3-(6-Pyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile derivatives and similar compounds as QPCTL and QPCT inhibitors for the treatment of cancer

Abstract

Compounds of formula (II) and formula (I) which are inhibitors of QPCTL and QPCT: (II) and (I) are provided herein. Also provided are pharmaceutical compositions containing this compound, as well as compounds for use in methods of treating cancer, neurodegenerative, inflammatory or autoimmune diseases. Exemplary compounds are, for example, 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (Example 1): (1), and pharmacological data are provided. TIFF2025524039000368.tif70128

Description

Technical Field

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 391,630, filed Jul. 22, 2022, which is incorporated herein by reference in its entirety.

Background Art

[0002] Glutaminyl cyclase belongs to the family of metal-dependent aminoacyltransferases and catalyzes the intramolecular cyclization of peptide or protein N-terminal glutamine or glutamate amino acid residues to pyroglutamic acid (pE). Glutaminyl cyclase utilizes a zinc-dependent catalytic mechanism to form pyroglutamic acid residues and release ammonia. The pyroglutamic acid modification can be important for biological activity as it can protect proteins from degradation by proteolytic enzymes or regulate the interaction of proteins with other proteins. (W. Busby et al., J Biol Chem. 262(18), 8532(1987) (Non-Patent Document 1); W. Fischer and J Spiess, Pro Natl Acad Sci U.S.A. 84, 3628(1987) (Non-Patent Document 2); A. Stephan et al., FEBS J. 276, 6522(2009) (Non-Patent Document 3).

[0003] Two human glutaminyl cyclase isoforms have been identified. The first isoform, QPCT (also known as QC, sQC), is secreted. The second isoform, QPCTL (also known as isoQC), contains an N-terminal sequence that results in its retention within the Golgi complex. QPCT and QPCTL share high sequence similarity and structure in the region of their active sites. However, they have different cell distributions and thus convert different substrates and result in different physiological roles. QPCT is abundant in the hypothalamus, medulla, and hippocampus, and most of the glutaminyl cyclase activity in the brain is mediated by QPCT. QPCTL is more widely expressed and acts on substrates such as cytokines in peripheral cells. (H. Cynis et al., J Mol Bio. 379(5), 966(2008) (Non-Patent Document 4); S. Schilling et al., J Biol Chem. 286(16), 14199(2011) (Non-Patent Document 5).

[0004] Both QPCT and QPCTL are strongly involved in disease states. For example, QPCT modifies amyloid beta (Aβ) peptide to obtain pE-Aβ. pE modification changes the biophysical characteristics of the Aβ peptide by increasing the aggregation behavior of the Aβ peptide. pE-Aβ has been shown to be one of the major components of Aβ deposits in patients with Alzheimer's disease (AD) and has been reported to induce neurotoxic events in the etiology of AD (K. Liu et al., Acta Neuropathol. 112(2), 163(2006) (Non-Patent Document 6); J. Nussbaum et al., Nature. 485, 7400(2012)651 (Non-Patent Document 7)). QPCTL catalyzes the formation of pE on the integrin-related transmembrane protein CD47, which enhances the interaction with the regulatory membrane glycoprotein SIRPα. CD47 expression is increased on tumor cells, and the CD47-SIRPα interaction provides a phagocytosis checkpoint that allows cancer cells to escape from immune surveillance (M. Logtenberg et al., Nat Med. 25, 612(2019) (Non-Patent Document 8); Z. Wu et al., Cell Res. 29, 502(2019) (Non-Patent Document 9)). QPCTL also catalyzes the formation of pE on chemotactic cytokines such as CCL2 and related family members, protecting them from proteolysis. CCL2 regulates the migration and infiltration of monocytes, which play an important role in inflammatory states. CCL2 also enables the recruitment of monocytes to the tumor microenvironment, where monocytes become tumor-associated macrophages (TAM) that support the growth and survival of related tumor cells (H. Cynis et al., EMBO Mol Med. 3, 545(2011) (Non-Patent Document 10); R. Barreira da Silva et al., Nat Immun. 23, 568(2022) (Non-Patent Document 11)).

[0005] Therefore, inhibiting either QPCT or QPCTL provides a therapeutic approach for treating disorders such as neurological diseases, cancer, and inflammation. Therefore, there is a need for compounds that can modulate or inhibit QPCT and QPCTL.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Summary of the Invention

[0007] In various embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof, TIFF2025524039000002.tif47128W 1 is N or CR 1 and W 2 is N or CR 2 and W 3 is N or CR 3 and W 1 , W 2 , and W 3 One or less of them is N,

[0008] X 1 and X 2 are independently selected from CR 4 and N.

[0009] In some embodiments, ring Y TIFF2025524039000003.tif11128 is of formula (a): TIFF2025524039000004.tif14128 thereof.

[0010] In formula (a), Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from CR 5 and N, and Y 1 , Y 2 , Y 3 , and Y 4 are not simultaneously N.

[0011] In other embodiments, ring Y TIFF2025524039000005.tif11128 is of formula (b): It is TIFF2025524039000006.tif14128.

[0012] In formula (b), Y 1 is CR 5 and Y 2 is NR 5’ respectively.

[0013] In still other embodiments, ring Y TIFF2025524039000007.tif11128 has the formula (c): It is TIFF2025524039000008.tif10128.

