (cyclobutylmethyl)((3R)-1-(6-((4-(6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-5-((4-methoxybenzyl)oxy)pyridazin-3-yl)piperidin-3-yl)carbamate IM117 was obtained as a light brown film: 18 mg, 38% yield, P=98% (gradient C), (M+H). + :674.

[0428] Step 6: Compound 39 was obtained from IM117 using general procedure A2 as a white powder: 7 mg, 52% yield, P=100%, retention time=2.0 min (gradient D), (M+H) + :490. 1 H NMR(400MHz,CD3OD)δ8.59(s,1H),8.39(d,J=0.8Hz,1H),7.27(d,J=2.0Hz,1H),6.96(d d,J=1.8,0.8Hz,1H),6.06(s,1H),5.69(s,2H),3.91(s,3H),3.90-3.85(m,1H),3.74-3. 62 (m, 1H), 3.11-3.00 (m, 1H), 2.95 (dd, J = 12.9, 9.2 Hz, 1H), 2.83-2.69 (m, 3H), 2.56-2.41 (m, 1H), 2.15-1.98 (m, 3H), 1.96-1.58 (m, 6H), 1.50-1.41 (m, 1H), 3H was exchanged with CD3OD.

[0429] Compound 40: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[5-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]-2-pyridyl]piperidin-3-amine.

[0430] Step 1: Using general procedure C (in ACN) between 6-fluoronicotinic acid methyl ester and IM3, methyl 6-[(3R)-3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyridine-3-carboxylate IM118 was obtained as a colorless oil: 261 mg, 74% yield, P=100%, retention time=2.8 min (gradient Z), (M+H). + :404.

[0431] Step 2: IM118 (261 mg, 0.55 mmol) in anhydrous THF (3.2 mL) was cooled to 0 °C under an argon atmosphere, and then lithium borohydride (40 mg, 1.65 mmol) was added in one portion. The reaction mixture was stirred at room temperature, and the reaction progress was monitored by HPLC-MS. After 16 h, lithium borohydride (40 mg, 1.65 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 21 h more. The reaction was quenched with water (5 mL) and concentrated under reduced pressure to give a yellow paste. EtOAc (50 mL) followed by water (10 mL) was added. The layers were separated, and the organic layer was washed with water (2 × 10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 250 mg as a pink oil. The latter was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 4 / 1) to give tert-butyl (R)-(cyclobutylmethyl)(1-(5-(hydroxymethyl)pyridin-2-yl)piperidin-3-yl)carbamate IM119 as a colorless oil: 206 mg, 100% yield, P=100%, retention time=2.4 min (gradient A), (M+H). + :376.

[0432] Step 3: Using general procedure M from IM119, tert-butyl N-[(3R)-1-[5-(azidomethyl)-2-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM120 was obtained as a colorless oil: 142 mg, 56% yield, P = 99%, retention time = 2.6 min (gradient D), (M+H). + :401.

[0433] Step 4: Using general procedure B between IM8 and IM120, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[5-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-2-pyridyl]-3-piperidyl]carbamate IM121 was obtained as a white solid: 107 mg, 80% yield, P=98%, retention time=2.7 min (gradient A), (M+H). + :657.

[0434] Step 6: Compound 40 was obtained from IM121 using general procedure A1 as a white powder: 50 mg, 70% yield, P=97%, retention time=2.8 min (gradient B), (M+H) + :473. 1 H NMR (300 MHz, CD3OD) δ 8.65 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 6.51 (s, 2H), 5.49 (s, 1H), 4.32 (d, J = 13.2 Hz, 1H), 3.90 (s, 4H), 3.12 (q, J = 9.6 Hz, 2H), 2.92-2.78 (m, 3H), 2.57-2.43 (m, 1H), 2.17-2.05 (m, 2H), 2.02-1.42 (m, 8H), 2H was exchanged with CD3OD.

[0435] Compound 41: General Scheme 1, Route B was used to provide 6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-3-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyrimidin-4-one.

[0436] Step 1: 6-chloro-3-(chloromethyl)pyrimidin-4-one IM122 was obtained from 6-chloro-4-hydroxypyrimidine using general procedure O1 as a pink oil: 152 mg, 78% yield, P=85%, retention time=2.2 min (gradient A), (M+H) + :178 / 180.

[0437] Step 2: 3-(azidomethyl)-6-chloropyrimidin-4-one IM123 was obtained from IM122 using general procedure N as a pink oil: 137 mg, 98% yield, P=80%, retention time=2.2 min (gradient A), (M+H) + :186 / 188.

[0438] Step 3: Using general procedure B between IM8 and IM123, 6-chloro-3-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyrimidin-4-one IM124 was obtained as a white solid: 77 mg, 83% yield, P=93%, retention time=2.7 min (gradient A), (M+H). + :442 / 444.

[0439] Step 4: Using general procedure C between IM3 and IM124, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-6-oxo-pyrimidin-4-yl]-3-piperidyl]carbamate IM125 was obtained as a yellow oil: 48 mg, 36% yield, P = 97%, retention time = 3.2 min (gradient A), (M+H). + :674.

[0440] Step 5: Compound 41 was obtained from IM125 using general procedure A1 as an off-white solid: 24 mg, 89% yield, P=96%, retention time=3.0 min (gradient B), (M+H) + :490. 1H NMR (300 MHz, CD3OD): δ 8.65 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 7.27 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 6.51 (s, 2H), 5.49 (s, 1H), 4.32 (d, J = 13.2 Hz, 1H), 4.00-3.83 (m, 4H), 3.19-3.02 (m, 2H), 2.92-2.78 (m, 3H), 2.57-2.43 (m, 1H), 2.17-2.05 (m, 3H), 2.01-1.85 (m, 1H), 1.83-1.68 (m, 4H), 1.61-1.47 (s, 2H), 1H was exchanged with CD3OD.

[0441] Compound 42: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]-3-pyridyl]piperidin-3-amine.

[0442] Step 1: Using general procedure S between IM3 and methyl 5-bromopicolinate, methyl 5-[(3R)-3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyridine-2-carboxylate IM126 was obtained as a pale yellow oil: 10.1 g, 82% yield, P = 93% ( 1 H-NMR), retention time = 2.7 min (gradient A), (M+H) + :404.

[0443] Step 2: To a solution of IM126 (1.21 g, 2.79 mmol) in anhydrous DCM (25 mL) at −78 °C under an argon atmosphere, a solution of diisobutylaluminum hydride in DCM (1 N, 14 mL, 14 mmol) was added dropwise over 2 minutes to give a yellow solution, which was stirred at −78 °C for 5 minutes and then at room temperature (the cooling bath was removed). After 1 hour, the reaction mixture was cooled to 0 °C (ice bath) and quenched by adding MeOH (3 mL), followed by stirring at room temperature for 10 minutes. Saturated Rochelle's salt solution (20 mL) was then carefully added at room temperature to give a jelly, which was stirred vigorously at room temperature and diluted with water (10 mL) and DCM (20 mL) to enhance stirring. The mixture was stirred at room temperature for 30 minutes, then diluted again with water (20 mL), DCM (20 mL), and saturated Rochelle's salt solution (10 mL). The mixture was stirred vigorously at room temperature for 16 hours to give two clear phases, which were separated. The organic phase was extracted with DCM (2 × 40 mL), and the combined organic phases were then washed with water (20 mL), dried over MgSO, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 1.164 g of a crude brown oil. This material was purified on an automated flash system (liquid injection in DCM, 0–20% MeOH / DCM over 30 min, 30SIHP-24G, 20 mL / min) to give tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-(hydroxymethyl)-3-pyridyl]-3-piperidyl]carbamate IM127 as a yellow oil: 504 mg, 47% yield, P = 99%, retention time = 2.5 min (gradient A), (M+H). + :376.

[0444] Step 3: Using general procedure M from IM127, tert-butyl N-[(3R)-1-[6-(azidomethyl)-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM128 was obtained as a pale yellow oil: 57 mg, 75% yield, P=97% ( 1 H-NMR), retention time = 2.6 min (gradient A), (M+H) + :401.

[0445] Step 4: Using general procedure B between IM8 and IM128, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-3-pyridyl]-3-piperidyl]carbamate IM129 was obtained as an off-white solid: 821 mg, 78% yield, P=95% ( 1 H-NMR), retention time = 2.9 min (gradient A), (M+H) + :657.

[0446] Step 5: Compound 42 was obtained from IM129 using general procedure A1 as an off-white solid: 490 mg, 84% yield, P=94%, retention time=2.9 min (gradient B), (M+H) + :473. 1 H NMR(300MHz,CD3OD):δ8.51(s,1H),8.40(s,1H),8.22(d,J=2.3Hz,1H),7.34(dd,J=8 .6,2.7Hz,1H),7.29(d,J=8.6Hz,1H),7.25(d,J=2.3Hz,1H),6.94(s,1H),5.65(s,2H) , 3.88 (s, 3H), 3.71 (q, J = 9.0 Hz, 1H), 3.59-3.45 (m, 1H), 2.83 (td, J = 11.5, 3.2 Hz, 1H), 2.74-2.59 (m, 4H), 2.45 (hept, J = 7.3 Hz, 1H), 2.16-1.54 (m, 10H), 1H was exchanged with CD3OD.

[0447] Compound 43: General Scheme 1, Route A was used to provide N-(cyclobutylmethyl)-1-[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyrimidin-5-yl]piperidin-3-amine.

[0448] Step 1: Using general procedure S between methyl 5-bromopyrimidine-2-carboxylate and IM79, methyl 5-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyrimidine-2-carboxylate IM130 was obtained as an off-white solid: 150 mg, 42% yield, P=100% ( 1 H-NMR), retention time = 3.0 min (gradient A), (M+H) + :405.

[0449] Step 2: IM130 (120 mg, 0.17 mmol) in anhydrous THF (1 mL) was cooled to 0 °C under an argon atmosphere, and then lithium borohydride (13 mg, 0.54 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then quenched with water (5 mL) and concentrated under reduced pressure to give a yellow paste. To the paste was added EtOAc (50 mL), followed by water (10 mL). The layers were separated, and the organic layer was washed with water (2 × 10 mL), dried over MgSO, filtered, and concentrated under reduced pressure to give 128 mg of a yellow oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 1 to 0 / 1 + 5% MeOH) to give tert-butyl N-(cyclobutylmethyl)-N-[1-[2-(hydroxymethyl)pyrimidin-5-yl]-3-piperidyl]carbamate IM131 as a colorless oil: 27 mg, 24% yield, P = 80%, retention time = 2.6 min (gradient A), (M+H). + :377.

[0450] Step 3: General procedure M was used from IM131 to give tert-butyl N-[1-[2-(azidomethyl)pyrimidin-5-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM132 as a colorless oil: 15 mg, 90% yield, P = 100%, retention time = 2.6 min (gradient A), (M+H). + :402.

[0451] Step 4: Using general procedure B between IM8 and IM132, tert-butyl N-(cyclobutylmethyl)-N-[1-[2-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyrimidin-5-yl]-3-piperidyl]carbamate IM133 was obtained as a colorless film: 14 mg, 38% yield, P=94%, retention time=3.4 min (gradient A), (M+H). + :658.

[0452] Step 5: Compound 43 was obtained from IM133 using general procedure A1 as a colorless film: 7 mg, 100% yield, P=93%, retention time=2.4 min (gradient A), (M+H) + :474.

[0453] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: DCM / MeOH / DEA: 95 / 5 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 96%, retention time = 6.4 min, chiral HPLC: P = 99.7%. Second eluting enantiomer: P = 100%, retention time = 7.5 min, chiral HPLC: P = 99.9%. 1 H NMR (300 MHz, CD3OD): δ 8.59 (s, 1H), 8.47 (s, 2H), 8.40 (s, 1H), 7.28 (s, 1H), 6.97 (s, 1H), 5.81 (s, 2H), 3.91 (s, 3H), 3.81 (d, J = 13.0 Hz, 1H), 3.58 (d, J = 11.5 Hz, 1H), 3.19-2.88 (m, 5H), 2.66-2.52 (m, 1H), 2.22-1.51 (m, 10H), 1H was exchanged with CD3OD.

[0454] Compound 44: General Scheme 1 Route B was used to provide (3R)—N-(1-cyclobutylethyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0455] Using general procedure H1 between 1-cyclobutylethanone and IM74, compound 44 was obtained as a white solid: 31 mg, 48% yield, P=94%, retention time=3.0 min (gradient B), (M+H). + :488. 1 H NMR (300MHz, CDCl3): δ8.51(s,1H),8.07(s,1H),7.32(d,J=9.5Hz,1H),7.16(d,J=1.9Hz,1H),6.91(d,J=9.5Hz,1H),6 .86(s,1H),5.78(s,2H),4.40(d,J=10.4Hz,1H),4.01(d,J=13.2Hz,1H),3.88(s,3H),3.13(t,J=11.8Hz,1H),2.99(br s,1H),2.80(br s, 2H), 2.28-2.11 (m, 1H), 2.01-1.40 (m, 11H), 1.00 (d, J = 6.1 Hz, 3H), NH was exchanged.

[0456] Compound 45: General Scheme 1 Route B was used to provide (3R)—N-(1-cyclopropylethyl)-1-[6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0457] Using general procedure H1 between 1-cyclopropylethanone and IM74, crude compound 45 was obtained as a colorless oil: 60 mg, 45% yield, P=44%, retention time=2.1 min (gradient A), (M+H). + :474.

[0458] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 5% to 40% solution "B" over 6.0 min, linear increase to 90% solution "B" over 1.0 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%.

[0459] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: EtOAc / EtOH / DEA: 85 / 15 / 0.1% at a flow rate of 7 mL / min. First eluting diastereomer: P = 100%, retention time = 9.8 min. Chiral HPLC: P = 98.9%, 1 H NMR(300MHz,CD3OD):δ8.59(s,1H),8.40(s,1H),7.48(d,J=9.5Hz,1H),7.28(d,J=9 .5Hz,1H),7.27(s,1H),6.97(s,1H),5.83(s,2H),4.51-4.35(m,1H),3.98(d,J=13. 6Hz, 1H), 3.90 (s, 3H), 3.24-3.08 (m, 3H), 2.49-2.37 (m, 1H), 2.14-2.00 (m, 1H), 1.85 (s, 1H), 1.62 (s, 2H), 1.27 (d, J = 6.3Hz, 3H), 0.88-0.16 (m, 5H). 1H was exchanged with CD3OD. The second eluting diastereomer: P = 97%, retention time = 10.8 min. Chiral HPLC: P = 99.1. 1 H NMR(300MHz,CD3OD):δ8.59(s,1H),8.40(s,1H),7.48(d,J=9.4Hz,1H),7.28(d,J=9.4 Hz,2H),7.27(s,1H),6.97(s,1H),5.83(s,2H),4.56(d,J=12.4Hz,1H),4.02(d,J=13.3 Hz, 1H), 3.90(s, 3H), 3.22-3.09(m, 3H), 2.52-2.41(m, 1H), 2.19-2.03(m, 1H), 1.82(s, 1H), 1.72-1.48(m, 2H), 1.25(d, J=6.9 Hz, 3H), 1.22-0.41(m, 8H), 1H was exchanged with CD3OD.

