Piperidine derivatives as nicotinamide n-methyltransferase inhibitors

Abstract

Disclosed are certain piperidine derivatives of Formula (I) and pharmaceutically acceptable salts thereof, as well as compositions containing them and their use in therapy. These compounds are inhibitors of nicotinamide N-methyltransferase (NNMT) and are therefore particularly suitable for the treatment or prevention of, for example, chronic kidney disease, acute kidney injury or heart failure.

Description

Technical Field

[0001] This technical field relates to certain piperidine derivatives of formula (I) and their use in the treatment of nicotinamide N-methyltransferase-related diseases or conditions, such as chronic kidney disease, acute kidney injury, or heart failure. Background Technology

[0002] Nicotinamide N-methyltransferase (NNMT) is a cytoplasmic methyltransferase expressed in many tissues, with the highest expression in the liver, adipose tissue, and blood vessels. Expression is very low in healthy kidney tissue but significantly increased in chronic kidney disease (CKD).

[0003] NNMT catalyzes the transfer of methyl groups from S-adenosyl-L-methionine (SAM) to nicotinamide, producing 1-methylnicotinamide (1-MNA) and S-adenosyl-L-homocysteine ​​(SAH), which can be further metabolized to homocysteine. Nicotinamide is metabolized to 1-MNA via NNMT, and further metabolized by aldehyde oxidase to N-methyl-2-pyridone-5-carboxamide (N-Me-2Py) and N-methyl-4-pyridone-3-carboxamide (N-Me-4Py) before being excreted (Trends Endocrinol Metab., 2017, 28(5), 340-353). N-Me-2Py has been reported as a uremic toxin (Toxins 2016, 8, 339). High NNMT activity can prevent nicotinamide from entering NAD+. + Rescue pathways to affect nicotinamide adenine dinucleotide (NAD) + Cellular homeostasis (Int JMol Sci., 2023, 24, 137).

[0004] The heart and kidneys are among the body's most energy-intensive organs. The renal tubules require a large amount of ATP to support solute transport. NAD + NADH is essential for glucose metabolism, pyruvate metabolism, and fatty acid metabolism to produce acetyl-CoA, and is also essential for acetyl-CoA metabolism in the Krebs cycle. The NADH produced in these processes is then used for ATP production in the electron transport chain. + Also NAD + Dependent enzymes: important cofactors of deacetylase, PARP and CD38 (Mol.Sci., 2023, 24, 137).

[0005] Increased NNMT activity in cells can also alter the SAM / SAH ratio, thereby affecting other SAM-dependent methyltransferases and potentially leading to epigenetic changes. High NNMT activity also results in increased homocysteine ​​production (Atherosclerosis, 2009, 204(2), 412-7).

[0006] Transcriptomic analysis has demonstrated that NNMT is highly increased in human CKD of various etiologies, including diabetic nephropathy (DKD), and its expression is highest in the tubulointerstitial compartment, particularly in proximal tubular cells (Int. J. Gen. Med., 2023, 3331-3344). Sci. Rep., 2022, 12, 6398 also reported that NNMT is localized in atrophic tubular cells in fibrotic lesions of human CKD.

[0007] In serum from CKD patients, N-Me-2Py and N-Me-4Py increased with increasing CKD stage, while nicotinamide decreased (Sci. Rep., 2022, 12, 6398). Doke, T et al. (Nat. Metab., 2023, Mar. 5, 414-430) reported reduced nicotinamide and NAD in renal biopsies from CKD patients. + level.

[0008] The current standard of care for chronic kidney disease (CKD) is the treatment of renin-angiotensin-aldosterone system (RAAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), as well as more recently, sodium / glucose cotransporter 2 (SGLT2) inhibitors, which have slowed the progression of CKD. Despite this treatment, many patients continue to lose kidney function and develop end-stage renal disease (ESKD), requiring renal replacement therapy—dialysis or kidney transplantation (N. Engl. J. Med., 2020, 383, 1436; Cardiovasc Diabetol., 2021, 20, 36).

[0009] Pharmacological inhibition of NNMT activity can prevent the progression of renal tubular and glomerular damage, thereby preventing the decline in renal function in different forms of CKD (including diabetic nephropathy and DKD) (Int. J. Gen. Med., 2023, 16, 3331-3344).

[0010] Acute kidney injury (AKI) and renal NAD + This is related to decreased levels. The aim is to increase renal NAD through supplementation with nicotinamide (NAM), nicotinamide nucleoside (NR), or nicotinamide mononucleotide (NMN). +Different methods at different levels have shown protective effects in preclinical models of AKI (Clin Kidney J, 2021, 14(12), 2453-2462). Inhibition of NNMT is expected to increase NAD... + Therefore, NNMT inhibitors may also be beneficial to AKI.

[0011] In heart failure with preserved ejection fraction (HFpEF), NAD + The cardiac levels were reduced, and in a preclinical model of HFpEF, nicotinamide supplementation improved cardiac function, suggesting that NNMT inhibition may also be beneficial for HFpEF (Sci.Trans.Med., 2021, 13, 580).

[0012] Molecules 2021, 26, 991 disclosed a small molecule inhibitor of NNMT.

[0013] J. Med. Chem. 2022, 65 (21), 14642 discloses an azidoindole carboxamide inhibitor of NNMT.

[0014] WO2021163583 and WO2023129513 disclose NNMT inhibitors and methods for inhibiting tumor growth.

[0015] J. Med. Chem. 2019, 62 (21), 9837 discloses an alkyne inhibitor of NNMT.

[0016] WO2023129512 discloses NNMT inhibitors and methods for inhibiting tumor growth.

[0017] Bioorg.Med.Chem.Lett.2018, 28, 922 and WO2021025975 disclose nicotinamide that inhibits NNMT.

[0018] US 10,087,449 B2 discloses a therapeutic agent for treating chronic kidney disease, which contains a substance that inhibits the enzyme activity of NNMT.

[0019] WO2018183668 discloses a quinoline-derived small molecule inhibitor of NNMT.

[0020] WO2012068463 discloses methods for inhibiting the production or activity of NNMT in cells, as well as methods for treating or preventing obesity or related metabolic diseases, including the administration of NNMT antagonists.

[0021] The aim is to provide compounds as inhibitors of nicotinamide N-methyltransferase (NNMT), their use as pharmaceuticals, pharmaceutical compositions containing them, and synthetic routes for their preparation. Summary of the Invention

[0022] A compound of formula (I) is provided.

[0023]

[0024] in

[0025] R 1 Selected from 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 8 R 10 and 0, 1 or 2 independently selected from R 9 Substituents;

[0026] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0027] R 3 Selected from 5- or 6-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents, or 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents;

[0028] R 4 C selected from H, OH, and optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0029] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0030] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0031] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, -CH(CH3)2, oxetane, cyPr or cyBu;

[0032] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0033] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0034] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0035] R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0036] R 12It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0037] R 13 Selected from a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3;

[0038] m can be 0, 1, or 2 independently;

[0039] Or its pharmaceutically acceptable salt.

[0040] The compounds of formula (I) are NNMT inhibitors. Therefore, the compounds of formula (I) can be used as medicines, specifically for disorders, diseases, or conditions that respond to inhibition of NNMT, and more specifically for chronic kidney disease or kidney disorders or conditions in mammals (including humans). Furthermore, the disclosed compounds are particularly suitable for treating acute kidney injury (AKI), diabetic nephropathy (DKD), heart failure (HF), cardiorenal syndrome (CRS), metabolic dysfunction-related steatohepatitis (MASH), and arrhythmia disorders or conditions in mammals (including humans).

[0041] Specific conditions or disorders that may be mentioned include diabetic nephropathy, hypertensive nephropathy, rapidly progressive glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, focal segmental glomerulosclerosis and acute kidney injury, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, in which NNMT plays a role. Detailed Implementation

[0042] The specific embodiments and examples described herein are intended for illustrative purposes only when indicating implementations. Therefore, there is no limitation on the exemplary embodiments described herein. Furthermore, it should be understood that, for clarity, various features described in the context of individual embodiments may be combined to form a single embodiment. Conversely, for brevity, various features described in the context of a single embodiment may also be combined to form sub-combinations.

[0043] The following is a list of definitions for the various terms used in the specification and claims.

[0044] It should be understood that in this specification, when a group is defined as “as defined above”, the group encompasses the first occurrence and the broadest definition, as well as every and all other definitions of that group.

[0045] It should be understood that in this specification, "C" means "C". 1-3 "This refers to a carbon group having one, two, or three carbon atoms."

[0046] It should be understood that in this specification, "C" means "C". 1-2 "This refers to a carbon group having one or two carbon atoms."

[0047] It should be understood that in this specification, "cyPr" refers to cyclopropyl.

[0048] It should be understood that in this specification, "cyBu" refers to cyclobutyl.

[0049] In this specification, unless otherwise stated, the term "alkyl" includes straight-chain and branched alkyl groups, and may be, but is not limited to, methyl, ethyl, n-propyl or isopropyl.

[0050] It should be understood that, in this specification, "8-, 9-, or 10-membered heteroaryl" means a bicyclic aromatic or partially aromatic ring having 8, 9, or 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] It should be understood that, in this specification, "5- or 6-membered heteroaryl" means an aromatic ring having 5 or 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0052] It should be understood that, in this specification, "6-membered heterocyclic alkyl" means a partially or fully saturated ring system having 6 atoms, wherein at least one ring carbon atom is independently replaced by a heteroatom selected from nitrogen, oxygen or sulfur.

[0053] It should be understood that, in this specification, "heterocyclic alkyl" substituents may be linked via a nitrogen atom having an appropriate valence or via any cyclic carbon atom.

[0054] In this specification, unless otherwise stated, the term "pharmaceutical acceptable" is used to characterize a portion (e.g., salt, dosage form, or excipient) suitable for use based on reasonable medical judgment. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potentially harmful effects that the portion might have. Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0055] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein R 1 -R 13 And m is as defined in equation (I).

[0056] In one implementation, R 1 Selected from 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 8 R 10 and 0, 1 or 2 independently selected from R 9 Substituents.

[0057] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0058] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0059] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0060] In another implementation, R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , .

[0061] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0062] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0063] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0064] n is 0, 1, or 2.

[0065] In yet another implementation scheme, R 1 Selected from , , , , , , , , , , , , , , , , , , , , , , .

[0066] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0067] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0068] R 10 Selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0069] n is 0, 1, or 2.

[0070] In yet another implementation scheme, R 1 Selected from , , , , , .

[0071] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0072] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0073] n is 0, 1, or 2.

[0074] In yet another implementation scheme, R 1 Selected from , , , , , .

[0075] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0076] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0077] n is 0, 1, or 2.

[0078] In yet another implementation scheme, R 1 Selected from .

[0079] R 8 Selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0080] R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs.1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0081] n is 0, 1, or 2.

[0082] In yet another implementation scheme, R 1 Selected from .

[0083] R 8 Selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0084] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0085] n is 0, 1, or 2.

[0086] In one implementation, R 2 It is independently selected from H, CH3, CH2F, CHF2 and CF3.

[0087] In another implementation, R 2 It is independently selected from H and CH3.

[0088] In yet another implementation scheme, R 2 For H.

[0089] In one implementation, R 3 Selected from 5- or 6-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R13 Substituents, or 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents.

[0090] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0091] R 11 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0092] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0093] R 13 Selected from a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3.

[0094] In another implementation, R 3 Selected from:

[0095] , , , , , , , , , , , , , , , , , , .

[0096] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0097] R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0098] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0099] R 13A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3.

[0100] p is 0, 1, or 2.

[0101] q is 0, 1, or 2.

[0102] In yet another implementation scheme, R 3 Selected from

[0103] , , , , , , , , , , , , , , , , , , .

[0104] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0105] R 10 Selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0106] R 11 It is independently selected from H, CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0107] R12 It is independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH.

[0108] R 13 Selected from H, , or .

[0109] p is 0, 1, or 2.

[0110] q is 0, 1, or 2.

[0111] In yet another implementation scheme, R 3 Selected from

[0112] , , , ,

[0113] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0114] R 11 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0115] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0116] R 13A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3.

[0117] p is 0, 1, or 2.

[0118] q is 0, 1, or 2.

[0119] In yet another implementation scheme, R 3 Selected from

[0120] , , , .

[0121] R 10 Selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0122] R 11 It is independently selected from H, CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0123] R 12 It is independently selected from H, OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH.

[0124] R 13 Selected from H, , or .

[0125] p is 0, 1, or 2.

[0126] q is 0, 1, or 2.

[0127] In yet another implementation scheme, R 3 Selected from

[0128] .

[0129] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0130] R 11 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0131] p is 0, 1, or 2.

[0132] In yet another implementation scheme, R 3 Selected from

[0133] .

[0134] R 10 Selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0135] R 11 It is independently selected from CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0136] p is 0, 1, or 2.

[0137] In one implementation, R 4 C selected from H, OH, and optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl.

[0138] In another implementation, R 4 OCs selected from H and OH, optionally substituted by 1, 2, 3, 4, or 5 F atoms. 1-3 Alkyl group, -CH2OH, CN, F.

[0139] In yet another implementation scheme, R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F.

[0140] In yet another implementation scheme, R 4 It is OH.

[0141] In yet another implementation scheme, R 4 It is OCH3.

[0142] In one implementation, R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3.

[0143] In another implementation, R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3.

[0144] In yet another implementation scheme, R 5 It is independently selected from H, F, OH, OCH3 or CH3.

[0145] In yet another implementation scheme, R 5 It is independently selected from H, F or OH.

[0146] In yet another implementation scheme, R 5 It is independently selected from H or OH.

[0147] In one implementation, R 6 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3 or F.

[0148] In another implementation, R 6 It is independently selected from H, CH3, CH2F, CHF2 or CF3.

[0149] In yet another implementation scheme, R 6 It is independently selected from H or CH3.

[0150] In one implementation, R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, -CH(CH3)2, oxobutane, cyPr or cyBu.

[0151] In another implementation, R 7 C selected from H, F, Cl, CN, or optionally substituted by 1, 2, 3, 4, or 5 F atoms. 1-2 alkyl.

[0152] In yet another implementation scheme, R 7 Selected from H, F, CH3 or CN.

[0153] In yet another implementation scheme, R 7 For H.

[0154] In one implementation, R 8 Selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl.

[0155] In another implementation, R 8 Selected from H, CH3, CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3 or Cl.

[0156] In yet another implementation scheme, R 8 Selected from H, CH3 or OCH3.

[0157] In yet another implementation scheme, R 8 It is CH3.

[0158] In one implementation, R 9 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl.

[0159] In another implementation, R 9 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, -CH(CH3)2, CN, F or Cl.

[0160] In yet another implementation scheme, R 9 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CN, F or Cl.

[0161] In yet another implementation scheme, R 9 It is independently selected from H, CH3, OCH3, CN, F or Cl.

[0162] In one implementation, R 10 Selected from H, CH3, CH2F, CHF2, CF3 or CH2CH3.

[0163] In another implementation, R 10 Selected from H or CH3.

[0164] In one implementation, R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3.

[0165] In another implementation, R 11 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0166] In yet another implementation scheme, R 11 It is independently selected from H, CH3, CH2CH3, OCH3, CH2OCH3, cyPr, CH2cyPr or cyBu.

[0167] In yet another implementation scheme, R 11 It is independently selected from H, CH3 or OCH3.

[0168] In one implementation, R 12 It is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH.

[0169] In another implementation, R 12It is independently selected from H, CH3, OCH3, CN, Cl or CH2OH.

[0170] In yet another implementation scheme, R 12 It is independently selected from H, CH3, OCH3, CN or Cl.

[0171] In one implementation, R 13 A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3.

[0172] In another implementation, R 13 Selected from H, , or .

[0173] In one implementation, m is 0, 1, or 2.

[0174] In another implementation, m is 0 or 1.

[0175] In yet another implementation, m is 2.

[0176] In yet another implementation, m is 1.

[0177] In yet another implementation, m is 0.

[0178] In one implementation, n is 0, 1, or 2.

[0179] In another implementation, n is 0 or 1.

[0180] In yet another implementation, n is 2.

[0181] In yet another implementation, n is 1.

[0182] In yet another implementation, n is 0.

[0183] In one implementation, p is 0, 1, or 2.

[0184] In another implementation, p is 0 or 1.

[0185] In yet another implementation, p is 2.

[0186] In yet another implementation, p is 1.

[0187] In yet another implementation, p is 0.

[0188] In one implementation, q is 0, 1, or 2.

[0189] In another implementation, q is 0 or 1.

[0190] In yet another implementation, q is 2.

[0191] In yet another implementation, q is 1.

[0192] In yet another implementation, q is 0.

[0193] In one embodiment, a compound of formula (I) is provided, wherein

[0194] R 1 Selected from 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 8 R 10 and 0, 1 or 2 independently selected from R 9 Substituents;

[0195] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0196] R 3 Selected from 5- or 6-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents, or 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents;

[0197] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0198] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0199] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0200] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0201] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0202] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0203] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0204] R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs.1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0205] R 12 It is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0206] R 13 A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3;

[0207] m can be 0, 1, or 2 independently;

[0208] Or its pharmaceutically acceptable salt.

[0209] In another embodiment, a compound of formula (I) is provided, wherein

[0210] R 1 Selected from

[0211] , , , , , , , , , , , , , , , , , , , , , , ;

[0212] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0213] R 3 Selected from

[0214] , , , , , , , , , , , , , , , , , , ;

[0215] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0216] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0217] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0218] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0219] R 8It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0220] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0221] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0222] R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0223] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0224] R 13A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3;

[0225] m can be 0, 1, or 2 independently;

[0226] n is 0, 1, or 2;

[0227] p is 0, 1, or 2;

[0228] q is 0, 1, or 2;

[0229] Or its pharmaceutically acceptable salt.

[0230] In another embodiment, a compound of formula (I) is provided, wherein

[0231] R 1 Selected from , , , , , ;

[0232] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0233] R 3 Selected from

[0234] , , , ;

[0235] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0236] R 5It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0237] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0238] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0239] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0240] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0241] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0242] R 11 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0243] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0244] R 13 Selected from a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3;

[0245] m can be 0, 1, or 2 independently;

[0246] n is 0, 1, or 2;

[0247] p is 0, 1, or 2;

[0248] q is 0, 1, or 2;

[0249] Or its pharmaceutically acceptable salt.

[0250] In yet another embodiment, a compound of formula (I) is provided, wherein

[0251] R 1 Selected from , , , , , ;

[0252] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0253] R 3 Selected from

[0254] , , , ;

[0255] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0256] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0257] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0258] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0259] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl;

[0260] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0261] R 10 Selected from H, CH3, CH2F, CHF2, CF3, or CH2CH3;

[0262] R 11Independently selected from CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr, or cyBu;

[0263] R 12 Independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH;

[0264] R 13 Selected from H, , or ;

[0265] m can be 0, 1, or 2 independently;

[0266] n is 0, 1, or 2;

[0267] p is 0, 1, or 2;

[0268] q is 0, 1, or 2;

[0269] Or its pharmaceutically acceptable salt.

[0270] In yet another embodiment, a compound of formula (I) is provided, wherein

[0271] R 1 Selected from , , , , , ;

[0272] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0273] R 3 Selected from

[0274] , , , ;

[0275] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0276] R5 It is independently selected from F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0277] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0278] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0279] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl;

[0280] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0281] R 10 Selected from H, CH3, CH2F, CHF2, CF3, or CH2CH3;

[0282] R 11 Independently selected from CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr, or cyBu;

[0283] R 12 Independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH;

[0284] R 13 Selected from H, , or ;

[0285] m can be 0, 1, or 2 independently;

[0286] n is 0, 1, or 2;

[0287] p is 0, 1, or 2;

[0288] q is 0, 1, or 2;

[0289] Or its pharmaceutically acceptable salt.

[0290] In yet another embodiment, a compound of formula (I) is provided, wherein

[0291] R 1 Selected from , , , , , ;

[0292] R 2 For H;

[0293] R 3 Selected from

[0294] , , , ;

[0295] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0296] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0297] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0298] R 7 Selected from H, F, CH3 or CN;

[0299] R 8 Independently selected from H, CH3, or OCH3;

[0300] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0301] R 10 Selected from H or CH3;

[0302] R 11 Independently selected from CH3 or OCH3;

[0303] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0304] R 13 Selected from H, , or ;

[0305] m can be 0, 1, or 2 independently;

[0306] n is 0, 1, or 2;

[0307] p is 0, 1, or 2;

[0308] q is 0, 1, or 2;

[0309] Or its pharmaceutically acceptable salt.

[0310] In yet another embodiment, a compound of formula (I) is provided, wherein

[0311] R 1 Selected from ;

[0312] R 2 For H;

[0313] R 3 Selected from

[0314] , , , ;

[0315] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0316] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0317] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0318] R 7 Selected from H, F, CH3 or CN;

[0319] R 8 Selected from H, CH3, or OCH3;

[0320] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0321] R 10 Selected from H or CH3;

[0322] R 11 Independently selected from CH3 or OCH3;

[0323] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0324] R 13 Selected from H, , or ;

[0325] m can be 0, 1, or 2 independently;

[0326] n is 0, 1, or 2;

[0327] p is 0, 1, or 2;

[0328] q is 0, 1, or 2;

[0329] Or its pharmaceutically acceptable salt.

[0330] In yet another embodiment, a compound of formula (I) is provided, wherein

[0331] R 1 Selected from , , , , , ;

[0332] R 2 For H;

[0333] R 3 Selected from ;

[0334] R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms.1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl;

[0335] R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3;

[0336] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0337] R 7 Selected from H, F, CH3 or CN;

[0338] R 8 Independently selected from H, CH3, or OCH3;

[0339] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0340] R 10 Selected from H or CH3;

[0341] R 11 Independently selected from CH3 or OCH3;

[0342] m can be 0, 1, or 2 independently;

[0343] n is 0, 1, or 2;

[0344] p is 0, 1, or 2;

[0345] Or its pharmaceutically acceptable salt.

[0346] In yet another embodiment, a compound of formula (I) is provided, wherein

[0347] R 1 Selected from ;

[0348] R 2 For H;

[0349] R 3 Selected from

[0350] , , , ;

[0351] R 4Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0352] R 5 Independently selected from H, F, or OH;

[0353] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0354] R 7 Selected from H, F, CH3 or CN;

[0355] R 8 Selected from H, CH3, or OCH3;

[0356] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0357] R 10 Selected from H or CH3;

[0358] R 11 Independently selected from CH3 or OCH3;

[0359] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0360] R 13 Selected from H, , or ;

[0361] m can be 0, 1, or 2 independently;

[0362] n is 0, 1, or 2;

[0363] p is 0, 1, or 2;

[0364] q is 0, 1, or 2;

[0365] Or its pharmaceutically acceptable salt.

[0366] In yet another embodiment, a compound of formula (I) is provided, wherein

[0367] R 1 Selected from , , , , , ;

[0368] R 2 For H;

[0369] R3 Selected from ;

[0370] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0371] R 5 Independently selected from H, F, or OH;

[0372] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0373] R 7 Selected from H, F, CH3 or CN;

[0374] R 8 Independently selected from H, CH3, or OCH3;

[0375] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0376] R 10 Selected from H or CH3;

[0377] R 11 Independently selected from CH3 or OCH3;

[0378] m can be 0, 1, or 2 independently;

[0379] n is 0, 1, or 2;

[0380] p is 0, 1, or 2;

[0381] Or its pharmaceutically acceptable salt.

[0382] In yet another embodiment, a compound of formula (I) is provided, wherein

[0383] R 1 Selected from ;

[0384] R 2 For H;

[0385] R 3 Selected from ;

[0386] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0387] R 5 Independently selected from H, F, or OH;

[0388] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0389] R 7 Selected from H, F, CH3 or CN;

[0390] R 8 Selected from H, CH3, or OCH3;

[0391] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0392] R 10 Selected from H or CH3;

[0393] R 11 Independently selected from CH3 or OCH3;

[0394] m can be 0, 1, or 2 independently;

[0395] n is 0, 1, or 2;

[0396] p is 0, 1, or 2;

[0397] Or its pharmaceutically acceptable salt.

[0398] In one embodiment, a compound of formula (IA) is provided.

[0399]

[0400] in

[0401] R 1 Selected from 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 8 R 10 and 0, 1 or 2 independently selected from R 9 Substituents;

[0402] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0403] R 3 Selected from 5- or 6-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents, or 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents;

[0404] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0405] R 5 Selected from F or OH;

[0406] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0407] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0408] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0409] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0410] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0411] R11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0412] R 12 It is independently selected from H, CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0413] R 13 A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3;

[0414] m can be 0, 1, or 2 independently;

[0415] Or its pharmaceutically acceptable salt.

[0416] In another embodiment, a compound of formula (IA) is provided, wherein

[0417] R 1 Selected from

[0418] , , , , , , , , , , , , , , , , , , , , , , ;

[0419] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0420] R 3 Selected from

[0421] , , , , , , , , , , , , , , , , , , ;

[0422] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0423] R 5 Selected from F or OH;

[0424] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0425] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0426] R 8It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0427] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0428] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0429] R 11 C, independently selected from H, and optionally replaced by 1, 2, 3, 4, or 5 Fs. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0430] R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0431] R 13A 6-membered heterocyclic alkyl ring selected from H, containing one or two heteroatoms independently selected from O, S or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1 or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or (CO)CH3;

[0432] m can be 0, 1, or 2 independently;

[0433] n is 0, 1, or 2;

[0434] p is 0, 1, or 2;

[0435] q is 0, 1, or 2;

[0436] Or its pharmaceutically acceptable salt.

[0437] In another embodiment, a compound of formula (IA) is provided, wherein

[0438] R 1 Selected from , , , , , ;

[0439] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0440] R 3 Selected from

[0441] , , , ;

[0442] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0443] R 5 Selected from F or OH;

[0444] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0445] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0446] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl;

[0447] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0448] R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0449] R 11 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3;

[0450] R 12It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH;

[0451] R 13 Selected from a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3;

[0452] m can be 0, 1, or 2 independently;

[0453] n is 0, 1, or 2;

[0454] p is 0, 1, or 2;

[0455] q is 0, 1, or 2;

[0456] Or its pharmaceutically acceptable salt.

[0457] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0458] R 1 Selected from , , , , , ;

[0459] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0460] R 3 Selected from

[0461] , , , ;

[0462] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0463] R 5 Selected from F or OH;

[0464] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0465] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0466] R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl;

[0467] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0468] R 10 Selected from H, CH3, CH2F, CHF2, CF3, or CH2CH3;

[0469] R 11 Independently selected from CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr, or cyBu;

[0470] R 12 Independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH;

[0471] R 13 Selected from H, , or ;

[0472] m can be 0, 1, or 2 independently;

[0473] n is 0, 1, or 2;

[0474] p is 0, 1, or 2;

[0475] q is 0, 1, or 2;

[0476] Or its pharmaceutically acceptable salt.

[0477] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0478] R 1 Selected from , , , , , ;

[0479] R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3;

[0480] R 3 Selected from

[0481] , , , ;

[0482] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0483] R 5 Selected from F or OH;

[0484] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0485] R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, -CH(CH3)2, oxetane, cyPr, or cyBu;

[0486] R 8It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl;

[0487] R 9 C is independently selected from those C's that are optionally replaced by one, two, three, four, or five F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl;

[0488] R 10 Selected from H, CH3, CH2F, CHF2, CF3, or CH2CH3;

[0489] R 11 Independently selected from CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr, or cyBu;

[0490] R 12 Independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH;

[0491] R 13 Selected from H, , or ;

[0492] m can be 0, 1, or 2 independently;

[0493] n is 0, 1, or 2;

[0494] p is 0, 1, or 2;

[0495] q is 0, 1, or 2;

[0496] Or its pharmaceutically acceptable salt.

[0497] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0498] R 1 Selected from , , , , , ;

[0499] R 2 For H;

[0500] R 3 Selected from

[0501] , , , ;

[0502] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0503] R 5 Selected from F or OH;

[0504] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0505] R 7 Selected from H, F, CH3 or CN;

[0506] R 8 Independently selected from H, CH3, or OCH3;

[0507] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0508] R 10 Selected from H or CH3;

[0509] R 11 Independently selected from CH3 or OCH3;

[0510] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0511] R 13 Selected from H, , or ;

[0512] m can be 0, 1, or 2 independently;

[0513] n is 0, 1, or 2;

[0514] p is 0, 1, or 2;

[0515] q is 0, 1, or 2;

[0516] Or its pharmaceutically acceptable salt.

[0517] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0518] R 1 Selected from ;

[0519] R 2 For H;

[0520] R 3 Selected from

[0521] , , , ;

[0522] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0523] R 5 Selected from F or OH;

[0524] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0525] R 7 Selected from H, F, CH3 or CN;

[0526] R 8 Selected from H, CH3, or OCH3;

[0527] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0528] R 10 Selected from H or CH3;

[0529] R 11 Independently selected from CH3 or OCH3;

[0530] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0531] R 13 Selected from H, , or ;

[0532] m can be 0, 1, or 2 independently;

[0533] n is 0, 1, or 2;

[0534] p is 0, 1, or 2;

[0535] q is 0, 1, or 2;

[0536] Or its pharmaceutically acceptable salt.

[0537] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0538] R 1 Selected from , , , , , ;

[0539] R 2 For H;

[0540] R 3 Selected from ;

[0541] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0542] R 5 Selected from F or OH;

[0543] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0544] R 7 Selected from H, F, CH3 or CN;

[0545] R 8 Independently selected from H, CH3, or OCH3;

[0546] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0547] R 10 Selected from H or CH3;

[0548] R 11 Independently selected from CH3 or OCH3;

[0549] m can be 0, 1, or 2 independently;

[0550] n is 0, 1, or 2;

[0551] p is 0, 1, or 2;

[0552] Or its pharmaceutically acceptable salt.