[0014] In formula (c), Y 1 , Y 2 , Y 3 , and Y 4 are each independently selected from CR 5 and N.

[0015] In some embodiments, either Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 represents a fused ring selected from C5-C8-cycloalkyl, C6-C 10 -aryl, 5-10-membered heteroaryl (where 1-4 heteroaryl members are each independently selected from N, O, and S), and 5-8-membered heterocycloalkyl (where 1-4 ring members are each independently selected from N, B, O, and S), and the ring is C1-C6-alkyl, C3-C8-cycloalkyl, 3-6-membered heterocycloalkyl (where 1-4 ring members are each independently selected from N, O, and S), C2-C6-alkenyl, C2-C6-alkynyl, halo, C1-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-Ra 、 -R b -OC(O)-OR a 、 -R b -OC(O)-N(R a )2、 -R b -N(R a )2、 -R b -OR a (N(R a )2)、 -R b -C(O)R a 、 -R b -C(O)OR a 、 -R b -C(O)N(R a )2、 -R b -O-R c -C(O)N(R a )2、 -R b -N(R a )C(O)OR a 、 -R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) and may be substituted with 1 to 3 substituents independently selected from the group consisting of.

[0016] A, B, and E are independently selected from C, N, O, and S, and D is C or N.

[0017] Symbol TIFF2025524039000009.tif5128 represents the presence of a double bond such that the ring ABDEN is aromatic and optionally substituted with one or two substituents independently selected from C1-C3-alkyl, C3-C5 cycloalkyl, OH, OMe, NH2, N(H)Me, NMe2. Furthermore, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0018] R 1 , R 2 , and R 3 are independently hydrogen, halo, cyano, nitro, -R b -OR a , -R b -OR c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -OR c -N(R a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -Rb -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C6-C 10 -aryl, -(C1-C6-alkyl)(C6-C 10 -aryl), optionally 5-10-membered heteroaryl fused to a 3-6-membered heterocycloalkyl (where 1-4 ring members are independently selected from N, O, and S) (where 1-4 heteroaryl members are independently selected from N, O, and S), and 3-6-membered heterocycloalkyl (where 1-4 ring members are independently selected from N, O, and S) selected from the group consisting of.

[0019] In some embodiments, R 1 and R 2 , or R 2 and R 3 together with the carbon atom to which they are attached form a fused C5-C8-cycloalkyl, C6-C 10 -aryl, 5-10-membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S), and 5-8-membered heterocycloalkyl (where 1-4 ring members are independently selected from N, O, and S).

[0020] R 1 、R 2 、and R 3 Any heteroaryl or heterocycloalkyl in is independently C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, heterocycloalkyl (where 1-4 ring members are independently selected from N, O, and S), and -Rb -N(R a )2 selected from the group consisting of may be substituted with 1 to 3 substituents.

[0021] In each example, R 4 is independently H, OH, halo, C1-C6-alkyl, or C1-C6-alkoxy.

[0022] In each example, R 5 is independently hydrogen, halo, cyano, nitro, -R b -OR a , -R b -O-R c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -B(OR a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) tR a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -OS(O) t F(where t is 1 or 2), -R b -S(O) t N(R a )2(where t is 1 or 2), C1 - C6 - alkyl, C2 - C6 - alkynyl, C3 - C8 - cycloalkyl, C6 - C 10 -aryl, 5 - to 10 - membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3 - to 6 - membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) is selected from the group consisting of.

[0023] R 5’ is hydrogen, -R c -R a , -R c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R c -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)ORa 、 -R b -N(R a )C(O)R a 、 -R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2), -R b -S(O) t N(R a )2(wherein, t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl (wherein, 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein, 1 to 4 ring members are independently selected from N, O, and S) are selected from the group consisting of.

[0024] R 5 and R 5’ Any heteroaryl or heterocycloalkyl in is independently substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, and -R b -N(R a )2.

[0025] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、and R 6h are independently selected from the group consisting of H, halo, NO2, OH, CN, -R b -N(R a )2, -R b -OH, C1-C6-alkyl, and C1-C6-alkoxy.

[0026] In some embodiments, optionally in combination with any other embodiment described herein, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently represents oxo, thioxo, imino, or oximo.

[0027] In yet further embodiments, optionally in combination with any other embodiment described herein, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h together with the carbon atom to which they are attached independently combine to form a fused ring selected from C3-C6-cycloalkyl and C3-C6-heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S).

[0028] In additional embodiments, optionally in combination with any other embodiment described herein, one of R 6c and R 6d together with one of R 6e and R 6f represents a bond between the ring carbon members to which they are attached.

[0029] In each instance, R a independently is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, -(C1-C6-alkyl)(C3-C8-cycloalkyl), C6-C 10-Aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0030] R in each instance b is independently selected from a direct bond, linear or branched C2-C6-alkylene, and C2-C6-alkenylene chains.

[0031] R a and R b Any heteroaryl or heterocycloalkyl in R may independently be substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, and hydroxy.

[0032] R in each instance c is independently selected from linear or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0033] In another embodiment, the disclosure provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0034] The disclosure also provides, in additional embodiments, a method of treating a patient afflicted with a disease that is associated with the expression of glutaminyl peptide cyclotransferase protein (QPCT) or glutaminyl peptide cyclotransferase-like protein (QPCTL). The method comprises administering to the patient a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0035] In yet another embodiment, the present disclosure provides a method of inhibiting glutaminyl - peptide cyclotransferase protein (QPCT) or glutaminyl - peptide cyclotransferase - like (QPCTL) enzyme. The method comprises contacting the enzyme with a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0036] In embodiments, the present disclosure provides a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease.