[0460] Compound 46: General Scheme 1, Route A was used to provide N-(cyclobutylmethyl)-1-[5-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyrimidin-2-yl]piperidin-3-amine.

[0461] Step 1: A solution of methyl 2-chloropyrimidine-5-carboxylate (100 mg, 0.56 mmol) in DCM (1.4 mL) was added to a solution of IM79 (157 mg, 0.58 mmol) and DIEA (240 μL, 1.37 mmol) under argon at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (25 mL) and extracted with DCM (2 × 25 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure to give 283 mg of a crude yellowish oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 4 / 1) to give methyl 2-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyrimidine-5-carboxylate IM134 as a colorless oil: 239 mg, 100% yield, P=99%, retention time=3.5 min (gradient A), (M+H). + :405.

[0462] Step 2: Diisobutylaluminum hydride (1N, 2.5 mL, 2.5 mmol) was added to a solution of IM134 (218 mg, 0.51 mmol) in anhydrous THF (5 mL) at −78° C. The reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by HPLC-MS. After 20 h, the same amount of diisobutylaluminum hydride was added, followed by a third portion 25 h later at −78° C. (The reaction mixture was then stirred at room temperature.) The reaction mixture was then stirred at room temperature for 72 h more. The reaction mixture was then diluted with diethyl ether (50 mL), cooled to 0° C., and water (0.3 mL) was added, followed by 1 M aqueous sodium hydroxide solution (0.3 mL) and water (0.76 mL). The mixture was stirred at room temperature for 15 min, MgSO4 was added, stirred for 15 min, and then filtered to remove salts and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 1) to give tert-butyl N-(cyclobutylmethyl)-N-[1-[5-(hydroxymethyl)pyrimidin-2-yl]-3-piperidyl]carbamate IM135 as colorless crystals: 79 mg, 41% yield, P=99%, retention time=2.7 min (gradient A), (M+H). + :377.

[0463] Steps 3 and 4: General procedure P was used to obtain the desired crude mesylate from IM135, which was used directly in general procedure N (assuming 100% yield) to give tert-butyl N-[1-[5-(azidomethyl)pyrimidin-2-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM136 as an orange-yellow oil: 68 mg, 82% yield, P = 99%, retention time = 3.3 min (gradient A), (M+H). + :402.

[0464] Step 5: Using general procedure B between IM8 and IM136, tert-butyl N-(cyclobutylmethyl)-N-[1-[5-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyrazin-2-yl]-3-piperidyl]carbamate IM137 was obtained as a white solid: 108 mg, 87% yield, P=96%, retention time=3.4 min (gradient A), (M+H). + :658.

[0465] Step 6: Compound 46 was obtained from IM137 using general procedure A1 as a yellow solid: 76 mg, 96% yield, P=92% (215 nm), retention time=3.2 min (gradient B), (M+H) + :474. 1 H NMR (300 MHz, CD3OD): δ 8.54 (s, 1H), 8.46 (s, 2H), 8.40 (s, 1H), 7.25 (d, J = 1.9 Hz, 1H), 6.96 (s, 1H), 5.53 (s, 2H), 4.66-4.54 (m, 1H), 4.42-4.29 (m, 1H), 3.89 (s, 3H), 3.22-3.10 (m, 1H), 3.03 (dd, J = 12.8, 9.2 Hz, 1H), 2.84-2.58 (m, 3H), 2.47 (hept, J = 7.6 Hz, 1H), 2.14-1.37 (m, 10H), 1H was exchanged with CD3OD.

[0466] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: EtOAc / EtOH / DEA: 90 / 10 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 100%, retention time = 9.8 min, chiral HPLC: P = 100%. Second eluting enantiomer: P = 96%, retention time = 10.8 min, chiral HPLC: P = 100%.

[0467] Compound 47: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[5-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]pyrazin-2-yl]piperidin-3-amine.

[0468] Step 1: To a solution of IM79 (280 mg, 1.04 mmol) and methyl 5-chloropyrazine-2-carboxylate (150 mg, 0.87 mmol) in anhydrous DMF (1 mL) was added DIEA (310 μL, 1.74 mmol) at room temperature under an argon atmosphere. The resulting mixture was stirred at room temperature for 1 h, and the reaction was diluted with EtOAc (20 mL), washed with saturated NaHCO solution (2 × 10 mL), dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 1) to give methyl 5-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyrazine-2-carboxylate IM138 as a colorless oil: 295 mg, 84% yield, P = 100%, retention time = 3.2 min (gradient A), (M+H). + :405.

[0469] Step 2: A solution of IM138 (253 mg, 0.6300 mmol) in anhydrous THF (2.2 mL) was cooled to 0 °C under an argon atmosphere, then lithium borohydride (23 mg, 0.95 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched with water (5 mL) and concentrated under reduced pressure to give a yellow paste. To the paste was added EtOAc (50 mL) followed by water (10 mL). The layers were separated, and the organic layer was washed with water (2 × 10 mL), dried over MgSO, filtered, and concentrated under reduced pressure to give 258 mg as a yellow oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 1 to 1 / 4) to give tert-butyl N-(cyclobutylmethyl)-N-[1-[5-(hydroxymethyl)pyrazin-2-yl]-3-piperidyl]carbamate IM139 as a colorless oil: 116 mg, 42% yield, P=100%, retention time=2.8 min (gradient A), (M+H). + :377.

[0470] Step 3: Using general procedure M from IM139, tert-butyl N-[1-[5-(azidomethyl)pyrazin-2-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM140 was obtained as a yellow oil: 100 mg, 73% yield, P = 97%, retention time = 3.4 min (gradient A), (M+H). + :402.

[0471] Step 4: Using general procedure B between IM8 and IM140, tert-butyl N-(cyclobutylmethyl)-N-[1-[5-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyrazin-2-yl]-3-piperidyl]carbamate IM141 was obtained as a white solid: 60 mg, 88% yield, P=96%, retention time=3.4 min (gradient A), (M+H). + :658.

[0472] Step 5: Compound 47 was obtained from IM141 using general procedure A1 as a white powder: 40 mg, 95% yield, P=97%, retention time=3.1 min (gradient B), (M+H) + :474. 1 H NMR (300 MHz, CD3OD): δ 8.51 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.93 (s, 1H), 5.62 (s, 2H), 4.37-4.25 (m, 1H), 4.10-3.99 (m, 1H), 3.87 (s, 3H), 3.09-2.79 (m, 3H), 2.75-2.53 (m, 3H), 2.43 (hept, J = 7.5 Hz, 1H), 2.07-1.37 (m, 10H), 1H was exchanged with CD3OD.

[0473] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak ID column (5 μm, 10 × 250 mm). Eluent used: DCM / MeOH / DEA: 94 / 6 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 97%, retention time = 6.3 min, chiral HPLC: P = 96.4%. Second eluting enantiomer: P = 98%, retention time = 7.6 min, chiral HPLC: P = 97.1%.

[0474] Compound 48: General Scheme 1 Route A was used to provide 3-[1-[[6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]pyridazin-3-yl]methyl]triazol-4-yl]-2H-isoquinolin-1-one.

[0475] Step 1: 3-Chloroisoquinolin-1-ol (250 mg, 1.32 mmol) was dissolved in anhydrous DMF (2.6 mL) at room temperature, and potassium carbonate (400 mg, 2.89 mmol) was added, followed by 4-methoxybenzyl bromide (370 mg, 1.84 mmol). The reaction mixture was heated to 80° C. for 2 h, then diluted with EtOAc (30 mL) and washed with water (3×10 mL), followed by brine (10 mL). The resulting organic layer was dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 386 mg as a light brown oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 4 / 1) to give 3-chloro-2-[(4-methoxyphenyl)methyl]isoquinolin-1-one IM142 as a colorless oil: 260 mg, 58% yield, P=95%, retention time=3.1 min (gradient A), (M+Na). + :322 / 324.

[0476] Step 2: To a solution of IM42 (123 mg, 0.36 mmol) in anhydrous toluene (3.6 mL, previously degassed) was added 1-tributylstannyl-2-trimethylsilylacetylene (450 μL, 1.08 mmol) and dichlorobis(triphenylphosphine)palladium (13 mg, 0.02 mmol). The resulting mixture was heated at reflux for 5 days. The reaction was then cooled to room temperature and concentrated to dryness under reduced pressure to give a black oil. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 9 / 1) to give 2-[(4-methoxyphenyl)methyl]-3-(2-trimethylsilylethynyl)isoquinolin-1-one IM143 as a brown oil: 68 mg, 33% yield, P = 71%, retention time = 3.4 min (gradient A), (M+H). + :362.

[0477] Step 3: 3-ethynyl-2-[(4-methoxyphenyl)methyl]isoquinolin-1-one IM144 was obtained from IM143 using general procedure D1 as a yellow solid: 27 mg, 71% yield, P=95%, retention time=2.8 min (gradient A), (M+H) + :290.

[0478] Step 4: Using general procedure B between IM39 and IM144, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[[4-[2-[(4-methoxyphenyl)methyl]-1-oxo-3-isoquinolyl]triazol-1-yl]methyl]pyridazin-3-yl]-3-piperidyl]carbamate IM145 was obtained as a yellow foam: 40 mg, 32% yield, P = 98%, retention time = 2.8 min (gradient A), (M+H). + :691.

[0479] Step 5: Compound 48 was obtained from IM145 using general procedure A2 as an off-white powder: 15 mg, 97% yield, P=89%, retention time=2.2 min (gradient A), (M+H) + :471.

[0480] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 25% to 50% solution "B" over 6.5 min, linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR (300MHz, CDCl3): δ8.40(d,J=8.0Hz,1H),8.35(s,1H),7.66(ddd,J=8.0,6.9,1.3Hz,1H ),7.58-7.46(2H),7.28(d,J=9.4Hz,1H),6.90(d,J=9.4Hz,1H),6.89(s,1H),5.76(s,2H),4 .42-4.31(m,1H), 4.16-4.03(m,1H), 3.20-3.04(m,1H), 2.90(dd,J=12.8,9.3Hz,1H), 2.78-2.58(m,3H), 2.41(hept,J=7.5Hz,1H), 2.10-1.77(m,6H), 1.71-1.36(m,4H), NH was exchanged.

[0481] Compound 49: General Scheme 1, Route A was used to provide N-(cyclobutylmethyl)-1-[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]thiazol-5-yl]piperidin-3-amine.

[0482] Step 1: Using general procedure S between IM79 and methyl 5-bromo-1,3-thiazole-2-carboxylate, methyl 5-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]thiazole-2-carboxylate IM146 was obtained as an orange-yellow oil: 443 mg, 89% yield, P = 88% ( 1 H-NMR), retention time = 3.3 min (gradient A), (M+H) + :410.

[0483] Step 2: Diisobutylaluminum hydride (1N in THF, 2.39 mL, 2.39 mmol) was added to a solution of IM146 (97 mg, 0.24 mmol) in anhydrous THF (2.5 mL) at −78° C., and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was then diluted with diethyl ether (20 mL), cooled to 0° C., and water (0.1 mL) was added, followed by 1N aqueous sodium hydroxide solution (0.1 mL) and water (0.25 mL). The mixture was stirred at room temperature for 15 min, MgSO4 was added, stirred for 15 min, then filtered to remove salts, rinsed thoroughly with AcOEt (150 mL), and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (2.5% MeOH / DCM) to give tert-butyl N-(cyclobutylmethyl)-N-[1-[2-(hydroxymethyl)thiazol-5-yl]-3-piperidyl]carbamate IM147 as a yellow oil: 69 mg, 73% yield, P=95%, retention time=2.7 min (gradient A), (M+H). + :382.

[0484] Steps 3 and 4: General procedure P was used from IM147 to give the desired crude mesylate, which was used directly in general procedure N (assuming 100% yield) to give tert-butyl N-[1-[2-(azidomethyl)thiazol-5-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM148 as a brown oil: 50 mg, 61% yield, P = 90% ( 1 H-NMR), retention time = 3.3 min (gradient A), (M+H) + :407.

[0485] Step 5: Using general procedure B between IM8 and IM148, tert-butyl N-(cyclobutylmethyl)-N-[1-[2-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]thiazol-5-yl]-3-piperidyl]carbamate IM149 was obtained as a brown oil: 63 mg, 81% yield, P=87% ( 1 H-NMR), retention time = 3.4 min (gradient A), (M+Na+MeCN+2H) + :364.

[0486] Step 6: Compound 49 was obtained from IM149 using general procedure A1 as a brown solid: 39 mg, 56% yield, P=63%, retention time=3.1 min (gradient B), (M+2H). + :240.

[0487] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 30% to 50% solution "B" over 5.0 min, linear increase to 51% solution "B" over 0.3 min, linear increase to 85% solution "B" over 1.2 min, hold at 85% for 0.2 min, and return to initial conditions over 0.8 min. Flow rate: 15 mL / min. P = 98%. 1H NMR (300 MHz, CD3OD): δ 8.57 (s, 1H), 8.41 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.97 (br s, 1H), 6.95 (s, 1H), 5.84 (s, 2H), 3.90 (s, 3H), 3.47 (d, J = 8.0 Hz, 1H), 2.95-2.80 (m, 1H), 2.77-2.61 (m, 4H), 2.45 (hept, J = 7.6 Hz, 1H), 2.14-1.64 (m, 10H), 1H was exchanged with CD3OD.

[0488] Compound 50: General Scheme 1 Route B was used to provide 4-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-1-[1-[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]ethyl]pyridin-2-one.

[0489] Step 1: 4-chloro-1-(1-chloroethyl)pyridin-2-one IM150 was obtained from 4-chloro-2-hydroxypyridine using general procedure O2 as an orange-yellow oil: 15.4 g, 91% yield, P=85% ( 1 H-NMR), retention time = 2.5 min (gradient A), (M+H) + :192 / 194.