[0553] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0554] R 1 Selected from ;

[0555] R 2 For H;

[0556] R 3 Selected from

[0557] , , , ;

[0558] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0559] R 5 Selected from F or OH;

[0560] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0561] R 7 Selected from H, F, CH3 or CN;

[0562] R 8 Selected from H, CH3, or OCH3;

[0563] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0564] R 10 Selected from H or CH3;

[0565] R 11 Independently selected from CH3 or OCH3;

[0566] R 12 Independently selected from CH3, OCH3, CN, or Cl;

[0567] R 13 Selected from H, , or ;

[0568] m can be 0, 1, or 2 independently;

[0569] n is 0, 1, or 2;

[0570] p is 0, 1, or 2;

[0571] q is 0, 1, or 2;

[0572] Or its pharmaceutically acceptable salt.

[0573] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0574] R 1 Selected from , , , , , ;

[0575] R 2 For H;

[0576] R 3 Selected from ;

[0577] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0578] R 5 Selected from F or OH;

[0579] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0580] R 7 Selected from H, F, CH3 or CN;

[0581] R 8 Independently selected from H, CH3, or OCH3;

[0582] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0583] R 10 Selected from H or CH3;

[0584] R 11 Independently selected from CH3 or OCH3;

[0585] m can be 0, 1, or 2 independently;

[0586] n is 0, 1, or 2;

[0587] p is 0, 1, or 2;

[0588] Or its pharmaceutically acceptable salt.

[0589] In yet another embodiment, a compound of formula (IA) is provided, wherein

[0590] R 1 Selected from ;

[0591] R 2 For H;

[0592] R 3 Selected from ;

[0593] R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F;

[0594] R 5 Selected from F or OH;

[0595] R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F;

[0596] R 7 Selected from H, F, CH3 or CN;

[0597] R 8 Selected from H, CH3, or OCH3;

[0598] R 9 It is independently selected from CH3, OCH3, CN, F, or Cl;

[0599] R 10 Selected from H or CH3;

[0600] R 11 Independently selected from CH3 or OCH3;

[0601] m can be 0, 1, or 2 independently;

[0602] n is 0, 1, or 2;

[0603] p is 0, 1, or 2;

[0604] Or its pharmaceutically acceptable salt.

[0605] In one embodiment, the compound of formula (I) is selected from:

[0606] 2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinoline,

[0607] 2-((4-(5-(4-isopropylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0608] 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine,

[0609] 6-Chloro-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0610] 8-Fluoro-4-methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0611] 8-Fluoro-4-methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0612] 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0613] 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine,

[0614] 2-((4-(5-(4-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0615] 4-Methyl-2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine,

[0616] 4-Methyl-2-((4-(5-(5-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine,

[0617] 4-Methyl-2-((4-(5-(2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine,

[0618] (3-(3-(1-((4-methylpyridino[2,3-d]pyrimidin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-4-yl)methanol,

[0619] 2-((4-(5-(2-ethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0620] 2-((4-(5-(2,4-diethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0621] 3-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-8-methylbenzo[e][1,2,4]triazine,

[0622] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0623] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine,

[0624] 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine,

[0625] 5-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-1,8-naphthylidine,

[0626] 4,7-Dimethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine,

[0627] 6-Chloro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0628] 5-Chloro-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0629] 4,6-Dimethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0630] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazolin-6-carboxynitrile,

[0631] 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[3,4-d]pyrimidine,

[0632] 8-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0633] 6-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0634] 5-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0635] 7-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0636] 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidine,

[0637] 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine,

[0638] 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine,

[0639] 4-(methoxy-d3)-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)thiopheno[3,2-d]pyrimidine,

[0640] 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0641] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine,

[0642] 6-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-1H-pyrrolo[2,3-d]pyridine,

[0643] 1-Ethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-1H-benzis[d]imidazolium,

[0644] rac-(R)-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine,

[0645] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine,

[0646] 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0647] 4-Chloro-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine,

[0648] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine,

[0649] rac-4-methyl-2-(((2R,4R)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0650] 4-Ethyl-2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0651] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine,

[0652] 4-Ethyl-2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0653] 2-((4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0654] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0655] 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0656] 2-((4-(1',5'-dimethyl-1H,2'H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0657] 2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0658] 4-Ethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0659] 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-ethyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0660] 4-Methyl-2-((4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0661] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine,

[0662] 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-4-ol,

[0663] (3R,4R)-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol

[0664] 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-4-ol,

[0665] (3R,4R)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazol]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0666] 2-((4-fluoro-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0667] 1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-4-carboxynitrile,

[0668] 2-((4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0669] 2-((4-methoxy-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0670] rac-4-methyl-2-(((2R,4S)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazolin,

[0671] (1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-yl)methanol

[0672] 1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-ol,

[0673] (3R,4R)-4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0674] (3R,4R)-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0675] 3R,4R)-4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol,

[0676] (3S,4S)-4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0677] 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxypiperidin-1-yl)methyl)-4-methylquinazoline,

[0678] 2-((4-methoxy-4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0679] (3R,4S)-4-methoxy-4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0680] (3R,4S)-4-(5'-(difluoromethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0681] (3R,4S)-4-methoxy-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0682] (3R,4S)-4-methoxy-4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazol]-5-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0683] (3R,4S)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazol]-5-yl)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0684] (3R,4S)-4-methoxy-4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0685] (3R,4S)-1-((5-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0686] (3R,4S)-1-((5-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0687] (3R,4S)-1-((6-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0688] (3R,4S)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol

[0689] (3S,4R)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol

[0690] (3R,4S)-4-methoxy-4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0691] (3R,4S)-4-(3',5'-dimethyl-1'H,2H-[3,4'-bipyrazol]-5-yl)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol,

[0692] (3R,4S)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-3-ol,

[0693] (3R,4S)-1-((8-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0694] (3R,4S)-1-((6-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0695] rac-(3R,4S)-3-fluoro-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-ol

[0696] rac-(3R,4R)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol

[0697] 4-Methyl-2-((4-(1',3',4,5'-tetramethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0698] 1',3',5'-Trimethyl-5-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1'H,2H-[3,4'-bipyrazole]-4-carboxynitrile,

[0699] N-Methyl-5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridine-3-amine,

[0700] 4-Methyl-2-((4-(5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0701] 4-Methyl-2-((4-(5-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0702] 4-Methyl-2-((4-(5-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0703] 4-Methyl-2-((4-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0704] 1-(4-(5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-3-yl)piperazin-1-yl)acet-1-one,

[0705] 4-Methyl-5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazole-5-yl)nicotinonitrile,

[0706] 4-(5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-3-yl)morpholine,

[0707] 2-((4-(5-(5-methoxypyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0708] 2-((4-(5-(5-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0709] 4-Methyl-2-((4-(5-(5-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0710] 4-Methyl-2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0711] 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0712] 4-Methyl-2-((4-(5-(2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0713] 4-Methyl-2-((4-(5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0714] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0715] 2-((4-(5-(4-(methoxymethyl)-2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0716] 2-({4-[3-(4-ethyl-2-methylpyridin-3-yl)-1H-pyrazol-5-yl]piperidin-1-yl}methyl)-4-methylquinazoline,

[0717] 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0718] 2-((4-(5-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0719] 4-Methyl-2-((4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazolin,

[0720] 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine,

[0721] 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine,

[0722] 2-((4-(5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0723] 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine,

[0724] 7-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-2,3-dihydropyrazolo[5,1-b]oxazole,

[0725] 3,5-Dimethyl-4-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazole-5-yl)isoxazole,

[0726] 4-Methyl-2-((4-(5-(1,2,4-trimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline,

[0727] 2-((4-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0728] 2,4-Dimethyl-5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)thiazole,

[0729] 5-Methyl-2-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)thiazole,

[0730] 3,5-Dimethyl-4-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazole-5-yl)isothiazol,

[0731] 2-((4-(5-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0732] 3,4-Dimethyl-5-(5-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazole-3-yl)isoxazole,

[0733] 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0734] 2-((4-(3',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0735] 4-Methyl-2-((4-(1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0736] 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0737] 2-((4-(5'-cyclobutyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0738] 2-((4-(5'-(difluoromethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0739] 4-Methyl-2-((4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0740] 2-((4-(5'-(methoxymethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0741] 2-((4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0742] 2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0743] 4-Methyl-2-((4-(2',4',5'-trimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline,

[0744] 2-((4-(4',5'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0745] 2-((4-(1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0746] 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0747] 2-((4-(5'-ethyl-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0748] 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline,

[0749] rac-(3R,4S)-4-ethyl-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol,

[0750] rac-(3R,4S)-4-methyl-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol, and

[0751] Its pharmaceutically acceptable salt.

[0752] It should be noted that any of these specific compounds may be excluded from any of the embodiments mentioned herein.

[0753] In one embodiment, a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided, as well as intermediates for its preparation.

[0754] Another implementation is the product that can be obtained through any of the methods or embodiments disclosed herein.

[0755] Medical and pharmaceutical uses

[0756] Compounds of formula (I) and their pharmaceutically acceptable salts are useful because they have pharmacological activity as inhibitors of the enzyme NNMT.

[0757] The compounds of formula (I) and their pharmaceutically acceptable salts are suitable for the treatment or prevention of diseases or conditions requiring regulation of nicotinamide N-methyltransferase (NNMT) activity. Specifically, the association of NNMT activity with disease is related to chronic kidney disease. Therefore, the disclosed compounds are particularly suitable for the treatment of chronic kidney disease or kidney disorders or impairments in mammals, including humans. Furthermore, the disclosed compounds are particularly suitable for the treatment of acute kidney injury (AKI), diabetic nephropathy (DKD), heart failure (HF), cardiorenal syndrome (CRS), metabolic dysfunction-related steatohepatitis (MASH), and arrhythmia disorders or impairments in mammals, including humans.

[0758] Specific conditions or disorders that may be mentioned include diabetic nephropathy, hypertensive nephropathy, rapidly progressive glomerulonephritis, systemic lupus erythematosus, IgA nephropathy, focal segmental glomerulosclerosis and acute kidney injury, coronary artery disease, acute coronary syndrome, heart failure, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction.

[0759] Preventive treatment is expected to be particularly suitable for individuals who have previously had a related disease or condition, or who are considered to be at higher risk of developing such a disease or condition. Individuals at risk of developing a specific disease or condition typically include those with a family history of the disease or condition, those already identified through genetic testing or screening, or those identified as particularly susceptible to developing the disease or condition by specific biomarker patterns.

[0760] For the above-mentioned therapeutic indications, the dosage will naturally vary depending on the compound used, the route of administration, and the treatment required.

[0761] Compounds of formula (I) and their pharmaceutically acceptable derivatives may be used alone or in the form of suitable pharmaceutical compositions in which the compound or derivative is mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Thus, another aspect relates to pharmaceutical compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. Administration may be, but is not limited to, enteric (including oral, sublingual, or rectal), intranasal, inhalation, intravenous, topical, or other parenteral routes. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, ME Aulton, Churchill Livingstone, 2nd edition 2002. Pharmaceutical compositions preferably comprise less than 80%, more preferably less than 50%, of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0762] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for therapeutic purposes, particularly for the prevention or treatment of chronic kidney disease or kidney disorders in mammals, especially humans.

[0763] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for therapy, particularly for prevention or treatment of conditions in which inhibition of NNMT would be beneficial.

[0764] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of chronic kidney disease in mammals, especially humans.

[0765] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of acute kidney injury in mammals, especially humans.

[0766] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of diabetic nephropathy in mammals, especially humans.

[0767] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of cardiorenal syndrome in mammals, especially humans.

[0768] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of heart failure in mammals, especially humans.

[0769] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of heart failure with reduced ejection fraction in mammals, especially humans.

[0770] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of heart failure with preserved ejection fraction in mammals, especially humans.

[0771] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of MASH in mammals, especially humans.

[0772] In yet another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided for use in therapy, particularly for the prevention or treatment of cardiac arrhythmias in mammals, especially humans.

[0773] In one embodiment, a method is provided for treating a disease or condition in which inhibiting the NNMT enzyme is beneficial or for reducing the risk thereof, the method comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0774] In another embodiment, a method is provided for treating or reducing the risk of chronic kidney disease or kidney condition or disorder or being at risk of said disease or condition in a person, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0775] In yet another embodiment, a method is provided for treating or reducing the risk of chronic kidney disease or condition in a person who has or is at risk of the disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0776] In yet another embodiment, a method is provided for treating or reducing the risk of said disease or condition in a person suffering from acute kidney injury or at risk of said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0777] In yet another embodiment, a method is provided for treating or reducing the risk of diabetic nephropathy in a person who has or is at risk of the disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0778] In yet another embodiment, a method is provided for treating or reducing the risk of cardiorenal syndrome in a person who has or is at risk of the disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0779] In yet another embodiment, a method is provided for treating or reducing the risk of heart failure or being at risk of said disease or condition in a person, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0780] In yet another embodiment, a method is provided for treating or reducing the risk of heart failure with reduced ejection fraction or for a person at risk of said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0781] In yet another embodiment, a method is provided for treating or reducing the risk of heart failure with preserved ejection fraction or for a person at risk of said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0782] In yet another embodiment, a method is provided for treating or reducing the risk of MASH in a person who has or is at risk of the disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0783] In yet another embodiment, a method is provided for treating or reducing the risk of a person suffering from or at risk of the arrhythmia or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0784] In one embodiment, a pharmaceutical formulation is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I), and a pharmaceutically acceptable diluent, excipient, and / or inert carrier.

[0785] In another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of conditions in which inhibition of NNMT would be beneficial.

[0786] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of chronic kidney disease in mammals, especially humans.

[0787] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapy, particularly for the prevention or treatment of acute kidney injury in mammals, especially humans.

[0788] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of diabetic nephropathy in mammals, especially humans.

[0789] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of heart failure in mammals, especially humans.

[0790] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of heart failure in mammals, especially humans, with reduced ejection fraction.

[0791] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of heart failure with preserved ejection fraction in mammals, especially humans.

[0792] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of MASH in mammals, especially humans.

[0793] In yet another embodiment, a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier is provided for therapies, particularly for the prevention or treatment of cardiac arrhythmias in mammals, especially humans.

[0794] A method for preparing this pharmaceutical composition is also provided, which includes mixing the components.

[0795] When tested in NNMT cell assays, such as in test A described below, the compound of formula (I) exemplified herein preferably has an IC50 of less than 50 µM. 50 Compounds of formula (I) also exhibit promising pharmacological characteristics by separating desired and undesired effects in vivo.

[0796] These and other implementation schemes are described in more detail below, and other aspects will become clear to those skilled in the art upon reading this specification.

[0797] Pharmacological properties

[0798] Compounds of formula (I) or pharmaceutically acceptable salts thereof are considered to be useful for the prevention or treatment of chronic kidney disease or kidney disease or disorder in mammals, particularly humans; acute kidney injury; heart failure; heart failure with reduced ejection fraction and heart failure with preserved ejection fraction; cardiorenal syndrome; fatty liver disease associated with metabolic dysfunction; and arrhythmia or disorder.

[0799] To avoid ambiguity, as used herein, the term “treatment” includes both therapeutic and / or preventative treatment.

[0800] When the compounds or salts described herein are used to treat a condition, a “therapeutic amount” means an amount sufficient to alleviate or completely relieve the symptoms or other adverse effects of the condition, cure the condition, reverse, completely stop or slow the progression of the condition, or reduce the risk of the condition worsening.

[0801] Therefore, the compounds described herein are suitable for the therapeutic and / or preventative treatment of these conditions.

[0802] Compared with compounds known in the prior art, the compounds described herein have the following advantages: they can be more effective, less toxic, more selective, more potent, produce fewer side effects, are easier to absorb, and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance).

[0803] Combination therapy

[0804] The compound of formula (I) or its pharmaceutically acceptable salt may also be administered in combination with other compounds used to treat the above-mentioned conditions.

[0805] In another embodiment, there is a combination therapy in which a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second active ingredient are administered simultaneously, sequentially, or in combination for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more other active ingredients.

[0806] The compounds described herein can be combined with the following agents for the treatment of cardiovascular diseases, metabolic diseases, and kidney diseases: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, glucagon-like peptide-1 modulators, or endothelin receptor antagonists.

[0807] When used in combination therapy, administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, along with other active ingredients, may be considered in a single composition, in completely separate compositions, or in a combination thereof. Simultaneous, concurrent, sequential, or separate administration of the active ingredients may also be considered. The specific composition and frequency of administration for combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the type of patient, any potential interactions between the active ingredients when combined as a single composition, any interactions between the active ingredients when administered to animal patients, and a variety of other factors known to physicians (in the case of human patients), veterinarians (in the case of non-human patients), and others skilled in the art.

[0808] Pharmaceutical Composition

[0809] A method for treating a condition requiring inhibition of NNMT is provided, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a person who has or is susceptible to the condition.

[0810] Compounds of formula (I) are typically administered in pharmaceutical formulations comprising the active ingredient or a pharmaceutically acceptable salt thereof, via oral, topical, parenteral, intravenous, intramuscular, subcutaneous, or other injectable routes, buccal, rectal, vaginal, transdermal, and / or nasal routes, and / or via inhalation, in pharmaceutically acceptable dosage forms. These compositions may be administered in different doses depending on the condition to be treated and the patient, as well as the route of administration. Conventional methods for selecting and preparing suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, ME Aulton, Churchill Livingstone, 2nd edition, 2002.

[0811] In human therapeutic treatment, the appropriate daily dose of the compound of formula (I) is about 0.0001 mg / kg body weight to 100 mg / kg body weight.

[0812] Particularly preferred oral formulations are tablets or capsules, which can be formulated by methods known to those skilled in the art to provide an active compound in doses ranging from 0.007 mg to 700 mg.

[0813] The optimal dosage and frequency of administration will depend on the specific condition being treated and its severity; the type of patient; the patient's age, sex, size and weight, diet and general physical condition; brain to body weight ratio; other medications the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and other skilled personnel in the art.

[0814] According to another aspect, a pharmaceutical formulation is thus provided comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof, mixed with a pharmaceutically acceptable adjuvant, diluent, and / or carrier.

[0815] The compound of formula (I) may be present in the pharmaceutical preparation at a concentration of 0.1% to 99.5% (such as 0.5% to 95%) of the total weight of the preparation.

[0816] Preparation of compounds

[0817] Those skilled in the art will understand that, in this method, certain functional groups in the reagents, such as hydroxyl or amino groups, may need to be protected by protecting groups. Therefore, the preparation of compounds of formula (I) may involve removing one or more protecting groups at appropriate stages.

[0818] The protection and deprotection of functional groups are described in “Protective Groups in Organic Synthesis”, 4th edition, TW Greene and PGM Uts, Wiley-Interscience (2006) and Protecting Groups, 3rd edition, PJ Kocienski, Georg Thieme Verlag (2005).

[0819] Those skilled in the art will recognize that, at any stage of the preparation of a compound of formula (I), a mixture of isomers (e.g., racemates) of the compound can be utilized. At any stage of preparation, a single stereoisomer can be obtained by separating it from the mixture of isomers (e.g., racemates) using, for example, chiral chromatographic separation.

[0820] Another implementation scheme covers pharmaceutically acceptable salts of compounds of formula (I).

[0821] Salts of compounds of formula (I) may have advantages due to one or more of their chemical or physical properties, such as stability at different temperatures and humidity levels, or desired solubility in H2O, oil, or other solvents. In some cases, the salt can be used to aid in the separation or purification of the compound. In some embodiments (particularly when the salt is intended for administration to animals (e.g., humans) or for the preparation of a reagent for the administration of a compound or salt intended to animals), the salt is pharmaceutically acceptable.

[0822] The term "pharmaceutically acceptable" is used to characterize a portion (e.g., a salt, dosage form, or excipient) suitable for use based on reasonable medical judgment. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potentially harmful effects. Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0823] Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts, when the compound is sufficiently basic.

[0824] For a review of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, PHStahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0825] When the acidic co-forming agent is solid at room temperature and there is no or only partial proton transfer between the compound of formula (I) and such an acidic co-forming agent, a co-crystal of the co-forming agent and the compound of formula (I) can be produced instead of a salt. This article covers all such co-crystal forms of the compound of formula (I).

[0826] It should also be understood that some compounds of formula (I) may exist in solvated forms (e.g., hydrates, including solvates of pharmaceutically acceptable salts of compounds of formula (I)).

[0827] In another embodiment, certain compounds of formula (I) may exist as racemic mixtures and racemic mixtures, single enantiomers, single diastereomers, and diastereomer mixtures. Certain compounds of formula (I) may also contain linking bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds, such as amide bonds), wherein bond rotation around that particular linking bond is restricted, for example, due to the presence of cyclic bonds or double bonds. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization, or stereoisomers can be prepared by stereoselective synthesis.

[0828] In another embodiment, the compounds of formula (I) encompass any isotopically labeled (or “radiolabeled”) derivatives of the compounds of formula (I). Such derivatives are derivatives of the compounds of formula (I) in which one or more atoms are replaced by atoms having an atomic mass or mass number different from those commonly found in nature. Examples of doped isotopes include… 2 H (also written as "D", meaning deuterium).

[0829] In another embodiment, the compound of formula (I) may also contain various tautomer forms. It should be understood that all such tautomer forms are covered.

[0830] In another embodiment, the compound of formula (I) may be administered in the form of a prodrug, which is broken down in a human or animal to obtain the compound of formula (I).

[0831] Various forms of prodrugs are known in the art. Examples of prodrug derivatives can be found in Nature Reviews DrugDiscovery 2008, 7, 255 and the references cited therein.

[0832] Intermediate compounds can also exist in enantiomeric form and can be used as purified enantiomers, diastereomers, racemates, or mixtures.

[0833] Pharmacological activity

[0834] The pharmacological activities of the compounds disclosed in this paper were tested in subsequent screening (Test A).

[0835] Test A — Cellular assay of human NNMT in RPTEC / TERT1 cells

[0836] Frozen RPTEC / TERT1 cells (CRL-4031 from ATCC) expressing endogenous human NNMT were thawed, centrifuged, and diluted in cell culture medium (DMEM / F-12 + GlutaMAX-I (Gibco 31331-028)) containing 0.1 mg / ml Genectin (Gibco, 10131027). The cell suspension was aliquoted into 384-well microplates (Corning 3764) containing compounds dissolved in DMSO using Multidrop Combi (ThermoFisher; 8000 cells / well, final assay volume 30 µL, 0.3% final DMSO). The microplates were incubated in a cell culture incubator (37°C, in a humidified 5% CO2 / air atmosphere). After 24 hours, the cell culture medium was removed, and the cells were washed with PBS using BlueWasher (BlueCatBio GmbH, Germany). Then, 20 µL of water (Multidrop Combi) was added, and the plates were frozen on dry ice. The plates were stored at -20°C until samples were prepared for LC-MS analysis. Cellular NNMT activity was determined by measuring 1-MNA (1-methylnicotinamide) levels using an LC-MS detection system. Frozen cell lysates were thawed and diluted in methanol / acetonitrile (50 / 50) containing 1-MNA-D3 (M323237, TRC, Toronto, Canada), centrifuged at 2600 g for 30 min, and then sampled on an API 5000 LC / MS / MS instrument with Qjet (Applied biosystems; sample volume 10 µL, phase A: 5 mM acetic acid / 0.2% formic acid, phase B: acetonitrile; column: Xbridge amide 3.5 mm 2.1 × 50 mm column, Waters / Bridge 186004859). 1-MNA levels were quantified as the area under the curve (AUC) of the 1-MNA peak and normalized using 1-MNA-D3. Data processing, assay quality control, and concentration response curve fitting were analyzed using Genedata Screener (Basel, Switzerland). Compound potency was determined from 10-point concentration response curves using a 3-fold dilution step, with the final assay concentration range from 30 mM to 15 nM. The Z' factor is between 0.5 and 0.8.

[0837] IC of the compound in the example 50 The values ​​(NNMT) are listed in Table 1 below.

[0838] Table 1

[0839]

[0840]

[0841] Example

[0842] The following examples are non-limiting examples.

[0843] General conditions

[0844] (i) Unless otherwise specified, operation shall be carried out at room temperature (rt) (i.e., in the range of 17°C to 25°C) and in an inert gas atmosphere such as N2 (g); optionally, an MBRAUN UNILab Plus ECO or MBRAUN UNILab SP Eco glove box workstation or Sigma-Aldrich KitAlysis shall be used. ™ A benchtop inerting chamber is recommended for the reaction in this case;

[0845] (ii) In cases where the reaction involves degassing or purging, this can be done, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 to 10 minutes) or by repeatedly evacuating the container and backfilling it with a suitable inert atmosphere (e.g., nitrogen (g) or argon (g)).

[0846] (iii) In cases where the reaction involves the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer;

[0847] (iv) In cases where the reaction involves LED irradiation, use commercially standardized EvoluChem LEDs from HepatoChem equipped with Kessil H150 blue LEDs (456nm, 34W). ™ PhotoRedOx Box photoreactors or commercially standardized photoreactors m2 from PennPhoton Devices equipped with LED modules (365nm), photochemical

[0848] (v) In the case where the reaction refers to the use of flow chemistry, unless otherwise specified, the components shall be injected into a 6.8 mL PFA coil reactor at room temperature using a syringe pump (od 3.2 mm) and the flow rate of the components shall be as indicated in the instructions.

[0849] (vi) Generally, the reaction process is tracked by thin-layer chromatography (TLC) and / or analytical high-performance liquid chromatography (HPLC or UPLC), which is usually coupled with a mass spectrometer (LCMS).

[0850] (vii) If necessary, dry the organic solution with anhydrous MgSO4 or Na2SO4, or by using ISOLUTE. ® The phase separator dries the organic layer, and post-processing steps are performed using conventional phase separation techniques. When a desiccant such as MgSO4 or Na2SO4 is used to dry the organic layer, it should be understood that the organic layer is filtered before concentration.

[0851] (viii) It should be understood that, unless otherwise stated, the washing solutions used in post-treatment processes or the reagents used for acidification, such as brine, NaHCO3, NH4Cl, HCl, and NaH2PO4, are considered to be aqueous solutions.

[0852] (ix) Evaporation is carried out by vacuum rotary evaporation or in Genevac HT-4 / EZ-2 or Biotage V10;

[0853] (x) Unless otherwise stated, rapid column chromatography uses Merck silica gel (Art. 9385) or pre-packed small columns such as Biotage on normal-phase silica. ® SNAP columns (40µm-63µm silica, 4g-330g), Biotage ® Sfär silica HC D column (20µm, 10g-100g), Interchim puriFlash ™ Small column (25µm, 4g-120g), Interchim puriFlash ™ Small column (50µm, 25g-330g), Grace ™ GraceResolv ™ The procedure can be performed using rapid silica columnar ingots (4g-120g) or Agela rapid columnar silica-CS columnar ingots (80g-330g), or using Agela Technologies C-18 spherical columnar ingots (20µm-35µm, 100A, 80g–330g) on ​​reversed silica using Grace Reveleris. ® The X2 Fast System or similar systems can be operated manually or automatically.