[0037] The present disclosure also provides the use of a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment of cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0038]

Figure 1

Figure 2

Figure 3

[0039] Detailed Description The present disclosure provides compounds of formula (I) and formula (II) which are potent inhibitors of QPCTL and QPCT enzymes. The compounds are useful for the treatment of diseases and conditions associated with the expression of QPCTL or QPCT, including various cancers and neurodegenerative diseases.

[0040] Definitions As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes reference to one or more cells (or a plurality of cells) and their equivalents known to those skilled in the art, etc. When ranges are used herein with respect to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and subcombinations of the range and specific embodiments therein are intended to be included. The term "about" when referring to a numerical value or numerical range means that the recited numerical value or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary, in some cases, by from 1% to 15% of the specified numerical value or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," "having," "including") does not exclude, in other particular embodiments, for example, embodiments of any composition, composition, method, or process of the substances described herein from "consisting of" or "consisting essentially of" the recited features.

[0041] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings set forth below.

[0042] "Amino" refers to the -NH2 moiety.

[0043] "Cyano" refers to the -CN moiety.

[0044] "Nitro" refers to the -NO2 moiety.

[0045] "Oxa" refers to the -O- moiety.

[0046] "Oxo" refers to the =O moiety.

[0047] "Thioxo" refers to the =S moiety.

[0048] "Imino" refers to the =N-H moiety.

[0049] "Oximo" refers to the =N-OH moiety.

[0050] "Hydrazino" refers to the =N-NH2 moiety.

[0051] "Alkyl" consists of only carbon and hydrogen atoms, contains no unsaturation, and has 1 to 15 carbon atoms (e.g., C1-C 15 alkyl) straight-chain or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 alkyl). In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15(alkyl). In other embodiments, the alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is bonded to the remainder of the molecule by a single bond. Unless otherwise specified herein, the alkyl group has the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), and -S(O) t N(R a )2 (wherein t is 1 or 2) may be substituted by one or more of them, wherein each R ais, independently, hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, the optionally substituted alkyl is haloalkyl. In other embodiments, the optionally substituted alkyl is fluoroalkyl. In other embodiments, the optionally substituted alkyl is a -CF3 group.

[0052] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0053] "Alkenyl" refers to a straight-chain or branched hydrocarbon radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. Alkenyl is bonded to the rest of the molecule by a single bond and includes, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specified herein, alkenyl groups are substituted with the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2) may be substituted by one or more of them, where each R ais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0054] "Alkynyl" refers to a straight-chain or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 6 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. Alkynyl is bonded to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specified herein, an alkyl group may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a, -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a )2(where t is 1 or 2) may be substituted by one or more of them, where each R a is independently hydrogen, alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which is substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0055] "Alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical group, contains no unsaturation, consists only of carbon and hydrogen, has 1 to 12 carbon atoms, and examples include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is bonded to the rest of the molecule via a single bond and to the radical group via a single bond. The bonding points of the alkylene chain to the rest of the molecule and the radical group are via one carbon within the alkylene chain or via any two carbons within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified herein, the alkylene chain has the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t Ra (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), and -S(O) t N(R a )2 (wherein t is 1 or 2) may be substituted by one or more of them, wherein each R a is independently hydrogen, alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0056] "Alkenylene" or "alkenylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting of only carbon and hydrogen, containing at least one carbon-carbon double bond, having 2 to 12 carbon atoms, and connecting the remaining part of the molecule to a radical group. The alkenylene chain is bonded to the remaining part of the molecule via a single bond and to the radical group via a single bond. In certain embodiments, alkenylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (e.g., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkenylene). Unless otherwise specified herein, the alkenylene chain may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (wherein t is 1 or 2), -S(O) t OR a (wherein t is 1 or 2), -S(O) t R a (wherein t is 1 or 2), and -S(O) t N(R a)2(wherein t is 1 or 2) may be substituted by one or more of them, and in the formula, each R a is independently hydrogen, alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0057] "Alkynylene" or "alkynylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, having 2 to 12 carbon atoms, and connecting the remaining part of the molecule to a radical group. The alkynylene chain is bonded to the remaining part of the molecule via a single bond and to the radical group via a single bond. In certain embodiments, alkynylene contains 2 to 8 carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (e.g., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise specified herein, the alkynylene chain has the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a)2 (wherein t is 1 or 2) may be substituted by one or more of them, and in the formula, each R a is independently hydrogen, alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclic alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (which may be substituted by halogen, hydroxy, methoxy, or trifluoromethyl).

[0058] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one of the rings in the ring system is completely unsaturated, that is, according to Hückel's theory, it contains a cyclic delocalized (4n + 2)π - electron system. For example, aryl is a C6~C 10 ring system. Examples of the ring system from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specified herein, the term "aryl" or the prefix "ar-" (such as in "aralkyl") refers to alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, halo, cyano, nitro, halo, cyano, nitro, -R b -OR a , -Rb -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2) and -R b -S(O) t N(R a )2(wherein, t is 1 or 2) and means optionally substituted with one or more substituents independently selected from an aryl radical, wherein each R ais, independently, hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is, independently, a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and R a R b or R c Each of the substituents is unsubstituted unless otherwise specified.