[0490] Step 2: 1-(1-azidoethyl)-4-chloropyridin-2-one IM151 was obtained from IM150 using general procedure N as a yellowish liquid: 300 mg, 92% yield, P=100% (215 nm), retention time=2.5 min (gradient A), (M+H) + :199 / 201.

[0491] Step 3: Using general procedure B between IM8 and IM151, 4-chloro-1-[1-[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]ethyl]pyridin-2-one IM152 was obtained as a pale beige foam: 193 mg, 96% yield, P = 91% (215 nm), retention time = 4.6 min (gradient B), (M+H) + :455 / 457.

[0492] Step 4: Using general procedure C between IM3 and IM152, crude tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[1-[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]ethyl]-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM153 was obtained as a brownish gum: 177 mg, 100% yield, P=92%, retention time=3.2 min (gradient A), (M+H). + :687.

[0493] Step 5: From IM153 using general procedure A1 crude compound 50 was obtained as a beige foam: 80 mg, 76% yield, P=96%, retention time=2.2 min (gradient A), (M+H) + :503.

[0494] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IE column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 60 / 40 / 0.1% at a flow rate of 7 mL / min. First eluting diastereomer: P = 100%, retention time = 8.1 min. Chiral HPLC: P = 94.7%, 1 H NMR (300MHz, CDCl3): δ8.51(s,1H),8.38(s,1H),7.67(q,J=6.9Hz,1H),7.48(d,J=8.1Hz,1H), 7.21(d,J=1.6Hz,1H),6.83(s,1H),5.99(dd,J=8.1,2.4Hz,1H),5.71(d,J=2.3Hz,1H),3.81(s, 3H), 3.74 (d, J = 11.7 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 2.96-2.81 (m, 1H), 2.76-2.51 (m, 4H), 2.36 (hept, J = 7.6 Hz, 1H), 2.18 (d, J = 7.0 Hz, 3H), 2.11-1.50 (m, 9H), 1.41-1.22 (m, 1H). NH was exchanged. Second-eluting diastereomer: P = 100%, retention time = 11.8 min. Chiral HPLC: P = 100%. 1H NMR (300MHz, CDCl3): δ8.51(s,1H),8.38(s,1H),7.67(q,J=6.8Hz,1H),7.48(d,J=8.1Hz,1H) ,7.20(s,1H),6.83(s,1H),5.98(dd,J=8.2,3.0Hz,1H),5.71(d,J=2.9Hz,1H),3.80(s,3H),3. 74 (d, J = 12.9 Hz, 1H), 3.58 (d, J = 13.0 Hz, 1H), 2.89 (t, J = 11.1 Hz, 1H), 2.77-2.53 (m, 4H), 2.38 (hept, J = 7.6 Hz, 1H), 2.18 (d, J = 6.9 Hz, 3H), 2.08-1.40 (m, 9H), 1.41-1.22 (m, 1H). The NH was exchanged.

[0495] Compound 51: General Scheme 2, Route A was used to provide N-[1-[6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]pyridazin-3-yl]ethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0496] Step 1: General procedure R was used from IM106 to give crude 1-(6-chloropyridazin-3-yl)ethanamine IM154 as an orange-yellow oil: 51 mg, 66% yield, P=98% ( 1 H-NMR), retention time = 0.3-0.6 min (gradient A), (M+H) + :158.

[0497] Step 2: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM154, crude N-[1-(6-chloropyridazin-3-yl)ethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide IM155 was obtained as a yellow oil: 61 mg, 52% yield, P = 90%, retention time = 2.4 min (gradient A), (M+H). + :330.

[0498] Step 3: Using general procedure C between IM3 and IM155, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[1-[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]ethyl]pyridazin-3-yl]-3-piperidyl]carbamate IM156 was obtained as a brown oil: 159 mg, 96% yield, P = 57% ( 1 H-NMR), retention time = 2.5 min (gradient A), (M+H) + :562.

[0499] Step 4: Compound 51 was obtained from IM156 using general procedure A1 as a brown solid: 74 mg, 75% yield, P=80%, retention time=2.0 min (gradient A), (M+H) + :462.

[0500] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 15% to 50% solution "B" over 5.0 min, linear increase to 85% solution "B" over 1.5 min, and return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%.

[0501] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 75 / 25 / 0.1% at a flow rate of 7 mL / min. First eluting diastereomer: P = 100%, retention time = 6.6 min. Chiral HPLC: P = 99.1%, 1H NMR(300MHz,CD3OD):δ9.08(d,J=7.2Hz,1H),8.01(dd,J=9.0,7.2Hz,1H),7.87(d,J=9.0Hz,1H),7. 46(d,J=9.5Hz,1H),7.41(t,J=7.2Hz,1H),7.25(d,J=9.5Hz,1H),7.07(s,1H),5.30(q,J=7.0Hz,1H ), 4.44-4.32 (m, 1H), 4.15-4.04 (m, 1H), 3.08 (t, J = 12.0 Hz, 1H), 2.91 (dd, J = 12.8, 9.4 Hz, 1H), 2.81-2.59 (m, 3H), 2.48 (hept, J = 7.6 Hz, 1H), 2.18-2.00 (m, 3H), 2.00-1.35 (m, 10H). 2H was exchanged with CD3OD. Second-eluting diastereomer: P = 100%, retention time = 7.2 min. Chiral HPLC: P = 97.3%. 1 H NMR(300MHz,CD3OD):δ9.07(d,J=7.1Hz,1H),8.01(dd,J=8.9,7.1Hz,1H),7.86(d,J=8.9Hz,1 H),7.46(d,J=9.5Hz,1H),7.40(t,J=7.1Hz,1H),7.24(d,J=9.5Hz,1H),7.06(s,1H),5.30(q, J = 7.0 Hz, 1H), 4.41-4.30 (m, 1H), 4.15-4.03 (m, 1H), 3.13-3.00 (m, 1H), 2.91 (dd, J = 12.7, 9.5 Hz, 1H), 2.81-2.58 (m, 3H), 2.48 (hept, J = 7.5 Hz, 1H), 2.18-1.34 (m, 13H), 2H was exchanged with CD3OD.

[0502] Compound 52: General Scheme 1, Route A was used to provide 6-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]-3-[3-(cyclobutylmethylamino)-1-piperidyl]-1H-pyridin-2-one.

[0503] Step 1: Silver carbonate (1.9 g, 6.89 mmol) and benzyl bromide (1 mL, 8.32 mmol) were added to a solution of methyl 5-bromo-6-oxo-1,6-dihydropyridine-2-carboxylate (994 mg, 4.2 mmol) in anhydrous toluene (23 mL) and stirred at 40 °C under argon for 6 h. The reaction mixture was filtered through Celite, rinsed with toluene (5 mL), and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 9 / 1) to give methyl 6-benzyloxy-5-bromopyridine-2-carboxylate IM157 as a colorless oil: 1.32 g, 98% yield, P = 99%, retention time = 3.1 min (gradient A), (M+H). + :321 / 323.

[0504] Step 2: Using the general procedure S between IM157 and IM79 (209 mg, 0.78 mmol), methyl 6-benzyloxy-5-[3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyridine-2-carboxylate IM158 was obtained as a white gum: 333 mg, 85% yield, P = 97% ( 1 H-NMR), retention time = 3.7 min (gradient A), (M+H) + :510.

[0505] Step 3: Diisobutylaluminum hydride (1N in THF, 5.2 mL, 5.2 mmol) was added to a solution of IM158 (282 mg, 0.53 mmol) in anhydrous THF (5 mL) at −78° C., and the reaction mixture was stirred at room temperature. After 14 h, additional diisobutylaluminum hydride (1N in THF, 2.6 mL, 2.6 mmol) was added at −78° C., and the reaction mixture was stirred at room temperature for 6 h (complete conversion by HPLC-MS). The reaction mixture was then diluted with diethyl ether (50 mL), cooled to 0° C., and water (0.3 mL) was added, followed by 1N aqueous sodium hydroxide solution (0.3 mL) and water (0.8 mL). The mixture was stirred at room temperature for 15 min, MgSO4 was added, stirred for 15 min, and then filtered to remove salts, rinsed thoroughly with AcOEt (150 mL), and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / EtOAc: 7 / 3) to give tert-butyl N-[1-[2-benzyloxy-6-(hydroxymethyl)-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM159 as a white gum: 254 mg, 97% yield, P=97% ( 1 H-NMR), retention time = 3.0 min (gradient A), (M+H) + :482.

[0506] Step 4: General procedure M was used from IM159 to give crude tert-butyl N-[1-[6-(azidomethyl)-2-benzyloxy-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM160 as a white gum: 271 mg, 100% yield, P = 84% (215 nm), retention time = 3.6 min (gradient A), (M+H) + :507.

[0507] Step 5: Using general procedure B between IM8 and IM160, tert-butyl N-[1-[2-benzyloxy-6-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM161 was obtained as a white foam: 305 mg, 83% yield, P=95% ( 1 H-NMR), retention time = 3.5 min (gradient A), (M+H) + :763.

[0508] Step 6: Using general procedure L from IM161, tert-butyl N-(cyclobutylmethyl)-N-[1-[2-hydroxy-6-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-3-pyridyl]-3-piperidyl]carbamate IM162 was obtained as an off-white foam: 258 mg, 99% yield, P = 100% (215 nm), retention time = 2.9 min (gradient A), (M+H). + :673.

[0509] Step 7: Compound 52 was obtained from IM162 using general procedure A1 as a white solid: 175 mg, 91% yield, P=95%, retention time=3.1 min (gradient B), (M+H) + :489. 1 H NMR (300 MHz, CD3OD): δ 8.53 (s, 1H), 8.39 (s, 1H), 7.27 (s, 1H), 6.97 (s, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 5.53 (s, 2H), 3.90 (s, 3H), 3.62-3.51 (m, 1H), 3.29-3.21 (m, 1H), 2.88-2.78 (m, 1H), 2.78-2.65 (m, 3H), 2.61-2.43 (m, 2H), 2.09 (d, J = 8.3 Hz, 2H), 2.00-1.61 (m, 8H), 1H was exchanged with CD3OD.

[0510] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: EtOAc / EtOH / DEA: 90 / 10 / 0.1% at a flow rate of 20 mL / min. First eluting enantiomer: P = 95%, retention time = 7.4 min, chiral HPLC: P = 99.4%. Second eluting enantiomer: P = 96%, retention time = 11.2 min, chiral HPLC: P = 99.2%.

[0511] Compound 53: General Scheme 1, Route B was used to provide N-(cyclobutylmethyl)-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-3-methylpiperidin-3-amine.

[0512] Step 1: General procedure C was used between IM112 and tert-butyl n-(3-methylpiperidin-3-yl)carbamate to give crude tert-butyl N-[1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-3-methyl-3-piperidyl]carbamate IM163 as a brown solid: 58 mg, 91% yield, P=95%, retention time=2.2 min (gradient A), (M+H). + :481.

[0513] Step 2: General procedure A1 was used from IM163 to give crude 1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-3-methylpiperidin-3-amine dihydrochloride IM164 as a brown solid: 76 mg, 99% yield, retention time = 1.8 min (gradient A), (M+H). + :381.

[0514] Step 3: Using general procedure H2 between cyclobutanecarboxaldehyde and IM164, crude compound 53 was obtained as a brown solid: 42 mg, 40% yield, P=52%, retention time=1.9 min (gradient A), (M+H). + :449.

[0515] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). Gradient used: linear increase from 25% to 40% solution "B" over 5.5 min, linear increase to 85% solution "B" over 1.0 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR(300MHz,CD3OD):δ8.58(s,1H),8.53(s,1H),8.20(d,J=2.7Hz,1H),7.83(s,1H), 7.44(d,J=9.5Hz,1H),7.27(d,J=9.5Hz,1H),5.78(s,2H),3.93(s,3H),3.84(s,1H),3 0.80(s,1H), 3.48-3.33(m,1H), 3.30-3.24(m,1H), 2.57(d,J=7.2Hz,2H), 2.31(hept,J=7.6Hz,1H), 2.04-1.91(m,2H), 1.83-1.39(m,8H), 1.09(s,3H), 1H was exchanged with CD3OD.

[0516] The mixture of enantiomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 65 / 35 / 0.1% at a flow rate of 6 mL / min. First eluting enantiomer: P = 100%, retention time = 7.6 min, chiral HPLC: P = 97.9%. Second eluting enantiomer: P = 100%, retention time = 10.6 min, chiral HPLC: P = 98.7%.

[0517] Compound 54: General Scheme 1, Route A was used to provide 5-fluoro-1-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]-4-[3-(cyclobutylmethylamino)-1-piperidyl]pyridin-2-one.

[0518] Step 1: Using general procedure C (in DMSO instead of NMP at 100 °C) between IM79 and 5-fluoro-4-iodo-1H-pyridin-2-one, tert-butyl N-(cyclobutylmethyl)-N-[1-(5-fluoro-2-oxo-1H-pyridin-4-yl)-3-piperidyl]carbamate IM165 was obtained as an off-white solid: 207 mg, 64% yield, P = 98% (215 nm), retention time = 2.7 min (gradient A), (M+H). + :380.

[0519] Step 2: To a solution of formaldehyde (37% aqueous solution, 1.0 mL, 13.43 mmol) in DMF (1.3 mL) were added triethylamine (0.37 mL, 2.63 mmol) and IM165 (100 mg, 0.26 mmol). The mixture was heated at 80 °C, and the reaction progress was monitored by HPLC-MS. After 16 h, additional formaldehyde (37% aqueous solution, 1.0 mL, 13.43 mmol) and triethylamine (0.37 mL, 2.63 mmol) were added, and the mixture was further stirred at 110 °C for 2 days, at which point both reagents were added again. After an additional 3 days at 110 °C, the reaction mixture was allowed to cool to room temperature, diluted with AcOEt (50 mL), and rinsed with water (50 mL). The aqueous layer was extracted with AcOEt (50 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to give a colorless oil. The crude product was purified using an automated flash system (liquid injection in DCM, DCM over 1 min, 0–10% MeOH / DCM over 25 min, 30SIHP-12G, 20 mL / min) to give tert-butyl N-(cyclobutylmethyl)-N-[1-[5-fluoro-1-(hydroxymethyl)-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM166 as a colorless oil: 98 mg, 45% yield, P = 49% (215 nm), retention time = 2.8 min (gradient A), (M+H). + :380.