[0854] (xi) Preparative reversed-phase HPLC and preparative reversed-phase SFC were performed using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fractionation collection instruments, respectively, with isocratic or gradient mobile phases as described in the Experimental Section and one of the following methods described below; Preparation method A: The compound was purified by preparative HPLC on a Kromasil C8 column (10 µm, 250 mm × 20 mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation method B: The compound was purified by preparative HPLC-MS on an XBridge column. ™ Purification was performed on a C18 ODB column (5µm, 100×10mm ID) using a gradient of MeCN in NH3 / H2O (0.2%, pH 10) as the mobile phase; preparation method C; the compound was purified by preparative SFC in Waters. ™ Purification was performed on BEH (5 μm, 250 × 30 mm ID) using MeOH / H2O (NH3, 50 mM) (97 / 3) in CO2 as the mobile phase; preparation method D; the compound was purified by preparative HPLC on XBridge. ™ Purification was performed on a C18 column (10µm, 250×19mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; preparation method E; the compound was purified by preparative HPLC on an XBridge column. ™ Purification was performed using a gradient of MeCN in H2O / NH4HCO3 (10 mM) as the mobile phase on a C18 OBD column (5 µm, 150 × 30 mm ID); Preparation method F; The compound was purified by preparative HPLC on an XBridge column. ™ Purification was performed on a C18 column (10µm, 250×50mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; Preparation method G; The compound was purified by preparative HPLC on a Kromasil C8 column (10µm, 250×50mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation method H; The compound was purified by preparative HPLC on a Waters C8 column (10µm, 250×50mm ID) using a gradient of MeCN in H2O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; ™ Sunfire ™ Purification was performed using a gradient of MeCN in H2O / FA ​​(0.1%) as the mobile phase on a C18 OBD column (5µm, 150×30mm ID); Preparation method I; The compound was purified by preparative HPLC on Xbridge. ™Purification was performed using a C18 ODB column (5 μm, 150 × 19 mm ID) with a gradient of MeCN in an H2O / NH3 (0.2%, pH 10) buffer system as the mobile phase; preparation method J; the compound was purified by preparative HPLC in Waters. ™ Sunfire ™ Purification was performed using a gradient of MeCN in H2O / FA ​​(0.1M) as the mobile phase on a C18 OBD column (5µm, 150×30mm ID); preparation method K; the compound was purified by preparative HPLC in Waters. ™ Sunfire ™ Purification was performed on a C18 ODB column (5µm, 150×19mm ID) using a gradient of MeCN in H2O / FA ​​(0.1M) as the mobile phase; preparation method L; the compound was purified by preparative SFC at Phenomenex Luna ® Purification was performed on a HILIC column (5µm, 250×30mm ID) using MeOH / NH3 (20mM) in CO2 as the mobile phase; preparation method N; the compound was purified by preparative HPLC on an XBridge column. ™ Purification was performed on a C18 OBD column (5µm, 150×30mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10mM) / NH3 (0.1%, aq) buffer system as the mobile phase; preparation method O; the compound was purified by preparative SFC at Waters. ™ Purification was performed on a BEH 2-EP (5 μm, 250 × 30 mm ID) using MeOH / NH3 (20 mM) in CO2 as the mobile phase; preparation method P; the compound was purified by preparative HPLC on an XBridge microarray. ™ Purification was performed on a Shield C18 column (5 µm, 150 × 30 mm ID) using a gradient of MeCN in an H2O / NH4CO3 (10 mM) / NH3 (0.1%, aq) buffer system as the mobile phase; Preparation method Q; The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5 µm, 150 × 30 mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10 mM) buffer system as the mobile phase; Preparation method R; The compound was purified by preparative HPLC on an XBridge ™ Purification was performed using a gradient of MeCN in H2O / NH4HCO3 (0.1M) as the mobile phase on a C18 OBD column (5µm, 150×19mm ID); preparation method T; the compound was purified by preparative HPLC on an XBridge column. ™Purification was performed on a C18 column (5µm, 150×25mm ID) using a gradient of MeCN in H2O / NH4HCO3 (0.01M) as the mobile phase; preparation method U; the compound was purified by preparative SFC in Waters. ™ Preparation method V: The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP column (5μm, 250×30) using a MeOH / H2O / NH3 (97 / 3 / 50mM) gradient in CO2 as the mobile phase; Preparation method W: The compound was purified by preparative HPLC on a Water Atlantis T3 C18 ODB column (5µm, 150×19mm ID) using a gradient in H2O / FA ​​(0.1M) as the mobile phase; Preparation method X: The compound was purified by preparative HPLC on an XBridge column. ™ Purification was performed on a C18 OBD column (5µm, 150×19mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (0.01M) buffer system as the mobile phase; preparation method Y; the compound was purified by preparative SFC at Waters. ™ Purification was performed on BEH (5 μm, 250 × 30 mm ID) using MeOH / NH3 (20 mM) in CO2 as the mobile phase; Preparation method Z; The compound was purified by preparative SFC on Kromasil DIOL (5 µM, 50 × 30 mm ID) using EtOH / NH3 (100 / 20 mM) in CO2 as the mobile phase; Preparation method CC; The compound was purified by preparative HPLC on XBridge ™ Purification was performed on a C18 column (10µm, 250×19mm ID) using a gradient of MeCN in an H2O / MeCN / NH4HCO3 (95 / 5 / 10mM) buffer system as the mobile phase. Preparation method DD: The compound was purified by preparative SFC on a Kromasil CN (5µm, 250×30mm ID) column using EtOH / DEA (100 / 20mM) in CO2 as the mobile phase. Preparation method EE: The compound was purified by preparative HPLC on a Waters Atlantis T3 C18 ODB column (5µm, 150×19mm ID) using a gradient of MeCN in H2O / TFA (0.15M) as the mobile phase. Preparation method FF: The compound was purified by preparative HPLC on an XBridge... ™Purification was performed on a C18 OBD column (5µm, 150×19mm ID) using a gradient of MeCN in an H2O / MeCN / TFA (95 / 5 / 150mM) buffer system as the mobile phase. Preparation method GG; The compound was purified by preparative HPLC on a Waters XSelect CSH fluorophenyl OBD column (5µm, 150×19mm ID) using a gradient of MeCN in an H2O / TFA (0.15M) buffer system as the mobile phase; Preparation method HH; The compound was purified by preparative HPLC on an XBridge... ™ Preparation Method II: The compound was purified by preparative HPLC on a C18 OBD column (5µm, 150×19mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10mM) / NH3 (0.1%, aq) buffer system as the mobile phase. Preparation Method JJ: The compound was purified by preparative HPLC on a YMC-Actus Triart C18 ExRS column (5µm, 150×30mm ID) using a gradient of MeCN in an H2O / NH4HCO3 (10mM) / NH3 (0.1%, aq) buffer system as the mobile phase. ™ The compound was purified by preparative HPLC on a Kromasil C8 column (10µm, 250×50mm ID) using a gradient of MeCN in H2O / MeCN / NH4HCO3 (95 / 5 / 10mM) buffer as the mobile phase; Preparation method NN; The compound was purified by preparative HPLC on a Kromasil C8 column (10µm, 250×50mm ID) using a gradient of MeCN in H2O / MeCN / AcOH (95 / 5 / 0.2) buffer as the mobile phase. Preparation method PP; The compound was purified by preparative HPLC on a Kromasil C8 column (10µm, 250×20mm ID) using a gradient of MeCN in H2O / MeCN / AcOH (95 / 5 / 0.2) buffer as the mobile phase.

[0855] Preparation method QQ; The compound was purified by preparative HPLC on an Xbridge BEH C18 column (5µm, 100×10mm ID) using a gradient of MeCN in H2O as the mobile phase.

[0856] Collect the relevant fractions, combine them, and freeze-dry them to obtain the purified compound; or collect the relevant fractions, combine them, concentrate them under reduced pressure, extract them with DCM or EtOAc, and dry the organic phase with Na2SO4 or by using a phase separator, and then concentrate it under reduced pressure to obtain the purified compound.

[0857] (xii) Chiral preparative chromatography was performed using HPLC or SFC on a standard HPLC or SFC instrument and with isocratic or gradient runs using the mobile phase as described in the experimental section.

[0858] (xiii) The yield (in the presence of the product) is not necessarily the maximum obtainable, and the reaction is repeated if a larger amount of the reaction product is required when needed;

[0859] (xiv) In cases where certain compounds are obtained as acid addition salts (e.g., monohydrochloride or dihydrochloride), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound, and the precise stoichiometry of the salt cannot usually be determined, for example, by elemental analysis data.

[0860] (xv) Generally, the structure of the final product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry; a Bruker Avance III 300, 400, 500 and 600 spectrometer (at 300 MHz, 400 MHz, 500 MHz and 600 MHz respectively) is used. 1(Operated at H frequency) Proton NMR chemical shift values ​​are measured on the delta scale. Experiments are typically recorded at 25 °C. Chemical shifts are given in ppm, with the solvent used as an internal standard. Protons on heteroatoms, such as NH and OH protons, are only reported if detected in the NMR and may therefore be lost. In some cases, protons may be masked or partially masked by solvent peaks and thus either lost and not reported or reported as multiplets overlapping with the solvent. The following abbreviations (and their derivatives, such as dd, doublet; ddd, double doublet; dt, double triplet; dq, double quartet, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qn, quintet; p, pentet; h, heptet. It should be understood that when the NMR spectrum contains residual impurities and / or residual solvents, this situation is not reported unless it coincides or partially coincides with the peaks of the intermediates and / or structures of formula (I). In this case, these peaks are reported as multiplets partially overlapping with the solvent or impurity, and the integration is omitted. In some cases, the structure of the final product of formula (I) may appear as a rotational isomer in the NMR spectrum. In this case, only the peak of the dominant rotational isomer is reported. In some cases, the structure of the final product of formula (I) may appear as a rotational isomer with more equivalent components. In such cases, if the signals of the rotational isomers partially overlap, the peaks of such rotational isomers are reported as multiplets, or if the signals of the rotational isomers are well separated, the peaks of such rotational isomers are reported as separate peaks. Electrospray ionization mass spectrometry (ESI-MS) data were acquired using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar device, acquiring both cation and anion data, and typically reporting only ions relevant to the parent structure; high-resolution ESI-MS data were acquired using a Waters XEVO qToF mass spectrometer coupled to a Waters Acquity UPLC or similar device, acquiring both cation and anion data, and typically reporting only ions relevant to the parent structure.

[0861] (xvi) Intermediates are not necessarily completely purified, but their structure and purity are assessed by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry.

[0862] (xvii) Unless otherwise stated, compounds containing asymmetric carbon and / or sulfur atoms are not resolved;

[0863] (xviii) Generally, the examples and intermediate compounds were named using ChemDraw Professional version 22.2.0 from PerkinElmer. ChemDraw Professional version 22.2.0 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names of chemical structures, and adheres as strictly as possible to the IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by the stereo descriptors referenced in their names and are assigned according to the CIP rules.

[0864] ChemDraw optionally uses symbols such as “&” and “or” in the illustration of the stereochemical center to describe the configuration of the stereochemical center present in the structure.

[0865] The numbers following the “&” and “or” signs are assigned to each cubic center present in the structure. The numbers increment automatically to indicate that the cubic centers can vary independently of each other.

[0866] Generally, for embodiments and intermediates containing more than one stereocenter with a fixed relative configuration, the same number is used after the symbols “&” and “or” to indicate that the stereocenter forms a group. A third stereocenter existing in the same chemical structure, independent of the preceding stereocenter, is indicated by a unique new number after the symbols “&” and “or”.

[0867] Generally, the chemical structure of an embodiment or intermediate containing the symbol "&" at the stereocenter indicates that the configuration of such an embodiment or intermediate at that stereocenter is a mixture of both (R) and (S); and the symbol "or" indicates that the configuration of such an embodiment or intermediate at that stereocenter is (S) or (R). Absolute, unspecified, "&", and "or" stereocenters can all exist in a single structure.

[0868] Generally, for embodiments and intermediates where all stereocenters are designated as "&", the structure is named with the "rac-" prefix. For embodiments and intermediates where all stereocenters are designated as "or", the structure is named with the "rel-" prefix.

[0869] Generally, examples and intermediate compounds are named using descriptors (RS) and (SR) to represent general '&' centers of chemical structures having multiple chiral centers, with only some designated as '&'. Descriptors (R*) and (S*) are used to represent general 'or' centers of chemical structures having multiple chiral centers, with only some designated as 'or'.

[0870] Generally, embodiments and intermediate compounds containing stereocenters with cis or trans arrangements are named using descriptors (RS, SR) or (RS, RS) to indicate chemical structures with multiple chiral centers, only some of which are designated as '&'.

[0871] Generally, all stereocenters present are structures of racemic embodiments and intermediates, no labels are specified for the stereocenters, and the structure is drawn with straight keys at each stereocenter.

[0872] Generally, for embodiments and intermediates in which two or more stereocenters exist within a ring and are fixed to each other and do not change independently (e.g., are cis or trans), the stereocenters are drawn with stereobonds indicating their internal relationships. The stereocenters are marked with "&1" to represent mixtures of cis-configurations or trans-configurations, or "or1" to represent a single cis-isomer or a single trans-isomer with unknown absolute stereochemistry. Generally, if the structure of the embodiment or intermediate also contains one or more racemic stereocenters that are not fixed relative to the previous stereocenters, the stereocenters are drawn with straight bonds at the stereocenters.

[0873] Generally, descriptors (r) and (s) are used to describe the absolute configuration of any pseudo-asymmetric centers in the structure of embodiments and intermediates.

[0874] Generally, on a given chiral HPLC column and eluent, “Isomer 1” corresponds to the first eluting isomer and “Isomer 2” corresponds to the second eluting isomer, and is used to distinguish two isomers containing one or more stereocenters and having an absolutely unknown configuration.

[0875] (xix) In addition to those mentioned above, the following abbreviations and units are also used:

[0876]

[0877]

[0878] Intermediate 1

[0879] Piperidine-4-carboxylic acid

[0880] TFA (6 mL) was added to a DCM (20 mL) solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid and stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness to give the TFA salt of the title compound (2.69 g, 100%).

[0881] Intermediate 2

[0882] 1-(1-(quinazolin-2-ylmethyl)piperidin-4-yl)ethyl-1-one

[0883] Piperidine-4-carboxylic acid TFA intermediate 1 (2.69 g, 11.15 mmol) and sodium triacetoxyborohydride (4.73 g, 22.3 mmol) were added to a DCM (30 mL) solution of quinoline-2-carboxaldehyde (2.63 g, 16.73 mmol), and the resulting mixture was stirred at room temperature for 42 h. 8% NaHCO3 (aq) was added, and stirring was continued for 20 min. The phases were separated using a phase separator, and the organic layer was concentrated. The crude product was purified by silica gel normal-phase rapid chromatography (gradient: 0%-100% EtOAc / heptane (1% TEA)) to give the title compound (2.25 g, 75%) as a brown oil. MS (ESI) m / z [M+H] + 269.3.

[0884] Intermediate 3

[0885] 1-(4-methylpyridin-3-yl)-3-(1-(quinolin-2-ylmethyl)piperidin-4-yl)propane-1,3-dione

[0886] A THF (1.5 mL) solution containing 4-methylnicotinic acid (73 mg, 0.53 mmol) and CDI (86 mg, 0.53 mmol) was stirred at room temperature for 1 h. Under a N2 (g) atmosphere, a THF solution of 1 M LiHMDS (0.533 mL, 0.53 mmol) was added to a THF (1.5 mL) solution of 1-(1-(quinazolin-2-ylmethyl)piperidin-4-yl)ethyl-1-one TFA intermediate 2 (110 mg, 0.41 mmol), and the reaction mixture was stirred for 30 min. An acid solution activated with CDI was added dropwise, and the reaction mixture was stirred at -78 °C for 30 min, then warmed to room temperature for 18 h. The mixture was diluted with EtOAc, washed with saturated NaHCO3 (aq) and brine, and concentrated. The residue was purified by preparative HPLC method D (gradient: 10%-55%) to give the title compound (5 mg, 3%) as a grayish-white solid. MS (ESI) m / z [M+H + 388.3.

[0887] Intermediate 4

[0888] 4-(5-(pyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-carboxylic acid tert-butyl ester

[0889] 4-Methylbenzenesulfonylhydrazine (1.72 g, 9.24 mmol) was added to a toluene (10 mL) solution of pyrimidine-5-carboxaldehyde (1 g, 9.25 mmol), and the reaction mixture was stirred at 20 °C under a N2 (g) atmosphere for 3 h. The mixture was cooled to 0 °C, and 5 M NaOH (aq, 1.85 mL, 9.25 mmol) was added to the suspension. The mixture was stirred at 0 °C for 20 min, and 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (5.81 g, 27.75 mmol) was added. The reaction mixture was stirred at 50 °C for 48 h. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 0%-100% MeCN / water) to give the title compound (1.5 g, 49%) as a yellow solid. MS (ESI) m / z [M+H] + 330.1.

[0890] Intermediate 5

[0891] 4-(5-(4-isopropylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0892] 2-Hydroxyisoindoline-1,3-dione (44.6 mg, 0.27 mmol) and DMAP (1.11 mg, 9.10 µmol) were added to isobutyric acid (29.9 µL, 0.33 mmol) in a microwave-safe vial. DMSO (0.86 mL) was added, followed by DIC (42.3 µL, 0.27 mmol), and the reaction mixture was stirred at room temperature for 24 h. A solution of 4-(5-(pyrimidin-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 4 (60.0 mg, 0.18 mmol) in DMSO (0.75 mL) and a solution of TFA (27.9 µL, 0.36 mmol) in DMSO (0.5 mL) were added to the reactants, followed by 4-CzIPN (1.437 mg, 1.82 µmol). The mixture was evacuated and filled three times with N2 (g), followed by vigorous degassing for 10 min. Use a 34W LED (λ) on the small bottle max Irradiate at 456 nm for 3 h. Filter the solution and purify the filtrate by preparative HPLC method D (gradient: 20%-65%) to obtain the title compound (27 mg, 40%) as a white solid. MS (ESI) m / z [M+H + 372.3.

[0893] Intermediate 6

[0894] 2-((3-acetylpyridin-2-yl)amino)-2-oxoethyl acetate

[0895] TEA (0.77 mL, 5.52 mmol) was added to a solution of 1-(2-aminopyridin-3-yl)ethyl-1-one (500 mg, 3.67 mmol) in DCM (17.2 mL), followed by the addition of ethyl 2-chloro-2-oxoacetate (0.40 mL, 3.67 mmol), and the reaction mixture was stirred at room temperature for 5 h. Additional ethyl 2-chloro-2-oxoacetate (0.08 mL, 0.734 mmol) was added, and the reaction mixture was stirred for another 1 h. The reaction was quenched with saturated NaHCO3 (aq) and stirred overnight. The mixture was passed through a phase separator and concentrated. The crude product was purified by silica gel normal-phase rapid chromatography (gradient: 50%-100% EtOAc / heptane) to give the title compound (720 mg, 83%) as a white solid. MS (ESI) m / z [M+H] + 237.1.

[0896] Intermediate 7

[0897] Methyl (4-methylpyrido[2,3-d]pyrimidin-2-yl)acetate

[0898] NH4OAc (34.3 g, 444.49 mmol) was added aliquots to a solution of 2-((3-acetylpyridin-2-yl)amino)-2-oxoethyl acetate intermediate 6 (21 g, 88.90 mmol) in 200 mL of AcOH. The reaction mixture was divided into seven equal portions, each stirred in a microwave reactor at 130 °C for 1 h. The portions were combined and concentrated. The concentrate was diluted with EtOAc and washed three times with saturated NaHCO3 (aq) solution. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel normal-phase rapid chromatography (gradient: 0%–15% MeOH / DCM) to give the title compound (14.0 g, 73%) as an orange solid. MS (ESI) m / z [M+H] + 218.3.

[0899] Intermediate 8

[0900] (4-Methylpyrido[2,3-d]pyrimidin-2-yl)methanol

[0901] Under a nitrogen (g) atmosphere, a solution of NaOMe in MeOH (3.94 g, 21.88 mmol) was slowly added to a solution of (4-methylpyrido[2,3-d]pyrimidin-2-yl)acetate intermediate 7 (12 g, 55.24 mmol) in MeOH (120 mL). The reaction mixture was stirred at 25 °C for 45 min. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel normal-phase rapid chromatography (gradient: 0%-100% EtOH / DCM) to give the title compound (8.70 g, 90%) as a pale yellow solid. MS (ESI) m / z [M+H] + 176.3.

[0902] Intermediate 9

[0903] Methyl (4-methylpyrido[2,3-d]pyrimidin-2-yl)methanesulfonate

[0904] DIPEA (418 µL, 2.40 mmol) was added to a suspension of (4-methylpyrido[2,3-d]pyrimidin-2-yl)methanol intermediate 8 (210 mg, 1.20 mmol) in DCM (5.58 mL), followed by the addition of MsCl (313 mg, 1.80 mmol). The reaction mixture was stirred for 1 h and then concentrated. The crude product was purified by silica gel normal-phase rapid chromatography (isocratic EtOAc) to give the title compound (0.28 g, 91%) as a pale yellow oil. MS (ESI) m / z [M+H] + 254.1.

[0905] Intermediate 10

[0906] 4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0907] 4-Ethynylpiperidin-1-carboxylic acid tert-butyl ester (1.83 g, 9.83 mmol) was added to a toluene (15 mL) solution of 4-methylpyrimidin-5-carboxaldehyde (1.2 g, 9.83 mmol), and the reaction mixture was stirred at 10 °C for 3 h. 5 M NaOH (aq, 1.97 mL, 9.85 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 30 min. 4-Methylbenzenesulfonyl hydrazine (6.17 g, 29.48 mmol) was added to the reaction mixture at 10 °C, and the mixture was stirred at 50 °C for 50 h. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 0%–100% MeCN / water) to give the title compound (1.00 g, 30%) as a yellow solid. MS (ESI) m / z [M+H] + 344.4.

[0908] Intermediate 11

[0909] 4,6-Dimethyl-5-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyrimidine

[0910] To a microwave-safe vial, charge 4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 10 (71.8 mg, 0.21 mmol) and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (4.69 mg, 4.18 μmol). Seal the vial, evacuate it, and fill it with N2 (g). Add MeCN (0.95 mL) and TFA (0.95 mL). Cool the reaction mixture in an ice bath and degas it with N2 (g) for 2 min, then add tert-butyl peracetate (200 µL, 0.63 mmol). Degas the mixture again for 5 min, then microwave using a 34 W LED (λ). max Irradiated at 456 nm for 1.5 h. The mixture was concentrated, and the residue was treated with water and MTBE. The layers were separated, and the MTBE layer was extracted with water. The combined aqueous layers were concentrated, and the resulting crude material was purified by preparative HPLC method D (gradient 40%) to give the title compound (11 mg, 21%) as a clear oil. MS (ESI) m / z [M+H + 258.2.

[0911] Intermediate 12

[0912] 2-((3-acetyl-6-methylpyridin-2-yl)amino)-2-oxoethyl acetate

[0913] TEA (19.31 mL, 138.5 mmol) was added to a solution of 1-(2-amino-6-methylpyridin-3-yl)ethyl-1-one (10.4 g, 69.25 mmol) and ethyl 2-chloro-2-oxoacetate (9.45 g, 69.25 mmol) in DCM (200 mL) over a 5-min time at 0 °C. The reaction mixture was stirred at 15 °C for 16 h. The solvent was removed under reduced pressure. The crude solid was milled with a 20% petroleum ether solution of EtOAc and filtered. The precipitate was washed with a 20% petroleum ether solution of EtOAc and dried under vacuum to give the title compound (17.2 g, 99%) as a brown solid. MS (ESI) m / z [M+H] + 372.3.

[0914] Intermediate 13

[0915] Methyl (4,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)acetate

[0916] A solution of 2-((3-acetyl-6-methylpyridin-2-yl)amino)-2-oxoethyl acetate intermediate 12 (247 mg, 0.99 mmol) and NH4OAc (380 mg, 4.93 mmol) in AcOH (2.47 mL) was heated in a microwave reactor at 130 °C for 40 min. The solution was concentrated, and the residue was purified by silica gel normal-phase rapid chromatography (gradient: 50%-100% EtOAc / heptane) to give the title compound (89 mg, 39%) as a yellow oil. MS (ESI) m / z [M+H + 232.2.

[0917] Intermediate 14

[0918] (4,7-Dimethylpyrido[2,3-d]pyrimidin-2-yl)methanol

[0919] NaOMe (30 wt% MeOH solution, 397 µL, 2.14 mmol) was added to a solution of (4,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)methyl acetate intermediate 13 (495 mg, 2.14 mmol) in 6.62 mL of MeOH. The reaction mixture was stirred at room temperature for 10 min, then AcOH (123 µL, 2.14 mmol) was added, followed by concentration. The residue was dissolved in DCM (and one drop of MeOH), filtered using a syringe filter, and purified by silica gel normal-phase chromatography (gradient: 0%–20% MeOH / EtOAc) to give the title compound (306 mg, 75%) as a pale yellow solid. MS (ESI) m / z [M+H] + 190.2.

[0920] Intermediate 15

[0921] Methyl (4,7-dimethylpyridino[2,3-d]pyrimidin-2-yl)methanesulfonate

[0922] At 0 °C, a solution of methanesulfonic anhydride (337 mg, 1.93 mmol) in DCM (2 mL) was added to a solution of (4,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)methanol intermediate 14 (305 mg, 1.61 mmol) and DIPEA (421 µL, 2.42 mmol) in DCM (6 mL). The reaction mixture was stirred for 15 min, quenched with saturated NaHCO3 (aq), and diluted with DCM. The aqueous layer was extracted with DCM, and the combined organic layers were washed once with water and once with brine, then dried over MgSO4. The organic layers were filtered and concentrated to give the title compound (424 mg, 98%) as a yellow solid. MS (ESI) m / z [M+H) + 268.1.

[0923] Intermediate 16

[0924] 4-(3-oxo-3-(pyridin-3-yl)propionyl)piperidin-1-carboxylic acid tert-butyl ester

[0925] CDI (3.89 g, 24.0 mmol) was added to a THF (42 mL) solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (5.00 g, 21.8 mmol), and the mixture was stirred at room temperature for 1 h. In a separate flask, a toluene solution of 1 M LiHMDS (43.6 mL, 43.6 mmol) was added dropwise to a THF (42 mL) solution of 3-acetylpyridine (4.79 mL, 43.6 mmol) at -78 °C and stirred for 30 min. A solution of carboxylic acid containing CDI-activated acetylpyridine was added dropwise to the acetylpyridine, and the reaction mixture was warmed to room temperature. The reaction mixture was diluted with EtOAc and washed successively with 10% citric acid (aq), NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 35%-65% EtOAc / heptane) to give the title compound (5.91 g). The product contained 3-acetylpyridine. MS (ESI) m / z [M+H] + 333.3.

[0926] Intermediate 17

[0927] 4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0928] 35% hydrazine hydrate (aq, 2.63 mL, 29.0 mmol) was added to a solution of tert-butyl 4-(3-oxo-3-(pyridin-3-yl)propionyl)piperidin-1-carboxylic acid intermediate 16 (8.12 g, 22.0 mmol) in 85 mL of EtOH. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and concentrated. 1.2 g of the crude product was purified by preparative HPLC method F (gradient: 25%-85%), and the remaining crude product was purified by washing with EtOAc. The two batches were combined to give the title compound (5.4 g, 70%) as a white solid. MS (ESI) m / z [M+H] + 329.3.

[0929] Intermediate 18

[0930] 3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[0931] TFA (5 mL, 64.9 mmol) was added to a solution of tert-butyl 4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid intermediate 17 (1 g, 3.04 mmol) in 30 mL of DCM, and the reaction mixture was stirred at 20 °C for 2 h. The solvent was removed under reduced pressure. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 9%–90% MeCN / water) to give the TFA salt of the title compound (0.70 g) as a pale yellow oil. MS (ESI) m / z [M+H] + 229.1.

[0932] Intermediate 19

[0933] 2-((4-chloro-2-formylphenyl)amino)-2-oxoethyl acetate

[0934] Ethyl 2-chloro-2-oxoethyl acetate (1.54 mL, 14.32 mmol) was added at room temperature to a solution of 2-amino-5-chlorobenzaldehyde (2.13 g, 13.69 mmol) and TEA (2.86 mL, 20.49 mmol) in DCM (63.9 mL). The reaction mixture was stirred at room temperature for 1.5 h, and then another ethyl 2-chloro-2-oxoethyl acetate (0.5 mL, 3.59 mmol) was added. The reaction mixture was stirred for another 1.5 h, and then diluted with water (50 mL). The layers were separated, and the organic layer was passed through a phase separator and concentrated. The residue was washed with EtOAc, and the product as a white solid was collected by filtration. The mother liquor was concentrated and purified by silica gel normal-phase rapid chromatography (gradient: EtOAc / heptane). The fraction containing the product was collected, evaporated, and combined with the precipitate to give the title compound as a white solid (2.25 g, 64%). MS (ESI) m / z [M+H) + 254.1 and 256.1.

[0935] Intermediate 20

[0936] (6-Chloroquinazolin-2-yl)methyl acetate

[0937] AcOH (16.7 mL) was added to a microwave-safe vial containing a mixture of 2-((4-chloro-2-formylphenyl)amino)-2-oxoethyl acetate intermediate 19 (1.71 g, 6.69 mmol) and NH4OAc (1.55 g, 20.01 mmol). The vial was sealed and heated to 130 °C with stirring for 5 min. The mixture was concentrated, redissolved in DCM, and treated with saturated NaHCO3 (aq). The aqueous layer was extracted, and the combined organic layers were concentrated to give the crude title compound (2.03 g). MS (ESI) m / z [M+H] + 237.2 and 239.2.

[0938] Intermediate 21

[0939] (6-Chloroquinazolin-2-yl)methanol

[0940] 1 M LiOH (aq, 12.87 mL, 12.87 mmol) was added to a solution of (6-chloroquinazoline-2-yl)methyl acetate intermediate 20 (2.03 g, 8.58 mmol) in THF (40 mL) and MeOH (20 mL), and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with DCM and saturated NaHCO3 (aq) and then passed through a phase separator. The filtrate was concentrated to give the title compound (1.595 g, 96%). MS (ESI) m / z [M+H] +195.1 and 197.1.

[0941] Intermediate 22

[0942] Methyl (6-chloroquinazoline-2-yl)methanesulfonate

[0943] DCM (35 mL) was added to a mixture of methanesulfonic anhydride (1.948 g, 11.18 mmol) and (6-chloroquinazoline-2-yl)methanol intermediate 21. TEA (2.08 mL, 14.92 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water, extracted with EtOAc, and concentrated. The crude residue was purified by silica gel normal-phase chromatography (gradient: 20%-50% EtOAc / heptane) to give the title compound (1.2 g, 59%) as a pale yellow solid. MS (ESI) m / z [M+H] + 273.2 and 275.2.

[0944] Intermediate 23

[0945] 2-((2-acetyl-6-fluorophenyl)amino)-2-oxoethyl acetate

[0946] 1-(2-amino-3-fluorophenyl)ethane-1-one (0.936 g, 5.81 mmol) was dissolved in DCM (20 mL) and cooled in an ice bath. 4-Methylmorpholine (1.28 mL, 11.64 mmol) was added, followed by dropwise addition of ethyl 2-chloro-2-oxoacetate (0.77 mL, 7.16 mmol). After 15 min, the cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. The solution was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound (1.714 g) as a brown oil. MS (ESI) m / z [M+H] + 254.0.

[0947] Intermediate 24

[0948] (8-Fluoro-4-methylquinazolin-2-yl)methanol

[0949] A solution (15.96 mL, 63.86 mmol) of 2-((2-acetyl-6-fluorophenyl)amino)-2-oxoethyl acetate intermediate 23 in MeOH containing 4 M NH3 was heated and stirred at 80 °C for 2 h under microwave irradiation. The solution was concentrated under reduced pressure, and the crude residue was redissolved in EtOAc, washed with NaHCO3, and the organic layer was concentrated to give the title compound (1.047 g, 94%). MS (ESI) m / z [M+H] + 193.0.