[0059] “Aralkyl” refers to a radical of the formula -R c -aryl, in which formula R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical may be substituted as described above for the alkylene chain. The aryl portion of the aralkyl radical may be substituted as described above for the aryl group.

[0060] “Alkenyl” refers to a radical of the formula -R d -aryl, in which formula R dis an alkenylene chain as defined above. The aryl portion of the aralkenyl radical may be substituted as described above for aryl groups. The alkenylene chain portion of the aralkenyl radical may be substituted as described above for alkenylene chains.

[0061] "Aralkynyl" refers to a radical of the formula -R e -aryl, in which R e is an alkynylene chain as defined above. The aryl portion of the aralkynyl radical may be substituted as described above for aryl groups. The alkynylene chain portion of the aralkynyl radical may be substituted as described above for alkynylene chains.

[0062] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c -aryl, in which R c is an alkylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl radical may be substituted as described above for alkylene chains. The aryl portion of the aralkyl radical may be substituted as described above for aryl groups.

[0063] "Carbocyclicryl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, including a condensed or bridged ring system having 3 to 15 carbon atoms. In certain embodiments, carbocyclicryl contains 3 to 10 carbon atoms. In other embodiments, carbocyclicryl contains 5 to 7 carbon atoms. Carbocyclicryl is bonded to the remainder of the molecule by a single bond. Carbocyclicryl is saturated (i.e., contains only single C-C bonds) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclicryl radical is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclicryl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclicryl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specified herein, the term "carbocyclicryl" may be substituted alkyl, substituted alkenyl, substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(Ra ) 2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein, t is 1 or 2) and means that it may be substituted with one or more substituents independently selected from a carbocyclic radical which may be substituted, wherein each R a is independently hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is independently a direct bond, or a linear or branched alkylene or alkenylene chain, and Rc is a linear or branched alkylene or alkenylene chain, and R a , R b , or R c Each of the substituents is unsubstituted unless otherwise specified.

[0064] "Carbocyclic alkyl" refers to a radical of the formula -R c -carbocyclic, where R c is the alkylene chain defined above. The alkynylene chain and the carbocyclic radical may be substituted as defined above.

[0065] "Carbocyclic alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic radical may be substituted as defined above.

[0066] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0067] "Fluoroalkyl" refers to an alkyl radical as defined above substituted by one or more fluoro radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical may be substituted as defined above for alkyl groups.

[0068] "Heterocyclyl" or, similarly, "heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. In embodiments, the heterocycloalkyl is a 3- to 6-membered ring (where 1 to 4 ring members are independently selected from N, O, and S), and the ring may be substituted with 1 to 3 substituents. Unless otherwise specified herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system optionally containing a fused or bridged ring system. The heteroatoms in the heterocyclyl radical are optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the remainder of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl, [1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified herein, the term "heterocyclyl" includes optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a)2. -R b -C(O)R a . -R b -C(O)OR a . -R b -C(O)N(R a )2. -R b -O-R c -C(O)N(R a )2. -R b -N(R a )C(O)OR a . -R b -N(R a )C(O)R a . -R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein, t is 1 or 2) and is optionally substituted with one or more substituents independently selected from the above-defined heterocyclyl radical as defined above, wherein each R ais, independently, hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is, independently, a direct bond, or a straight-chain or branched alkylene or alkenylene chain, and R c is a straight-chain or branched alkylene or alkenylene chain, and R a R b or R c Each of the substituents is unsubstituted unless otherwise specified.

[0069] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. One to four heteroaryl members independently contain a 5- to 10-membered ring selected from N, O, and S. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and at least one of the rings in the ring system is completely unsaturated, i.e., contains a cyclic, delocalized (4n + 2)π - electron system in accordance with Hückel's theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) within the heteroaryl radical are optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring(s). Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 - benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2 - d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7 - dihydro - 5H - cyclopenta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6 - dihydrobenz[h]quinazolinyl, 5,6 - dihydrobenz[h]cinnolinyl, 6,7 - dihydro - 5H - [6,7]cyclohepta[1,2 - c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2 - c]pyridinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10 - hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooct[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyldinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl), among others, are included but not limited to these. Unless otherwise specified herein, the term "heteroaryl" refers to optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalkynyl, oxo, thioxo, cyano, nitro, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2) and means optionally substituted with one or more substituents independently selected from the above-defined heteroaryl radicals as defined above, where each R ais, independently, hydrogen, alkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (which may be substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and each R b is, independently, a direct bond, or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and R a , R b , or R c Each of the substituents is unsubstituted unless otherwise specified.

[0070] "Heteroarylalkoxy" refers to a radical of the formula -R c -heteroaryl, wherein R c is the alkylene chain defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to the alkyl radical at the nitrogen atom. The alkylene chain portion of the heteroarylalkyl radical may be substituted as defined above for the alkylene group. The heteroaryl portion of the heteroarylalkyl radical may be substituted as defined above for the heteroaryl group. "Heteroarylalkoxy" is of the formula -O-R c- refers to a radical bonded through an oxygen atom of a heteroaryl, wherein R c is an alkylene chain as defined above. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally bonded to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical may be substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical may be substituted as defined above for the heteroaryl group.