[0520] Step 3: Using general procedure M from IM166, tert-butyl N-[1-[1-(azidomethyl)-5-fluoro-2-oxo-4-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM167 was obtained as a colorless oil: 20 mg, 39% yield, P = 100% (215 nm), retention time = 3.1 min (gradient A), (M+H). + :435.

[0521] Step 5: Using general procedure B between IM8 and IM167, tert-butyl N-(cyclobutylmethyl)-N-[1-[5-fluoro-1-[[4-(6-methoxy-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM168 was obtained as a colorless glass: 25 mg, 79% yield, P = 100% (215 nm), retention time = 3.2 min (gradient A), (M+H). + :691.

[0522] Step 6: Compound 54 was obtained from IM168 using general procedure A1 as a yellowish glass: 17 mg, 83% yield, P=80%, retention time=2.2 min (gradient B), (M+H) + :507. 1 H NMR (300 MHz, CDCl): δ 8.52 (s, 1H), 8.36 (s, 1H), 7.21 (s, 2H), 6.79 (s, 1H), 5.59 (s, 2H), 3.83 (s, 4H), 3.49-2.30 (m, 8H), 2.09-1.91 (m, 2H), 1.91-1.40 (m, 8H), NH was exchanged.

[0523] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IE column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 73 / 20 / 7 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 93%, retention time = 6.6 min, chiral HPLC: P = 97.2%. Second eluting enantiomer: P = 97%, retention time = 7.7 min, chiral HPLC: P = 97.2%.

[0524] Compound 55: General Scheme 1, Route B was used to provide 4-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-1-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridin-2-one.

[0525] Step 1: Using general procedure B between IM44 and IM151, 4-chloro-1-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridin-2-one IM169 was obtained as a yellow solid: 151 mg, 83% yield, P=92%, retention time=2.1 min (gradient A), (M+H). + :332 / 334.

[0526] Step 2: Using general procedure C between IM3 and IM169, crude tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM170 was obtained as an off-white solid: 335 mg, 99% yield, P=70%, retention time=3.6 min (gradient A), (M+H). + :564.

[0527] Step 3: Using general procedure A1 from IM170, crude compound 55 was obtained as an off-white solid: 173 mg, 89% yield, P=100%, retention time=2.0 min (gradient A), (M+H). + :464.

[0528] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 50 / 30 / 30 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 8.3 min. Chiral HPLC: P = 100%, 1H NMR (300MHz, CDCl3): δ8.53(s,1H),8.20(d,J=2.6Hz,1H),8.12(s,1H),7.63(s,1H),7.50(q,J =7.0Hz,1H),7.37(d,J=8.1Hz,1H),5.94(dd,J=8.1,2.5Hz,1H),5.59(d,J=2.4Hz,1H),3.83(s, 3H), 3.69 (d, J = 12.5 Hz, 1H), 3.54 (d, J = 13.3 Hz, 1H), 2.90-2.78 (m, 2H), 2.72-2.44 (m, 4H), 2.33 (hept, J = 7.6 Hz, 1H), 2.11 (d, J = 7.0 Hz, 3H), 2.05-1.41 (m, 9H), 1.36-1.17 (m, 1H). The NH was exchanged. The second eluting diastereomer: P = 100%, retention time = 11.8 min. Chiral HPLC: P = 99.4%. 1 H NMR (300MHz, CDCl3): δ8.54(s,1H),8.22(d,J=2.6Hz,1H),8.13(s,1H),7.65(s,1H),7.51(q,J =7.0Hz,1H),7.39(d,J=8.1Hz,1H),5.95(dd,J=8.1,2.5Hz,1H),5.61(d,J=2.4Hz,1H),3.85(s, 3H), 3.71 (d, J = 11.9 Hz, 1H), 3.56 (d, J = 13.3 Hz, 1H), 2.97-2.78 (m, 2H), 2.74-2.47 (m, 4H), 2.34 (hept, J = 7.3 Hz, 1H), 2.13 (d, J = 7.0 Hz, 3H), 2.08-1.42 (m, 9H), 1.39-1.20 (m, 1H). The NH was exchanged.

[0529] Compound 56: General Scheme 1 Route B was used to provide (3R,5S)—N-(cyclobutylmethyl)-5-fluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0530] Step 1: General procedure C was used between IM112 and tert-butyl N-[(3R,5S)-5-fluoropiperidin-3-yl]carbamate to give tert-butyl N-[(3R,5S)-5-fluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-3-piperidyl]carbamate IM171 as a yellow oil: 21 mg, 34% yield, P = 95%, retention time = 2.2 min (gradient A), (M+H). + :485.

[0531] Step 2: General procedure A1 was used from IM171 to give crude (3R,5S)-5-fluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine dihydrochloride IM172 as a yellow solid: 31 mg, 100% yield, retention time = 1.7 min (gradient A), (M+H). + :385.

[0532] Step 3: Using general procedure H2 between cyclobutanecarboxaldehyde and the dihydrochloride salt of IM172, compound 56 was obtained as a pale yellow powder: 23 mg, 100% yield, P=96%, retention time=2.5 min (gradient B), (M+H). + :453. 1 H NMR (300MHz, CDCl3): δ8.53(d,J=1.7Hz,1H),8.26(d,J=2.8Hz,1H),8.02(s,1H),7.73(dd,J=2.8,1 .7Hz,1H),7.32(d,J=9.5Hz,1H),7.00(d,J=9.5Hz,1H),5.75(s,2H),4.90-4.54(m,1H),4.25-4.02 (m, 2H), 3.90 (s, 3H), 3.59-3.46 (m, 1H), 3.29 (dd, J = 13.2, 8.2 Hz, 1H), 2.92-2.78 (m, 1H), 2.78-2.67 (m, 2H), 2.53-2.23 (m, 2H), 2.11-1.98 (m, 2H), 1.95-1.75 (m, 3H), 1.72-1.55 (m, 2H). The NH was exchanged. 19F NMR (282MHz, CDCl3): δ-177.78 (d,J=45.9Hz).

[0533] Compound 57: General Scheme 1 Route B was used to provide (3R)-1-[6-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]-N-(cyclobutylmethyl)piperidin-3-amine.

[0534] Step 1: A round-bottom flask equipped with a reflux condenser and a nitrogen balloon was charged with 4-bromo-6-chloro-1H-indazole (500 mg, 2.07 mmol), anhydrous EtOAc (6 mL), and 3,4-dihydro-2H-pyran (663 μL, 7.05 mmol). The reaction mixture was stirred at room temperature for 2 minutes, after which trifluoroacetic acid (162 μL, 2.08 mmol) was added. The resulting mixture was stirred for 1.15 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous NaHCO3 (2 × 20 mL), followed by brine (30 mL). The resulting organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a red / orange oil (1.2 g). The crude product was purified on an automated flash system (liquid injection in n-heptane, n-heptane over 0.9 min, 0-10% EtOAc / n-heptane over 9.1 min, 30SIHP-12G, 15 mL / min) to give 4-bromo-6-chloro-1-tetrahydropyran-2-yl-indazole IM173 as an orange-yellow solid: 534 mg, 80% yield, P=98%, retention time=3.3 min (gradient A), (M+H). + :315 / 317.

[0535] Step 2: 2-(6-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)ethynyltrimethylsilane IM174 was obtained from IM173 using general procedure E1 as a yellow oil: 438 mg, 75% yield, P=95%, retention time=3.7 min (gradient A), (M+H) + :333 / 335.

[0536] Step 3: Using general procedure D1 from IM174, 6-chloro-4-ethynyl-1-tetrahydropyran-2-yl-indazole IM175 was obtained as a yellow solid: 307 mg, 88% yield, P=95%, retention time=3.1 min (gradient A), (M+H). + :261.

[0537] Step 4: Using general procedure B between IM175 and IM5, 6-chloro-4-[1-[(6-chloropyridazin-3-yl)methyl]triazol-4-yl]-1-tetrahydropyran-2-yl-indazole IM176 was obtained as a white solid: 125 mg, 79% yield, P=100%, retention time=2.8 min (gradient A), (M+H). + :430 / 432.

[0538] Step 5: Using general procedure C between IM3 and IM176, tert-butyl N-[(3R)-1-[6-[[4-(6-chloro-1-tetrahydropyran-2-yl-indazol-4-yl)triazol-1-yl]methyl]pyridazin-3-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM177 was obtained as a yellow oil: 100 mg, 87% yield, P = 90%, retention time = 2.7 min (gradient A), (M+H). + :662 / 664.

[0539] Step 6: From IM177, crude compound 57 was obtained using general procedure A1 as a white solid: 55 mg, 78% yield, P=94%, retention time=3.1 min (gradient B), (M+H). + :478. 1H NMR(300MHz,CD3OD):δ8.66(s,1H),8.56(s,1H),7.61(d,J=1.6Hz,1H),7.55(d,J=1.6 Hz,1H),7.46(d,J=9.5Hz,1H),7.26(d,J=9.5Hz,1H),5.82(s,2H),4.39(d,J=14.0Hz,1 H), 4.10 (d, J = 13.6 Hz, 1H), 3.18-3.02 (m, 1H), 2.95 (dd, J = 12.9, 9.4 Hz, 1H), 2.77-2.55 (m, 3H), 2.54-2.40 (m, 1H), 2.14-1.98 (m, 3H), 1.92-1.37 (m, 8H), 1H was exchanged with CD3OD.

[0540] Compound 58: General Scheme 2, Route B was used to provide N-[1-[5-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-2-pyridyl]ethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0541] Step 1: To a suspension of lithium aluminum hydride (146 mg, 3.65 mmol) in anhydrous THF (13 mL) was added dropwise over 5 min at −78° C. under an argon atmosphere at −78° C. A solution of IM127 (1.12 g, 2.57 mmol) in anhydrous THF (10 mL) was added dropwise over 5 min. The reaction mixture was stirred at −78° C. for 2 h, followed by the addition of additional lithium aluminum hydride (55 mg, 1.38 mmol), followed 1 h later by a third portion (75 mg, 1.88 mmol). After 30 min, the reaction mixture was warmed to 0° C. and quenched by the slow addition of EtOAc (40 mL). The resulting mixture was stirred at 0° C. for 5 min, followed by the very slow addition of saturated Rochelle's salt solution (30 mL) at 0° C. (violent reaction during the first addition), and the mixture was vigorously stirred at room temperature for 17 h. The phases were then separated, and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 1.11 g as a yellow oil. The crude material was purified on an automated flash system (liquid injection in DCM, 0–15% MeOH / DCM over 30 min, 30SIHP-40G, 20 mL / min) to give tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-(hydroxymethyl)-3-pyridyl]-3-piperidyl]carbamate IM178 as a yellow oil: 658 mg, 67% yield, P = 100%, retention time = 2.5 min (gradient A), (M+H). + 376, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-formyl-3-pyridyl]-3-piperidyl]carbamate IM179 was obtained as a green oil: 152 mg, 14% yield, P=90%, retention time=2.9 min (gradient A), (M+H) + :374.

[0542] Step 2: Using general procedure Q from IM179, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-(1-hydroxyethyl)-3-pyridyl]-3-piperidyl]carbamate IM180 was obtained as a yellow oil: 155 mg, 96% yield, P = 88%, retention time = 2.5 min (gradient A), (M+H). + :390.

[0543] Step 3: Using general procedure M from IM180, tert-butyl N-[(3R)-1-[6-(1-azidoethyl)-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM181 was obtained as a colorless oil: 85 mg, 44% yield, P = 75%, retention time = 2.7 min (gradient A), (M+H). + :415.

[0544] Step 4: General procedure R was used from IM181 to give crude tert-butyl N-[(3R)-1-[6-(1-aminoethyl)-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM182 as a yellow oil: 60 mg, 76% yield, P = 58%, retention time = 2.4 min (gradient A), (M+H). + :389.

[0545] Step 5: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM182, crude tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[1-[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]ethyl]-3-pyridyl]-3-piperidyl]carbamate IM183 was obtained as a brown oil: 90 mg, 94% yield, P = 70%, retention time = 2.6 min (gradient A), (M+H). + :561.

[0546] Step 6: From IM183 using general procedure A1 crude compound 58 was obtained as an orange-yellow oil: 60 mg, 93% yield, P=80%, retention time=2.0 min (gradient A), (M+H) + :461.

[0547] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: 35% solution "B" held for 1.5 min, linear increase from 35% to 40% solution "B" over 3.5 min, linear increase to 85% solution "B" over 1.2 min, hold at 85% solution "B" for 0.3 min, return to initial conditions over 1.0 min. Flow rate: 15 mL / min. P = 100%.

[0548] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DEA: 75 / 25 / 0.1% at a flow rate of 7 mL / min. First eluting diastereomer: P = 100%, retention time = 3.0 min. Chiral HPLC: P = 99.6%, 1 H NMR (300 MHz, CDCl): δ 9.07 (d, J = 6.8 Hz, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.30 (s, 1H), 7.77 (br s, 2H), 7.26-7.11 (m, 4H), 5.31-5.19 (m, 1H), 4.08-3.90 (m, 1H), 3.45-3.32 (m, 1H), 3.23-3.09 (m, 2H), 3.06-2.74 (m, 5H), 2.29-2.09 (m, 3H), 1.98-1.71 (m, 6H), 1.57 (d, J = 6.5 Hz, 3H), 1.43 (t, J = 7.1 Hz, 1H). NH was exchanged. Second eluting diastereomer: P = 99%, retention time = 8.7 min; Chiral HPLC: P = 100%; 1H NMR (300 MHz, CDCl): δ 9.00 (d, J = 7.0 Hz, 1H), 8.83 (d, J = 7.5 Hz, 1H), 8.21 (s, 1H), 7.72 (d, J = 3.7 Hz, 2H), 7.21 (s, 1H), 7.16-7.10 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 5.23-5.11 (m, 1H), 4.03-3.89 (m, 1H), 3.36-3.24 (m, 1H), 3.18-2.72 (m, 6H), 2.20-2.02 (m, 3H), 1.89-1.68 (m, 6H), 1.48 (d, J = 6.7 Hz, 3H), 1.36 (t, J = 7.2 Hz, 1H). NH was exchanged.

[0549] Compound 59: General Scheme 1, Route B was used to provide N-(cyclobutylmethyl)-4,4-difluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine.

[0550] Step 1: General procedure C was used between IM112 and tert-butyl N-(4,4-difluoropiperidin-3-yl)carbamate to give tert-butyl N-[4,4-difluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]-3-piperidyl]carbamate IM184 as a dark yellow oil: 37 mg, 56% yield, P=95%, retention time=2.3 min (gradient A), (M+H). + :503.