[0950] Intermediate 25

[0951] 2-(chloromethyl)-6-methoxy-4-methylquinazoline

[0952] 1-(2-amino-5-methoxyphenyl)ethane-1-one (190 mg, 1.15 mmol) was dissolved in dioxane (0.5 mL) and cooled to 0 °C. A solution of 4 M HCl in dioxane (1.73 mL, 6.90 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0 °C, and a solution of 2-chloroacetonitrile (109 µL, 1.73 mmol) in dioxane (0.1 mL) was added dropwise, and the reaction mixture was stirred at room temperature over the entire weekend. 2-chloroacetonitrile (109 µL, 1.73 mmol) was added, and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was added dropwise to 2 M NaOH (aq, 6.90 mL, 13.80 mmol) at room temperature, stirred for 15 min, and then extracted with DCM. The organic layer was filtered through a phase separator and concentrated. The residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%-50% EtOAc / heptane) to give the title compound (33 mg, 13%) as a brownish-red solid. MS (ESI) m / z [M+H) + 222.9 and 224.8.

[0953] Intermediate 26

[0954] 4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propionyl)piperidine-1-carboxylic acid tert-butyl ester

[0955] 1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethane-1-one (21.6 g, 0.14 mol) was dissolved in THF (600 mL) under an Ar(g) atmosphere. The turbid solution was cooled to 3 °C in an ice bath. A 1 M KHMDS THF solution (250 mL, 0.25 mol) and a 1 M NaHMDS THF solution (34 mL, 0.03 mol) were added dropwise over 15 min, maintaining the temperature below 5 °C. The reaction mixture was stirred for 30 min, and then 1-(tert-butyl)-4-methylpiperidine-1,4-dicarboxylic acid ester (69.1 g, 0.28 mol) was added in five fractions over 10 min. The reaction mixture was heated to 60 °C for 16 h. The mixture was cooled to room temperature and brine (200 mL) was added. The organic solvent was removed under vacuum, and the residue was extracted with EtOAc (4 × 150 mL). The combined organic layers were dried over Na₂SO₄, filtered, and then concentrated under vacuum. The crude residue was dissolved in MeOH (200 mL). A solution of LiOH hydrate (6.30 g, 0.15 mol) in water (200 mL) was added, and the reaction mixture was rapidly stirred at room temperature for 2 h. The precipitate was separated by filtration. The filtrate was concentrated under reduced pressure to approximately half its volume, and after standing for 2 h, a second batch of precipitate was separated by filtration. The solids were combined, washed with a small amount of water, and dried under vacuum to give a colorless solid (39.02 g, 76%). MS (ESI) m / z [M+H] + 364.4.

[0956] Intermediate 27

[0957] 4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[0958] Intermediate 26 (39.0 g, 107.30 mmol) of 4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propionyl)piperidine-1-carboxylic acid tert-butyl ester was suspended in 99.5% EtOH (350 mL), and 64% hydrazine hydrate (aq, 16.31 mL, 215 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then heated to 70 °C for 20 h. The mixture was concentrated under vacuum, and then DMF (100 mL) was added. More 64% hydrazine hydrate (aq, 8.15 mL, 168.01 mmol) was added, and the mixture was heated to 70 °C for 18 h. H3PO4 (2.372 mL, 36 mmol) was added, and stirring was continued at 70 °C for 16 h. The mixture was concentrated under vacuum. The residue was absorbed into EtOAc (350 mL), filtered, and the filtrate was washed with brine (×4), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was stirred in a mixture of EtOAc (40 mL) and heptane (160 mL) for 12 h. The solid was separated by filtration and dried under vacuum to give the title compound (30.26 g, 78%) as a colorless solid. 1 H NMR (500MHz, DMSO-d6) 1.38 – 1.42(9H, m), 1.49 (2H, qd), 1.86 – 1.92 (2H, m), 2.15 – 2.2 (3H, m), 2.30 (3H,s), 2.81 (3H, bs), 3.66 (3H, s), 4.00 (2H, d), 6.06 (1H, s), 12.2 – 12.49(1H, m). MS (ESI) m / z [M+H] + 360.4.

[0959] Intermediate 28

[0960] 1',3',5'-Trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-Bipyrazole

[0961] Intermediate 27 (30.25 g, 84.15 mmol) of 4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in a mixture of water (50 mL) and 37% HCl (aq, 50 mL), and the reaction mixture was stirred for 20 min. The mixture was concentrated under vacuum and dried under vacuum overnight. IPA (120 mL) was added to the solid, and the mixture was stirred for 6 h. The solid precipitate formed was separated by filtration and washed with small amounts of IPA, IPA / MTBE (1:1), and MTBE. The precipitate was dried under vacuum to give the HCl salt of the title compound (26.733 g, 96%) as a colorless solid.1 H NMR (500MHz, D2O, 25℃) δ 1.88–2.00 (2H, m), 2.24–2.30 (2H, m), 2.35 (6H, d), 3.11–3.26 (3H,m), 3.52 (2H, dt), 3.88 (3H, s), 6.49–6.53 (1H, m). MS (ESI) m / z [M+H] + 260.4.

[0962] Intermediate 29

[0963] 4-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)piperazine tert-butyl 1-pyridinium carboxylate and 4-(3-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole- 5-yl)piperidine-1-carboxylic acid tert-butyl ester (1:1 mixture)

[0964] NaH (60 wt% mineral oil solution) (102 mg, 2.55 mmol) was added at 0 °C to a mixture of 4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 17 (558 mg, 1.70 mmol) and SEM-Cl (331 µL, 1.87 mmol) in THF (8.16 mL). The reaction mixture was stirred for 1 h and then quenched by adding saturated NaHCO3 (aq). The mixture was diluted with DCM, filtered through a phase separator, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 33%–66% EtOAc / heptane) to give the title compound (0.486 g, 62%) as a yellow oil. Two regioisomers were formed in a 1:1 ratio. MS (ESI) m / z [M+H] + 459.5.

[0965] Intermediate 30

[0966] (3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-5-yl)pyridin-4-yl)diphenyl(6-(trifluoromethyl)pyridin-3-yl)trifluoromethanesulfonate phosphonium and (3-(5-(1- (tert-butoxycarbonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)pyr Phosphorus-4-yl)diphenyl(6-(trifluoromethyl)pyridin-3-yl)trifluoromethanesulfonate (1:1 mixture)

[0967] A 1M methanesulfonic anhydride solution in DCM (598 µL, 0.60 mmol) was added dropwise at -46 °C to a solution of tert-butyl 4-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid intermediate 29 (218 mg, 0.66 mmol) in DCM (5.30 mL). The reaction mixture was stirred for 2 h, then cooled to -78 °C, and DBU (89 µL, 0.60 mmol) was added. The mixture was warmed to room temperature and stirred for 30 min, then diluted with DCM and washed with water. The organic layer was passed through a phase separator and concentrated to give the title compound (542.8 mg, 97%), a (1:1) mixture of regioisomers. MS (ESI) m / z [M+H + 788.7.

[0968] Intermediate 31

[0969] 4-Chloro-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[0970] Transfer vials containing intermediate 30 (0.563 g, 0.6 mmol) of (3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)pyridine-4-yl)diphenyl(6-(trifluoromethyl)pyridine-3-yl)trifluoromethanesulfonate and (3-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-yl)pyridine-4-yl)diphenyl(6-(trifluoromethyl)pyridine-3-yl)trifluoromethanesulfonate (1:1 mixture) to a glove box. Add anhydrous LiCl (0.102 g, 2.40 mmol), followed by dioxane (3 mL). Remove the vial from the glove box, heat to 80°C, and stir over the entire weekend. Cool the mixture to room temperature and concentrate. Dissolve the crude residue in DCM (4 mL) and treat with TFA (4 mL, 0.60 mmol). Stir the reaction mixture overnight and concentrate. Purify the crude residue by preparative HPLC method D (gradient: 15%–55%) to give the title compound (33 mg, 21%) as a colorless thin film. MS (ESI) m / z [M+H] + 263.1 and 265.1.

[0971] Intermediate 32

[0972] 4-(3-(4-methylpyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[0973] The reaction for synthesizing this intermediate was carried out in a flow reactor. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.08 g, 43.95 mmol) was added to a 400 mL solution of CDI (6.80 g, 41.95 mmol) in THF at 25 °C and stirred for 1 h. 1-(4-methylpyridin-3-yl)ethane-1-one (5.40 g, 39.95 mmol) was added to the mixture. A second solution containing 1 M LiHMDS in THF was prepared, and the two solutions were mixed in a flow reactor such that a pumping rate of 1 mL / min of the 1 M LiHMDS in THF solution was mixed with a pumping rate of 2 mL / min of CDI-activated acid solution. The eluted solution was stirred for 10 min under a N2 (g) atmosphere and then concentrated. The concentrate was diluted with EtOAc and washed successively with 0.5 M citric acid (aq), water, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound (12.8 g, 92%) as a yellow oil. MS (ESI) m / z [M+H + 347.1.

[0974] Intermediate 33

[0975] 4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0976] Hydrazine monohydrate (5.06 g, 101.03 mmol) was added dropwise to a solution of 4-(3-(4-methylpyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester intermediate 32 (7.00 g, 20.21 mmol) in 150 mL of EtOH, and the reaction mixture was stirred at 20 °C for 1 h. The mixture was concentrated, and the crude residue was purified by reversed-phase rapid chromatography on a C18 column (gradient: 5%–40% MeCN / water) to give the title compound (4.90 g, 71%) as a white solid. MS (ESI) m / z [M+H] + 343.1.

[0977] Intermediate 34

[0978] 4-Methyl-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[0979] TFA (3 mL, 3.02 mmol) was added to a solution of 4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 33 (1.03 g, 3.01 mmol) in DCM (9 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and redissolved in MeOH (10 mL). Et₂O (50 mL) was added, the solution was stirred, a white precipitate formed, which was filtered off and washed with MTBE. The precipitate was dried under vacuum to give the TFA salt of the title compound (1.33 g, 93%) as a white solid. MS (ESI) m / z [M+H] + 243.2.

[0980] Intermediate 35

[0981] 4-(3-(5-chloropyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[0982] CDI (2.78 g, 17.15 mmol) was added to a THF (31.2 mL) solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.98 g, 17.36 mmol) and stirred at room temperature for 1 h. In a separate flask, 1 M LiHMDS (18.01 mL, 18.01 mmol) was added dropwise to a THF (36.5 mL) solution of 1-(5-chloropyridin-3-yl)ethane-1-one (2.67 g, 17.15 mmol) at -78 °C and stirred for 30 min. A solution of carboxylic acid activated by CDI was added dropwise, and the reaction mixture was warmed to room temperature. The reaction mixture was diluted with EtOAc and washed successively with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 20%-35% EtOAc / heptane), followed by further purification by preparative HPLC method G (gradient 20%-80%), yielding the title compound (2.88 g, 46%) as a white solid. MS (ESI) m / z [M+H + 365.2.

[0983] Intermediate 36

[0984] 4-(5-(5-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0985] Hydrazine hydrate (aq, 0.796 mL, 16.36 mmol) was added to a solution of 35 (3.0 g, 8.18 mmol) of intermediate tert-butyl 4-(3-(5-chloropyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester in EtOH (26.5 mL). The reaction mixture was heated to 50 °C and stirred overnight. The solvent was concentrated, and the residue was purified by silica gel normal-phase rapid chromatography (gradient: 5%-50% EtOAc / heptane) to give the title compound as a white solid. MS (ESI) m / z [M+H + 363.3.

[0986] Intermediate 37

[0987] 3-Chloro-5-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[0988] TFA (8 mL) was added to a suspension of tert-butyl 4-(5-(5-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid intermediate 36 (2.86 g, 7.88 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated to give a yellow oil, which was treated with Et2O. The product precipitate was collected by filtration and washed with additional Et2O to give the TFA salt of the title compound (3.72 g, 96%) as a grayish-white solid. MS (ESI) m / z [M+H] + 263.3.

[0989] Intermediate 38

[0990] 2-((4-(5-(5-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2, 3-d]pyrimidine

[0991] (4-methylpyrido[2,3-d]pyrimidin-2-yl)methanesulfonate intermediate 9 (71.4 mg, 0.28 mmol) and DIPEA (196 µL, 1.13 mmol) were added to a solution of 3-chloro-5-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine, 2-TFA intermediate 37 (160 mg, 0.33 mmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 3 h and then filtered using a syringe filter. The resulting solution was purified by preparative HPLC method D (gradient: 15%–55%) to give the title compound (0.067 g, 57%) as a pale yellow solid. MS (ESI) m / z [M+H] + 220.3.

[0992] Intermediate 39

[0993] 4-(3-(2-methylpyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[0994] The reaction for synthesizing this intermediate was carried out in a flow reactor. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.08 g, 43.95 mmol) was added to a 400 mL solution of CDI (6.80 g, 41.95 mmol) in THF, and the mixture was stirred at 20 °C for 1 h. 1-(2-methylpyridin-3-yl)ethane-1-one (5.40 g, 39.95 mmol) was added to this solution. A second solution containing 1 M LiHMDS in THF was prepared, and the two solutions were mixed in a flow environment such that a pumping rate of 1 mL / min of the 1 M LiHMDS in THF solution was mixed with a 2 mL / min flow rate of the CDI-activated acid solution, without cooling. The eluted solution was stirred for 10 min under a N2 (g) atmosphere, and then concentrated under vacuum. The concentrate was diluted with EtOAc and washed successively with 0.5 M citric acid (aq), water, and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated to obtain the title compound (12.1 g, 87%) as a yellow oil. MS (ESI) m / z [M+H] + 347.1.

[0995] Intermediate 40

[0996] 4-(5-(2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[0997] Hydrazine monohydrate (4.34 g, 86.60 mmol) was added dropwise at 20 °C to a solution of EtOH (150 mL) containing intermediate 39 (6.00 g, 17.32 mmol) of 4-(3-(2-methylpyridin-3-yl)-3-oxopropionyl)piperidin-1-carboxylic acid tert-butyl ester. The reaction mixture was stirred at 20 °C for 1 h, and then concentrated under reduced pressure. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 5%-40% MeCN / water) to give the title compound (4.30 g, 73%) as a white solid. MS (ESI) m / z [M+H] + 343.2.

[0998] Intermediate 41

[0999] 2-Methyl-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[1000] TFA (3 mL, 3.12 mmol) was added to a solution of 2-methyl-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine intermediate 40 (1.07 g, 3.12 mmol) in DCM (9 mL), and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and redissolved in MeOH (10 mL). Et₂O (50 mL) was added, and the solution was stirred. The precipitate formed was collected by filtration, washed with MTBE, and dried under vacuum to give the TFA salt of the title compound as a white solid (1.376 g, 94%). MS (ESI) m / z [M+H) + 243.2.

[1001] Intermediate 42

[1002] 3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-4-(hydroxymethyl)pyridine 1-oxide

[1003] 70% mCPBA (aq, 91 mg, 0.37 mmol) was added to a solution of 106 mg, 0.31 mmol, of intermediate 33 (tert-butyl piperidine-1-carboxylic acid) in DCM (1.55 mL), and stirred at room temperature for 1 h. The mixture was purified by silica gel normal-phase rapid chromatography (gradient: 0%–20% MeOH / EtOAc) to give the title compound (96 mg, 87%) as a white solid. MS (ESI) m / z [M+H] + 359.3.

[1004] Intermediate 43

[1005] 4-(5-(4-(hydroxymethyl)pyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[1006] A solution of 3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-4-(hydroxymethyl)pyridine 1-oxide intermediate 41 (42.0 mg, 0.12 mmol) in Ac₂O (0.7 mL, 0.12 mmol) was heated to 80 °C and stirred for 6 h. The solvent was concentrated and MeOH (1 mL) was added. 2M NaOH (aq, 0.293 mL, 0.59 mmol) was added, and the mixture was stirred at room temperature for 1 h, then concentrated. The residue was treated with DMSO and filtered using a syringe filter. The filtrate was purified by preparative HPLC method D (gradient: 15%-55%) to give the title compound (20 mg, 48%) as a clear oil. MS (ESI) m / z [M+H] + 359.3.

[1007] Intermediate 44

[1008] 4-(5-(2-ethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[1009] Propionic acid (68.1 µL, 0.91 mmol) and DIC (106 µL, 0.69 mmol) were added to a solution of 2-hydroxyisoindoline-1,3-dione (149 mg, 0.91 mmol) and DMAP (5.58 mg, 0.05 mmol) in DMSO (2.197 mL). The reaction mixture was stirred at room temperature for 24 h. A solution of 4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 17 (150 mg, 0.46 mmol) and (1R)-(-)-CSA (212 mg, 0.91 mmol) in DMSO (2.2 mL) was added to the reaction mixture, followed by the addition of 4-CzIPN (3.60 mg, 4.57 μmol). The reaction mixture was evacuated and filled three times with N2 (g), followed by vigorous degassing with N2 (g) for 10 min. The vials were then filled with a 34 W LED (λ). max Irradiated with 456 nm for 24 h, then purified by preparative HPLC (gradient: 30%-70%) to obtain the title compound (10.0 mg, 6%). MS (ESI) m / z [M+H + 287.4.

[1010] Intermediate 45

[1011] 4-(5-(2,4-diethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[1012] Step a) 1,3-Dioxoisoindoline-2-ylpropionate

[1013] DIC (0.313 mL, 2.00 mmol) was added to a solution of propionic acid (148 mg, 2 mmol), DMAP (12 mg, 0.10 mmol), and 2-hydroxyisoindoline-1,3-dione (0.326 g, 2.00 mmol) in anhydrous DMSO (5.67 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered to give a 0.3 M solution of the title compound. This solution was used for the next step.

[1014] Step b) 4-(5-(2,4-diethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[1015] To a microwave-safe vial, add 4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-carboxylic acid tert-butyl ester intermediate 33 (66 mg, 0.20 mmol), 4CzIPN (3.17 mg, 4.02 μmol), and CSA (93 mg, 0.40 mmol), then add DMSO (1.1 mL) and 1,3-dioxoisoindoline-2-yl propionate intermediate 45 (step a) (0.3 M solution in DMSO, 1.34 mL, 0.40 mmol). Seal the vial, evacuate, and refill three times with N2 (g). Filter the reaction mixture using a 34W LED (λ). max Irradiated at 456 nm for 2.5 h. The mixture was filtered and purified by preparative HPLC method D (gradient: 25%-75%) to give the title compound (4.6 mg, 6%). MS (ESI) m / z [M+H + 385.5.

[1016] Intermediate 46

[1017] 4-(3-(2,4-dimethylpyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1018] The reaction for synthesizing this intermediate was carried out in a flow reactor. 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.38 g, 14.75 mmol) was added at 20 °C to a THF (400 mL) solution of CDI (2.28 g, 14.08 mmol). The resulting solution was stirred at 55 °C for 1 h. 1-(2,4-dimethylpyridin-3-yl)ethane-1-one (2.00 g, 13.41 mmol) was added to this solution. A second solution containing 1 M LiHMDS in THF was prepared, and the two solutions were mixed in a flow reactor such that a pumping rate of 1 mL / min of 1 M LiHMDS in THF was mixed with a pumping rate of 2 mL / min of CDI-activated acid solution. The eluted solution was stirred for 10 min under a N2 (g) atmosphere and then quenched with brine. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 0%-100% MeCN / water) to give the title compound (2.00 g, 41%) as a brown oil. MS (ESI) m / z [M+H + 361.1.

[1019] Intermediate 47

[1020] 4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester

[1021] Under a nitrogen (g) atmosphere, hydrazine hydrate (aq, 3.12 g, 62.42 mmol) was added at 20 °C to a solution of 4-(3-(2,4-dimethylpyridin-3-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester intermediate 46 (4.5 g, 12.48 mmol) in 50 mL of EtOH, and stirred at 80 °C for 3 h. The solvent was removed under reduced pressure. The crude product was purified by reversed-phase rapid chromatography on a C18 column (gradient: 0%-100% MeCN / water) to give the title compound (3.75 g, 84%) as a white solid. MS (ESI) m / z [M+H] + 357.2.

[1022] Intermediate 48

[1023] (Z)-2-chloro-2-(2-(2-methyl-6-nitrophenyl)hydrazine)ethyl acetate

[1024] 12.5 M HCl (aq, 5.26 mL, 65.72 mmol) was added at 0 °C to a MeOH solution of 2-methyl-6-nitroaniline (2 g, 13.14 mmol) (12.6 mL), and the reaction mixture was stirred for 15 min under a N2 (g) atmosphere. A solution of NaNO2 (0.998 g, 14.46 mmol) in water (2.40 mL) was added, and the reaction mixture was stirred at 0 °C for 2 h. The mixture was filtered through a CELITE pad, and ethyl 2-chloro-3-oxobutyrate (2.81 g, 17.09 mmol) was added to the filtrate. The reaction mixture was stirred at 20 °C for 2 h. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (3.50 g, 93%) as a yellow solid. MS (ESI) m / z [M+H] + 286.0.

[1025] Intermediate 49

[1026] 8-Methylbenzo[e][1,2,4]triazine-3-carboxylic acid ethyl ester

[1027] Under a N2(g) atmosphere, 12.5 M HCl (aq, 1.80 mL, 22.53 mmol) was added at 20 °C to a solution of (Z)-2-chloro-2-(2-(2-methyl-6-nitrophenyl)hydrazine)ethyl acetate intermediate 48 (3 g, 11.27 mmol) in AcOH (17.8 mL). The solution was added dropwise to a solution of Fe(s) (3.15 g, 56.34 mmol) in water (4.3 mL), and the reaction mixture was stirred for 16 h. The mixture was poured into brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-50% EtOAc / heptane) to give the title compound (2 g, 82%) as a yellow solid. MS (ESI) m / z [M+H] + 218.1.

[1028] Intermediate 50

[1029] (8-Methylbenzo[e][1,2,4]triazine-3-yl)methanol

[1030] Under a N2(g) atmosphere, a 2M LiAlH4 solution in THF (9.21 mL, 18.41 mmol) was added dropwise over 30 min at 0 °C to a 2 mL solution of ethyl 8-methylbenzo[e][1,2,4]triazine-3-carboxylic acid intermediate 49 (2 g, 9.21 mmol) in THF. The reaction mixture was stirred at 0 °C for 2 h, and then the reaction was quenched by adding 2M NaOH(aq). The mixture was filtered through a CELITE filter, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC method N (gradient: 5%–30%) to give the title compound (1 g, 62%) as a yellow solid. MS (ESI) m / z [M+H] + 176.1.

[1031] Intermediate 51

[1032] Methyl (8-methylbenzo[e][1,2,4]triazine-3-yl)methanesulfonate

[1033] DIPEA (253 µL, 1.45 mmol) was added to a solution of (8-methylbenzo[e][1,2,4]triazine-3-yl)methanol intermediate 50 (212 mg, 1.21 mmol) in DCM (6 mL), and the mixture was cooled to 0 °C. A solution of methanesulfonic anhydride (232 mg, 1.33 mmol) in DCM (1 mL) was added, and the reaction mixture was stirred at room temperature for 1 h. Further methanesulfonic anhydride (200 mg, 1.96 mmol) was added, and the reaction mixture was stirred for 5 min. The mixture was concentrated and purified by silica gel normal-phase rapid chromatography (gradient: 25%–50% EtOAc / heptane) to give the title compound (0.266 g, 87%) as a yellow solid. MS (ESI) m / z [M+H] + 254.2.

[1034] Intermediate 52

[1035] 2,4-Dimethyl-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[1036] Under a nitrogen (g) atmosphere, a 3.51 mL solution (14.03 mmol) of dioxane in 4 M HCl was added to a 5 mL solution of dioxane containing 500 mg (1.40 mmol) of 4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 47. The reaction mixture was stirred at 20 °C for 1 h. The solvent was removed under reduced pressure to give a 500 mg TFA salt of the title compound as a yellow solid. 1 H NMR (300MHz, DMSO) δ 8.67 (1H, d), 7.89 (1H, d), 6.36(1H, s), 3.37 – 3.25 (2H, m), 3.13 – 2.93 (3H, m), 2.59 (s, 3H), 2.42 (s,3H), 2.17 (2H, m), 1.88 (2H, m).

[1037] Intermediate 53

[1038] 5-Methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride

[1039] 5-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (0.131 g, 0.8 mmol) was suspended in DCM (2.2 mL). Oxaloyl chloride (0.143 mL, 1.60 mmol) was added, and the mixture was cooled in an ice bath. DMF (6.19 µL, 0.08 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and co-evaporated with DCM to give the title compound (0.137 g, 98%). 1 H NMR (500MHz, DMSO-d6) 3.60 (3H, s), 4.06 (3H, s), 7.63 (1H, s).

[1040] Intermediate 54

[1041] 4-(3-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tertiary Butyl acetate

[1042] Pd(PPh3)2Cl2 (0.017 g, 0.02 mmol) was added to a solution of 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (0.103 g, 0.493 mmol), 5-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride intermediate 53 (0.129 g, 0.74 mmol), CuI (4.7 mg, 0.02 mmol), and TEA (0.412 mL, 2.96 mmol) in THF (0.85 mL) and toluene (0.85 mL). The reaction mixture was stirred at room temperature for 3 h under a N2 (g) atmosphere. DCM (7 mL) and saturated NaHCO3 (aq, 7 mL) were added. The mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-40% (EtOAc / 4M NH3 in MeOH solution (9 / 1)) / DCM) to give the title compound (0.038 g, 22%). MS (ESI) m / z [(M-Boc)+H] + 248.1. 1 H NMR (500MHz, CDCl3) 1.46 (9H, s), 1.64 – 1.75 (2H,m), 1.86 – 1.94 (2H, m), 2.76 – 2.87 (1H, m), 3.22 (2H, ddd), 3.67 (3H, s),3.70 – 3.80 (2H, m), 4.21 (3H, s), 7.86 (1H, s).

[1043] Intermediate 55

[1044] 4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1045] Intermediate 54 (0.037 g, 0.11 mmol) of 4-(3-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 99.5% EtOH (0.7 mL). 64% hydrazine hydrate (aq, 0.026 mL, 0.53 mmol) was added, and the reaction mixture was stirred overnight at room temperature. DCM and NaHCO3 (aq) were added, the mixture was stirred, filtered through a phase separator, and concentrated to give the title compound (0.039 g). This was used as is in the next step.

[1046] MS (ESI) m / z [M+H] + 362.3.

[1047] Intermediate 56

[1048] 5'-Methoxy-1'-methyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole

[1049] TFA (15.77 mg, 0.14 mmol) was added at 10 °C to a solution of 55 (50 mg, 0.14 mmol) of 4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 55 in DCM (1 mL), and the reaction mixture was stirred for 2 h. The mixture was concentrated to give the TFA salt of the title compound (40 mg). MS (ESI) m / z [M+H) + 262.1.

[1050] Intermediate 57

[1051] 5-Methyl-1,8-naphthyl-2-carboxylic acid

[1052] Under a nitrogen (N2) atmosphere, NaOH (1.175 g, 29.38 mmol) was added to a solution of 2-amino-4-methylnicotinaldehyde (1 g, 7.34 mmol) and methyl 2-oxopropionate (1.5 g, 14.69 mmol) in IPA (50 mL) and water (50 mL). The reaction mixture was stirred at 20 °C for 16 h. The mixture was filtered, and the solvent was removed under reduced pressure to give the title compound (1.3 g, 94%) as a yellow solid. MS (ESI) m / z [M+H] + 188.8.

[1053] Intermediate 58

[1054] 5-Methyl-1,8-naphthyl-2-carboxylic acid methyl ester

[1055] SOCl2 (0.465 mL, 6.38 mmol) was added at 0 °C to a MeOH (10 mL) solution of 5-methyl-1,8-naphthidine-2-carboxylic acid intermediate 57 (1.2 g, 6.38 mmol). The reaction mixture was stirred at 60 °C for 2 h. The solvent was removed under reduced pressure to give a crude product, which was purified by silica gel normal-phase rapid chromatography (gradient: 30%-50% EtOAc / petroleum ether) to give the title compound (0.750 g, 58%) as a yellow solid. MS (ESI) m / z [M+H] + 203.2.

[1056] Intermediate 59

[1057] (5-Methyl-1,8-naphthid-2-yl)methanol

[1058] NaBH4 (374 mg, 9.89 mmol) was added at 0 °C to a MeOH (20 mL) solution of methyl 5-methyl-1,8-naphthyl-2-carboxylic acid intermediate 58 (500 mg, 2.47 mmol). The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with ice water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by preparative HPLC method Q (gradient: 10%-25%) to give the title compound (265 mg, 62%) as a white solid. MS (ESI) m / z [M+H) + 175.3.

[1059] Intermediate 60

[1060] 2-((2-acetyl-4-chlorophenyl)amino)-2-oxoethyl acetate

[1061] Ethyl 2-chloro-2-oxoethyl acetate (310 µL, 2.79 mmol) was added dropwise at 0 °C to a solution of 1-(2-amino-5-chlorophenyl)ethane-1-one (395 mg, 2.33 mmol) and NMM (512 µL, 4.66 mmol) in DCM (9 mL) and stirred for 15 min. The cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. The solution was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (769 mg) as a brown oil. MS (ESI) m / z [M+H] + 270.2.

[1062] Intermediate 61

[1063] (6-Chloro-4-methylquinazolin-2-yl)methanol

[1064] 2-((2-acetyl-4-chlorophenyl)amino)-2-oxoethyl acetate intermediate 60 (628 mg, 2.33 mmol) was dissolved in a 4 M NH3 solution of MeOH (6.4 mL, 25.6 mmol) and stirred in a microwave reactor at 85 °C for 10 h. The mixture was concentrated, redissolved in EtOAc, and washed with saturated NaHCO3 (aq). The organic layer was concentrated to give the title compound (449 mg, 92%) as a beige solid. MS (ESI) m / z [M+H] + 209.1.