[0071] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined as (R)- or (S)- from the perspective of absolute stereochemistry. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be embraced by this disclosure. When the compounds described herein contain an alkene double bond, unless otherwise specified, this disclosure is intended to include both E geometric isomers and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a benzene ring.

[0072] As used in the present invention, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to the carboxylic acid moiety. Examples of carboxylic acid bioisosteres include TIFF2025524039000010.tif36128 and the like, but are not limited thereto.

[0073] "Tautomers" refer to molecules in which a proton shift is possible from one atom of the molecule to another atom of the same molecule. The compounds presented in this specification exist as tautomers in certain embodiments. In situations where tautomerism is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including the physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include the following: TIFF2025524039000011.tif83128。

[0074] The compounds disclosed in this specification, in some embodiments, are in different enriched isotopic forms, for example, 2 H, 3 H, 11 C, 13 C, and / or 14 C are used with enriched content. In one embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and / or efficacy of the compound, thereby increasing the duration of the therapeutic action of the compound.

[0075] Unless otherwise specified, the structures shown in this specification are intended to include different compounds only in the presence of one or more isotope-enriched atoms. For example, compounds having the structure of the present invention, excluding substitution of hydrogen by deuterium or tritium, or substitution of carbon by 13 C or 14 C-enriched carbon, are within the scope of this disclosure.

[0076] The compounds of this disclosure optionally contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, these compounds may be radiolabeled with radioactive isotopes such as deuterium (2H), tritium (3H), iodine-125 (125I), or carbon-14 (14C).2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions with H, C, C, C, C, N, N, N, N, O, O, F, F, F, F, F, F, S, S, S, S, Cl, Cl, Br, Br, I are contemplated. In some embodiments, isotopic substitution with 18F is contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the invention.

[0077] In some embodiments, the compounds disclosed herein 2 have some or all of the 1 H atoms replaced by H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0078] Deuterium-substituted compounds are synthesized using a variety of methods as described below: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0079] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and building blocks are commercially available from chemical vendors such as Aldrich Chemical Co.

[0080] Deuterium transfer reagents suitable for use in nucleophilic substitution reactions such as iodomethane - d3 (CD3I) are readily available and can be employed to transfer deuterium-substituted carbon atoms to the reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is exemplified only as an example in the following reaction scheme. TIFF2025524039000012.tif40128

[0081] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are employed to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is exemplified only as an example in the following reaction scheme. TIFF2025524039000013.tif11155

[0082] Deuterium gas and a palladium catalyst are employed to reduce an unsaturated carbon-carbon bond and effect a reductive substitution of an aryl carbon-halogen bond, as exemplified only as an example, in the following reaction scheme. TIFF2025524039000014.tif34143

[0083] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by the synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0084] With respect to the compounds provided herein, when the position of a particular atom is designated as having deuterium or "D", it should be understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. The positions designated as having deuterium typically have a minimum isotopic enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom in certain embodiments. The isotopic enrichment and isotopic enrichment factors of the compounds provided herein can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0085] The present disclosure describes compounds that are compatible by chemical name and chemical structure. To the extent that there may be a conflict between a given chemical name and chemical structure of a compound, the chemical structure controls.

[0086] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass every pharmaceutically suitable salt form. Examples of pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0087] The term "pharmaceutically acceptable acid addition salts" refers to salts that retain the biological effectiveness and properties of the free base, are not undesirable in a biological or other respect, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. are also included, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also, salts of amino acids such as alginates, gluconates, and galacturonates are contemplated (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid according to methods and techniques well known to those skilled in the art to produce the salt.

[0088] "Pharmaceutically acceptable basic addition salts" refers to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable basic addition salts are, in some embodiments, formed with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine theobromine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0089] "Pharmaceutically acceptable solvates" refers to compositions of substances in a solvent-added form. In some embodiments, the solvate contains either a stoichiometric or non-stoichiometric amount of the solvent and is formed during the process of preparation using a pharmaceutically acceptable solvent such as water, ethanol, or the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein are prepared in a timely manner or are formed during the processes described herein. The compounds provided herein exist in either non-solvated or solvated forms.

[0090] As used herein, and unless otherwise specified to the contrary, the term "compound" is inclusive in that it encompasses a compound or a pharmaceutically acceptable salt, stereoisomer, isotopic substituent, and / or tautomer thereof. Thus, for example, a compound of formula (I) or formula (II) includes a pharmaceutically acceptable salt of a tautomer of the compound. Similarly, a compound of formula (I) or formula (II) includes a pharmaceutically acceptable salt of an isotopic substituent of the compound.

[0091] The terms "subject" or "patient" encompass mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees, as well as other apes and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; laboratory animals such as rabbits, dogs, and cats; experimental animals including rodents such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0092] As used herein, "treat" or "treating" or "alleviate" or "ameliorate" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means the eradication or improvement of the underlying disorder being treated. Also, a therapeutic benefit is achieved by the eradication or improvement of one or more of the physiological symptoms associated with the underlying disorder such that improvement is observed in the patient even if the patient may still suffer from the underlying disorder. From the perspective of prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease or to a patient reporting one or more of the physiological symptoms of a disease even when no diagnosis of the disease has been made.