[0551] Step 2: General procedure A1 was used from IM184 to give crude 4,4-difluoro-1-[6-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-yl]piperidin-3-amine dihydrochloride IM185 as a light brown solid: 42 mg, 100% yield, retention time = 1.8 min (gradient A), (M+H). + :403.

[0552] Step 3: Using general procedure H2 between cyclobutanecarboxaldehyde and IM185, crude compound 59 was obtained as a yellow solid: 23 mg, 100% yield, P=94%, retention time=2.0 min (gradient A), (M+H). + :471. 1 H NMR (300 MHz, CDCl): δ 8.54 (s, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.33 (d, J = 9.4 Hz, 1H), 6.96 (d, J = 9.4 Hz, 1H), 5.76 (s, 2H), 4.07-3.94 (m, J = 13.2 Hz, 2H), 3.91 (s, 3H), 3.66-3.45 (m, 2H), 2.90 (br s, 1H), 2.84-2.68 (m, 2H), 2.37 (hept, 1H), 2.30 (s, 1H), 2.00 (br s, 2H), 1.92-1.77 (m, 2H), 1.69-1.46 (m, 4H). NH was exchanged. 19 F NMR (282MHz, CDCl3): δ-99.42(dd,J=239.1,16.0Hz),-111.04(d,J=240.0Hz).

[0553] The racemic mixture was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 60 / 20 / 20 / 0.1% at a flow rate of 7 mL / min. First eluting enantiomer: P = 100%, retention time = 8.2 min, chiral HPLC: P = 94.7%. Second eluting enantiomer: P = 100%, retention time = 9.4 min, chiral HPLC: P = 100%.

[0554] Compound 60: General Scheme 2, Route B was used to provide N-[[5-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-2-pyridyl]methyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0555] Step 1: General procedure R was used from IM128 to give crude tert-butyl N-[(3R)-1-[6-(aminomethyl)-3-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM186 as an orange-yellow oil: 44 mg, 81% yield, P = 60%, retention time = 2.4 min (gradient A), (M+H). + :375.

[0556] Step 2: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM186, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-3-pyridyl]-3-piperidyl]carbamate IM187 was obtained as a colorless oil: 25 mg, 65% yield, P = 100%, retention time = 2.6 min (gradient A), (M+H). + :547.

[0557] Step 3: Compound 60 was obtained from IM187 using general procedure A1 as a white solid: 19 mg, 89% yield, P=96%, retention time=2.5 min (gradient B), (M+H) + :447. 1 H NMR (300MHz, CDCl3): δ9.06(d,J=7.2Hz,1H),8.18(d,J=2.8Hz,1H),7.99(ddd,J=8.5,6 .7,1.6Hz,1H),7.82(d,J=8.8Hz,1H),7.43-7.32(m,2H),7.28(d,J=8.8Hz,1H),7.08(br s, 1H), 4.62 (s, 2H), 3.72-3.64 (m, 1H), 3.55-4.46 (m, 1H), 2.95-2.77 (m, 1H), 2.77-2.64 (m, 4H), 2.48 (hept, J = 7.5 Hz, 1H), 2.18-1.59 (m, 9H), 1.43-1.27 (m, 1H), NH was exchanged.

[0558] Compound 61: General Scheme 2, Route B was used to provide N-[[6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-3-pyridyl]methyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0559] Step 1: General procedure L was used from IM120 to give crude tert-butyl N-[(3R)-1-[5-(aminomethyl)-2-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM188 as a yellow oil: 87 mg, 81% yield, P = 75%, retention time = 2.3 min (gradient A), (M+H). + :375.

[0560] Step 2: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM188, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[5-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-2-pyridyl]-3-piperidyl]carbamate IM189 was obtained as a colorless oil: 71 mg, 69% yield, P = 92%, retention time = 2.5 min (gradient A), (M+H). + :547.

[0561] Step 3: Compound 61 was obtained from IM189 using general procedure A1 as an off-white solid: 35 mg, 64% yield, P=97%, retention time=2.5 min (gradient B), (M+H). + :447. 1H NMR(300MHz,CD3OD)δ9.06(d,J=7.0Hz,1H),8.11(d,J=2.5Hz,1H),7.98(ddd,J=9.0,7.0,1.5Hz,1H),7.8 1(d,J=9.0Hz,1H),7.58(dd,J=8.9,2.5Hz,1H),7.39(td,J=7.0,1.3Hz,1H),7.08(s,1H),6.78(d,J=8.9H z, 1H), 4.47 (s, 2H), 4.24 (d, J = 12.1 Hz, 1H), 3.98 (d, J = 13.2 Hz, 1H), 3.02-2.86 (m, 1H), 2.82-2.66 (m, 3H), 2.67-2.52 (m, 1H), 2.47 (hept, J = 7.6 Hz, 1H), 2.15-1.49 (m, 9H), 1.46-1.26 (m, 1H). 2H was exchanged with CD3OD.

[0562] Compound 62: General Scheme 1, Route B was used to provide 5-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-2-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-one.

[0563] Step 1: Using general procedure B between IM44 and IM88, 5-chloro-2-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridazin-3-one IM190 was obtained as a white solid: 52 mg, 56% yield, P=93%, retention time=2.0 min (gradient A), (M+H). + :319 / 321.

[0564] Step 2: Using general procedure C between IM3 and IM190, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]-6-oxopyridazin-4-yl]-3-piperidyl]carbamate IM191 was obtained as a light brown solid: 60 mg, 69% yield, P=99%, retention time=2.6 min (gradient A), (M+H). + :551.

[0565] Step 3: Compound 62 was obtained from IM191 using general procedure A1 as a beige solid: 45 mg, 90% yield, P=96%, retention time=2.0 min (gradient A), (M+H) + :451. 1 H NMR(300MHz,CD3OD)δ8.59(d,J=1.6Hz,1H),8.59(s,1H),8.21(d,J=2.9Hz,1H),8.02(d,J=2 .9Hz,1H),7.84(dd,J=2.9,1.6Hz,1H),6.57(s,2H),5.89(d,J=2.9Hz,1H),3.94(s,3H),3.92 -3.82 (m, 1H), 3.82-3.71 (m, 1H), 3.13-2.98 (m, 1H), 2.91 (dd, J = 13.2, 9.3 Hz, 1H), 2.70-2.57 (m, 2H), 2.44 (hept, J = 7.1 Hz, 1H), 2.11-1.97 (m, 3H), 1.95-1.37 (m, 7H). 1H was exchanged with CD3OD.

[0566] Compound 63: General Scheme 1, Route B was used to provide 4-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-1-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridin-2-one.

[0567] Step 1: Using general procedure B between IM44 and IM84, 4-chloro-1-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]pyridin-2-one IM192 was obtained as a white solid: 300 mg, 97% yield, P=95%, retention time=2.1 min (gradient A), (M+H). + :318 / 320.

[0568] Step 2: Using general procedure C between IM3 and IM192, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM193 was obtained as a yellow oil: 105 mg, 81% yield, P = 100%, retention time = 2.6 min (gradient A), (M+H).+ :550.

[0569] Step 3: Compound 63 was obtained from IM193 using general procedure A1 as a white solid: 79 mg, 88% yield, P=96%, retention time=2.5 min (gradient B), (M+H) + :450.

[0570] 1 H NMR(300MHz,CD3OD)δ8.61(s,1H),8.60(d,J=1.7Hz,1H),8.21(d,J=2.7Hz,1H),7.87-7.81(m ,1H),7.68(d,J=7.9Hz,1H),6.43(s,2H),6.31(dd,J=7.9,2.8Hz,1H),5.67(d,J=2.8Hz,1H),3 0.94 (s, 3H), 3.92-3.84 (m, 1H), 3.81-3.71 (m, 1H), 3.05-2.93 (m, 1H), 2.82 (dd, J=13.1, 9.6Hz, 1H), 2.67 (d, J=7.3Hz, 2H), 2.64-2.51 (m, 1H), 2.45 (hept, J=7.6Hz, 1H), 2.17-1.26 (m, 10H). 1H was exchanged with CD3OD.

[0571] Compound 64: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[2,2,2-trifluoro-1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazin-3-yl]piperidin-3-amine.

[0572] Step 1: To a solution of 6-chloropyridazine-3-carbaldehyde (897 mg, 6.10 mmol) in anhydrous THF (17 mL) was added (trifluoromethyl)trimethylsilane (1.35 mL, 9.04 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and then TBAF (1 N in THF, 17 mL, 17 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water (40 mL) and extracted with DCM (3 × 35 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to give a black oil. The crude residue was purified by silica gel flash chromatography (n-heptane / EtOAc: 1 / 0 to 6 / 4) to give 1-(6-chloropyridazin-3-yl)-2,2,2-trifluoroethanol IM194 as an orange-yellow solid: 651 mg, 48% yield, P=95%, retention time=2.3 min (gradient A), (M+H). + :213 / 215.

[0573] Step 2: Using general procedure C between IM3 and IM194, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-(2,2,2-trifluoro-1-hydroxyethyl)pyridazin-3-yl]-3-piperidyl]carbamate IM195 was obtained as a beige foam: 397 mg, 98% yield, P = 98%, retention time = 2.6 min (gradient A), (M+H). + :445.

[0574] Step 3: General procedure P was used from IM195 to give crude [1-[6-[(3R)-3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]pyridazin-3-yl]-2,2,2-trifluoroethyl]methanesulfonate IM196 as an orange-yellow solid: 489 mg, 98% yield, P = 92% (215 nm), retention time = 2.9 min (gradient A).

[0575] Step 4: General procedure N was used from crude IM196 to give tert-butyl N-(3R)-1-[6-(1-azido-2,2,2-trifluoroethyl)pyridazin-3-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM197 as an orange-yellow sticky oil: 186 mg, 42% yield, P = 95%, retention time = 3.0 min (gradient A), (M+H). + :470.

[0576] Step 5: Using general procedure B between IM44 and IM197, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[2,2,2-trifluoro-1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazin-3-yl]-3-piperidyl]carbamate IM198 was obtained as a yellowish sticky oil: 78 mg, 70% yield, P=95%, retention time=2.8 min (gradient A), (M+H). + :603.

[0577] Step 6: From IM198 using general procedure A1 crude compound 64 was obtained as a yellow foam: 62 mg, 88% yield, P=88%, retention time=2.2 min (gradient A), (M+H) + :503.

[0578] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 35% to 50% solution "B" over 4.5 min, linear increase to 85% solution "B" over 1.7 min, hold at 85% solution "B" for 0.3 min, and return to initial conditions over 0.8 min. Flow rate: 15 mL / min. P = 100%.

[0579] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 10 × 250 mm). Eluent used: EtOAc / MeOH / DCM / DEA: 90 / 5 / 5 / 0.1% at a flow rate of 7 mL / min. First eluting diastereomer: P = 100%, retention time = 4.1 min. Chiral HPLC: P = 95.3%,1 H NMR(300MHz,CDCl3)δ8.65(d,J=1.7Hz,1H),8.55(s,1H),8.30(d,J=2.6Hz,1H),7.76(dd,J= 2.6,1.7Hz,1H),7.49(d,J=9.6Hz,1H),6.96(d,J=9.6Hz,1H),6.48(q,J=7.3Hz,1H),4.43-4 .35(m,1H),4.20-4.07(m,1H),3.93(s,3H),3.21-3.11(m,1H),2.99(dd,J=12.6,9.2Hz,1H) ,2.76-2.62(m,3H),2.57-2.35(m,1H),2.06(s,2H),1.95-1.80(m,3H),2.12-1.45(m,10H), 19 F NMR (282 MHz, CDCl3) δ -68.79 (d, J = 7.5 Hz). Second eluting diastereomer: P = 100%, retention time = 10.3 min. Chiral HPLC: P = 95.6%. 1 H NMR(300MHz,CDCl3)δ8.65(d,J=1.7Hz,1H),8.54(s,1H),8.30(d,J=2.6Hz,1H),7.76(dd,J=2.6 ,1.7Hz,1H),7.50(d,J=9.6Hz,1H),6.96(d,J=9.6Hz,1H),6.48(q,J=7.3Hz,1H),4.44-4.32(m, 1H), 4.19-4.09 (m, 1H), 3.93 (s, 3H), 3.24-3.13 (m, 1H), 3.09-2.95 (m, 1H), 2.78-2.62 (m, 3H), 2.44 (hept, J = 7.6 Hz, 1H), 2.11-1.99 (m, 2H), 1.95-1.81 (m, 2H), 1.69-1.40 (m, 6H), NH was exchanged. 19 F NMR (282MHz, CDCl3) δ-68.75(d,J=6.8Hz).

[0580] Compound 65: General Scheme 2, Route B was used to provide N-[1-[6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]pyridazin-3-yl]-2,2,2-trifluoroethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0581] Step 1: General procedure L was used from IM197 to give crude tert-butyl N-[(3R)-1-[6-(1-amino-2,2,2-trifluoroethyl)pyridazin-3-yl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM199 as a yellow sticky oil: 77 mg, 83% yield, P = 92%, retention time = 2.5 min (gradient A), (M+H). + :444.

[0582] Step 2: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM199, tert-butyl N-((cyclobutylmethyl)-N-[(3R)-1-[6-[2,2,2-trifluoro-1-[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]ethyl]pyridazin-3-yl]-3-piperidyl]carbamate IM200 was obtained as a yellow gum: 67 mg, 77% yield, P = 82%, retention time = 2.9 min (gradient A), (M+H). + :616.

[0583] Step 3: Using general procedure A1 from IM200, crude compound 65 was obtained as a yellow sticky oil: 64 mg, 100% yield, P=83%, retention time=2.3 min (gradient A), (M+H) + :516.