[1065] Intermediate 62

[1066] 6-Chloro-2-(chloromethyl)-4-methylquinazoline

[1067] NCS (316 mg, 2.37 mmol) was added at 0 °C to a solution of (6-chloro-4-methylquinazolin-2-yl)methanol intermediate 61 (449 mg, 2.15 mmol) and PPh3 (621 mg, 2.37 mmol) in DCM (7 mL) and stirred for 3 h. The reaction mixture was concentrated and purified by silica gel normal-phase rapid chromatography (gradient: 5%-40%) to give the title compound (217 mg, 44%) as a white solid. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.95 (3H, s), 4.84 (2H, s), 7.83 (1H, m), 7.98 (1H, m), 8.07 (1H, m).

[1068] Intermediate 63

[1069] 2-((3-chloro-2-formylphenyl)amino)-2-oxoethyl acetate

[1070] Ethyl 2-chloro-2-oxoethyl acetate (3.7 mL, 34.4 mmol) was added dropwise at 0 °C to a solution of 2-amino-6-chlorobenzaldehyde (4.46 g, 28.67 mmol) and DIPEA (7.49 mL, 43.0 mmol) in DCM (60 mL) and stirred for 2 h. Additional ethyl 2-chloro-2-oxoethyl acetate (0.616 mL, 5.73 mmol) was added, and the reaction mixture was stirred for 45 min. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (6.46 g, 88%) as a brown solid. MS (ESI) m / z [MH] - 253.9.

[1071] Intermediate 64

[1072] (5-Chloroquinazolin-2-yl)methyl acetate

[1073] Intermediate 63 of 2-((3-chloro-2-formylphenyl)amino)-2-oxoethyl acetate (6.97 g, 27.26 mmol) and NH4OAc (6.30 g, 81.79 mmol) were suspended in AcOH (91 mL). The mixture was aliquoted into seven microwave-safe vials, each stirred at 130 °C for 3 min under microwave irradiation. All mixtures were then combined, and the solvent was removed under reduced pressure. The residue was diluted with toluene and washed with water, saturated NaHCO3 (aq), and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (5.46 g, 85%) as a brown solid. MS (ESI) m / z [M+H] + 209.1.

[1074] Intermediate 65

[1075] (5-Chloroquinazolin-2-yl)methanol

[1076] LiOH (0.112 g, 4.67 mmol) was added to a solution of (5-chloroquinazoline-2-yl)methyl acetate intermediate 64 (0.85 g, 3.59 mmol) in THF (9 mL), MeOH (6 mL), and water (5 mL), and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated to give the title compound (0.640 g, 92%) as a yellow solid.

[1077] Intermediate 66

[1078] Methyl (5-chloroquinazoline-2-yl)methanesulfonate

[1079] Methanesulfonyl chloride (258 µL, 3.33 mmol) was added at 0 °C to a solution of (5-chloroquinazoline-2-yl)methanol intermediate 65 (499 mg, 2.56 mmol) and DIPEA (672 µL, 3.85 mmol) in 10 mL of DCM. The reaction mixture was stirred for 90 min, then diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (689.6 mg, 99%) as a brown oil. MS (ESI) m / z [M+H] + 273.0.

[1080] Intermediate 67

[1081] 2-((2-acetyl-4-bromophenyl)amino)-2-oxoethyl acetate

[1082] Ethyl 2-chloro-2-oxoethyl acetate (0.616 mL, 5.56 mmol) was added dropwise at 0 °C to a solution of 1-(2-amino-5-bromophenyl)ethane-1-one (0.992 g, 4.63 mmol) and NMM (1.019 mL, 9.27 mmol) in 16 mL of DCM. The reaction mixture was stirred for 15 min, then the cooling bath was removed, and the reaction mixture was warmed to room temperature overnight. The mixture was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (1.623 g) as a brown solid. MS (ESI) m / z [MH] - 312.0 and 314.0.

[1083] Intermediate 68

[1084] (6-Bromo-4-methylquinazolin-2-yl)methanol

[1085] Intermediate 67 of 2-((2-acetyl-4-bromophenyl)amino)-2-oxoethyl acetate (1.456 g, 4.63 mmol) was dissolved in a 4 M NH3 solution of MeOH (12.75 mL, 50.98 mmol) and heated in a microwave reactor at 85 °C for 8 h. The solution was concentrated under vacuum, redissolved in EtOAc, and washed with saturated NaHCO3 (aq). The organic layer was concentrated to give the title compound (1.112 g, 95%) as a beige solid. MS (ESI) m / z [M+H] + 252.9 and 254.9.

[1086] Intermediate 69

[1087] 6-Bromo-2-(chloromethyl)-4-methylquinazoline

[1088] PPh3 (1.268 g, 4.83 mmol) was added to a solution of (6-bromo-4-methylquinazolin-2-yl)methanol intermediate 68 (1.112 g, 4.39 mmol) in DCM (15 mL). The mixture was cooled to 0 °C, NCS (0.645 g, 4.83 mmol) was added, and the reaction mixture was stirred for 3 h. The mixture was concentrated and purified by silica gel normal-phase rapid chromatography (gradient: 10%-40% EtOAc / heptane) to give the title compound (0.581 g, 49%) as a white solid. MS (ESI) m / z [MH] - 269.0 and 271.0.

[1089] Intermediate 70

[1090] 6-Bromo-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1- methylquinoline

[1091] A solution of 1',3',5'-trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl intermediate 28 (156 mg, 0.60 mmol), 6-bromo-2-(chloromethyl)-4-methylquinazoline intermediate 69 (158 mg, 0.58 mmol), and K₂CO₃ (663 mg, 4.80 mmol) in MeCN (9 mL) was stirred overnight at 42 °C. After cooling to room temperature, the precipitated solid was filtered off and washed with MeCN. The filtrate was concentrated and purified by reversed-phase rapid chromatography on a C18 column (gradient: 5%-95% MeCN / 0.1% NH₄OH (aq)) to give the title compound (217 mg, 73%) as a beige solid. MS (ESI) m / z [M+H] + 494.2 and 496.1.

[1092] Intermediate 71

[1093] (4-acetyl-6-methoxypyridin-2-yl)tert-butyl carbamate

[1094] A dry Et₂O (100 mL) solution of (4-acetyl-6-methoxypyridin-2-yl)carbamate tert-butyl ester (5.25 g, 23.41 mmol) and TMEDA (10.9 mL, 23.41 mmol) was cooled to -70 °C under an Ar (g) atmosphere, and a heptane solution of 1.6 MnBuLi (43.9 mL, 70.24 mmol) was slowly added. After complete addition, the reaction mixture was stirred at -15 °C for 2 h. The mixture was cooled to -70 °C, and N-methoxy-N-methylacetamide (5 mL, 52.37 mmol) was added dropwise over 10 min. The cooling bath was removed, and the reaction mixture was warmed to room temperature overnight. The mixture was poured into a solution of NH₄Cl (aq) and ice. The layers were separated, the aqueous layer was extracted with MTBE, and the combined organic layers were washed with 5% citric acid (aq) and brine. The organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (15% EtOAc / heptane) to give 1.48 g of the title compound as a yellow solid. MS (ESI) m / z [M+H + 267.1.

[1095] Intermediate 72

[1096] 1-(5-amino-2-methoxypyridin-4-yl)ethane-1-one

[1097] TFA (5.79 mL, 75.10 mmol) was added to a solution of (4-acetyl-6-methoxypyridin-3-yl)carbamate intermediate 71 (1 g, 3.76 mmol) in DCM (12.4 mL), and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The organic layers were combined, filtered through a hydrophobic glass frit, and concentrated to give the title compound (0.616 g, 99%) as a yellow solid. MS (ESI) m / z [M+H] + 167.1.

[1098] Intermediate 73

[1099] 2-((4-acetyl-6-methoxypyridin-3-yl)amino)-2-oxoethyl acetate

[1100] Ethyl 2-chloro-2-oxoethyl acetate (0.427 mL, 3.97 mmol) was added at 0 °C to a solution of DCM (20 mL) containing TEA (2.52 mL, 18.05 mmol) and 1-(5-amino-2-methoxypyridin-4-yl)ethane-1-one intermediate 72 (600 mg, 3.61 mmol), and stirred for 3 h. The mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (0%–50% EtOAc / heptane) to give the title compound (869 mg, 90%) as a yellow solid. 1 H NMR (500MHz, CDCl3,25℃) δ 2.18 (3H, s), 2.55 (3H, s), 3.88 (4H, s), 4.64 (2H, s), 7.23 (1H, ds, 8.62 (1H, s).

[1101] Intermediate 74

[1102] (6-methoxy-4-methylpyridino[3,4-d]pyrimidin-2-yl)methanol

[1103] Intermediate 73 (869 mg, 3.26 mmol) of 2-(4-acetyl-6-methoxypyridin-3-yl)amino)-2-oxoethyl acetate in 10 mL of 4 M NH3 MeOH solution was heated at 80 °C for 4 h under microwave irradiation. The mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The combined organic layers were washed with brine, filtered through a hydrophobic glass frit, and concentrated. The residue was redissolved in 10 mL of 4 M NH3 MeOH solution and heated at 80 °C for 3 h under microwave irradiation. The mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The combined organic layers were washed with brine, filtered through a hydrophobic glass frit, and concentrated to give the title compound (547 mg, 82%). MS (ESI) m / z [M+H] + 206.0.

[1104] Intermediate 75

[1105] 2-(chloromethyl)-8-fluoro-4-methylquinazoline

[1106] (8-fluoro-4-methylquinazolin-2-yl)methanol intermediate 24 (111 mg, 0.58 mmol) was dissolved in DCM (2 mL), and PPh3 (166 mg, 0.63 mmol) was added. The reaction mixture was cooled in an ice bath, and NCS (85 mg, 0.63 mmol) was added. The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 25%-50% EtOAc / heptane) to give the title compound (0.093 g, 77%) as a white solid. MS (ESI) m / z [M+H] + 211.0. 1 H NMR (500MHz, CDCl3) 3.00 (3H, s), 4.89 (2H, s), 7.57 – 7.64 (2H, m), 7.87 – 7.94 (1H, m).

[1107] Intermediate 76

[1108] 2-((2-acetyl-4-fluorophenyl)amino)-2-oxoethyl acetate

[1109] 1-(2-amino-5-fluorophenyl)ethane-1-one (4.95 g, 31.35 mmol) was dissolved in DCM (90 mL) and cooled in an ice bath. NMM (6.89 mL, 62.70 mmol) was added, followed by dropwise addition of acetoxyacetyl chloride (4.17 mL, 37.62 mmol). After 15 min, the cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (8.72 g) as a brown oil. MS (ESI) m / z [M+H] + 254.0. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.36 (3H, s), 2.65 (3H, s), 4.72 (2H, s), 7.29 (1H,ddd), 7.58 (1H, dd), 8.80 (1H, dd), 12.10 (1H, s). 19 F NMR (471MHz, CDCl3) δ -117.68.

[1110] Intermediate 77

[1111] (6-Fluoro-4-methylquinazolin-2-yl)methanol

[1112] Intermediate 76 of 2-((2-acetyl-4-fluorophenyl)amino)-2-oxoethyl acetate (1.498 g, 5.92 mmol) was suspended in a 4 M NH3 solution of MeOH (16.27 mL, 65.07 mmol) and heated in a microwave reactor at 85 °C for 8 h. The mixture was concentrated under vacuum, redissolved in EtOAc, and washed with saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (1.00 g, 88%) as a beige solid. MS (ESI) m / z [M+H] + 193.0. 1 HNMR (500MHz, CDCl3, 25℃) δ 2.92 (3H, s), 3.90 – 4.00 (1H, m), 4.91–4.96 (2H,m), 7.62 – 7.73 (2H, m), 8.00 – 8.04 (1H, m). 19 F NMR (471MHz, CDCl3) δ -110.22.

[1113] Intermediate 78

[1114] 2-(chloromethyl)-6-fluoro-4-methylquinazoline

[1115] (6-fluoro-4-methylquinazolin-2-yl)methanol intermediate 77 (0.111 g, 0.58 mmol) was dissolved in DCM (2 mL), and PPh3 (0.167 g, 0.64 mmol) was added. The reaction mixture was cooled in an ice bath, and NCS (0.085 g, 0.64 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 15%-50% EtOAc / heptane) to give the title compound (0.085 g, 70%) as a white solid. 1 HNMR (500MHz, CDCl3, 25℃) δ 2.94 (3H, s), 4.85 (2H, s), 7.64–7.72 (2H, m), 8.03 – 8.09 (1H, m). 19 F NMR (470MHz, CDCl3) δ -109.02.

[1116] Intermediate 79

[1117] 2-((2-acetyl-3-fluorophenyl)amino)-2-oxoethyl acetate

[1118] 1-(2-amino-6-fluorophenyl)ethane-1-one (0.998 g, 6.52 mmol) was dissolved in DCM (21 mL) and cooled in an ice bath. NMM (1.433 mL, 13.03 mmol) was added, followed by dropwise addition of acetoxyacetyl chloride (0.867 mL, 7.82 mmol). After 15 min, the cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.895 g) as a brown oil. MS (ESI) m / z [M+H] + 254.1 1 H NMR(500MHz, CDCl3, 25℃) δ 2.36 (3H, s), 2.67 (3H, d), 4.71 (2H, s), 6.90 (1H,ddd), 7.49 (1H, td), 8.47 – 8.52 (1H, m), 11.86 (1H, s). 19 F NMR (471MHz, CDCl3) δ -103.84.

[1119] Intermediate 80

[1120] (5-Fluoro-4-methylquinazolin-2-yl)methanol

[1121] 2-((2-acetyl-3-fluorophenyl)amino)-2-oxoethyl acetate intermediate 79 (1.650 g, 6.52 mmol) was suspended in a 4 M NH3 solution of MeOH (17.92 mL, 71.67 mmol) and heated in a microwave reactor at 85 °C for 8 h. The mixture was concentrated under vacuum. The residue was redissolved in EtOAc and washed with saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (1.164 g, 93%) as a brown solid. MS (ESI) m / z [M+H] + 193.0. 1 H NMR (500MHz, CDCl3, 25℃) δ 3.08 (3H, d), 3.86–4.21 (1H, m), 4.95 (2H, s), 7.78–7.86 (2H, m). 19 F NMR (471MHz, CDCl3) δ -107.38.

[1122] Intermediate 81

[1123] 2-(chloromethyl)-5-fluoro-4-methylquinazoline

[1124] (5-fluoro-4-methylquinazolin-2-yl)methanol intermediate 80 (0.222 g, 1.16 mmol) was dissolved in DCM (4 mL), and PPh3 (0.333 g, 1.27 mmol) was added. The mixture was cooled in an ice bath, and NCS (0.170 g, 1.27 mmol) was added. The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 15%-45% EtOAc / heptane) to give the title compound (0.106 g, 44%) as an off-white solid. MS (ESI) m / z [M+H] + 211.0. 1 H NMR (500MHz, CDCl3, 25℃) δ 3.09 (3H, d), 4.84 (2H, s), 7.30 (1H, ddd), 7.79–7.89 (2H, m). 19 F NMR (471MHz, CDCl3) δ -107.43.

[1125] Intermediate 82

[1126] 2-((2-acetyl-5-fluorophenyl)amino)-2-oxoethyl acetate

[1127] 1-(2-amino-4-fluorophenyl)ethane-1-one (1.041 g, 6.80 mmol) was dissolved in DCM (21 mL) and cooled in an ice bath. NMM (1.495 mL, 13.59 mmol) was added, followed by dropwise addition of acetoxyacetyl chloride (0.904 mL, 8.16 mmol). After 15 min, the cooling bath was removed, and the reaction mixture was stirred at room temperature for the entire weekend. The mixture was diluted with DCM and washed with 10% citric acid (aq), saturated NaHCO3 (aq), and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.940 g) as a brown solid. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.37(3H, s), 2.65 (3H, s), 4.73 (2H, s), 6.85 (1H, ddd), 7.93 (1H, dd), 8.59 (1H,dd), 12.50 (1H, s).

[1128] Intermediate 83

[1129] (7-Fluoro-4-methylquinazolin-2-yl)methanol

[1130] Intermediate 82 (1.719 g, 6.79 mmol) of 2-((2-acetyl-5-fluorophenyl)amino)-2-oxoethyl acetate was suspended in 18.67 mL (74.67 mmol) of 4 M NH3 in MeOH solution and heated at 85 °C for 9 h in a microwave reactor. The mixture was concentrated under vacuum, redissolved in EtOAc, and washed with saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (1.218 g, 93%) as a light brown solid. MS (ESI) m / z [M+H] + 193.0. 1 HNMR (500MHz, CDCl3, 25℃) δ 2.93 (3H, s), 3.93–4.11 (1H, m), 4.91 (2H, s), 7.38 (1H, ddd), 7.60 (1H, dd), 8.12 (1H, dd). 19 F NMR (470MHz, CDCl3) δ -101.96.

[1131] Intermediate 84

[1132] 2-(chloromethyl)-7-fluoro-4-methylquinazoline

[1133] (7-fluoro-4-methylquinazolin-2-yl)methanol intermediate 83 (0.266 g, 1.38 mmol) was dissolved in DCM (4.7 mL), and PPh3 (0.399 g, 1.52 mmol) was added. The mixture was cooled in an ice bath, and NCS (0.203 g, 1.52 mmol) was added. The reaction mixture was stirred for 3 h, and then concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 15%-50% EtOAc / heptane) to give the title compound (0.178 g, 61%) as a pale yellow solid. MS (ESI) m / z [M+H] + 210.9. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.97 (3H, s), 4.83 (2H, s), 7.42 (1H, ddd), 7.65 (1H, ddd), 8.14 (1H, ddd). 19 F NMR (471MHz, CDCl3) δ -101.90.

[1134] Intermediate 85

[1135] 2-(chloromethyl)-6-methoxypyrido[3,2-d]pyrimidin-4(3H)-one

[1136] Methyl 3-amino-6-methoxypyridinecarboxylate (0.225 g, 1.2 mmol) and 2-chloroacetonitrile (0.379 mL, 6.00 mmol) were dissolved in a 4 M HCl solution of 1,4-dioxane (4.50 mL, 18.00 mmol). The reaction mixture was heated at 60 °C overnight. The mixture was cooled to room temperature and Et₂O was added. The mixture was stirred, and the precipitate formed was collected by filtration, washed with Et₂O, and dried under vacuum to give the title compound as an HCl salt (0.322 g). MS (ESI) m / z [M+H] + 226.1. 1 H NMR (500MHz, DMSO-d6, 25℃) δ 3.96 (3H, s), 4.55 (2H, s), 7.29 (1H, d), 8.01 (1H, d).

[1137] Intermediate 86

[1138] 6-Methoxy-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl) Methylpyrido[3,2-d]pyrimidin-4-ol

[1139] 1',3',5'-Trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl salt intermediate 28 (0.164 g, 0.63 mmol), 2-(chloromethyl)-6-methoxypyrido[3,2-d]pyrimidin-4(3H)-one, HCl salt intermediate 85 (0.191 g, 0.64 mmol), and DIPEA (0.884 mL, 5.06 mmol) were mixed in DMSO (4.0 mL) and stirred overnight at room temperature. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous phase was sublimated. EtOAc was added to the lyophilized substance, and the solids were filtered off to give the title compound (0.226 g, 80%). MS (ESI) m / z [M+H] + 449.2.

[1140] Intermediate 87

[1141] 4-Chloro-6-methoxy-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine- 1-yl)methyl)pyrido[3,2-d]pyrimidine

[1142] A suspension of 6-methoxy-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-ol intermediate 86 (0.226 g, 0.50 mmol) and DIPEA (0.176 mL, 1.01 mmol) in POCl3 (0.892 mL, 9.57 mmol) was heated at 100 °C for 3 h. The mixture was concentrated under reduced pressure, and EtOAc was added, followed by the addition of ice water. The organic layer was separated, washed with saturated NaHCO3 (aq), filtered through a phase separator, and concentrated to give the title compound (0.095 g, 40%). MS (ESI) m / z [M+H] + 467.2.

[1143] Intermediate 88

[1144] 4-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1145] Step a) 1,4-Dimethyl-1H-pyrazole-5-carbonyl chloride

[1146] 1,4-Dimethyl-1H-pyrazole-5-carboxylic acid, HCl salt (200 mg, 1.13 mmol), was treated with 1 M NaOH (aq, 1.132 mL, 1.13 mmol) and MeOH (a few mL) and stirred until all substances dissolved, then concentrated under reduced pressure. The residue was treated with THF / MeOH (1:1) and filtered using a syringe filter. The resulting solution was concentrated and then treated with SOCl2 (3 mL, 1.13 mmol), stirred at 70 °C for 2 h, and then concentrated under reduced pressure to give the subtitle compound.

[1147] Step b) 4-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1148] 4-Acetylpiperidin-1-carboxylic acid tert-butyl ester (309 mg, 1.36 mmol) was dissolved in THF (8 mL) and cooled to -78 °C. A 2 M LDA solution of THF / heptane / ethylbenzene (0.736 mL, 1.47 mmol) was added dropwise. The mixture was stirred for 1 h, and then 1,4-dimethyl-1H-pyrazole-5-carbonyl chloride intermediate 88 (step a) was added dropwise in THF (3 mL). The cooling bath was removed, and the reaction mixture was warmed to room temperature, quenched with water, and diluted with EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 20%-35% EtOAc / heptane) to give the title compound (0.052 g, 13%) as a clear oil. MS (ESI) m / z [MH] - 348.5. 1 H NMR (500MHz, CDCl3) δ 7.28 (s, 1H), 5.80 (s, 1H), 4.12 –4.26 (m, 2H), 4.07 (s, 3H), 2.71 – 2.82 (m, 2H), 2.41 (tt, 1H), 2.22 (s, 3H), 1.84 – 1.90 (m, 2H), 1.60 (qd, 2H), 1.45 (s, 9H).

[1149] Intermediate 89

[1150] 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1151] Intermediate 88 (52 mg, 0.15 mmol) of 4-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in EtOH (2 mL), and 64% hydrazine hydrate (aq, 100 µL, 2.20 mmol) was added at room temperature. The reaction mixture was heated to 65 °C and stirred for 1 h, then cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 30%-100% EtOAc / heptane) to give the title compound (0.038 g, 74%) as a white solid. MS (ESI) m / z [M+H] + 346.4. 1 H NMR (500MHz, CDCl3) δ 7.32 (s,1H), 6.16 (s, 1H), 4.00 – 4.29 (m, 2H), 3.89 (s, 3H), 2.64 – 2.88 (m, 3H), 2.07 (s, 3H), 1.95 – 1.85 (m, 2H), 1.59 (qd, 2H), 1.45 (s, 9H).

[1152] Intermediate 90

[1153] 2,4-Dimethyl-5'-(piperidin-4-yl)-2H,2'H-3,3'-bipyrazole

[1154] Intermediate 89 (37.9 mg, 0.11 mmol) of 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (1 mL), and TFA (0.5 mL, 0.11 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure to give the TFA salt of the title compound (40 mg). MS (ESI) m / z [M+H) + 246.3. 1 ¹H NMR (500MHz, methanol-d⁴) δ 7.41 (s, 1H), 6.41 (s, 1H), 3.88 (s, 3H), 3.54– 3.47 (m, 2H), 3.23 - 3.10 (m, 3H), 2.36 - 2.24 (m, 2H), 2.09 (s, 3H), 2.02- 1.91 (m, 2H).

[1155] Intermediate 91

[1156] 2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)thiopheno[3,2-d]pyrimidine-4 (3H)-ketone

[1157] DIPEA (695 µL, 3.99 mmol) was added to a solution of 3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine, TFA intermediate 18 (500 mg, 1.10 mmol), and 2-(chloromethyl)thieno[3,2-d]pyrimidin-4(3H)-one (200 mg, 1.00 mmol) in DMSO (4.29 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was purified by preparative HPLC method D (gradient: 10%–55%) to give the title compound as a white solid. MS (ESI) m / z [M+H] + 393.4.

[1158] Intermediate 92

[1159] 4-Chloro-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)thiopheno[3,2-d]pyrimidine pyridine

[1160] A suspension of 2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)thieno[3,2-d]pyrimidin-4(3H)-one intermediate 91 (26.0 mg, 0.07 mmol) in POCl3 (0.5 mL, 0.07 mmol) was heated to 100 °C for 1 h. The reaction mixture was cooled to room temperature and poured into a stirred saturated NaHCO3(aq) solution. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (25 mg, 87%) as a yellow residue. MS (ESI) m / z [M+H] + 411.4.

[1161] Intermediate 93

[1162] 2-(chloromethyl)-4-methyl-5,6,7,8-tetrahydroquinazoline

[1163] MeCN (6 mL) and 2-acetylcyclohexane-1-one (879 µL, 6.74 mmol) were added to a vial containing 2-chloroacetimidinamide and HCl (956 mg, 7.41 mmol). The reaction mixture was heated to 140 °C in a microwave reactor for 4 h. The solvent was evaporated, and the residue was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude substance was purified by silica gel normal-phase rapid chromatography (gradient: 18%–25% EtOAc / heptane) to give the title compound (0.192 g, 15%) as a pale yellow oil. MS (ESI) m / z [M+H + 197.2.

[1164] Intermediate 94

[1165] N-(4-cyano-1-methyl-1H-pyrrolo-3-yl)-2-(4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazole- 3-yl)piperidin-1-yl)acetamide

[1166] Step a) 2,4-Dimethyl-3-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine

[1167] TFA (2 mL, 1.25 mmol) was added to a solution of 4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 47 (447 mg, 1.25 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h, then concentrated to dryness and redissolved in DMSO (5 mL).

[1168] Step b) 2-Chloroacetyl chloride (0.110 mL, 1.38 mmol) was added to a solution of 2-amino-1-methyl-1H-pyrrole-3-carboxynitrile (152 mg, 1.25 mmol) in dioxane (5 mL), and the mixture was stirred at room temperature for 6 h. Intermediate 94 of the DMSO solution from step a) was added, followed by DIPEA (2.7 mL, 15.50 mmol), and the reaction mixture was stirred for 2 days. The mixture was concentrated to remove dioxane, and the resulting dark solution was purified by preparative HPLC method F (gradient: 10%-55%) to give the title compound (0.137 g, 26%) as a reddish-brown solid. MS (ESI) m / z [M+H] + 417.0.

[1169] Intermediate 95

[1170] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl-3, 7-Dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one

[1171] 12M HCl (aq, 1 mL, 0.27 mmol) was added to a stirred solution of N-(4-cyano-1-methyl-1H-pyrrolo-3-yl)-2-(4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)acetamide intermediate 94 (113 mg, 0.27 mmol) in AcOH (3 mL), and the mixture was heated to 80 °C for 1 h. The mixture was concentrated to dryness and redissolved in 2M NaOH (aq, 2 mL, 4.00 mmol) and MeOH (4 mL), and stirred at 65 °C for 2 h. The mixture was concentrated, and the residue was diluted with water and DCM. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (57 mg, 50%) as a pinkish-purple film. MS (ESI) m / z [M+H] + 418.4.

[1172] Intermediate 96

[1173] 4-Chloro-2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl 7H-pyrrolo[2,3-d]pyrimidine

[1174] A suspension of 95 mg (57.0 mg, 0.14 mmol) of 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one intermediate in POCl3 (2 mL, 0.14 mmol) was heated to 100 °C and stirred for 2 h. The reaction mixture was cooled to room temperature and added dropwise to a stirred solution of saturated NaHCO3 (aq). The mixture was extracted with DCM, the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the title compound (50 mg, 84%) as a transparent film. MS (ESI) m / z [M+H) + 436.4 and 438.2.

[1175] Intermediate 97

[1176] rac-(3,4-dihydro-2H-benzo[b][1,4]oxazine-2-yl)methanol

[1177] rac-(3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol, HCl (1 g, 4.96 mmol) was dissolved in MeOH (10 mL). Carbonate from a solid support (3.5 mmol / g, 2 g, 16.79 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The polymer was filtered off, and the filtrate was concentrated to give the title compound (0.65 g, 79%) as a dark oil. MS (ESI) m / z [M+H] + 166.0.

[1178] Intermediate 98

[1179] rac-tert-butyl-2-(hydroxymethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid ester

[1180] The rac-(3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol intermediate 97 (0.65 g, 3.93 mmol) was dissolved in 12 mL of THF in a microwave-safe vial and washed with N2 (g). A solution of Boc2O (3.65 mL, 15.74 mmol) in 3 mL of THF was added dropwise, the vial was sealed, and the mixture was stirred at 60 °C for 19 h. The solvent was removed under vacuum, and the remaining mixture was diluted with DCM. The organic layer was washed with water, filtered through a phase separator, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-50% EtOAc / heptane) to give the title compound (250 mg, 24%) as a brownish-brown semi-solid. MS (ESI) m / z [MH] - 264.1.

[1181] Intermediate 99

[1182] rac-tert-butyl-2-((toluenesulfonyloxy)methyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid ester

[1183] TsCl (287 mg, 1.51 mmol) was added to a mixture of rac-tert-butyl-2-(hydroxymethyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid intermediate 98 (250 mg, 0.94 mmol) in pyridine (5 mL), and stirred overnight at room temperature. DCM and 10% citric acid (aq) were added, the mixture was stirred, filtered through a phase separator, and concentrated. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%–25% EtOAc / heptane) to give the title compound (320 mg, 81%) as a brown foam. 1H NMR (500MHz, CDCl3) 1.52 (9H, s), 2.45 (3H, s), 3.49 (1H,d), 4.03 – 4.14 (1H, m), 4.14 – 4.23 (2H, m), 4.35 (1H, m), 6.77 (1H, m), 6.87 (1H, m), 6.95 (1H, m), 7.35 (2H, d), 7.69 (1H, s), 7.76 – 7.85 (2H, m).