[0093] The term "effective amount" refers to the amount of the compounds described herein, or other active ingredients sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with the disease. Further, a therapeutically effective amount with respect to the compounds described herein means the amount of the therapeutic agent, alone or in combination with other therapies that provide a therapeutic benefit in the treatment or prevention of a disease. When used in connection with the compounds described herein, this term can include an amount that improves the overall therapy, reduces or avoids the symptoms or causes of a disease, enhances the therapeutic effectiveness of another therapeutic agent, or is synergistic with another therapeutic agent.

[0094] Compound In various embodiments, the present disclosure provides compounds of formula (II) or pharmaceutically acceptable salts and / or solvates thereof: TIFF2025524039000015.tif47128.

[0095] W 1 is N or CR 1 and W 2 is N or CR 2 and W 3 is N or CR 3 and W 1 W 2 and W 3 One or fewer of are N.

[0096] X 1 and X 2 are independently selected from CR 4 and N.

[0097] In some embodiments, ring Y TIFF2025524039000016.tif11128 is of formula (a): TIFF2025524039000017.tif14128.

[0098] In formula (a), Y 1 Y 2 Y3 and Y 4 is independently CR 5 and N, and Y 1 Y 2 Y 3 and Y 4 is not N at the same time.

[0099] In other embodiments, ring Y TIFF2025524039000018.tif11128 is of formula (b): TIFF2025524039000019.tif14128.

[0100] In formula (b), Y 1 is CR 5 and Y 2 is NR 5’ and is.

[0101] In still other embodiments, ring Y TIFF2025524039000020.tif11128 is of formula (c): TIFF2025524039000021.tif10128.

[0102] In formula (c), Y 1 Y 2 Y 3 and Y 4 is independently selected from CR 5 and N.

[0103] In some embodiments, Y 1 and Y 2 or Y 2 and Y 3 or Y 3 and Y 4 any of which is C5 - C8 - cycloalkyl, C6 - C 10-Aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, B, O, and S), representing a fused ring selected from, the ring being C1-C6-alkyl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), C2-C6-alkenyl, C2-C6-alkynyl, halo, C1-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -OR a (N(R a )2)、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a(wherein t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2), and may be substituted with 1 to 3 substituents independently selected from the group consisting of.

[0104] A, B, and E are independently selected from C, N, O, and S, and D is C or N.

[0105] The symbol TIFF2025524039000022.tif5128 represents the presence of a double bond such that the ring A-B-D-E-N is aromatic and may be substituted with 1 or 2 substituents independently selected from C1-C3-alkyl, C3-C5-cycloalkyl, OH, OMe, NH2, N(H)Me, NMe2. Further, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0106] R 1 R 2 and R 3 are independently hydrogen, halo, cyano, nitro, -R b -OR a -R b -O-R c -O-R a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -Rb -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2), -R b -S(O) t N(R a )2 (wherein, t is 1 or 2), C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C6-C 10 -aryl, -(C1-C6-alkyl)(C6-C 10 -aryl), optionally 5-10 membered heteroaryl fused to a 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S) (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S) are selected from the group consisting of.

[0107] In some embodiments, R 1 and R 2 , or R 2 and R 3 together with the carbon atom to which they are attached form a fused C5-C8-cycloalkyl, C6-C 10-Aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) are formed.

[0108] R 1 、R 2 、and R 3 Any heteroaryl or heterocycloalkyl in, is independently C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and -R b -N(R a )2 may be substituted with 1 to 3 substituents selected from the group consisting of.

[0109] R in each example 4 is independently H, OH, halo, C1-C6-alkyl, or C1-C6-alkoxy.

[0110] R in each example 5 is independently hydrogen, halo, cyano, nitro, -R b -OR a 、-R b -O-R c -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -O-Rc -N(R a )2, -B(OR a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -OS(O) t F(where t is 1 or 2), -R b -S(O) t N(R a )2(where t is 1 or 2), C1 - C6 - alkyl, C2 - C6 - alkynyl, C3 - C8 - cycloalkyl, C6 - C 10 -aryl, 5 - to 10 - membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3 - to 6 - membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) is selected from the group consisting of.

[0111] R 5’ is hydrogen, -R c -R a , -R c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a)2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2), -R b -S(O) t N(R a )2 (wherein, t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl (wherein, 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein, 1 to 4 ring members are independently selected from N, O, and S) are selected from the group consisting of.

[0112] R 5 and R 5’ Any heteroaryl or heterocycloalkyl in is independently C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, and -R b -N(Ra ) It may be substituted with 1 to 3 substituents selected from the group consisting of 2.

[0113] R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h are independently H, halo, NO2, OH, CN, -R b -N(R a )2, -R b -OH, C1-C6-alkyl, and C1-C6-alkoxy.

[0114] In some embodiments, optionally in combination with any other embodiment described herein, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently represent oxo, thioxo, imino, or oximo.

[0115] In still further embodiments, optionally in combination with any other embodiment described herein, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h together with the carbon atom to which they are attached independently bond to form a fused ring selected from C3-C6-cycloalkyl and C3-C6-heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S).

[0116] In additional embodiments, optionally in combination with any other embodiment described herein, R 6c and R 6dOne of them is R 6e and R 6f together with one of them represents the bond between the ring carbon members to which they are attached.

[0117] In each instance, R a is independently selected from hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, -(C1-C6-alkyl)(C3-C8-cycloalkyl), C6-C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0118] In each instance, R b is independently selected from a direct bond, linear or branched C2-C6-alkylene, and C2-C6-alkenylene chains.