[0584] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 40 / 40 / 20 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 4.4 min. Chiral HPLC: P = 99.5%, 1H NMR(300MHz,CDCl3)δ9.46(d,J=9.4Hz,1H),9.09(d,J=7.1Hz,1H),7.89-7. 78(m,2H),7.33-7.18(m,2H),6.94(d,J=9.5Hz,1H),5.92(q,J=7.4Hz,1H),4 .45-4.37(m,1H),4.18-4.04(m,1H),3.20-3.06(m,1H),3.01-2.87(m,1H), 2.78-2.66(m,3H),2.62-2.36(m,2H),2.13-1.97(m,2H),1.96-1.36(m,8H), 19 F NMR (282 MHz, CDCl3) δ -71.13 (d, J = 7.0 Hz). Second eluting diastereomer: P = 100%, retention time = 5.3 min. Chiral HPLC: P = 100%, 1 H NMR(300MHz,CDCl3)δ9.47(d,J=9.3Hz,1H),9.10(d,J=7.1Hz,1H),7.90-7. 78(m,2H),7.33-7.18(m,2H),6.95(d,J=9.4Hz,1H),5.92(q,J=7.4Hz,1H),4 .46-4.47(m,1H),4.18-4.08(m,1H),3.22-3.80(m,1H),3.02-2.88(m,1H), 2.79-2.68(m,3H),2.58-2.36(m,2H),2.11-1.96(m,2H),1.95-1.39(m,8H), 19 F NMR (282MHz, CDCl3) δ-71.15(d,J=6.8Hz).

[0585] Compound 66: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazin-3-yl]piperidin-3-amine.

[0586] Step 1: Using general procedure B between IM106 and IM44, 3-chloro-6-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazine IM201 was obtained as a yellow oil: 123 mg, 81% yield, P = 100%, retention time = 2.1 min (gradient A), (M+H)+ :317 / 319.

[0587] Step 2: Using general procedure C between IM3 and IM201, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazin-3-yl]-3-piperidyl]carbamate IM202 was obtained as a yellowish solid: 115 mg, 52% yield, P=95%, retention time=3.5 min (gradient B), (M+H). + :549.

[0588] Step 3: Crude compound 66 was obtained from IM202 using general procedure A1 as a yellow sticky foam: 100 mg, 100% yield, P=96%, retention time=3.5 min (gradient B), (M+H) + :449.

[0589] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 40 / 40 / 25 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 99%, retention time = 4.5 min. Chiral HPLC: P = 99.2%, 1H NMR(300MHz,CDCl3)δ8.55(d,J=1.7Hz,1H),8.26(d,J=2.9Hz,1H),8.04(s,1H),7.73(br s, 1H), 7.23 (d, J = 9.6 Hz, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.04 (q, J = 7.1 Hz, 1H), 4.43-4.31 (m, 1H), 4.12-4.02 (m, 1H), 3.91 (s, 3H), 3.19-3.04 (m, 1H), 2.90 (dd, J = 12.8, 9.2 Hz, 1H), 2.80-2.59 (m, 3H), 2.59-2.34 (m, 2H), 2.11 (d, J = 7.2 Hz, 3H), 2.10-1.97 (m, 2H), 1.93-1.77 (m, 2H), 1.73-1.36 (m, 6H). The N-H bond was exchanged. Second eluting diastereomer: P = 99%, retention time = 14.7 min; Chiral HPLC: P = 99.4%, 1 H NMR(300MHz,CDCl3)δ8.55(s,1H),8.27(s,1H),8.04(s,1H),7.73(s,1H),7.23(d,J=9.4Hz ,1H),6.90(d,J=9.4Hz,1H),6.04(q,J=7.1Hz,1H),4.42-4.04(m,2H),4.13-4.03(m,1H),3 0.91(s,3H), 3.19-3.04(m,1H), 3.02-2.86(m,1h), 2.80-2.62(m,3H), 2.56-2.38(m,2H), 2.11(d,J=7.1Hz,3H), 2.06-1.96(m,2H), 1.88-1.74(m,2H), 1.71-1.52(m,6H), NH was exchanged.

[0590] Compound 67: General Scheme 1, Route B was used to provide 2-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-5-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]pyridazin-3-one.

[0591] Step 1: 5-Chloropyridazin-3(2H)-one was used to obtain 5-chloro-2-(1-chloroethyl)pyridazin-3-one IM203 as a yellow oil using general procedure O2: 0.96 g, 66% yield, P=100% (1 H-NMR), retention time = 2.6 min (gradient A), (M+H) + :193 / 195.

[0592] Step 2: 2-(1-azidoethyl)-5-chloropyridazin-3-one IM204 was obtained from IM203 using general procedure N as a yellow oil: 550 mg, 50% yield, P=97%, retention time=3.7 min (gradient B), (M+H) + :200 / 202.

[0593] Step 3: Using general procedure B between IM44 and IM204, 5-chloro-2-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridazin-3-one IM205 was obtained as an off-white solid: 150 mg, 66% yield, P=99%, retention time=2.1 min (gradient A), (M+H). + :333 / 335.

[0594] Step 4: Using general procedure C between IM3 and IM205, crude tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[1-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-6-oxopyridazin-4-yl]-3-piperidyl]carbamate IM206 was obtained as a yellowish solid: 201 mg, 81% yield, P=100%, retention time=3.5 min (gradient B), (M+H). + :565.

[0595] Step 5: From IM206, crude compound 57 was obtained using general procedure A1 as a yellow foam: 136 mg, 82% yield, P=99%, retention time=2.6 min (gradient B), (M+H) + :465.

[0596] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DCM / DEA: 40 / 40 / 25 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 4.6 min. Chiral HPLC: P = 100%, 1 H NMR(300MHz,CDCl3)δ8.56(d,J=1.3Hz,1H),8.26(d,J=2.8Hz,1H),8.15(s,1H),7.75(s,2H),7.58(q,J= 6.9Hz,1H),5.82(d,J=2.9Hz,1H),3.90(s,3H),3.76-3.67(m,1H),3.63-3.48(m,1H),3.06-2.91(m,1H), 2.80 (dd, J = 12.9, 9.1 Hz, 1H), 2.65 (d, J = 7.2 Hz, 2H), 2.63-2.55 (m, 1H), 2.38 (hept, J = 7.3 Hz, 1H), 2.15 (d, J = 6.9 Hz, 3H), 2.13-1.95 (m, 3H), 1.93-1.74 (m, 3H), 1.69-1.48 (m, 3H), 1.47-1.28 (m, 1H). NH was exchanged. Second-eluting diastereomer: P = 100%, retention time = 5.6 min. Chiral HPLC: P = 100%. 1 H NMR(300MHz,CDCl3)δ8.56(s,1H),8.25(d,J=2.7Hz,1H),8.15(s,1H),7.75(s,2H),7.58(q,J=6. 8Hz,1H),5.82(d,J=2.8Hz,1H),3.90(s,3H),3.76-3.64(m,1H),3.63-3.52(m,1H),3.05-2.92(m, 1H), 2.79 (dd, J = 12.9, 9.1 Hz, 1H), 2.64 (d, J = 7.1 Hz, 2H), 2.62-2.56 (m, 1H), 2.37 (hept, J = 7.5 Hz, 1H), 2.15 (d, J = 6.9 Hz, 3H), 2.08-1.74 (m, 6H), 1.70-1.54 (m, 3H), 1.53-1.29 (m, 1H). The NH was exchanged.

[0597] Compound 68: General Scheme 1, Route A was used to provide (3R)-N-(cyclobutylmethyl)-1-[4-[[4-(5-methoxy-3-pyridyl)triazol-1-yl]methyl]phenyl]piperidin-3-amine.

[0598] Step 1: Using general procedure S (using 1,4-dioxane instead of toluene) between IM3 and methyl 4-bromobenzoate, methyl 4-[(3R)-3-[tert-butoxycarbonyl(cyclobutylmethyl)amino]-1-piperidyl]benzoate IM207 was obtained as a colorless oil: 776 mg, 39% yield, P = 93% ( 1 H-NMR), retention time = 3.5 min (gradient A), (M+H)+: 403.

[0599] Step 2: Diisobutylaluminum hydride (1N in THF, 2.3 mL, 2.3 mmol) was added to a solution of IM207 (104 mg, 0.24 mmol) in anhydrous THF (2.3 mL) at −78° C., and the reaction mixture was stirred at room temperature. After 14 h, additional diisobutylaluminum hydride (1N in THF, 2.3 mL, 2.3 mmol) was added at −78° C., and the reaction mixture was stirred at room temperature for 4 h (complete conversion by HPLC-MS). The reaction mixture was then diluted with diethyl ether (10 mL), cooled to 0° C., and water (0.2 mL) was added, followed by 1N aqueous sodium hydroxide solution (0.2 mL) and water (0.5 mL). The mixture was stirred at room temperature for 15 min, MgSO4 was added, stirred for 15 min, and then filtered to remove salts, rinsed thoroughly with AcOEt (100 mL), and concentrated under reduced pressure. The crude product was purified on an automated flash system (liquid injection in DCM, 0–4% MeOH / DCM over 19 min, 30SIHP-4G, 10 mL / min) to give tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[4-(hydroxymethyl)phenyl]-3-piperidyl]carbamate IM208 as a colorless oil: 72 mg, 70% yield, P = 88% (215 nm), retention time = 2.5 min (gradient A), (M+H). + :375.

[0600] Step 3: Using general procedure M from IM208, tert-butyl N-[(3R)-1-[4-(azidomethyl)phenyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM209 was obtained as a white gum: 48 mg, 70% yield, P = 99% (215 nm), retention time = 2.9 min (gradient A), (M+H). + :400.

[0601] Step 5: Using general procedure B between IM44 and IM209, tert-butyl N-[(3R)-1-[4-(azidomethyl)phenyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM210 was obtained as a colorless oil: 61 mg, 88% yield, P = 91% ( 1 H-NMR), retention time = 2.6 min (gradient A), (M+H) + :533.

[0602] Step 6: Compound 68 was obtained from IM210 using general procedure A1 as a colorless oil: 44 mg, 96% yield, P=99%, retention time=2.9 min (gradient B), (M+H) + :433. 1 H NMR(300MHz,CD3OD)δ8.53(d,J=1.7Hz,1H),8.35(s,1H),8.15(d,J=2.8Hz,1H),7.76 (d,J=1.1Hz,1H),7.25(d,J=8.7Hz,2H),6.92(d,J=8.7Hz,2H),5.49(s,2H),3.88(s, 3H), 3.70-3.56 (m, 1H), 3.43 (d, J = 12.4 Hz, 1H), 2.84-2.53 (m, 5H), 2.45 (hept, J = 7.4 Hz, 1H), 2.15-2.00 (m, 2H), 2.00-1.52 (m, 7H), 1.39-1.16 (m, 1H), 1H was exchanged with CD3OD.

[0603] Compound 69: (3R)—N-(cyclobutylmethyl)-1-[6-[[5-(5-methoxy-3-pyridyl)-4H-1,2,4-triazol-3-yl]methyl]pyridazin-3-yl]piperidin-3-amine was obtained using the following procedure.

[0604] Step 1: Cesium carbonate (21.6 g, 65.8 mmol) was added to a solution of 3,6-dichloropyridazine (5.00 g, 32.9 mmol) and diethyl malonate (7.57 mL, 49.3 mmol) in DMSO (11 mL) at room temperature. The flask was equipped with a condenser, and the reaction mixture was stirred at 110 °C for 2.25 h. The reaction was then cooled to room temperature, poured into water (120 mL), and extracted with EtOAc (3 × 30 mL). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography on a 100 g cartridge eluting with a gradient of EtOAc / hexanes (0-30%) to give IM211 as an orange-yellow oil: 7.09 g, 73% yield, P = 92%, retention time = 0.9 min (gradient C), (M+H). + :273.

[0605] Step 2: IM211 (1.59 g, 5.36 mmol), NaCl (1.25 g, 21.5 mmol) were solubilized in DMSO (8.44 mL) and water (141 μL). The reaction mixture was heated at 150 °C for 2.75 h. The reaction was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (4 × 30 mL). The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography on a 35 g cartridge eluting with a gradient of EtOAc / hexanes (0-50%) to give ethyl 2-(6-chloropyridazin-3-yl)acetate IM212 as a beige solid: 953 mg, 81% yield, P = 92%, retention time = 0.8 min (gradient C), (M+H). + :201.

[0606] Step 3: Using general procedure C between IM3 and IM212, (R)-ethyl 2-(6-(3-((tert-butoxycarbonyl)(cyclobutylmethyl)amino)piperidin-1-yl)pyridazin-3-yl)acetate IM213 was obtained as a white solid: 153 mg, 46% yield, P=99%, retention time=1.7 min (gradient C), (M+H). + :433.

[0607] Step 4: Hydrazine hydrate solution (201 μL, 3.48 mmol) was added to a solution of IM213 (152 mg, 348 μmol) in EtOH (6.96 mL). The solution was stirred at room temperature for 2.25 h and then heated to reflux for 17 h. The reaction mixture was stirred at room temperature for 2 days and then heated to reflux again for 8 h. Additional hydrazine hydrate solution (401 μL, 6.96 mmol) was added and stirring at reflux was continued for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with DCM (25 mL), washed with water (10 mL), and concentrated in vacuo to give crude tert-butyl (R)-(cyclobutylmethyl)(1-(6-(2-hydrazinyl-2-oxoethyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM214 as an off-white solid: 148 mg, 99% yield, P=98%, retention time=1.3 min (gradient C), (M+H). + :419.

[0608] Step 5: IM214 (88 mg, 206 μmol) was dissolved in butan-1-ol (412 μL). 5-Methoxynicotinonitrile (83 mg, 618 μmol) and potassium carbonate (29 mg, 206 μmol) were added and the reaction mixture was stirred at 125° C. for 3 hours. The reaction was cooled to room temperature overnight and concentrated under reduced pressure. The residue was directly purified by reverse-phase chromatography on a 40 g C cartridge eluting with a gradient of MeCN / basic water (10 mM NHHCO / NHOH buffer (pH = 10)) to give tert-butyl (R)-(cyclobutylmethyl)(1-(6-((5-(5-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl)methyl)pyridazin-3-yl)piperidin-3-yl)carbamate IM215 as a beige solid: 95 mg, 78% yield, P = 90%, retention time = 1.4 min (gradient C), (M+H). + :535.

[0609] Step 6: Compound 69 was obtained from IM215 using general procedure A2 as a white solid: 27 mg, 37% yield, P=96%, retention time=1.8 min (gradient C), (M+H) + :435. 1H-NMR(400MHz,CD3OD):δ8.75(d,J=1.5Hz,1H),8.27(d,J=2.8Hz,1H),7.98-7.94(m,1H),7.43(d,J=9 .5Hz,1H),7.27(d,J=9.5Hz,1H),4.45-4.38(m,1H),4.37(s,2H),4.12-4.04(m,1H),3.94(s,3H),3.12 -3.04 (m, 1H), 2.94 (dd, J = 12.8, 9.5 Hz, 1H), 2.79-2.68 (m, 3H), 2.50 (sept, J = 7.6 Hz, 1H), 2.15-2.05 (m, 3H), 1.98-1.79 (m, 3H), 1.77-1.68 (m, 2H), 1.65-1.54 (m, 1H), 1.52-1.41 (m, 1H). 2H was exchanged with CD3OD.