[1184] Intermediate 100

[1185] rac-(3,4-dihydro-2H-benzo[b][1,4]oxazine-2-yl)methyl-4-methylbenzenesulfonate

[1186] A 6M HCl solution of IPA (0.397 mL, 2.38 mmol) was added to a DCM solution of rac-tert-butyl-2-((toluenesulfonyloxy)methyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid intermediate 99 (200 mg, 0.48 mmol), and the reaction mixture was stirred overnight at room temperature. A 6M HCl solution of IPA (0.397 mL, 2.38 mmol) was added, and the reaction mixture was stirred overnight at 30 °C. The mixture was concentrated and redissolved in MeOH (5 mL). The carbonate on the solid support (3.5 mmol / g, 1 g, 8.39 mmol) was added, and the mixture was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was concentrated to give the title compound (144 mg, 95%) as a brownish-brown oil. MS (ESI) m / z [M+H] + 320.0.

[1187] Intermediate 101

[1188] rac-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-yl)methyl-4-methylbenzenesulfonate

[1189] In a microwave-safe vial, a DMF solution of rac-(3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate intermediate 100 (145 mg, 0.45 mmol) and K₂CO₃ (75 mg, 0.54 mmol) was stirred at room temperature for 20 min. The mixture was cooled to 0 °C and MeI (0.043 mL, 0.68 mmol) was added. The vial was sealed and stirred at 50 °C for 3 h. MeI (0.043 mL, 0.68 mmol) was added, and the reaction mixture was stirred overnight at 50 °C. The mixture was diluted with saturated NaHCO₃(aq) and DCM and stirred, filtered through a phase separator, and concentrated. Another batch was prepared as described above, using rac-(3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl 4-methylbenzenesulfonate intermediate 100 (55 mg, 0.17 mmol) as the starting material. Following the post-processing stage, the batches were combined and purified by normal-phase rapid column chromatography (gradient: 0%-40% EtOAc / heptane) to give the title compound (73 mg, 35%) as a colorless oil. MS (ESI) m / z [M+H) + 334.1.

[1190] Intermediate 102

[1191] 2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-3,5, 7,8-Tetrahydro-4H-pyrano[4,3-d]pyrimidin-4-one

[1192] 2-(chloromethyl)-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-4-one (87 mg, 0.43 mmol) was added to a mixture of 1',3',5'-trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl salt intermediate 28 (109 mg, 0.42 mmol), and DIPEA (0.732 mL, 4.20 mmol) in DMF (1.368 mL). The reaction mixture was stirred at room temperature for 3 h, then at 70 °C for 8 h. The mixture was cooled to room temperature and water was added, and the mixture was extracted with EtOAc (×2). The aqueous layer was concentrated, and the residue was purified by preparative HPLC method D (gradient: 0%–30%) to give the title compound (0.106 g, 60%) as a beige solid. MS (ESI) m / z [M+H] + 424.2. 1H NMR (500MHz, DMSO-d6, 25℃) δ 1.69 (2H, qd), 1.84–1.92 (2H, m), 2.1–2.38 (8H, m), 2.55–2.66(3H, m), 2.85–2.93 (2H, m), 3.37 (2H, s), 3.66 (3H, s), 3.84 (2H, t), 4.33–4.38 (2H, m), 6.04 (1H, s), 11.74–12.53 (2H, m).

[1193] Intermediate 103

[1194] 4-Chloro-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl )-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine

[1195] Intermediate 102 (105.9 mg, 0.25 mmol) of 2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidin-4-one was dissolved in POCl3 (4 mL, 42.92 mmol) and stirred at 110 °C for 2 h. The mixture was cooled to room temperature and 10% NaHCO3 (aq) solution was added. The mixture was alkalized with 1N NaOH (aq) solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.096 g, 87%) as a brown solid. MS (ESI) m / z [M+H] + 442.3.

[1196] Intermediate 104

[1197] 3-Acetyltetrahydro-2H-pyran-2-one

[1198] Tetrahydro-2H-pyran-2-one (1.446 g, 14.44 mmol) was dissolved in THF (37 mL) and cooled to -78 °C. A THF solution of 1 M LiHMDS (28.9 mL, 28.88 mmol) was added, and the reaction mixture was stirred for 10 min, followed by the addition of Ac₂O (1.362 mL, 14.44 mmol). The reaction mixture was stirred for 10 min, then warmed to room temperature and stirred for 1 h. HOAc (6 mL) was added, followed by the addition of MTBE (40 mL). The precipitate was filtered off and washed with MTBE. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-30% EtOAc / heptane) to give the title compound (0.886 g, 43%).1 HNMR (500MHz, CDCl3, 25℃) δ 1.89–1.95 (2H, m), 2.01 (3H, s), 2.41 (2H, t), 4.26–4.32 (2H, m), 13.70 (1H, s).

[1199] Intermediate 105

[1200] 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol

[1201] 3-Acetyltetrahydro-2H-pyran-2-one intermediate 104 (97 mg, 0.68 mmol) was dissolved in MeOH (1 mL) in a microwave-safe vial. 2-Chloroacetimine amide, HCl salt (152 mg, 1.18 mmol), and K₂CO₃ (229 mg, 1.66 mmol) were added. The vial was sealed and heated to 50 °C for 30 min. The suspension was filtered using a syringe filter and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%–20% MeOH / EtOAc) to give the title compound (0.065 g, 44%) as an orange solid. MS (ESI) m / z [M+H] + 217.1. 1 ¹H NMR (500MHz, methanol-d⁴, 25℃) δ 1.67–1.74 (2H, m), 2.34 (3H, s), 2.55–2.62 (2H, m), 3.57 (2H, t), 4.41 (2H, s).

[1202] Intermediate 106

[1203] 2-((4-ethynylpiperidin-1-yl)methyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol

[1204] 4-Ethynylpiperidine, TFA salt (670 mg, 3.00 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol intermediate 5 (650 mg, 3.00 mmol), and DIPEA (2.62 mL, 15.00 mmol) were stirred overnight at room temperature in DMSO (6 mL). The substance was purified by preparative HPLC method D (gradient: 10%-50%) to give the title compound (622 mg, 72%) as a brown solid. MS (ESI) m / z [M+H] + 290.4. 1¹H NMR (500MHz, methanol-d⁴, 25℃) δ 1.64–1.76 (4H, m), 1.84–1.93 (2H, m), 2.29–2.37 (5H, m), 2.38 (1H, d), 2.4–2.5 (1H, m), 2.55–2.61 (2H, m), 2.72–2.81 (2H, m), 3.42 (2H, s), 3.57 (2H, t).

[1205] Intermediate 107

[1206] 2-((4-ethynylpiperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine

[1207] Intermediate 1 of 2-((4-ethynylpiperidin-1-yl)methyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol (460 mg, 1.59 mmol) and PPh3 (625 mg, 2.38 mmol) were dissolved in THF (25 mL) and cooled in an ice bath. DIAD (0.469 mL, 2.38 mmol) was added dropwise. The reaction mixture was stirred for 10 min, then warmed to room temperature and stirred for 1 h. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel normal-phase rapid chromatography (gradient: 0%-10% MeOH (2M NH3) / DCM), followed by preparative HPLC preparation method G (gradient: 5%-50%) to give the formate salt of the title compound as a brown solid (327 mg, 76%). A portion of the salt (264 mg, 0.83 mmol) was dissolved in DCM (5 mL) and saturated NaHCO3 (aq) (3 mL). The mixture was stirred for 5 minutes, then filtered through a phase separator and concentrated under reduced pressure to obtain the free base of the title compound (223 mg, 99%) as a brown solid. 1 ¹H NMR (500MHz, methanol-d⁴, 25℃) δ 1.61–1.71 (2H, m), 1.82–1.89 (2H, m), 2.01–2.1 (2H, m), 2.27–2.4 (3H, m), 2.41 (3H, s), 2.74 (2H, t), 2.77–2.85 (2H, m), 3.53 (2H, s), 4.36–4.41 (2H, m), 5.49 (1H, s).

[1208] Intermediate 108

[1209] 1-(1,4-Dimethyl-1H-pyrazol-5-yl)-3-(1-((4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine) (Pyridin-2-yl)methyl)piperidin-4-yl)prop-2-yn-1-one

[1210] 2-((4-ethynylpiperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine intermediate 107 (70 mg, 0.26 mmol) was dissolved in THF (0.5 mL) and toluene (0.5 mL). 1,4-Dimethyl-1H-pyrazole-5-carbonyl chloride (61.4 mg, 0.39 mmol), CuI (2.5 mg, 0.01 mmol), and TEA (0.216 mL, 1.55 mmol) were added, followed by Pd(PPh3)2Cl2 (9.1 mg, 0.01 mmol), and the reaction mixture was stirred at room temperature for 2.5 h under N2 (g) atmosphere. DCM (5 mL) and saturated NaHCO3 (aq, 5 mL) were added. The mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 1%-10% MeOH (2M NH3) / DCM) to give the title compound (80 mg, 79%). MS (ESI) m / z [M+H) + 394.6. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.66–1.76(1H, m), 1.79–1.88 (2H, m), 1.89–2.09 (4H, m), 2.24–2.32 (2H, m), 2.33–2.4(5H, m), 2.61–2.68 (2H, m), 2.78–3.00 (2H, m), 3.58 (2H, d), 4.07 (3H, d), 4.27–4.35 (2H, m), 7.24–7.28 (1H, m).

[1211] Intermediate 109

[1212] 2-(chloromethyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-4-ol

[1213] Ethyl 3-oxotetrahydro-2H-pyran-2-carboxylate (0.740 g, 4.30 mmol) was dissolved in MeOH (6 mL) under a N2 (g) atmosphere. 2-Chloroacetimine amide, HCl salt (0.642 g, 4.73 mmol), was added, followed by dropwise addition of a 30% NaOMe solution in MeOH (0.959 mL, 5.16 mmol) over several minutes. The reaction mixture was stirred overnight at room temperature. The mixture was filtered and concentrated under reduced pressure to give the title compound (1.140 g). MS (ESI) m / z [M+H] + 201.1.

[1214] Intermediate 110

[1215] 2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8- Dihydro-6H-pyrano[3,2-d]pyrimidin-4-ol

[1216] A mixture of 1',3',5'-trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl salt intermediate 28 (0.197 g, 0.53 mmol), 2-(chloromethyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-4-ol intermediate 109 (0.107 g, 0.53 mmol), and DIPEA (0.553 mL, 3.17 mmol) in DMSO (4.0 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and water. The aqueous layer was sublimated, EtOAc was added, and the solids were filtered off to give the title compound (0.206 g, 92%). MS (ESI) m / z [M+H] + 424.2.

[1217] Intermediate 111

[1218] rac-tert-butyl(2R,4R)-2-methyl-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propionyl (I)piperidine-1-carboxylic acid ester

[1219] A mixture of rac-(2R,4R)-1-(tert-butoxycarbonyl)-2-methylpiperidin-4-carboxylic acid (823 mg, 3.38 mmol) and CDI (680 mg, 4.19 mmol) in THF (14 mL) was stirred at room temperature for 2 h. A solution of 1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethane-1-one (669 mg, 4.40 mmol) in THF (14 mL) was prepared in a separate flask, cooled to -78 °C, and a solution of 1 M LiHMDS in THF (4.57 mL, 4.57 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h, and then the CDI-activated carboxylic acid was added. After 10 min, the cooling bath was removed, the reaction mixture was allowed to reach room temperature, and stirred for 1 h. The reaction was quenched with saturated NaHCO3 (aq), and the mixture was diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (1.276 g). MS (ESI) m / z [M+H + 378.2.

[1220] Intermediate 112

[1221] rac-tert-butyl(2R,4R)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5- (I)piperidine-1-carboxylic acid ester

[1222] Intermediate 111 (1.276 g, 3.38 mmol) of rac-tert-butyl(2R,4R)-2-methyl-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propionyl)piperidine-1-carboxylic acid ester was dissolved in EtOH (2 mL), and 64% hydrazine hydrate (aq, 200 µL, 4.11 mmol) was added. The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC method D (gradient: 25%–65%) to give the title compound (90 mg, 7%) as a white solid. MS (ESI) m / z [M+H] + 374.2. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.06 (3H, d), 1.44 (9H,s), 1.67–1.77 (1H, m), 1.8–1.9 (1H, m), 2.01–2.14 (2H, m), 2.23 (6H, s), 2.88–3.00 (1H, m), 3.14–3.26 (1H, m), 3.70 (3H, s), 3.80 (1H, ddd), 3.97–4.09(1H, m), 6.02 (1H, s).

[1223] Intermediate 113

[1224] rac-5-(3-hydroxypropyl)-6-methyl-2-(((2R,4R)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H- [3,4'-Bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrimidin-4-ol

[1225] Intermediate 112 (90 mg, 0.24 mmol) of rac-tert-butyl(2R,4R)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid ester was dissolved in DCM (2 mL) and treated with TFA (1 mL). The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL), and intermediate 5 (59 mg, 0.27 mmol) of 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol was added and K2CO3 (165 mg, 1.19 mmol). The reaction mixture was stirred overnight at room temperature, filtered using a syringe filter, and purified by preparative HPLC method D (gradient: 10%-50%) to give the title compound (78 mg, 71%) as a white solid. MS (ESI) m / z [M+H] + 454.4.

[1226] Intermediate 114

[1227] 3-Propionyltetrahydro-2H-pyran-2-one

[1228] Tetrahydro-2H-pyran-2-one (2.54 g, 25.37 mmol) was dissolved in THF (51 mL) and cooled to -78 °C. A THF solution of 1 M LiHMDS (50.7 mL, 50.74 mmol) was added, and the reaction mixture was stirred for 10 min. Propionic anhydride (3.25 mL, 25.37 mmol) was added, and the reaction mixture was stirred for 10 min, then warmed to room temperature and stirred for 1 h. HOAc (8 mL) was added, followed by MTBE. The precipitate formed was filtered off and washed with MTBE. The filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-30% EtOAc / heptane) to give the title compound (1.458 g, 37%). MS (ESI) m / z [M+H] + 157.1.

[1229] Intermediate 115

[1230] 2-(chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol

[1231] Under a N2 (g) atmosphere, 1.455 g (9.32 mmol) of 3-propionyltetrahydro-2H-pyran-2-one intermediate 114 was dissolved in 10 mL of MeOH. 2-Chloroacetylimine amide, HCl salt (1.391 g, 10.25 mmol), was added, followed by dropwise addition of a 30% NaOMe solution in MeOH (2.080 mL, 11.18 mmol) over several minutes. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%–50% (EtOAc / MeOH(4 / 1)) / heptane) to give the title compound as a solid (0.649 g, 30%). MS (ESI) m / z [M+H] + 231.1. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.24 (3H, t), 1.73–1.82 (2H, m), 2.65 (2H, q), 2.72(2H, t), 3.56 (2H, t), 4.53 (2H, s).

[1232] Intermediate 116

[1233] 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5- (1-yl)piperidin-1-yl)methyl)pyrimidin-4-ol

[1234] A mixture of 5'-methoxy-1'-methyl-5-(piperidin-4-yl)-1H,1'H-3,4'-bipyrazole, TFA salt intermediate 56 (0.041 g, 0.11 mmol), 2-(chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol intermediate 115 (0.024 g, 0.105 mmol), and DIPEA (0.110 mL, 0.63 mmol) in DMSO (1 mL) was stirred overnight at room temperature. The product was purified by preparative HPLC using a CC (gradient: 15%–45%) method to give the title compound (0.030 g, 63%). MS (ESI) m / z [M+H] + 456.4. 1 H NMR (500MHz, DMSO-d6, 25℃) δ 1.12 (3H, t), 1.50–1.58 (2H, m), 1.67 (2H, qd), 1.83–1.89 (2H, m), 2.15–2.25 (2H, m), 2.38–2.45(2H, m), 2.85–2.92 (2H, m), 3.31 (1H, s), 3.34 (2H, s), 3.37–3.41 (2H, m), 3.64 (3H, s), 3.89 (3H, s), 4.47 (1H, t), 6.14 (1H, s), 7.54 (1H, s), 11.86(1H, s), 12.41 (1H, s).

[1235] Intermediate 117

[1236] 2-(chloromethyl)-5,8-dihydro-6H-pyrano[3,4-d]pyrimidin-4-ol

[1237] Ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (0.917 g, 5.33 mmol) was dissolved in MeOH (7 mL) under a N2 (g) atmosphere. 2-Chloroacetimine amide, HCl salt (0.795 g, 5.86 mmol), was added, followed by dropwise addition of a 30% NaOMe solution in MeOH (1.189 mL, 6.39 mmol) over several minutes. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC method G (gradient: 0%–30%) to give the title compound as a solid (0.431 g, 40%). MS (ESI) m / z [MH] - 199.1. 1H NMR (500MHz, DMSO-d6, 25℃) δ2.37–2.44 (2H, m), 3.81 (2H, t), 4.31–4.36 (2H, m), 4.43 (2H, s), 12.74 (1H,s)

[1238] Intermediate 118

[1239] 2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-5,8- Dihydro-6H-pyrano[3,4-d]pyrimidin-4-ol

[1240] A mixture of 1',3',5'-trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl salt intermediate 28 (0.093 g, 0.25 mmol), 2-(chloromethyl)-5,8-dihydro-6H-pyrano[3,4-d]pyrimidin-4-ol intermediate 117 (0.048 g, 0.238 mmol), and DIPEA (0.249 mL, 1.43 mmol) in DMSO (1.5 mL) was stirred overnight at room temperature. The product was purified by preparative HPLC using a CC (gradient: 15%–55%) method to give the title compound (0.057 g, 57%) as a beige solid. MS (ESI) m / z [M+H] + 424.2. 1 H NMR (500MHz, DMSO-d6, 25℃) δ1.68 (2H, qd), 1.82–1.91 (2H, m), 2.12–2.24 (5H, m), 2.30 (3H, s), 2.37–2.42(2H, m), 2.55–2f.65 (1H, m), 2.85–2.92 (2H, m), 3.33 (2H, s), 3.66 (3H, s), 3.81 (2H, t), 4.3–4.38 (2H, m), 6.04 (1H, s), 12.07 (1H, s), 12.40 (1H, s).

[1241] Intermediate 119

[1242] 4-Chloro-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl 5,8-dihydro-6H-pyrano[3,4-d]pyrimidine

[1243] Intermediate 118 of 2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-5,8-dihydro-6H-pyrano[3,4-d]pyrimidin-4-ol (0.055 g, 0.13 mmol) was suspended in POCl3 (1.440 mL, 15.45 mmol) and heated to 106 °C for 90 min. The reaction mixture was cooled and concentrated under vacuum. The residue was mixed with toluene (10 mL) and concentrated again. The remaining oil was partitioned between DCM and saturated NaHCO3 (aq). The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC method CC (gradient: 30%-70%) to give the title compound (0.034 g, 59%). MS (ESI)m / z [M+H] + 442.2. 1 H NMR (500MHz, DMSO-d6, 25℃) δ 1.59–1.71 (2H, m), 1.82–1.9(2H, m), 2.12–2.24 (5H, m), 2.30 (3H, s), 2.55–2.63 (1H, m), 2.77 (2H, t), 2.87–2.98 (2H, m), 3.61–3.68 (5H, m), 3.97 (2H, t), 4.66 (2H, s), 6.04 (1H, s), 12.34 (1H, s).

[1244] Intermediate 120

[1245] 4-(3-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1246] CDI (0.175 g, 1.08 mmol) was added to a THF (3 mL) solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.243 g, 1.06 mmol), and the reaction mixture was stirred at room temperature for 2 h. In a separate flask, a THF (6 mL) solution of 1-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)ethane-1-one (0.173 g, 1.03 mmol) was cooled to -78 °C. A THF solution of 1 M LiHMDS (2.57 mL, 2.57 mmol) was added, and the reaction mixture was stirred at -78 °C for 30 min, followed by dropwise addition of the CDI-activated acid over 10 min. The cold bath was removed, and the reaction mixture was stirred at room temperature overnight. 10% citric acid (aq, 3 mL) was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, filtered through a phase separator, and concentrated under reduced pressure to give the title compound (0.430 g). MS (ESI) m / z [M+H] + 380.3.

[1247] Intermediate 121

[1248] 4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1249] Intermediate 120 (0.390 g, 1.03 mmol) of 4-(3-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 99.5% EtOH (3.5 mL) and 64% hydrazine hydrate (aq, 0.150 mL, 3.08 mmol) was added. The reaction mixture was stirred overnight at room temperature and then co-evaporated with toluene under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%-100% (EtOAc / MeOH (9 / 1)) / heptane) to give the title compound (0.242 g, 63%) as a yellow solid. MS (ESI) m / z [M+H] + 376.1.

[1250] Intermediate 122

[1251] 5'-Methoxy-1',3'-Dimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-Bipyrazole

[1252] Intermediate 121 (0.242 g, 0.64 mmol) of 4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4.5 mL), and TFA (0.745 mL, 9.67 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure to give the TFA salt of the title compound (0.250 g, 100%). MS (ESI) m / z [M+H) + 276.2.

[1253] Intermediate 123

[1254] 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyridine]) [Azazole]-5-yl)piperidin-1-yl)methyl)pyrimidin-4-ol

[1255] A mixture of 5'-methoxy-1',3'-dimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, TFA salt intermediate 122 (0.250 g, 0.64 mmol), 2-(chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol intermediate 115 (0.148 g, 0.64 mmol), and DIPEA (0.672 mL, 3.85 mmol) in DMSO (5.5 mL) was stirred overnight at room temperature. The product was purified by preparative HPLC using a CC (gradient: 15%–40%) method to give the title compound (0.544 g). MS (ESI) m / z [M+H] + 470.2.

[1256] Intermediate 124

[1257] 4-(3-(5-cyclopropyl-1-methyl-1H-pyrazole-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1258] 5-Cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.133 g, 0.80 mmol) was suspended in THF (2.5 mL), and CDI (0.131 g, 0.81 mmol) was added. The suspension was stirred at room temperature for 4 h. In a separate flask, a THF (5 mL) solution of 4-acetylpiperidin-1-carboxylic acid tert-butyl ester (0.175 g, 0.77 mmol) was cooled to -78 °C, and a THF solution of 1 M LiHMDS (1.925 mL, 1.93 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h, and then a solution of acid activated by CDI was added dropwise. The reaction mixture was stirred at -78 °C for 5 min, and then stirred overnight at room temperature. The reaction was quenched by adding saturated NaHCO3 (aq), and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.323 g). MS (ESI) m / z [M+H] + 376.3.

[1259] Intermediate 125

[1260] 4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1261] Intermediate 124 (0.289 g, 0.77 mmol) of 4-(3-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 99.5% EtOH (7.5 mL) and cooled in an ice bath. 64% hydrazine hydrate (aq, 0.056 mL, 1.16 mmol) was added, followed by HOAc (0.075 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was poured into water (5 mL) and saturated NaHCO3 (aq, 0.5 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%–100% (EtOAc / MeOH (9 / 1)) / heptane) to give the title compound (0.156 g, 55%). MS (ESI) m / z [M+H] + 372.2. 1H NMR(500MHz, DMSO, 25℃) δ 0.53 (2H, s), 1.01 (2H, d), 1.41 (9H, s), 1.43–1.52(2H, m), 1.8–1.93 (3H, m), 2.74–2.93 (3H, m), 3.83 (3H, s), 3.93–4.02 (2H,m), 6.19 (1H, s), 7.54 (1H, s), 12.42 (1H, s).

[1262] Intermediate 126

[1263] 5'-Cyclopropyl-1'-Methyl-5-(piperidin-4-yl)-1'H,2H-3,4'-Bipyrazole

[1264] Intermediate 125 (0.154 g, 0.41 mmol) of 4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4 mL) and cooled in an ice bath. TFA (0.592 mL, 7.69 mmol) was added, the cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was ground with Et2O (5 mL). The solvent was decanted, and the resulting precipitate was dried under vacuum to give the TFA salt of the title compound (0.160 g, 100%). MS (ESI) m / z [M+H] + 272.1.

[1265] Intermediate 127

[1266] 2-((4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-5- (3-hydroxypropyl)-6-methylpyrimidin-4-ol

[1267] A mixture of 5'-cyclopropyl-1'-methyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, TFA salt intermediate 126 (0.160 g, 0.42 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol intermediate 5 (0.090 g, 0.415 mmol), and DIPEA (0.435 mL, 2.49 mmol) in DMSO (4 mL) was stirred overnight at room temperature. EtOAc and saturated NaHCO3 (aq) were added, and the mixture was filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.162 g, 86%). MS (ESI) m / z [M+H] + 452.5.

[1268] Intermediate 128

[1269] Ethyl 3-(2-amino-4-hydroxy-6-methylpyrimidin-5-yl)propionate

[1270] Diethyl 2-acetylglutarate (13.51 g, 58.67 mmol) was dissolved in 99.5% EtOH (dried to a 3 Å molecular sieve, 100 mL). Guanidine carbonate (12.1 g, 67.16 mmol) was added, and the reaction mixture was heated to reflux for 12 h. The mixture was concentrated under vacuum. Water (40 mL) and concentrated HCl (aq, 5.8 mL) were added, and the mixture was shaken. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to give (12.6 g) of a colorless solid. The product was re-cured from 95% EtOH (approximately 150 mL) to give the title compound (7.396 g, 49%) as a colorless solid. MS (ESI) m / z [M+H] + 226.3. 1 H NMR (500MHz, DMSO-d6, 25℃) δ 1.16 (3H, t), 2.05 (3H, s), 2.32–2.38 (2H, m), 2.48–2.54(zm), 4.03 (2H, q), 6.30 (2H, s), 10.80 (1H, s).

[1271] Intermediate 129

[1272] Ethyl 3-(2,4-dihydroxy-6-methylpyrimidin-5-yl)propionate

[1273] A concentrated solution of NaNO2 (3.38 g, 48.99 mmol) in water (4.5 mL) was added dropwise to a mixture of ethyl 3-(2-amino-4-hydroxy-6-methylpyrimidin-5-yl)propionate intermediate 128 (7.37 g, 32.72 mmol) in HOAc (60 mL) and water (20 mL). The reaction mixture was stirred at room temperature for 2 h, then slowly heated to 60 °C and stirred for 2 h. The mixture was concentrated under vacuum to half its volume and acidified to pH 3 by adding HCl. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to give the title compound (2.45 g, 33%). MS (ESI) m / z [M+H] + 227.3. 1 H NMR (500MHz, DMSO-d6, 25℃) δ 1.16 (3H, t), 2.06 (3H, s), 2.31–2.48 (4H, m), 4.03 (2H, q), 10.67 (1H, s), 10.96 (1H, s).

[1274] Intermediate 130

[1275] Ethyl 3-(2,4-dichloro-6-methylpyrimidin-5-yl)propionate

[1276] POCl3 (20 mL) was added to ethyl 3-(2,4-dihydroxy-6-methylpyrimidin-5-yl)propionate intermediate 129 (2.45 g, 10.83 mmol), followed by N,N-dimethylaniline (20 drops, 10.83 mmol), and the reaction mixture was heated to approximately 100 °C for 2 h. The mixture was cooled and concentrated under vacuum. The residue was mixed with toluene and concentrated again. The residue was partitioned between ice water and EtOAc. The organic layer was washed with water (×2) and brine. The organic layer was dried over NaSO4 and filtered through silica gel. The filtrate was concentrated under vacuum to give the title compound (2.48 g, 87%) as an orange oil. 1 H NMR(500MHz, CDCl3) 1.26 (3H, t), 2.56 – 2.6 (2H, m), 2.61 (3H, s), 3.05 – 3.09(2H, m), 4.16 (2H, q). 13 C NMR (126MHz, CDCl3) δ 171.67, 170.54, 163.31, 157.86, 131.70, 55.02, 32.66, 25.54, 22.53, 15.63.

[1277] Intermediate 131

[1278] 3-(2,4-Dichloro-6-methylpyrimidin-5-yl)prop-1-ol

[1279] Ethyl 3-(2,4-dichloro-6-methylpyrimidin-5-yl)propionate intermediate 130 (2.48 g, 9.43 mmol) was dissolved in THF (85 mL) and cooled to -78 °C. A 1 M DIBAL-H heptane solution (28.4 mL, 28.40 mmol) was added dropwise over 30 min. After complete addition and further stirring for 30 min, the cooling bath was removed, and stirring continued for 19 h at room temperature. The reaction mixture was poured into a 200 mL solution of Rochelle salt (52 g). After gas escaping ceased, the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO4, filtered, and concentrated under vacuum to give the title compound (2.010 g, 96%) as a deep orange oil. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.62 (1H, s), 1.77–1.85 (2H, m), 2.59 (3H, s), 2.83–2.91 (2H, m), 3.74 (2H, t). 13C NMR (126MHz, CDCl3) δ170.38, 161.95, 156.96, 130.56, 61.84, 30.61, 25.21, 22.42.

[1280] Intermediate 132

[1281] 2-Chloro-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine

[1282] NaH (60 wt% mineral oil solution, 0.367 g, 9.17 mmol) was washed with heptane until oil-free and suspended in THF (15 mL). 3-(2,4-dichloro-6-methylpyrimidin-5-yl)prop-1-ol intermediate 131 (2.01 g, 8.73 mmol) was dissolved in THF (30 mL) and added dropwise to the NaH suspension over 20 min under an Ar (g) atmosphere. The reaction mixture was stirred overnight at room temperature, filtered through a CELITE filter, and the filtrate was concentrated under vacuum to give the title compound (1.601 g, 99%) as a pale yellow solid. MS (ESI) m / z [M+H] + 185.2. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.04–2.11 (2H, m), 2.40 (3H, s), 2.68 (2H, t), 4.35–4.41 (2H, m).