[0119] R a and R b Any heteroaryl or heterocycloalkyl in may be independently substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, and hydroxy.

[0120] In each instance, R c is independently selected from linear or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0121] In some embodiments, W 1 is N, W 2 is CR 2 and W 3 is CR 3 In other embodiments, W 1 is CR 1 and W 2 is CR 2 and W 3 is N. In still further embodiments, W 1 is CR 1and W 2 is CR 2 and W 3 is CR 3 is as follows.

[0122] In various embodiments, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof: TIFF2025524039000023.tif48128.

[0123] X 1 and X 2 are independently selected from CR 4 and N.

[0124] In some embodiments, ring Y TIFF2025524039000024.tif11128 is of formula (a): TIFF2025524039000025.tif14128.

[0125] In formula (a), Y 1 , Y 2 , Y 3 , and Y 4 are independently selected from CR 5 and N, and Y 1 , Y 2 , Y 3 , and Y 4 are not simultaneously N.

[0126] In other embodiments, ring Y TIFF2025524039000026.tif11128 is of formula (b): TIFF2025524039000027.tif14128.

[0127] In formula (b), Y 1 is CR 5 , and Y 2 is NR 5’ is as follows.

[0128] In some embodiments, Y1 and Y 2 or Y 2 and Y 3 or Y 3 and Y 4 Any of which is a fused ring selected from C5-C8-cycloalkyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and the ring is C1-C6-alkyl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), C2-C6-alkenyl, C2-C6-alkynyl, halo, C1-C6-haloalkyl, C2-C6-haloalkenyl, C2-C6-haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -OR a (N(R a )2), -R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a )S(O) t R a(where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) and may be substituted with 1 to 3 substituents independently selected from the group consisting of.

[0129] A, B, and E are independently selected from C, N, O, and S, and D is C or N. TIFF2025524039000028.tif5128 represents the presence of a double bond such that the ring A - B - D - E - N is aromatic and may be substituted with 1 or 2 substituents independently selected from C1 - C3 - alkyl, C3 - C5 - cycloalkyl, OH, OMe, NH2, N(H)Me, NMe2. Further, no more than 2 of A, B, D, and E are simultaneously N, O, or S.

[0130] R 1 、R 2 、and R 3 are independently hydrogen, halo, cyano, nitro, -R b -OR a 、-R b -O - R a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O - R c -C(O)N(Ra ) 2, -R b -O-R c -N(R a ) 2, -R b -N(R a ) -R c -N(R a ) 2, -R b -N(R a ) C(O)OR a , -R b -N(R a ) C(O)R a , -R b -N(R a ) S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t R a (wherein, t is 1 or 2), -R b -S(O) t OR a (wherein, t is 1 or 2), -R b -S(O) t N(R a ) 2 (wherein, t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C 10 -aryl, -(C1-C6-alkyl)(C6-C 10 -aryl), 5-10-membered heteroaryl (wherein, 1-4 heteroaryl members are independently selected from N, O, and S), and 3-6-membered heterocycloalkyl (wherein, 1-4 ring members are independently selected from N, O, and S) is selected from the group consisting of.

[0131] In some embodiments, R 1 and R 2 , or R 2 and R 3 together with the carbon atom to which they are attached form a fused C5-C8-cycloalkyl, C6-C 10-Aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) are formed.

[0132] R in each example 4 is independently H, OH, halo, C1-C6-alkyl, or C1-C6-alkoxy.

[0133] R in each example 5 is independently hydrogen, halo, cyano, nitro, -R b -OR a , -R b -O-R c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a(where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) is selected from the group consisting of.

[0134] R 5’ is hydrogen, -R c -R a -R c -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -O-R c -N(R a )2, -R b -N(R a )-R c -N(R a )2, -R b -N(R a )C(O)OR a -Rb -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2(where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) are selected from the group consisting of.

[0135] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、and R 6h are independently selected from the group consisting of H, halo, NO2, OH, CN, -R b -N(R a )2, -R b -OH, C1-C6-alkyl, and C1-C6-alkoxy.

[0136] In some embodiments, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently represent oxo, thioxo, imino, or oximo.

[0137] In other embodiments, R 6a and R 6b or R 6c and R 6d or R 6e and R 6f or R 6g and R 6h together with the carbon atoms to which they are attached, independently bond to form a fused ring selected from C3-C6-cycloalkyl and C3-C6-heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S).

[0138] In each instance, R a is independently hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, -(C1-C6-alkyl)(C3-C8-cycloalkyl), C6-C 10 -aryl, -(C1-C6-alkyl)(C6-C 10 -aryl), 5-10 membered heteroaryl or (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3-6 membered heterocycloalkyl or -(C1-C6-alkyl)(3-6 membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) is selected.

[0139] In each instance, R b is independently selected from a direct bond, straight or branched C2-C6-alkylene, and C2-C6-alkenylene chain.

[0140] In each instance, R c is independently selected from straight or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0141] In some embodiments, ring member D is C. In additional embodiments, A, B, and E are independently selected from C and N. For example, at least one of A, B, and E is N, or in some embodiments, two of A, B, and E are N. Specific examples of the A-B-D-E-N ring are optionally substituted rings selected from the group consisting of TIFF2025524039000029.tif37158.