[0610] Compound 70: General Scheme 2, Route B was used to provide N-[[4-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]phenyl]methyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0611] Step 1: Using general procedure R from IM209, tert-butyl N-[(3R)-1-[4-(aminomethyl)phenyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM216 was obtained as a colorless oil: 56 mg, 36% yield, P = 87%, retention time = 2.4 min (gradient A), (M+H). + :374.

[0612] Step 2: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM216, tert-butyl N-((cyclobutylmethyl)-N-[(3R)-1-[4-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]phenyl]-3-piperidyl]carbamate IM217 was obtained as a yellowish gum: 51 mg, 64% yield, P = 94%, retention time = 2.6 min (gradient A), (M+H). + :546.

[0613] Step 3: From IM217, crude compound 70 was obtained using general procedure A1 as a yellow oil: 48 mg, 100% yield, P=97%, retention time=2.9 min (gradient B), (M+H) + :446.

[0614] The product was further purified by reverse-phase preparative HPLC purification (Waters XBridge C18, 5 μm, 19 × 100 mm). The gradient used was: linear increase from 25% to 40% solution "B" over 5.0 min, linear increase to 85% solution "B" over 1.0 min, hold at 85% solution "B" for 0.4 min, and return to initial conditions over 0.8 min. Flow rate: 15 mL / min. P = 100%. 1 H NMR (300 MHz, CDCl) δ 9.08 (d, J = 7.3 Hz, 1H), 8.18 (s, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.35-7.11 (m, 4H), 6.93 (d, J = 8.4 Hz, 2H), 4.58 (d, J = 6.0 Hz, 2H), 3.67-3.55 (m, 1H), 3.49-3.35 (m, 1H), 2.89-2.56 (m, 5H), 2.48 (hept, J = 7.6 Hz, 1H), 2.13-1.18 (m, 10H). The NH was exchanged.

[0615] Compound 71: General Scheme 1, Route B was used to provide (3R)—N-(cyclobutylmethyl)-1-[5-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-2-pyridyl]piperidin-3-amine.

[0616] Step 1: 1-(6-chloro-3-pyridyl)ethanone (1 g, 6.3 mmol) was dissolved in anhydrous methanol (60 mL) at 0 °C. Sodium borohydride (240 mg, 6.34 mmol) was then added in one portion. The reaction was stirred at 0 °C for 20 min. Acetone (3 mL) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 min and then at room temperature for 2 min. The mixture was concentrated to dryness under reduced pressure. EtOAc (50 mL) was added to the residue, and the resulting solution was washed with brine (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give crude 1-(6-chloro-3-pyridyl)ethanol IM218 as an orange-yellow oil: 1.0 g, 93% yield, P = 95%, retention time = 2.1 min (gradient A), (M+H). + :158 / 160.

[0617] Step 2: General procedure P was used from IM218 to give crude 1-(6-chloro-3-pyridyl)ethyl methanesulfonate IM219 as a yellow oil: 650 mg, 87% yield, P=87%( 1 H-NMR), retention time = 2.5 min (gradient A), (M+H) + :236 / 238.

[0618] Step 3: Using general procedure N from IM219, 2 5-(1-azidoethyl)-2-chloropyridine IM220 was obtained as a yellow oil: 380 mg, 96% yield, P=86%, retention time=2.7 min (gradient A), (M+H) + :182 / 184.

[0619] Step 4: Using general procedure B between IM44 and IM220, 2-chloro-5-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]pyridine IM221 was obtained as a yellow oil: 103 mg, 60% yield, P=100%, retention time=2.2 min (gradient A), (M+H). + :316 / 318.

[0620] Step 5: Using general procedure C between IM3 and IM221, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[5-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-2-pyridyl]-3-piperidyl]carbamate IM222 was obtained as a colorless oil: 30 mg, 15% yield, P=90%, retention time=2.4 min (gradient A), (M+H). + :548.

[0621] Step 6: Crude compound 71 was obtained from IM222 using general procedure A1 as a light brown film: 21 mg, 71% yield, P=93%, retention time=2.5 min (gradient B), (M+H) + :448.

[0622] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DEA: 70 / 30 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 6.7 min. Chiral HPLC: P = 100%, 1 H NMR(300MHz,CDCl3)δ8.48(s,1H),8.23(dd,J=15.5,2.6Hz,2H),7.75(s,1H),7.68(s,1H) ,7.42(dd,J=8.9,2.6Hz,1H),6.65(d,J=8.9Hz,1H),5.76(q,J=7.1Hz,1H),4.29-4.19(m,1 1H), 4.07-3.97 (m, 1H), 3.90 (s, 3H), 2.99 (td, J = 12.1, 3.1 Hz, 1H), 2.86-2.56 (m, 4H), 2.43 (hept, J = 7.6 Hz, 1H), 2.14-1.75 (m, 9H), 1.75-1.47 (m, 3H), 1.44-1.32 (m, 1H). The NH was exchanged. The second eluting diastereomer: P = 100%, retention time = 8.4 min. Chiral HPLC: P = 99.5%. 1H NMR(300MHz,CDCl3)δ8.48(d,J=1.6Hz,1H),8.22(dd,J=15.6,2.7Hz,2H),7.75(t,J=2.2Hz, 1H),7.68(s,1H),7.42(dd,J=8.8,2.6Hz,1H),6.65(d,J=8.9Hz,1H),5.76(q,J=7.0Hz,1H),4 .31-4.18(m,1H), 4.07-3.96(m,1H), 3.90(s,3H), 3.07-2.92(m,1H), 2.87-2.56(m,4H), 2.44(hept,J=7.6Hz,1H), 2.13-1.72(m,7H), 1.71-1.44(m,5H), 1.46-1.23(m,1H), NH was exchanged.

[0623] Compound 72: General Scheme 2, Route B was used to provide N-[1-[6-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-3-pyridyl]ethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide.

[0624] Step 1: General procedure C was used between IM3 and 1-(6-chloro-3-pyridyl)ethanone to give tert-butyl N-[(3R)-1-(5-acetyl-2-pyridyl)-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM223 as a colorless oil: 613 mg, 80% yield, P = 95%, retention time = 2.8 min (gradient A), (M+H). + :388.

[0625] Step 2: General procedure H1 was used between ammonia (7N in methanol) and IM224 to give crude tert-butyl N-[(3R)-1-[5-(1-aminoethyl)-2-pyridyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate as a colorless oil: 250 mg, 67% yield, P=85%, retention time=2.3 min (gradient A), (M+H). + :389.

[0626] Step 3: Using general procedure F between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and IM224, tert-butyl N-((cyclobutylmethyl)-N-[(3R)-1-[5-[1-[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]ethyl]-2-pyridyl]-3-piperidyl]carbamate IM225 was obtained as a white foam: 113 mg, 66% yield, P = 97%, retention time = 2.5 min (gradient A), (M+H). + :561.

[0627] Step 4: Using general procedure A1 from IM225, crude compound 72 was obtained as an off-white solid: 75 mg, 77% yield, P=95%, retention time=2.6 min (gradient B), (M+H). + :461.

[0628] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: TBME / MeOH / DEA: 70 / 30 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 6.8 min. Chiral HPLC: P = 98.9%, 1H NMR(300MHz,CDCl3)δ9.07(d,J=7.2Hz,1H),8.24(d,J=2.5Hz,1H),8.11(d,J=8.2Hz,1H),7.78(ddd,J=8.2,6 .8,1.6Hz,1H),7.65(d,J=9.0Hz,1H),7.50(dd,J=8.8,2.5Hz,1H),7.28(s,1H),7.18(td,J=6.8,1.5Hz,1H), 6.65 (d, J = 8.8 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 4.30-4.18 (m, 1H), 4.06-3.93 (m, 1H), 2.96 (ddd, J = 13.3, 10.8, 3.2 Hz, 1H), 2.83-2.66 (m, 3H), 2.67-2.56 (m, 1H), 2.45 (hept, J = 7.6 Hz, 1H), 2.12-1.23 (m, 13H). The NH was exchanged. The second eluting diastereomer: P = 100%, retention time = 8.5 min. Chiral HPLC: P = 98.6%. 1 H NMR(300MHz,CDCl3)δ9.07(d,J=7.2Hz,1H),8.24(d,J=2.3Hz,1H),8.11(d,J=8.3Hz,1H),7.83-7 .72(m,1H),7.65(d,J=8.9Hz,1H),7.50(dd,J=8.8,2.3Hz,1H),7.31-7.23(m,1H),7.18(t,J=6.9 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 5.22 (p, J = 7.1 Hz, 1H), 4.28-4.17 (m, 1H), 4.00 (d, J = 13.1 Hz, 1H), 3.04-2.89 (m, 1H), 2.84-2.58 (m, 4H), 2.45 (hept, J = 7.5 Hz, 1H), 2.11-1.23 (m, 13H), NH was exchanged.

[0629] Compound 73: General Scheme 1, Route B was used to provide (3R)—N-(cyclobutylmethyl)-1-[6-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-3-pyridyl]piperidin-3-amine.

[0630] Step 1: 1-(5-Bromo-2-pyridyl)ethanol IM226 was obtained from 5-bromopyridine-2-carboxaldehyde using general procedure Q as a yellow oil: 208 mg, 86% yield, P = 95%, retention time = 2.0 min (gradient A), (M+H) + :202 / 204.

[0631] Step 2: General procedure P was used from IM226 to give crude 1-(5-bromo-2-pyridyl)ethyl methanesulfonate IM230 as a yellow oil: 250 mg, 96% yield, P = 100%, retention time = 2.5 min (gradient A), (M+H). + :280 / 282.

[0632] Step 3: General procedure N was used from IM230 to give crude 2-(1-azidoethyl)-5-bromopyridine IM231 as a yellow oil: 205 mg, 94% yield, P=95%, retention time=2.7 min (gradient A), (M+H). + :227 / 229.

[0633] Step 4: Using general procedure B between IM44 and IM231, 3-[1-[1-(5-bromo-2-pyridyl)ethyl]triazol-4-yl]-5-methoxypyridine IM232 was obtained as a yellow oil: 150 mg, 47% yield, P=100%, retention time=2.3 min (gradient A), (M+H). + :360 / 362.

[0634] Step 5: Using general procedure S between IM3 and IM232, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[6-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]-3-pyridyl]-3-piperidyl]carbamate IM233 was obtained as a colorless oil: 128 mg, 65% yield, P=88%, retention time=2.6 min (gradient A), (M+H)+: 548.

[0635] Step 6: From IM233, crude compound 73 was obtained using general procedure A1 as a colorless oil: 100 mg, 98% yield, P=90%, retention time=2.0 min (gradient A), (M+H). + :448.

[0636] The mixture of diastereomers was further purified by chiral preparative HPLC purification using a Chiralpak IA column (5 μm, 20 × 250 mm). Eluent used: EtOAc / MeOH / DEA: 95 / 5 / 0.1% at a flow rate of 20 mL / min. First eluting diastereomer: P = 100%, retention time = 5.6 min. Chiral HPLC: P = 99.8%, 1 H NMR(300MHz,CDCl3)δ8.53(s,1H),8.32-8.22(m,2H),8.00(s,1H),7.79-7.75(m,1H),7. 15(s,2H),5.92(q,J=7.0Hz,1H),3.90(d,J=1.5Hz,3H),3.65(d,J=9.2Hz,1H),3.48(d,J = 12.2 Hz, 1H), 2.87 (t, J = 10.4 Hz, 1H), 2.69 (t, J = 6.5 Hz, 4H), 2.44 (p, J = 7.6 Hz, 1H), 2.11-1.96 (m, 6H), 1.96-1.76 (m, 4H), 1.66 (d, J = 9.5 Hz, 3H), 1.37-1.24 (m, 1H). The NH was exchanged. The second eluting diastereomer: P = 100%, retention time = 9.0 min. Chiral HPLC: P = 99.8%. 1 H NMR (300 MHz, CDCl) δ 8.53 (s, 1H), 8.31–8.15 (m, 2H), 8.00 (s, 1H), 7.76 (s, 1H), 7.14 (s, 2H), 5.95–5.82 (m, 1H), 3.89 (s, 3H), 3.69–3.60 (m, 1H), 3.53–3.43 (m, 1H), 2.93–2.79 (m, 1H), 2.74–2.60 (m, 4H), 2.43 (hept, J = 7.6 Hz, 1H), 2.12–1.75 (m, 9H), 1.66–1.50 (m, 3H), 1.37–1.23 (m, 1H). NH was exchanged.

[0637] Compound 74: General Scheme 2, Route A was employed to provide N-((S)-1-(4-((R)-3-((cyclobutylmethyl)amino)piperidin-1-yl)phenyl)ethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide.

[0638] Step 1: General procedure F was used between 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid hydrochloride and (S)-(−)-1-(4-bromophenyl)ethylamine to give crude N-[(1S)-1-(4-bromophenyl)ethyl]-4-oxopyrido[1,2-a]pyrimidine-2-carboxamide IM234 as a yellow oil: 240 mg, 93% yield, P=100%, retention time=2.8 min (gradient A), (M+H) + :372 / 374.

[0639] Step 2: Using general procedure S between IM3 and IM234, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[4-[(1S)-1-[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]ethyl]phenyl]-3-piperidyl]carbamate IM235 was obtained as a colorless oil: 150 mg, 42% yield, P = 100%, retention time = 2.6 min (gradient A), (M+H). + :560.

[0640] Step 3: Using general procedure A1 from IM235, crude compound 74 was obtained as an off-white solid: 120 mg, 92% yield, P=98%, retention time=3.3 min (gradient B), (M+H). + :460. 1H NMR(300MHz,CDCl3)δ9.07(d,J=7.0Hz,1H),8.14(d,J=8.4Hz,1H),7.77(ddd,J=8.4,7.0,1.6Hz,1H),7 .65(d,J=8.9Hz,1H),7.32-7.27(m,2H),7.17(t,J=7.0Hz,1H),6.92(d,J=8.4Hz,2H),5.32-5.14(m,1H ), 3.68-3.54 (m, 1H), 3.48-3.38 (m, 1H), 2.87-2.68 (m, 4H), 2.61 (dd, J = 11.5, 8.8 Hz, 1H), 2.45 (hept, J = 7.6 Hz, 1H), 2.14-1.98 (m, 2H), 1.96-1.75 (m, 5H), 1.71-1.56 (m, 5H), 1.36-1.21 (m, 1H). NH was exchanged. Chiral HPLC (IA, TBME / MEOH / DEA: 70 / 30 / 0.1%, flow rate: 1 mL / min): P = 99.0%.