[1283] Intermediate 133

[1284] 4-Methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2-carboxynitrile

[1285] 3-Quinonicol (0.13 g, 1.02 mmol) was added to a mixture of 2-chloro-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine intermediate 132 (1.599 g, 8.66 mmol) and KCN (0.80 g, 12.29 mmol) in DMSO (15 mL) and water (0.2 mL), and the reaction mixture was stirred at 60 °C for 24 h. The mixture was cooled to room temperature and partitioned between iPrOAc and water. The aqueous layer was extracted with iPrOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.402 g, 92%) as a red solid. 1 H NMR (500MHz, CDCl3, 25℃) δ2.07–2.16 (2H, m), 2.45 (3H, s), 2.76 (2H, t), 4.39–4.45 (2H, m).13 C NMR (126MHz, CDCl3) δ 167.65, 167.08, 141.83, 116.75, 115.64, 67.95, 21.52, 21.09, 20.82.

[1286] Intermediate 134

[1287] 4-Methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2-carboxylic acid methyl ester

[1288] Intermediate 133 of 4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2-carboxynitrile (1.398 g, 7.98 mmol) was dissolved in MeOH (80 mL). A solution of 4.37 M NaOMe in MeOH (5.3 mL, 23.16 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into water (80 mL) containing H3PO4 (2.5 mL), and the mixture was stirred for 1 h. The MeOH was removed by vacuum concentration. The remaining liquid was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (1.486 g, 89%) as a pale orange solid. MS (ESI) m / z [M+H] + 209.3. 1 H NMR (500MHz, CDCl3, 25℃) δ 2.07–2.15 (2H, m), 2.51 (3H,s), 2.76 (2H, t), 3.99 (3H, s), 4.37–4.42 (2H, m). 13 C NMR (126MHz, CDCl3) δ167.35, 167.20, 163.92, 153.72, 115.63, 67.60, 53.35, 21.56, 21.31, 21.06.

[1289] Intermediate 135

[1290] (4-Methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidin-2-yl)methanol

[1291] 4-Methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-2-carboxylic acid methyl ester intermediate 134 (104 mg, 0.50 mmol) was dissolved in MeOH (5 mL) and cooled in an ice bath. NaBH4 (56.7 mg, 1.5 mmol) was added, and the reaction mixture was stirred for 2 h. Additional NaBH4 (28 mg, 0.75 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. Saturated NH4Cl (aq, 5 mL) was added, and the mixture was stirred at room temperature for 10 min, then concentrated under vacuum. The residue was extracted with EtOAc, and the organic layer was concentrated under vacuum to give the title compound (85 mg, 94%) as a pale yellow solid. MS (ESI) m / z [M+H] + 181.2. 13 C NMR (126MHz, methanol-d4) δ 167.17, 166.49, 165.62, 111.69, 67.63, 63.74, 20.97, 20.51, 19.27.

[1292] Intermediate 136

[1293] 1-(5-methoxy-1-methyl-1H-pyrazol-4-yl)-3-(1-((4-methyl-6,7-dihydro-5H-pyrano[2, [3-d]pyrimidin-2-yl)methyl)piperidin-4-yl)prop-2-yn-1-one

[1294] 2-((4-ethynylpiperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine intermediate 107 (45 mg, 0.17 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). 5-methoxy-1-methyl-1H-pyrazole-4-carbonyl chloride intermediate 53 (43.4 mg, 0.25 mmol), CuI (3.2 mg, 0.02 mmol), and TEA (0.139 mL, 0.99 mmol) were added, followed by Pd(PPh3)2Cl2 (11.6 mg, 0.02 mmol). The reaction mixture was stirred at room temperature for 2 h under N2 (g) atmosphere. DCM (5 mL) and saturated NaHCO3 (aq, 5 mL) were added, the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 0%-10% MeOH / DCM) to give the title compound (36 mg, 53%). MS (ESI) m / z [M+H + 410.4.

[1295] Intermediate 137

[1296] 1-(1,5-dimethyl-1H-pyrazol-4-yl)-3-(1-((4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine) (Pyridin-2-yl)methyl)piperidin-4-yl)prop-2-yn-1-one

[1297] 2-((4-ethynylpiperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine intermediate 107 (60 mg, 0.22 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). 1,5-Dimethyl-1H-pyrazole-4-carbonyl chloride (52.6 mg, 0.33 mmol), CuI (2.1 mg, 0.01 mmol), and TEA (0.185 mL, 1.33 mmol) were added, followed by Pd(PPh3)2Cl2 (7.8 mg, 0.01 mmol), and the reaction mixture was stirred overnight at room temperature under N2 (g) atmosphere. DCM (5 mL) and saturated NaHCO3 (aq, 5 mL) were added, the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 1%-10% MeOH (2M NH3) / DCM) to give the title compound (47 mg, 54%). MS (ESI) m / z [M+H) + 394.5. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.8–1.9(2H, m), 1.92–2.01 (2H, m), 2.01–2.07 (2H, m), 2.31–2.44 (5H, m), 2.54 (3H,s), 2.59–2.7 (3H, m), 2.82–2.95 (2H, m), 3.63 (2H, s), 3.77 (3H, s), 4.29–4.34 (2H, m), 7.85 (1H, s).

[1298] Intermediate 138

[1299] 5-Methoxy-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride

[1300] 5-Methoxy-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (0.324 g, 1.90 mmol) was suspended in DCM (6.7 mL), and oxalyl chloride (0.340 mL, 3.81 mmol) was added. The reaction mixture was cooled to 0 °C, and DMF (0.015 mL, 0.19 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The residue was concentrated twice more from DCM to give the title compound (0.359 g, 100%). 1 H NMR (500MHz, CDCl3, 25℃) δ 2.44 (3H, s), 3.68 (3H, s), 4.07 (3H, s).

[1301] Intermediate 139

[1302] 1-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-(1-((4-methyl-6,7-dihydro-5H-pyrano) [2,3-d]pyrimidin-2-yl)methyl)piperidin-4-yl)prop-2-yn-1-one

[1303] 2-((4-ethynylpiperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine intermediate 107 (60 mg, 0.22 mmol) was dissolved in THF (0.4 mL) and toluene (0.4 mL). 5-methoxy-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride intermediate 138 (63 mg, 0.33 mmol), CuI (2.1 mg, 0.01 mmol), and TEA (0.185 mL, 1.33 mmol) were added to the mixture, followed by Pd(PPh3)2Cl2 (7.8 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 3 h under a N2 (g) atmosphere. DCM (5 mL) and saturated NaHCO3 (aq, 5 mL) were added, the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 1%-10% MeOH (2% NH3) / DCM) to give the title compound (37 mg, 40%). MS (ESI) m / z [M+H) + 424.3.

[1304] Intermediate 140

[1305] 6-Ethyl-5-(3-hydroxypropyl)-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl) Piperidin-1-yl)methyl)pyrimidin-4-ol

[1306] A mixture of 1',3',5'-trimethyl-5-(piperidin-4-yl)-1'H,2H-3,4'-bipyrazole, HCl salt intermediate 28 (0.093 g, 0.25 mmol), 2-(chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol intermediate 115 (0.055 g, 0.238 mmol), and DIPEA (0.249 mL, 1.43 mmol) in DMSO (1.5 mL) was stirred overnight at room temperature. The crude product was purified by preparative HPLC using a CC (gradient: 20%–55%) method to give the title compound (0.125 g). MS (ESI) m / z [M+H] + 454.4.

[1307] Intermediate 141

[1308] 4-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[1309] TEA (11.92 mL, 87.44 mmol), followed by Pd(PPh3)2Cl2 (0.614 g, 0.87 mmol), was added to a mixture of 4-ethynylpiperidin-1-carboxylic acid tert-butyl ester (3.66 g, 17.49 mmol), 1,5-dimethyl-1H-pyrazole-4-carbonyl chloride (3.17 g, 20 mmol), and CuI (0.167 g, 0.87 mmol) in THF (37.8 mL) and toluene (37.8 mL). The flask was evacuated and filled with N2 (g), and stirred overnight at room temperature. EtOAc was added, and the mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 30%–50% EtOAc / heptane) to give the title compound (4.38 g, 76%) as an orange oil. MS (ESI) m / z [(M-Boc)+H] + 232.1 1 H NMR (500MHz, CDCl3, 25℃) δ 1.45 (9H, s), 1.66–1.75 (2H, m), 1.84–1.95 (2H, m), 2.57 (3H, s), 2.79–2.85 (1H, m), 3.21 (2H, ddd), 3.71–3.79 (2H, m), 3.80 (3H, s), 7.89 (1H, s).

[1310] Intermediate 142

[1311] 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1312] Intermediate 141 (4.38 g, 13.22 mmol) of 4-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in EtOH (41 mL), and 64% hydrazine hydrate (aq, 3 mL, 61.66 mmol) was added. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure and dissolved in hot EtOAc, immediately filtered and cooled to give the title compound (2.480 g, 54%) as a white solid. MS (ESI) m / z [M+H] + 346.4. 1HNMR (500MHz, CDCl3, 25℃) δ 1.47 (9H, s), 1.65 (2H, qd), 1.91–2.01 (2H, m), 2.43 (3H, s), 2.78–2.9 (3H, m), 3.83 (3H, s), 4.08-4.29 (2H,m), 6.11 (1H,s), 7.59 (1H,s).

[1313] Intermediate 143

[1314] 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6-ethyl- 5-(3-hydroxypropyl)pyrimidin-4-ol

[1315] TFA (1 mL, 0.30 mmol) was added to a 2 mL solution of tert-butyl 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid intermediate 142 (113 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was dissolved in 2 mL DMSO, and K₂CO₃ (210 mg, 1.52 mmol) and 2-(chloromethyl)-6-ethyl-5-(3-hydroxypropyl)pyrimidin-4-ol intermediate 115 (70 mg, 0.30 mmol) were added. The reaction mixture was stirred overnight at room temperature. The mixture was filtered using a syringe filter and purified by preparative HPLC method D (gradient: 10%–55%) to give the title compound (96 mg, 72%) as a white solid. MS (ESI) m / z [M+H] + 440.3. 1 H NMR(500MHz, CDCl3, 25℃) δ 1.14 (3H, t), 1.71 (2H, p), 1.75–1.87 (2H, m), 1.88–1.95 (2H, m), 2.21–2.31 (2H, m), 2.35 (3H, s), 2.53 (2H, q), 2.58–2.71 (3H,m), 2.8–2.89 (2H, m), 3.43 (2H, s), 3.55 (2H, t), 3.75 (3H, s), 6.05 (1H, s), 7.59 (1H, s).

[1316] Intermediate 144

[1317] 4-(3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester

[1318] CDI (0.131 g, 0.81 mmol) was added to a suspension of 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.158 g, 0.80 mmol) in THF (2.5 mL), and the mixture was stirred at room temperature for 4 h. In a separate flask, a THF solution of 1 M LiHMDS (1.925 mL, 1.93 mmol) was added dropwise to a THF solution of 4-acetylpiperidine-1-carboxylic acid tert-butyl ester (0.175 g, 0.77 mmol) at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h. A solution of acid activated by CDI was added dropwise, and the reaction mixture was stirred at -78 °C for 5 min, then stirred overnight at room temperature. The mixture was diluted with EtOAc by quenching the reaction with saturated NaHCO3 (aq). The layers were separated, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.311 g, 100%). MS (ESI) m / z [MH] - 402.0

[1319] Intermediate 145

[1320] 4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1321] Intermediate 144 (0.311 g, 0.77 mmol) of 4-(3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-3-oxopropionyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 99.5% EtOH (7.5 mL) and cooled in an ice bath. 64% hydrazine hydrate (aq, 0.056 mL, 1.16 mmol) was added, followed by HOAc (0.075 mL), and the reaction mixture was stirred overnight at room temperature. Water (5 mL) and saturated NaHCO3 (aq, 0.5 mL) were added to the mixture, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%-100% (EtOAc / MeOH(9 / 1)) / heptane) to give the title compound (0.197 g, 64%). MS (ESI) m / z [M+H) + 400.3. 1H NMR (500MHz, DMSO-d6, 25℃) δ 1.40 (9H, d), 1.42–1.52 (2H, m), 1.83–1.92 (2H, m), 2.7–2.94 (3H, m), 3.85–4.13 (5H, m), 6.18(1H, s), 7.76 (1H, s), 12.75 (1H, s). 19 F NMR (471MHz, DMSO-d6) δ -56.02.

[1322] Intermediate 146

[1323] 1'-Methyl-5-(piperidin-4-yl)-5'-(trifluoromethyl)-1'H,2H-3,4'-bipyrazole

[1324] Intermediate 145 (0.197 g, 0.49 mmol) of 4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4 mL) and cooled in an ice bath. TFA (0.704 mL, 9.14 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the TFA salt of the title compound (0.203 g, 100%). MS (ESI) m / z [M+H] + 300.1.

[1325] Intermediate 147

[1326] 5-(3-hydroxypropyl)-6-methyl-2-((4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyridine] [Azazole]-5-yl)piperidin-1-yl)methyl)pyrimidin-4-ol

[1327] A mixture of 1'-methyl-5-(piperidin-4-yl)-5'-(trifluoromethyl)-1'H,2H-3,4'-bipyrazole, TFA salt intermediate 146 (0.203 g, 0.49 mmol), 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol intermediate 5 (0.106 g, 0.49 mmol), and DIPEA (0.513 mL, 2.94 mmol) in DMSO (4.5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 (aq). The organic layer was filtered through a phase separator and concentrated under reduced pressure to give the crude title compound (0.260 g). MS (ESI) m / z [M+H] + 480.4.

[1328] Intermediate 148

[1329] 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-5-(3-hydroxypropyl) 6-methylpyrimidin-4-ol

[1330] TFA (0.5 mL, 0.23 mmol) was added to a solution of 4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 47 (83 mg, 0.23 mmol) in DCM (1 mL), and the reaction mixture was stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in DMSO (1.5 mL). DIPEA (250 µL, 1.44 mmol) and 2-(chloromethyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol intermediate 5 (65.0 mg, 0.30 mmol) were added, and the reaction mixture was stirred at room temperature for 24 h. The mixture was filtered using a syringe filter, and the residue was purified by preparative HPLC method D (gradient: 10%-50%) to give the title compound (0.078 g, 77%) as a white solid. MS (ESI) m / z [M+H] + 437.4. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.62–1.71 (2H, m), 1.72–1.85 (2H, m), 1.88–1.97 (5H, m), 2.19–2.31 (8H, m), 2.55–2.60 (2H, m), 2.61–2.7 (1H, m), 2.77–2.87 (2H, m), 3.40 (2H, d), 3.44–3.52 (2H, m), 5.93 (1H, d), 6.93 (1H,d), 8.22 (1H, d).

[1331] Intermediate 149

[1332] 5-(2,4-Dimethylpyridin-3-yl)-3-(1-((4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine- 2-yl)methyl)piperidin-4-yl)-1H-pyrazole-1-carboxylic acid isopropyl ester

[1333] Intermediate 148 (78 mg, 0.18 mmol) of 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-5-(3-hydroxypropyl)-6-methylpyrimidin-4-ol was dissolved in THF (2 mL) and cooled in an ice bath. DIAD (52.8 µL, 0.27 mmol) was added, and the reaction mixture was stirred for 10 min, then warmed to room temperature and stirred for 1 h. The crude product was purified by preparative HPLC method D (gradient: 15%-55%) to give the title compound (0.056 g, 62%) as a clear oil. MS (ESI) m / z [M+H]+ 505.6. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.42 (6H, d), 1.75–1.88 (2H, m), 1.99–2.06 (4H, m), 2.11 (3H,s), 2.25–2.34 (5H, m), 2.38 (3H, s), 2.65 (2H, t), 3.08–3.18 (2H, m), 3.37(1H, tt), 3.66 (2H, s), 4.29–4.34 (2H, m), 5.19–5.29 (1H, m), 6.13 (1H, s),6.96 (1H, d), 8.29 (1H, d).

[1334] Intermediate 150

[1335] 4-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-3-oxoprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[1336] Pd(PPh3)2Cl2 (0.021 g, 0.03 mmol) was added to a solution of TEA (0.247 mL, 1.77 mmol), 4-ethynyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.133 g, 0.59 mmol), 1,4-dimethyl-1H-pyrazole-5-carbonyl chloride (0.103 g, 0.65 mmol), and CuI (5.63 mg, 0.03 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was diluted with saturated NaHCO3 (aq) and extracted with DCM. The combined organic layers were filtered through a phase separator and concentrated. The crude material was purified by silica gel normal-phase rapid chromatography (10%–100% EtOAc / heptane) to give the title compound (98 mg, 48%) as a yellow oil. 1 H NMR (500MHz, CDCl3) 1.46 (9H, s), 1.82 – 1.89 (2H, m), 1.95 – 2.03 (2H, m), 2.41 (3H, s), 3.48 (2H, m), 3.64 (2H, m), 4.12 (3H, s), 7.32 (1H, m).

[1337] Intermediate 151

[1338] 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[1339] Hydrazine hydrate (aq, 28.0 µL, 0.58 mmol) was added to a solution of 150 (100 mg, 0.29 mmol) of 4-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-3-oxoprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester intermediate in EtOH (1.1 mL), and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the title compound as a white foam. MS (ESI) m / z [M+H] + 362.1.

[1340] Intermediate 152

[1341] 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-4-ol

[1342] TFA (320 µL, 4.15 mmol) was added to a solution of 1 mL of DCM containing 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester intermediate 151 (100 mg, 0.28 mmol) and stirred at room temperature for 30 min. The mixture was concentrated to give the TFA salt of the title compound as a brown foam (assuming quantitative yield). MS (ESI) m / z [M+H] + 262.0.

[1343] Intermediate 153

[1344] 4-Hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester

[1345] Ethynyltrimethylsilane (5.94 mL, 42.05 mmol) was dissolved in THF (118 mL) and cooled to -78 °C. A solution of 2.5 M nBuLi in hexane (16.82 mL, 42.05 mmol) was added dropwise, and the reaction mixture was stirred at -78 °C for 40 min, then allowed to reach room temperature. After 70 min, the reaction mixture was cooled to -78 °C, and a solution of 4-oxopiperidin-1-carboxylic acid tert-butyl ester (7.12 g, 35.04 mmol) in THF (72 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 3 h. The reaction was quenched with saturated NH4Cl (aq), and then EtOAc was added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Heptane was added to the residue, and the mixture was heated to 45 °C and sonicated. After cooling to room temperature, a white solid precipitated. The solid was filtered off and washed with cold heptane. The mother liquor was concentrated and purified by silica gel normal-phase rapid chromatography (gradient: 2%-32% EtOAc / heptane), and the fraction containing the product was collected and combined with the precipitate to give the title compound (9.444 g, 91%).1 H NMR (500MHz, CDCl3, 18℃) δ 0.17 (9H, s), 1.45 (9H, s), 1.67 (2H, ddd), 1.83 – 2.10 (3H, m), 3.20 (2H, ddd), 3.76 -3.84 (2H, m).

[1346] Intermediate 154

[1347] 4-((trimethylsilyl)ethynyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1348] Intermediate 153 of 4-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylic acid tert-butyl ester (12.775 g, 42.95 mmol) was dissolved in DCM (120 mL) and cooled in an ice bath. DMAP (5.77 g, 47.24 mmol) was added, followed by TEA (17.96 mL, 128.84 mmol), and methanesulfonyl chloride (10.04 mL, 128.84 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 18 h. The mixture was poured into water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1 M HCl and saturated NaHCO3 (aq), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in heptane and filtered. The filtered solid was washed with heptane. The combined filtrates were concentrated to give the title compound (12.18 g). 1 H NMR (500MHz, CDCl3, 18℃) δ 0.17 (9H, s), 1.45 (9H, s), 2.19 - 2.28 (2H, m), 3.47 (2H, t), 3.92 - 3.97 (2H, m), 6.06 (1H, s).

[1349] Intermediate 155

[1350] 4-Ethynyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1351] Intermediate 154 (7.31 g, 26.16 mmol) of 4-((trimethylsilyl)ethynyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in MeOH (132 mL). K2CO3 (7.23 g, 52.32 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered and concentrated under reduced pressure. EtOAc and water were added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was dissolved in heptane and filtered to give the title compound (5.27 g, 97%) as a yellow-brown oil. 1 H NMR (500MHz, CDCl3, 19℃) δ1.46 (9H, s), 2.25 (2H, s), 2.89 (1H, s), 3.45 – 3.54 (2H, m), 3.96 (2H, s), 6.10 (1H, s).

[1352] Intermediate 156

[1353] 4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)prop-1-yn-1-yl)-3,6-dihydropyridine-1 (2H)-tert-butyl carboxylate

[1354] Intermediate 155 (3.35 g, 16.16 mmol) of 4-ethynyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in toluene (76 mL). CuI (0.154 g, 0.81 mmol), 1,3,5-trimethyl-1H-pyrazole-4-carbonyl chloride (3.36 g, 19.46 mmol), and TEA (4.73 mL, 33.94 mmol) were added, followed by Pd(PPh3)2Cl2 (0.567 g, 0.81 mmol). The reaction mixture was stirred at room temperature under N2 (g) atmosphere for 3 h, and then diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 50%-80% EtOAc / heptane) to give the title compound (3.47 g, 63%) as an orange solid. MS (ESI) m / z [M+H + 344.3. 1 H NMR (500MHz, CDCl3) 1.47 (9H, s),2.30 – 2.39 (2H, m), 2.52 (3H, s), 2.57 (3H, s), 3.54 (2H, t), 3.75 (3H, s),4.01 – 4.09 (2H, m), 6.36 (1H, s).

[1355] Intermediate 157

[1356] 4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1357] 64% hydrazine hydrate (aq, 0.983 mL, 20.21 mmol) was added to a solution of 4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)prop-1-yn-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester intermediate 156 (3.47 g, 10.10 mmol) in EtOH (32.7 mL), and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (isocratic EtOAc) to give the title compound (2.64 g, 73%) as a white solid. MS (ESI) m / z [M+H] + 358.5. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.47 (9H,s), 2.25 (6H, d), 2.49–2.59 (2H, m), 3.59 (2H, t), 3.72 (3H, s), 4.00–4.08(2H, m), 6.16 (1H, s), 6.25 (1H, s), 10.93 (1H, s).

[1358] Intermediate 158

[1359] 4-(1',3',5'-trimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H,1'H-[3,4'-bi pyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and

[1360] 4-(1',3',5'-trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1'H,2H-[3,4'-bi pyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[1361] Intermediate 157 (5.38 g, 15.04 mmol) of 4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in THF (72.3 mL), and NaH (60 wt% mineral oil solution, 0.902 g, 22.56 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, then cooled in an ice bath. SEM-Cl (2.86 mL, 15.79 mmol) was added, and the reaction mixture was stirred for 30 min, then warmed to room temperature and stirred for 2 h. The reaction mixture was cooled in an ice bath, and the reaction was quenched with saturated NaHCO3(aq). The mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%-50% EtOAc / heptane) to give a mixture of regioisomers of the title compound (5.83 g, 79%) as a brown gel. MS (ESI) m / z [M+H + 488.4.

[1362] Intermediate 159

[1363] rac-tert-butyl(3R,4R)-3-hydroxy-4-(1',3',5'-trimethyl-2-((2-(trimethylsilyl)ethyl) (Oxy)methyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid ester

[1364] BH3·S(CH3)2 (0.401 mL, 4.22 mmol) was added to a solution of tert-butyl 4-(1',3',5'-trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid intermediate 158 (1.03 g, 2.11 mmol) in THF (5.64 mL) and stirred overnight at room temperature. The reaction was quenched by adding water (1 mL) and EtOH (1 mL) and stirred for 1 h. 10% NaOH (aq, 4 mL, 2.11 mmol) and H₂O₂ (0.518 mL, 16.89 mmol) were added, and the reaction mixture was stirred overnight at room temperature, then heated to 50 °C for 4 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated. The crude residue was purified by preparative HPLC method F (gradient: 30%-70%) to give the title compound (0.457 g, 43%) as a yellow oil. MS (ESI) m / z [M+H] + 506.3. 1 H NMR (500MHz, CDCl3) -0.14 (9H, s), 0.69 – 0.76 (2H, m), 1.36 (9H, s), 1.59 (1H, m), 1.91 – 1.97(1H, m), 1.98 (3H, s), 2.02 (3H, s), 2.55 – 2.77 (3H, m), 3.39 – 3.48 (2H,m), 3.54 – 3.61 (1H, m), 3.66 (3H, s), 3.95 – 4.37 (2H, m), 5.06 (2H, s), 5.94 (1H, s).

[1365] Intermediate 160

[1366] rac-(3R,4R)-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3, 4'-Bipyrazole]-5-yl)piperidin-3-ol

[1367] TFA (1 mL, 0.15 mmol) was added to a solution of rac-(3R,4R)-3-hydroxy-4-(1',3',5'-trimethyl-2-((2-(trimethylsilyl)ethoxy)methyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 159 (50.2 mg, 0.10 mmol) in DCM (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and redissolved in DMSO (1 mL). 2-(chloromethyl)-4-methylquinazoline (31.2 mg, 0.16 mmol) and DIPEA (0.128 mL, 0.74 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The mixture was filtered using a syringe filter, and the filtrate was purified by preparative HPLC method A (gradient: 5%-45%) to give the product. The product was further purified by preparative HPLC method D (gradient: 15%-55%) to give the title compound (24 mg, 56%) as a white solid. HRMS (ESI) m / z [M+H] + C 24 H 30 Calculated value of N7O: 432.2506, measured value: 432.2498.

[1368] Intermediate 161

[1369] 4-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)-3,6-dihydropyridine-1 (2H)-tert-butyl carboxylate

[1370] Under a N2 (g) atmosphere, Pd(PPh3)2Cl2 (0.254 g, 0.36 mmol) was added to a mixture of 4-ethynyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester intermediate 155 (1.5 g, 7.24 mmol), 1,5-dimethyl-1H-pyrazole-4-carbonyl chloride (1.721 g, 10.86 mmol), CuI (0.069 g, 0.36 mmol), and TEA (5.04 mL, 36.18 mmol) in toluene (31.1 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with water and DCM, filtered through a phase separator, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 40%-100% EtOAc / heptane) to give the title compound (945 mg). MS (ESI) m / z [M+H] + 330.2

[1371] Intermediate 162

[1372] 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary Butyl acetate

[1373] Intermediate 161 (940 mg, 2.85 mmol) of 4-(3-(1,5-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was dissolved in EtOH (13.7 mL) and 64% hydrazine hydrate (aq, 0.555 mL, 11.41 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC method D (gradient: 15%–55%) to give the title compound (468 mg, 48%). MS (ESI) m / z [M+H] + 344.4. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.47–1.5 (9H, m), 2.42 (3H, d), 2.51–2.61 (2H, m), 3.58–3.67 (2H, m), 3.83 (3H, d), 4.03–4.11 (2H, m), 6.16 (1H, s), 6.31 (1H, d), 7.59 (1H, s).

[1374] Intermediate 163

[1375] rac-tert-butyl(3R,4R)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3-hydroxypiperazine pyridine-1-carboxylic acid esters and

[1376] 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[1377] BMS (0.388 mL, 4.09 mmol) was added at 0 °C to a THF (6.6 mL) solution of 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester intermediate 169 (468 mg, 1.36 mmol). The reaction mixture was heated to 50 °C and stirred for 2 h. The mixture was cooled to 0 °C, the reaction was quenched with water (2 mL) and EtOH (2 mL), and then stirred for 10 min. 10% NaOH (aq, 1.5 mL, 1.36 mmol) and 30% H2O2 (aq, 0.557 mL, 5.45 mmol) were added, the reaction mixture was heated to 50 °C and stirred overnight. The mixture was cooled to room temperature, diluted with brine and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative HPLC method F (gradient: 15%-55%) to give the title compound (195 mg, 40%), which was a mixture of non-separable regioisomers. MS (ESI) m / z [M+H + 362.4.

[1378] Intermediate 164

[1379] rac-(3R,4R)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-3-ol and

[1380] 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-ol

[1381] TFA (1 mL, 0.54 mmol) was added to a 2 mL solution of DCM containing a mixture of regioisomers of rac-tert-butyl(3R,4R)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-3-hydroxypiperidine-1-carboxylic acid ester and 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester intermediate 163, and the reaction mixture was stirred at room temperature for 30 min. The mixture was concentrated to give the TFA salt of the title compound as a regioisomer mixture (141 mg). MS (ESI) m / z [M+H] + 262.2.

[1382] Intermediate 165

[1383] 4-Hydroxy-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)prop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester

[1384] 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (1.65 g, 10.70 mmol) was suspended in DCM (45 mL), and oxalyl chloride (3.8 mL, 44.91 mmol) was added. DMF (10 µL) was added, and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in THF (45 mL), and tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylic acid (2.253 g, 10 mmol), CuI (0.10 g, 0.53 mmol), Pd(PPh3)2Cl2 (0.3 g, 0.43 mmol), and TEA (3.9 mL, 27.90 mmol) were added under Ar (g) atmosphere. The reaction mixture was stirred at room temperature overnight. The solids formed were filtered off and set aside. The filtrate was collected and filtered through silica gel. The second filtrate was collected and combined with the solids, and concentrated to dryness to give the title compound (3.75 g) as a yellow oil. MS (ESI) m / z [M+H] + 362.4.

[1385] Intermediate 166

[1386] 4-Hydroxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1387] 64% hydrazine hydrate (aq, 1 mL, 14.02 mmol) was added to a 99.5% EtOH (50 mL) solution of tert-butyl 4-hydroxy-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)prop-1-yn-1-yl)piperidin-1-carboxylic acid intermediate 165 (3.61 g, 10 mmol), and the reaction mixture was stirred at room temperature for 20 h. Insoluble substances were removed by filtration, and the filtrate was concentrated under vacuum. The crude substance was dissolved in DMSO (20 mL) and filtered through a CELITE filter. The residue was purified by preparative HPLC method G (gradient: 15%-55%), and the fraction containing the product was neutralized by adding NaHCO3(s). MeCN was removed under reduced pressure, and the remaining solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (2.76 g, 74%). MS (ESI) m / z [M+H] + 376.4. 1H NMR (500MHz, DMSO, 25℃) δ 1.40 (9H,s), 1.71–1.79 (2H, m), 1.80–1.88 (2H, m), 2.18 (3H, s), 2.30 (3H, s), 3.10–3.28 (2H, m), 3.64–3.74 (5H, m), 5.17 (1H, s), 6.17 (1H, s), 12.45 (1H, s).

[1388] Intermediate 167

[1389] 4-Fluoro-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1390] Under an Ar(g) atmosphere, intermediate 166 (188 mg, 0.5 mmol) of 4-hydroxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (9 mL) and cooled to -78 °C. DAST (100 µL, 0.76 mmol) was added, and the reaction mixture was stirred at -78 °C for 20 min, then warmed to room temperature. After 2 h at room temperature, the reaction mixture was cooled to -78 °C, and additional DAST (100 µL, 0.76 mmol) was added. The reaction mixture was stirred at -78 °C for 20 min, then warmed to room temperature. After 2 h at room temperature, the mixture was washed with saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (161 mg, 85%). MS (ESI) m / z [M+H] + 378.5. 1 H NMR (500MHz, CDCl3) 1.46 (9H, s), 2.05 – 2.22 (4H, m), 2.27 (3H, s), 2.29 (3H, s), 3.19 – 3.35 (2H, m), 3.75 (3H, s), 3.88 – 4.07 (2H, m), 6.22 –6.25 (1H, m). 19 F NMR (471MHz, CDCl3) -152.41.

[1391] Intermediate 168

[1392] 5-(4-Fluoroperidin-4-yl)-1',3',5'-trimethyl-1'H,2H-3,4'-bipyrazole

[1393] Intermediate 167 (213 mg, 0.56 mmol) of 4-fluoro-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (1 mL), and TFA (1.00 mL) was added. The reaction mixture was stirred at room temperature for 30 min, and then concentrated under vacuum to give the TFA salt of the title compound (374 mg). 19 F NMR (471MHz, D2O)δ -75.72 (s, 9H), -150.87 (s, 1H).

[1394] 1 H NMR (500MHz, D2O) δ 2.35 (s, 6H), 2.37 - 2.58 (m, 4H), 3.39 - 3.50 (m, 4H), 3.90 (s, 3H), 6.61 (d, 1H).

[1395] MS (ESI) m / z [M+H] + 278.4.

[1396] Intermediate 169

[1397] 4-Methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1398] A 25% NaOMe solution in MeOH (0.4 mL, 1.6 mmol) was added to intermediate 167 (151 mg, 0.40 mmol) of 4-fluoro-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester, and the reaction mixture was stirred at room temperature for 10 min. Saturated NH4Cl (aq) was added, and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (140 mg, 90%) as a yellow oil. MS (ESI) m / z [M+H] + 390.5. 1 H NMR (500MHz, CDCl3) δ 1.45 (s, 9H), 1.94 -2.12 (m, 4H), 2.29 (s, 3H), 2.31 (s, 3H), 3.10 (s, 3H), 3.25 - 3.34 (m, 2H), 3.70 - 3.84 (m, 5H), 6.18 (s, 1H).

[1399] Intermediate 170

[1400] 5-(4-methoxypiperidin-4-yl)-1',3',5'-trimethyl-1'H,2H-3,4'-bipyrazole

[1401] TFA (0.5 mL) was added to a solution of 4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester intermediate 169 (137 mg, 0.35 mmol) in DCM (0.5 mL), and the reaction mixture was stirred at room temperature for 20 min. The mixture was concentrated under vacuum to give the TFA salt of the title compound (220 mg, 99%). MS (ESI) m / z [M+H) + 290.4.

[1402] Intermediate 171

[1403] 4-Ethynyl-4-methoxypiperidine-1-carboxylic acid tert-butyl ester

[1404] 4-Ethynyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (8.9 g, 37.53 mmol) was dissolved in anhydrous DMF (100 mL), and NaH (60 wt% mineral oil solution, 1.876 g, 46.91 mmol) was added dropwise over 5 min at room temperature under N2 (g) atmosphere. The reaction mixture was stirred at room temperature for 25 min, and then MeI (2.92 mL, 46.91 mmol) was added dropwise over 10 min under N2 (g) atmosphere. The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with EtOAc when it reached room temperature. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 5%-40% EtOAc / heptane) to give the title compound (6.6 g, 74%) as a colorless oil. 1 HNMR (500MHz, CDCl3) 1.45 (9H, s), 1.66 - 1.74 (2H, m), 1.85 - 1.95 (2H, m), 2.52 (1H, s), 3.24 - 3.33 (2H, m), 3.38 (3H, s), 3.64 - 3.76 (2H,m).

[1405] Intermediate 172

[1406] 4-Methoxy-4-(3-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl) Piperidine-1-carboxylic acid tert-butyl ester

[1407] Intermediate 171 (0.123 g, 0.515 mmol), intermediate 138 (0.146 g, 0.77 mmol), CuI (4.9 mg, 0.03 mmol), and TEA (0.431 mL, 3.09 mmol) were mixed in THF (0.9 mL) and toluene (0.9 mL). Pd(PPh3)2Cl2 (0.018 g, 0.03 mmol) was added, and the reaction mixture was stirred overnight at room temperature under N2 (g) atmosphere. DCM and saturated NaHCO3 (aq) were added, the mixture was stirred, filtered through a phase separator, and concentrated under reduced pressure to give the title compound (0.240 g). MS (ESI) m / z [M+H] + 392.3.

[1408] Intermediate 173

[1409] 4-Methoxy-4-(5'-Methoxy-1',3'-Dimethyl-1'H,2H-[3,4'-Bipyrazole]-5-yl)piperidine-1- tert-butyl carboxylate

[1410] Intermediate 172 (0.202 g, 0.52 mmol) of 4-methoxy-4-(3-(5-methoxy-1,3-dimethyl-1H-pyrazol-4-yl)-3-oxoprop-1-yn-1-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in 99.5% EtOH (3.8 mL) and cooled in an ice bath. 64% hydrazine hydrate (aq, 0.126 mL, 2.58 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was poured into water (7 mL) and saturated NaHCO3 (aq), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 10%-100% (EtOAc / MeOH (9 / 1)) / heptane) to give the title compound (0.083 g, 40%). MS (ESI) m / z [M+H] + 406.3. 1 HNMR (500MHz, DMSO-d6) 1.40 (9H, s), 1.80 – 1.92 (2H, m), 1.96 – 2.05 (2H, m), 2.16 (3H, s), 2.95 (3H, s), 3.13 – 3.28 (2H, m), 3.51 – 3.63 (5H, m), 3.78 (3H, s), 6.25 (1H, s), 12.58f (1H, s).

[1411] Intermediate 174

[1412] 5'-Methoxy-5-(4-Methoxypiperidin-4-yl)-1',3'-Dimethyl-1'H,2H-3,4'-Bipyrazole

[1413] Intermediate 173 (0.083 g, 0.20 mmol) of 4-methoxy-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (3 mL) and cooled in an ice bath. TFA (0.292 mL, 3.79 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was ground with Et2O (5 mL). The solvent was decanted, and the resulting precipitate was dried under vacuum to give the TFA salt of the title compound (0.086 g, 100%). MS (ESI) m / z [M+H] + 306.3.

[1414] Intermediate 175

[1415] rac-tert-butyl(2R,4S)-2-methyl-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propyl-1- 1-yl)piperidine-1-carboxylic acid ester

[1416] rac-tert-butyl(2R,4S)-4-ethynyl-2-methylpiperidine-1-carboxylic acid ester (0.198 g, 0.89 mmol) was dissolved in THF (3.2 mL) and added to a THF (1.6 mL) solution of 1,3,5-trimethyl-1H-pyrazole-4-carbonyl chloride (0.230 g, 1.33 mmol). CuI (0.034 g, 0.18 mmol) and Pd(PPh3)2Cl2 (0.064 g, 0.09 mmol) were added, followed by TEA (0.865 mL, 6.21 mmol). The reaction mixture was evacuated and refilled with N2 (g) (×3). The reaction mixture was stirred overnight at room temperature under N2 (g) atmosphere. DCM and saturated NaHCO3 (aq) were added, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (0.319 g, 100%). MS (ESI) m / z [M+H] + 360.4.

[1417] Intermediate 176

[1418] rac-tert-butyl(2R,4S)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5- (I)piperidine-1-carboxylic acid ester

[1419] Intermediate 175 (0.319 g, 0.89 mmol) of rac-tert-butyl(2R,4S)-2-methyl-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)prop-1-yn-1-yl)piperidine-1-carboxylic acid ester was dissolved in EtOH (4.2 mL) and cooled in an ice bath. 64% hydrazine hydrate (aq, 0.215 mL, 4.44 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water and saturated NaHCO3 (aq), and the mixture was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 40%-100% (EtOAc / MeOH (9 / 1)) / heptane). The resulting product was dissolved in EtOAc and treated with SILIAMETS imidazole for 1 h. The solution was filtered, and the solid was washed with EtOAc. The combined filtrates were concentrated to give the title compound (0.200 g, 60%). MS (ESI) m / z [M+H) + 374.2.

[1420] Intermediate 177

[1421] rac-1',3',5'-trimethyl-5-((2R,4S)-2-methylpiperidin-4-yl)-1'H,2H-3,4'-bipyrazole

[1422] Intermediate 176 (0.195 g, 0.52 mmol) of rac-tert-butyl(2R,4S)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid ester was dissolved in EtOAc (2.6 mL). A solution of IPA in 6 M HCl (0.870 mL, 5.22 mmol) was added dropwise, and the reaction mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the HCl salt of the title compound (0.224 g). MS (ESI) m / z [M+H] + 274.2.

[1423] Intermediate 178

[1424] 1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-4-carboxylic acid

[1425] 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (0.662 g, 2.55 mmol) and imidazole (0.521 g, 7.66 mmol) were mixed in DCM (15 mL). TBDMS-Cl (0.770 g, 5.11 mmol) was added, and the reaction mixture was stirred overnight at room temperature. 5% citric acid (aq, 18 mL) was added, and the mixture was stirred for 1 h. The mixture was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by silica gel normal-phase rapid chromatography (isocratic DCM (1% HOAc)). 0.1 M HCl (aq) was added to the crude product, and the mixture was stirred and then extracted with EtOAc. The organic layer was concentrated, and the crude product was purified by silica gel normal-phase rapid chromatography (isocratic DCM, 1% HOAc) to give the title compound (0.510 g, 54%). 1 H NMR(500MHz, CDCl3, 25℃) δ 0.03 (6H, s), 0.87 (9H, s), 1.37–1.48 (11H, m), 2.01–2.1 (2H, m), 2.96–3.06 (2H, m), 3.62 (2H, s), 3.83–3.92 (2H, m).

[1426] Intermediate 179

[1427] 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyridine) tert-butyl azole-4-yl)propionyl)piperidine-1-carboxylic acid

[1428] Intermediate 178 (0.490 g, 1.31 mmol) of 1-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)piperidine-4-carboxylic acid was dissolved in THF (4.5 mL), and CDI (0.223 g, 1.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. In a separate flask, a solution of 1-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethane-1-one (0.200 g, 1.31 mmol) in THF (8.7 mL) was cooled to -78 °C, and a solution of 1 M LiHMDS in THF (3.28 mL, 3.28 mmol) was added. The reaction mixture was stirred at -78 °C for 30 min. At -78 °C, the CDI-activated acid was added dropwise to the mixture over 10 min. The cold bath was removed, and the reaction mixture was stirred at room temperature overnight. Add 10% citric acid (aq, 6 mL) and extract the mixture with EtOAc. Wash the organic layer with brine, filter through a phase separator, and concentrate under reduced pressure to give the title compound (0.666 g, 100%). MS (ESI) m / z [MH] - 506.2

[1429] Intermediate 180

[1430] 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'- [Bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester

[1431] Intermediate 179 (0.666 g, 1.31 mmol) of 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-(3-oxo-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propionyl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in EtOH (6 mL) and cooled in an ice bath. 64% hydrazine hydrate (aq, 0.318 mL, 6.56 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was poured into water and saturated NaHCO3 (aq), and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 40%-100% (EtOAc / MeOH (9 / 1)) / heptane) to give the title compound (0.271 g, 41%). MS (ESI) m / z [M+H] + 504.4.

[1432] Intermediate 181

[1433] (4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-yl)methanol

[1434] Intermediate 180 (0.270 g, 0.54 mmol) of 4-(((tert-butyldimethylsilyl)oxy)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-1-carboxylic acid tert-butyl ester was dissolved in EtOAc (3.3 mL). A solution of IPA in 6 M HCl (1.072 mL, 6.43 mmol) was added dropwise, and the reaction mixture was stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure to give the HCl salt of the title compound (0.235 g) - MS (ESI) m / z [M+H] + 290.1. 1 H NMR(500MHz, DMSO, 25℃) δ 1.96–2.06 (2H, m), 2.15–2.39 (9H, m), 2.71–2.83 (2H,m), 3.20 (2H, d), 3.40 (1H, s), 3.74 (3H, s), 6.39 (1H, s), 8.82 (1H, s), 9.06 (1H, s).

[1435] Intermediate 182

[1436] rac-tert-butyl(3R,4R)-3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylic acid ester

[1437] Ethynyltrimethylsilane (4.17 mL, 30.11 mmol) was dissolved in Et₂O (189 mL) and cooled in an ice bath. A 2.5 M n-BuLi solution in hexane (12.05 mL, 30.11 mmol) and a 2 M AlMe₃ solution in toluene (13.80 mL, 27.60 mmol) were added, and the reaction mixture was warmed to room temperature. A 25.3 mL solution of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (5.00 g, 25.09 mmol) in Et₂O was added. The reaction mixture was cooled to -78 °C, and BF₃•OEt₂ (6.19 mL, 50.19 mmol) was added. The reaction mixture was stirred at -78 °C for 2 h, then quenched with anhydrous MeOH (20 mL) and stirred for 15 min. Saturated NH₄Cl (aq) (13 mL) was added. The mixture was warmed to room temperature and diluted with MTBE and water. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel normal-phase rapid chromatography (gradient: 20%-30% EtOAc / heptane) to give the title compound (6.34 g, 85%) as a colorless oil. 1 H NMR (500MHz, CDCl3, 25℃) δ 0.16 (9H, s), 1.22–1.34 (2H, m), 1.46 (9H, s), 1.9–2 (1H, m), 2.21 (1H, d), 2.39–2.54 (1H, m), 2.9–3.03 (1H, m), 3.59 (1H, s), 3.66–3.92 (1H, m), 4.00 (1H, dd).

[1438] Intermediate 183

[1439] 1-Methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl chloride

[1440] Oxaloyl chloride (0.092 mL, 1.08 mmol) was added to a suspension of 1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (70.0 mg, 0.42 mmol) in DCM (1.3 mL), followed by the addition of DMF (4.17 µL, 0.05 mmol). The reaction mixture was stirred at room temperature for 6 h and then concentrated to give the title compound as a white solid.

[1441] Intermediate 184

[1442] rac-tert-butyl(3R,4R)-4-ethynyl-3-hydroxypiperidine-1-carboxylic acid ester

[1443] Intermediate 182 (6.34 g, 21.31 mmol) of rac-tert-butyl(3R,4R)-3-hydroxy-4-((trimethylsilyl)ethynyl)piperidine-1-carboxylic acid ester was dissolved in MeOH (107 mL), and K2CO3 (5.89 g, 42.62 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h, and then concentrated under reduced pressure. EtOAc and water were added to the residue, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (4.52 g, 94%) as a clear oil. 1 H NMR (500MHz, CDCl3, 25℃) δ 1.46 (9H, s), 1.52–1.61 (1H,m), 1.95–2.02 (1H, m), 2.19 (1H, d), 2.29 (1H, s), 2.42–2.51 (1H, m), 2.83–3.11 (2H, m), 3.62 (1H, s), 3.69–3.93 (1H, m), 4.01 (1H, dd).

[1444] Intermediate 185

[1445] rac-(3R,4R)-4-ethynyl-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol

[1446] Intermediate 191 of rac-tert-butyl(3R,4R)-4-ethynyl-3-hydroxypiperidine-1-carboxylic acid ester (4.52 g, 20.05 mmol) was dissolved in DCM (65 mL), and TFA (30 mL, 20.05 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The residue was dissolved in MeCN (65 mL), and 2-(chloromethyl)-4-methylquinazoline (5.02 g, 26.07 mmol) and K₂CO₃ (16.63 g, 120.33 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 21 h, and then concentrated. The reaction mixture was diluted with DCM and water, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure to give the title compound (5.64 g) as a yellow oil. MS (ESI) m / z [M+H] + 282.1. 1H NMR (500MHz, CDCl3, 25℃) δ 1.7–1.78 (1H, m), 2.07–2.18(2H, m), 2.4–2.6 (3H, m), 2.81–2.89 (1H, m), 2.95 (3H, s), 3.04 (1H, d),3.78–3.85 (1H, m), 3.91–4 (2H, m), 7.58–7.65 (1H, m), 7.86 (1H, ddd), 7.98–8.02 (1H, m), 8.06–8.1 (1H, m)

[1447] Intermediate 186

[1448] rac-2-(((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-ethynylpiperidin-1-yl)methyl 4-methylquinazoline

[1449] Intermediate 185 (439 mg, 1.56 mmol) of rac-(3R,4R)-4-ethynyl-1-((4-methylquinazolin-2-yl)methyl)piperidin-3-ol was dissolved in DCM (3.9 mL). Imidazole (234 mg, 3.43 mmol), DMAP (19.06 mg, 0.16 mmol), and TBDMSCl (259 mg, 1.72 mmol) were added, and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with water, and the mixture was diluted with DCM. The aqueous layer was extracted with DCM, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by preparative HPLC method D (gradient: 50%-100%) to give the title compound (471 mg, 76%) as a yellow oil. MS (ESI) m / z [M+H] + 396.6. 1 H NMR (500MHz, CDCl3, 25℃) δ -0.01–0.11 (6H, m), 0.82 (9H, s), 1.75–1.86 (1H, m), 1.88–1.95 (1H, m), 1.95–2.04 (2H, m), 2.05–2.14 (1H, m), 2.20 (1H, dddd), 2.88–2.98 (4H, m), 3.18–3.29 (1H, m), 3.80 (1H, td), 3.88–3.98 (2H, m), 7.57 (1H, ddd), 7.82 (1H,ddd), 7.96–8.01 (1H, m), 8.02–8.06 (1H, m).

[1450] Intermediate 187

[1451] rac-3-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-((4-methylquinazolin-2-yl) (Methyl)piperidin-4-yl)-1-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)prop-2-yn-1-one

[1452] Under a N2(g) atmosphere, a solution of rac-2-(((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-4-ethynylpiperidin-1-yl)methyl)-4-methylquinazoline intermediate 186 (237 mg, 0.60 mmol) in toluene (2.4 mL) and THF (1.2 mL) was added to a mixture of 1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl chloride intermediate 183 (111 mg, 0.60 mmol), Pd(PPh3)2Cl2 (21.06 mg, 0.03 mmol), and CuI (5.71 mg, 0.03 mmol). TEA (409 µL, 3.00 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with EtOAc and washed with...

Claims

1. A compound of formula (I) in R 1 Selected from 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 8 R 10 and 0, 1 or 2 independently selected from R 9 Substituents; R 2 Independently selected from H, CH3, CH2F, CHF2, and CF3; R 3 Selected from 5- or 6-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents, or 8-, 9-, or 10-membered heteroaryl groups substituted with the following groups: R 10 0, 1, or 2 are independently selected from R 11 The substituents, 0, 1, or 2, are independently selected from R. 12 Substituents, and 0 or 1 independently selected from R 13 Substituents; R 4 C selected from H, OH, and optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl; R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3; R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F; R 7 C selected from H, F, Cl, CN, and optionally replaced by 1, 2, 3, 4, or 5 F atoms. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, -CH(CH3)2, oxetane, cyPr or cyBu; R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, -CH(CH3)2, cyPr, cyBu, CN, F or Cl; R 9 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl groups, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, and -O (oxetane) substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, -CH(CH3)2, CN, F or Cl; R 10 CyPr, selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu, substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3; R 11 C is independently selected from those C's that are optionally replaced by 1, 2, 3, 4, or 5 F's. 1-2 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-2 Alkyl group, CH2OCH3, CH2cyPr, cyPr substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3, or cyBu substituted with 0 or 1 substituent selected from F, CH3, CH2F, CHF2 or CF3; R 12 It is independently selected from CH3, OH, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3 or CH2OH; R 13 Selected from a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N, wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3 or -O (a 6-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from O, S, or N), wherein the 6-membered heterocyclic alkyl ring is optionally substituted with 0, 1, or 2 substituents independently selected from F, OH, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, or (CO)CH3; m can be 0, 1, or 2 independently; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein... R 1 Selected from 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； R 3 Selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ； n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2; Or its pharmaceutically acceptable salt.

3. The compound according to claim 2, wherein... R 8 It is independently selected from H, CH3, CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3 or Cl; R 10 Selected from H, CH3, CH2F, CHF2, CF3, or CH2CH3; R 11 Independently selected from H, CH3CH2F, CHF2, CF3, CH2CH3, OCH3, OCH2F, OCHF2, OCF3, CH2OCH3, cyPr, CH2cyPr, or cyBu; R 12 Independently selected from OH, CH3, OCH3, CH2F, CHF2, CF3, CH2CH3, CH2OCH3, -CH(CH3)2, CN, Cl, NHCH3, CH2OH; R 13 Selected from H, , or .

4. The compound according to any one of claims 1 to 3, wherein R 4 Selected from OH, OCH3, OCH2F, OCHF2, OCF3, -CH2OH, CN, F.

5. The compound according to claim 4, wherein... R 1 Selected from , , , , , .

6. The compound according to claim 4, wherein... R 3 Selected from , , , .

7. The compound according to claim 1, wherein... R 1 Selected from , , , , , ; R 2 For H; R 3 Selected from 、 、 、 ； R 4 C selected from OH, optionally substituted by 1, 2, 3, 4 or 5 F atoms. 1-3 Alkyl groups, optionally substituted with 1, 2, 3, 4 or 5 F atoms, are OCs. 1-3 Alkyl groups, -CH2OH, -CH2OCH3, CN, F, Cl; R 5 It is independently selected from H, F, OH, OCH3, OCH2F, OCHF2, OCF3, CH3, CH2F, CHF2, or CF3; R 6 It is independently selected from CH3, CH2F, CHF2, CF3, CH2CH3, or F; R 7 Selected from H, F, CH3 or CN; R 8 Independently selected from H, CH3, or OCH3; R 9 It is independently selected from CH3, OCH3, CN, F, or Cl; R 10 Selected from H or CH3; R 11 Independently selected from CH3 or OCH3; R 12 Independently selected from CH3, OCH3, CN, or Cl; m can be 0, 1, or 2 independently; n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, or 2.

8. The compound according to claim 1, wherein the compound is selected from... 2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinoline; 2-((4-(5-(4-isopropylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyridino[2,3-d]pyrimidine; 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidinyl; 6-Chloro-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 8-Fluoro-4-methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 8-Fluoro-4-methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine; 2-((4-(5-(4-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine; 4-Methyl-2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine; 4-Methyl-2-((4-(5-(5-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine; 4-Methyl-2-((4-(5-(2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine; (3-(3-(1-((4-methylpyridino[2,3-d]pyrimidin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-4-yl)methanol; 2-((4-(5-(2-ethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine; 2-((4-(5-(2,4-diethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine; 3-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-8-methylbenzo[e][1,2,4]triazine; 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine; 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine; 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine; 5-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-1,8-naphthidine; 4,7-Dimethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[2,3-d]pyrimidine; 6-Chloro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 5-Chloro-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4,6-Dimethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazolin-6-carboxynitrile; 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[3,4-d]pyrimidine; 8-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 6-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 5-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 7-Fluoro-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 6-Methoxy-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)pyrido[3,2-d]pyrimidine; 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4,7-dimethylpyrido[2,3-d]pyrimidine; 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylpyrido[2,3-d]pyrimidine; 4-(methoxy-d3)-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)thiopheno[3,2-d]pyrimidine; 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4,7-dimethyl-7H-pyrrolo[2,3-d]pyrimidine; 6-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-1H-pyrrolo[2,3-d]pyridine; 1-Ethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-1H-benzis[d]imidazolium; rac-(R)-4-methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine; 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Chloro-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine; rac-4-methyl-2-(((2R,4R)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Ethyl-2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine; 4-Ethyl-2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(1',5'-dimethyl-1H,2'H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Ethyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-ethyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-Methyl-2-((4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methyl-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine; 4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-4-ol; (3R,4R)-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; 4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-4-ol; (3R,4R)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; 2-((4-fluoro-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidine-4-carboxynitrile; 2-((4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-methoxy-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; rac-4-methyl-2-(((2R,4S)-2-methyl-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; (1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-yl)methanol; 1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-ol; (3R,4R)-4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4R)-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; 3R,4R)-4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3S,4S)-4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxypiperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-methoxy-4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; (3R,4S)-4-methoxy-4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-(5'-(difluoromethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxy-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-methoxy-4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-methoxy-4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxy-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-methoxy-4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-1-((5-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3R,4S)-1-((5-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3R,4S)-1-((6-chloro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3R,4S)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3S,4R)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3R,4S)-4-methoxy-4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-(3',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)-4-methoxy-1-((4-methylquinazoline-2-yl)methyl)piperidin-3-ol; (3R,4S)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-3-ol; (3R,4S)-1-((8-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; (3R,4S)-1-((6-fluoro-4-methylquinazolin-2-yl)methyl)-4-methoxy-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; rac-(3R,4S)-3-fluoro-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-4-ol; rac-(3R,4R)-4-methoxy-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; 4-Methyl-2-((4-(1',3',4,5'-tetramethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 1',3',5'-Trimethyl-5-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1'H,2H-[3,4'-bipyrazole]-4-carboxynitrile; N-Methyl-5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridine-3-amine; 4-Methyl-2-((4-(5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 1-(4-(5-(3-(1-(((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-3-yl)piperazin-1-yl)acetoone; 4-Methyl-5-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)nicotinonitrile; 4-(5-(3-(1-((4-methylquinazoline-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-3-yl)morpholine; 2-((4-(5-(5-methoxypyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5-(5-chloropyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 4-Methyl-2-((4-(5-(5-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(4-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(5-(2-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(5-(2,4-dimethylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5-(4-(methoxymethyl)-2-methylpyridin-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-({4-[3-(4-ethyl-2-methylpyridin-3-yl)-1H-pyrazol-5-yl]piperidin-1-yl}methyl)-4-methylquinazoline; 2-((4-(5-(4,6-dimethylpyrimidin-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5-(1,4-dimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 4-Methyl-2-((4-(5-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine; 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine; 2-((4-(5-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 3-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine; 7-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-2,3-dihydropyrazolo[5,1-b]oxazole; 3,5-Dimethyl-4-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)isoxazole; 4-Methyl-2-((4-(5-(1,2,4-trimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(5-(1,2-dimethyl-1H-imidazol-5-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2,4-Dimethyl-5-(3-(1-((4-methylquinazoline-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)thiazole; 5-Methyl-2-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)thiazole; 3,5-Dimethyl-4-(3-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-5-yl)isothiazol; 2-((4-(5-(4-ethyl-5-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 3,4-Dimethyl-5-(5-(1-((4-methylquinazolin-2-yl)methyl)piperidin-4-yl)-1H-pyrazol-3-yl)isoxazole; 2-((4-(1',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(3',5'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 4-Methyl-2-((4-(1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 4-Methyl-2-((4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(5'-cyclobutyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5'-(difluoromethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 4-Methyl-2-((4-(1'-methyl-5'-(trifluoromethyl)-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(5'-(methoxymethyl)-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5'-cyclopropyl-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5'-methoxy-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 4-Methyl-2-((4-(2',4',5'-trimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)quinazoline; 2-((4-(4',5'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(2',4'-dimethyl-2H,2'H-[3,3'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5'-ethyl-1',3'-dimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; 2-((4-(5'-methoxy-1'-methyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-1-yl)methyl)-4-methylquinazoline; rac-(3R,4S)-4-ethyl-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; rac-(3R,4S)-4-methyl-1-((4-methylquinazolin-2-yl)methyl)-4-(1',3',5'-trimethyl-1'H,2H-[3,4'-bipyrazole]-5-yl)piperidin-3-ol; Or its pharmaceutically acceptable salt.

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, used as a medicine.

10. A pharmaceutical composition comprising a compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A method of treating a disease or condition in which inhibition of NNMT enzyme is beneficial or of reducing the risk of said disease or condition, the method comprising administering to a person suffering from said disease or condition or at risk of said disease or condition a therapeutically effective amount of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the disease or condition is chronic kidney disease (CKD).

13. The method of claim 11, wherein the disease or condition is acute kidney injury (AKI).

14. The method of claim 11, wherein the disease or condition is diabetic nephropathy (DKD).

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, used as a medicine.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, for the treatment of chronic kidney disease (CKD).

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, for the treatment of acute kidney injury (AKI).

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, for the treatment of diabetic nephropathy (DKD).

19. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 in the preparation of a medicament for treating or preventing a disease or condition in which inhibition of NNMT enzyme is beneficial.

20. The use according to claim 19, wherein the disease or condition is chronic kidney disease (CKD).

21. The use according to claim 19, wherein the disease or condition is acute kidney injury (AKI).

22. The use according to claim 19, wherein the disease or condition is diabetic nephropathy (DKD).

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