[0641] Compound 75: 4-[(3R)-3-(cyclobutylmethylamino)-1-piperidyl]-1-[[1-(5-methoxy-3-pyridyl)triazol-4-yl]methyl]pyridin-2-one was obtained using the following procedure.

[0642] Step 1: Sodium azide (100 mg, 1.52 mmol) and copper(II) sulfate pentahydrate (32 mg, 0.13 mmol) were placed in a round-bottom flask. Anhydrous methanol (2.5 mL) and 5-methoxypyridine-3-boronic acid (200 mg, 1.27 mmol) were added at room temperature. The mixture was stirred at room temperature for 40 h. The mixture was concentrated under reduced pressure. Diethyl ether (20 mL) was added to the resulting solid, and the suspension was sonicated (2 min), filtered through Celite, and rinsed with diethyl ether (30 mL). The filtrate was dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give crude IM236 as a yellow liquid: 28 mg, 12% yield, P = 98%, retention time = 1.4 min (gradient A), (M+H). + :151.

[0643] Step 2: A solution of propargyl bromide in toluene (375 μL, 3.37 mmol) was added to a solution of 4-chloro-2-hydroxypyridine (300 mg, 2.25 mmol) and potassium carbonate (630 mg, 4.51 mmol) in dry DME (4.5 mL). The mixture was stirred at 60° C. for 4 h, then allowed to cool to room temperature and stirred at room temperature overnight. The suspension was filtered, and the solid was rinsed with DCM (20 mL). The filtrate was concentrated to dryness under reduced pressure. The resulting oil was solubilized in DCM (40 mL), washed with water (30 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give crude IM237 as a brown oil: 356 mg, 95% yield, P=100%, retention time=2.2 min (gradient A), (M+H). + :168 / 170.

[0644] Step 3: Using general procedure B between IM236 and IM237, 4-chloro-1-[[1-(5-methoxy-3-pyridyl)triazol-4-yl]methyl]pyridin-2-one IM238 was obtained as a white solid: 15 mg, 29% yield, P=94%, retention time=2.3 min (gradient A), (M+H). + :318 / 320.

[0645] Step 4: Using general procedure C between IM3 and IM238, tert-butyl N-[(3R)-1-[1-[[1-(5-methoxy-3-pyridyl)triazol-4-yl]methyl]-2-oxo-4-pyridyl]-3-piperidyl]carbamate IM239 was obtained as a yellow sticky oil: 22 mg, 83% yield, P = 99%, retention time = 2.8 min (gradient A), (M+H). + :550.

[0646] Step 5: Compound 75 was obtained from IM239 using general procedure A1 as a beige solid: 15 mg, 91% yield, P=100%, retention time=2.8 min (gradient B), (M+H) + :450. 1H NMR(300MHz,CDCl3)δ8.65(d,J=2.1Hz,1H),8.55(s,1H),8.36(d,J=2.6Hz,1H),7.87(t,J=2.3Hz,1H),7.59(d, J=7.8Hz,1H),6.27(dd,J=7.8,2.8Hz,1H),5.73(d,J=2.8Hz,1H),5.22(s,2H),3.97(s,3H),3.94-3.84(m,1H), 3.79-3.69 (m, 1H), 3.05-2.90 (m, 1H), 2.83 (dd, J = 13.0, 9.6 Hz, 1H), 2.76-2.71 (m, 2H), 2.71-2.62 (m, 1H), 2.49 (hept, J = 7.6 Hz, 1H), 2.18-2.00 (m, 4H), 1.98-1.84 (m, 2H), 1.81-1.66 (m, 3H), 1.62-1.42 (m, 1H). The NH was exchanged.

[0647] Compound 76: General Scheme 1, Route A was used to provide (3R)—N-(cyclobutylmethyl)-1-[4-[1-[4-(5-methoxy-3-pyridyl)triazol-1-yl]ethyl]phenyl]piperidin-3-amine.

[0648] Step 1: Using general procedure S between IM3 and 4-bromobenzaldehyde, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-(4-formylphenyl)-3-piperidyl]carbamate IM240 was obtained as a yellowish oil: 170 mg, 28% yield, P = 98% (215 nm), retention time = 3.3 min (gradient A), (M+H). + :373.

[0649] Step 2: Using general procedure Q (replacing MeMgBr with MeMgCl) from IM240, tert-butyl N-(cyclobutylmethyl)-N-[(3R)-1-[4-(1-hydroxyethyl)phenyl]-3-piperidyl]carbamate IM241 was obtained as a colorless oil: 177 mg, 96% yield, P=94% ( 1 H-NMR), retention time = 2.5 min (gradient A), (M+H) + :389.

[0650] Step 3: Using general procedure M from IM241, tert-butyl N-[(3R)-1-[4-(1-azidoethyl)phenyl]-3-piperidyl]-N-(cyclobutylmethyl)carbamate IM242 w...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt and / or solvate thereof (In the formula, R １ is C ２～１２ Alkyl, C ２～１２ Haloalkyl, C ３～８ Cycloalkyl-C １～３ Alkyl, heterocyclyl-C １～３ Alkyl, C ３～８ is cycloalkyl or heterocyclyl, wherein the cycloalkyl and heterocyclyl moieties are C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy and C １～４ optionally substituted with one or more substituents selected from haloalkoxy; and / or said cycloalkyl and heterocyclyl moieties are C ３～６ Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy and C １～４ haloalkoxy; and / or said cycloalkyl and heterocyclyl moieties are optionally bridged ring systems; R ２ is H, or halo, cyano, hydroxy, C １～４ Alkoxy and C １～４ C optionally substituted with one or more substituents selected from haloalkoxy １～４ Alkyl, or C ３～６ is cycloalkyl, or Or R １ and R ２ form a heterocyclic ring together with the nitrogen atom to which they are attached, wherein the heterocycle is C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy and C １～４ optionally substituted with one or more substituents selected from haloalkoxy; and / or the heterocycle is C ３～６ Optionally spiro-fused to a cycloalkyl or heterocyclyl ring, the spiro ring being C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy and C １～４ haloalkoxy; and / or said heterocyclyl ring is optionally a bridged ring system; Each R ３ is independently C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy, C １～４ haloalkoxy, oxo, or thioxo; Two R groups present on the same carbon atom ３ The groups are spiro-fused together with the carbon atoms to which they are attached. ３～６ forming a cycloalkyl, or Two R groups on two adjacent carbon atoms ３ The groups, together with the carbon atoms to which they are attached, form fused C ３～６ forming a cycloalkyl, or Two R groups present on two non-adjacent carbon atoms ３ The group is bonded to C １～４ It forms an alkyl bridge, m is 0, 1, 2, 3 or 4; n is 1 or 2; R ４ and R ５ are each independently H, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ cycloalkyl, halo, cyano, or hydroxy; R ４ and R ５ together with the carbon atoms to which they are attached form a heterocyclyl ring or C ３～４ forming a cycloalkyl ring, wherein the heterocyclyl and cycloalkyl moieties are C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ optionally substituted with one or more substituents selected from haloalkyl, halo, or cyano; R ４ and R ５ together with the carbon atom to which they are attached form an ethylenyl, Ar １ Is (Ar １ａ ), (Ar １ｂ ) and (Ar １ｃ ): 【Chemistry 2】 an aryl or heteroaryl group selected from During the ceremony, p is 0, 1, 2, 3 or 4; R ６ is C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ haloalkyl, halo, or cyano; Each X is independently N, NR ７ , C.R. ８ , C(O) and C(S), wherein at least one of X is N or NR ７ and R ７ is H, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ is haloalkyl, R ８ is H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, Each Y is independently N, NR ９ ,S,O,C,CR １０ , C(O) and C(S), wherein at least one of Y is N, NR ９ , S or O; R ９ is H, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ is haloalkyl, R １０ is H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, 【Transformation 3】 represents a single or double bond depending on X or Y, * represents the point of attachment to the piperidine ring, and ** is -CR ４ R ５ represents the point of attachment to the - moiety, L is (L １ ), (L ２ ) and 5-membered heteroaryl (L ３ ): 【Chemistry 4】 is selected from During the ceremony, X １ is O or S, preferably X １ is O, Each Z is independently N, NR １１ ,S,O,C,CR １２ , C(O) and C(S), wherein at least one of Z is N, NR １１ , S or O; R １１ is H, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ is haloalkyl, R １２ is H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, 【Transformation 5】 represents a single or double bond depending on Z, ●Ha-CR ４ R ５ represents the point of attachment to the - moiety, and ●● is Ar ２ represents the point of attachment to Ar ２ is preferably halo, cyano, oxo, hydroxy, amino, C １～４ Alkylamino, C １～４ Haloalkylamino, di(C １～４ alkyl)amino, di(C １～４ haloalkyl)amino, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)amino, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～６ cycloalkyloxy, (C １～４ alkyl)aminocarbonyl, (C １～４ haloalkyl)aminocarbonyl, di(C １～４ alkyl)aminocarbonyl, di(C １～４ haloalkyl)aminocarbonyl, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)aminocarbonyl, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C ２～４ Alkynyl, C ６～１０ a 5-10 membered mono- or bicycloaryl or heteroaryl group optionally substituted with one or more substituents selected from aryl, heteroaryl and heterocyclyl, wherein said substituents are preferably halo, cyano, oxo, hydroxy, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, Amino, C １～４ Alkylamino, C １～４ Haloalkylamino, di(C １～４ alkyl)amino, di(C １～４ haloalkyl)amino, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)amino, or one or more C ３～６ A cycloalkyl or heterocyclyl group may be fused to said heterocyclyl substituent, or may be one or more C optionally substituted with one or more halo. ３～６ The cycloalkyl or heterocyclyl group may be spiro-fused to said heterocyclyl substituent.

2. -NR １ R ２ teeth, 【Transformation 6】 is selected from During the ceremony, 【Transformation 7】 represents the point of attachment to the remainder of the compound.

3. Ar １ teeth, 【Transformation 8】 is selected from During the ceremony, R ７ is H, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ haloalkyl, preferably R ７ is H, R ８ is H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, preferably R ８ is H, methyl, halo, more preferably R ８ is H, R １０ is H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, preferably R １０ is H, * represents the point of attachment to the piperidine ring, and ** is -CR ４ R ５ 3. The compound of claim 1 or claim 2, wherein - represents a point of attachment to a moiety.

4. L is, 【Chemistry 9】 is selected from During the ceremony, Each R １１ are independently H, C １～４ Alkyl, C ３～６ Cycloalkyl or C １～４ haloalkyl, preferably R １１ is H or methyl, more preferably R １１ is H, Each R １２ are independently H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Haloalkyl, halo, cyano, hydroxy, C １～４ Alkoxy or C １～４ haloalkoxy, preferably R １２ is H, methyl, halo, cyano or methoxy, more preferably R １２ is H, ●Ha-CR ４ R ５ represents the point of attachment to the - moiety, and ●● is Ar ２ A compound according to any one of claims 1 to 3, wherein the compound represents a point of attachment to

5. Ar ２ teeth, 【Chemistry 10】 is selected from During the ceremony, R １３ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , R ２０ and R ２１ are each independently H, halo, cyano, oxo, hydroxy, amino, C １～４ Alkylamino, C １～４ Haloalkylamino, di(C １～４ alkyl)amino, di(C １～４ haloalkyl)amino, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)amino, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～６ cycloalkyloxy, (C １～４ alkyl)aminocarbonyl, (C １～４ haloalkyl)aminocarbonyl, di(C １～４ alkyl)aminocarbonyl, di(C １～４ haloalkyl)aminocarbonyl, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)aminocarbonyl, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C ２～４ Alkynyl, C ６～１０ aryl, heteroaryl and heterocyclyl, where these substituents are preferably halo, cyano, oxo, hydroxy, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, Amino, C １～４ Alkylamino, C １～４ Haloalkylamino, di(C １～４ alkyl)amino, di(C １～４ haloalkyl)amino, N—(C １～４ alkyl)-N-(C １～４ haloalkyl)amino, or one or more C ３～６ A cycloalkyl or heterocyclyl group may be fused to said heterocyclyl substituent, or may be one or more C optionally substituted with one or more halo. ３～６ a cycloalkyl or heterocyclyl group may be spiro-fused to said heterocyclyl substituent; and 【Chemistry 11】 The compound of any one of claims 1 to 4, wherein represents the point of attachment to the remainder of the compound.

6. The compound according to any one of claims 1 to 5, wherein n is 1.

7. Compound of formula (I-2): 【Chemistry 12】 or a pharmaceutically acceptable salt and / or solvate thereof, wherein R １ , R ２ , R ３ , R ４ , R ５ , m, n, Ar １ and Ar ２ A compound according to any one of claims 1 to 6, wherein is as defined in any of the preceding claims.

8. Compound of formula (I-3): 【Chemistry 13】 or a pharmaceutically acceptable salt and / or solvate thereof, wherein R １ , R ２ , R ３ , R ４ , R ５ , m, n, L ３ , Ar １ and Ar ２ is as defined in any preceding claim, and L ３ is preferably 【Chemistry 14】 wherein ● is selected from -CR ４ R ５ represents the point of attachment to the - moiety, and ●● represents Ar ２ A compound according to any one of claims 1 to 6, wherein the compound represents a point of attachment to

9. below: Table 1 and pharmaceutically acceptable salts and solvates thereof.

10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt and / or solvate thereof and at least one pharmaceutically acceptable carrier.

11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt and / or solvate thereof for use as a medicine.

12. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of a proliferative disease, preferably cancer.

13. 13. The compound for use according to claim 12, wherein the cancer is selected from acute lymphocytic leukemia, acute myeloid leukemia (AML), chronic myeloid leukemia, leukemia, lymphoma, multiple myeloma, non-Hodgkin's lymphoma (NHL), bladder cancer, bone cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal / upper gastrointestinal cancer, glioblastoma, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), head and neck cancer, oral squamous cell carcinoma, melanoma, mesothelioma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, and thyroid cancer.

14. 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of an autoimmune disease, a neurological disease, an inflammatory disease, or an infectious disease.

15. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt and / or solvate thereof for use in inhibiting METTL3 activity.

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