[0142] In some embodiments, the optionally substituted A-B-D-E-N ring is selected from the group consisting of TIFF2025524039000030.tif22128.

[0143] In a specific embodiment, the optionally substituted A-B-D-E-N ring is TIFF2025524039000031.tif14128.

[0144] In some embodiments of the present disclosure, ring Y is of formula (a). Examples of ring Y include those where 1 Y 2 Y 3 Y 4 one of them is N and each of the remaining three is CR 5 Examples include those where, in an embodiment, each of Y 1 Y 2 Y 3 is CR 5 and Y 4 is N. Exemplary embodiments of ring Y include those where each of Y 1 and Y 2 is CH and Y 3 is CF.

[0145] In other embodiments, two of Y 1 Y 2 Y 3 Y 4 and the remaining two are each CR 5 For example, Y 1 and Y2 Each of them is CR 5 and Y 3 and Y 4 each of them is N.

[0146] In some embodiments where ring Y is of formula (a) or formula (b), Y 1 and Y 2 or Y 3 and Y 4 any one of which represents an optionally substituted fused ring. For example, the fused rings in various embodiments are optionally substituted fused 5- to 6-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S) or 5- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S).

[0147] In various embodiments, X 1 and X 2 one or each of them is N. For example, X 1 is N, and X 2 is CR 4 or X 1 is CR 4 and X 2 is N, or X 1 and X 2 each is CR 4 or X 1 and X 2 each is N. Optionally, in combination with these embodiments, R 4 is H.

[0148] In additional embodiments, R 1 is selected from the group consisting of H, halo, C1-C6-alkoxy, C6-C 10 -aryl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and 5- to 6-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S).

[0149] In yet a further embodiment, R 2 and R 3 each independently is H, halo, cyano, CH3, or CF3.

[0150] Other embodiments provide compounds of formula (I) wherein R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h each independently is selected from the group consisting of H, halo, C1-C6-alkyl and C1-C6-alkoxy. By way of example, compounds are provided wherein each of R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , and R 6h is H.

[0151] The present disclosure also provides, in embodiments, compounds of formula (I) or (II) that are compounds of formula (IA): TIFF2025524039000032.tif48128.

[0152] Optionally, in combination with any of the embodiments described herein, R 1 is selected from the group consisting of H, halo, C1-C6-alkoxy, C6-C 10 -aryl, C3-C6-cycloalkyl, 5-6 membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and each of R 2 and R 3 independently is H, F, cyano, CH3, or CF3.

[0153] The present disclosure also provides, in various embodiments, compounds of formula (I) or (II) that are compounds of formula (IB), (IC), or (ID): TIFF2025524039000033.tif48143。

[0154] In formulae (IB), (IC), and (ID), according to some embodiments, R 1 is selected from the group consisting of H, halo, C1-C6-alkoxy, C6-C 10 -aryl, C3-C6-cycloalkyl, 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and each of R 2 and R 3 , when present, is independently H, F, cyano, CH3, or CF3.

[0155] In additional embodiments, optionally, with respect to any of formulae (IA), (B), (IC), and (ID), one of Y 1 , Y 2 , Y 3 , and Y 4 is N, and each of the remaining three is CR 5 . For example, each of Y 1 and Y 2 is CH, and Y 3 is CF.

[0156] In some embodiments, two of Y 1 , Y 2 , Y 3 , and Y 4 are N, and each of the remaining two is CR 5 .

[0157] In still further embodiments, the ring containing Y 1 , Y 2 , Y 3 , and Y 4 is TIFF2025524039000034.tif is 21128. In an exemplary embodiment, Y 1 Y 2 Y 3 and Y 4 The ring containing is TIFF2025524039000035.tif is 19128.

[0158] In additional embodiments, the disclosure provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, the compound being selected from Table 1.

[0159] (Table 1) Exemplary compounds of the disclosure TIFF2025524039000036.tif183165TIFF2025524039000037.tif182165TIFF2025524039000038.tif192165TIFF2025524039000039.tif195165TIFF2025524039000040.tif195165TIFF2025524039000041.tif194165TIFF2025524039000042.tif193165TIFF2025524039000043.tif198165TIFF2025524039000044.tif195165TIFF2025524039000045.tif202165TIFF2025524039000046.tif201165TIFF2025524039000047.tif195165TIFF2025524039000048.tif198165TIFF2025524039000049.tif200165TIFF2025524039000050.tif199165TIFF2025524039000051.tif204165TIFF2025524039000052.tif204165TIFF2025524039000053.tif196165TIFF2025524039000054.tif202165TIFF2025524039000055.tif199165TIFF2025524039000056.tif193165TIFF2025524039000057.tif198165TIFF2025524039000058.tif195165TIFF2025524039000059.tif194165TIFF2025524039000060.tif196165TIFF2025524039000061.tif196165TIFF2025524039000062.tif70165

[0160] In additional embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound is selected from Table 2.

[0161] (Table 2) Additional exemplary compounds of the present disclosure TIFF2025524039000063.tif55128TIFF2025524039000064.tif212117TIFF2025524039000065.tif230117TIFF2025524039000066.tif217117TIFF2025524039000067.tif254117

[0162] Pharmaceutical composition The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of Formula I or Formula II, or a pharmaceutically acceptable salt, stereoisomer, isotope-substituted form, and / or tautomer thereof, in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further comprises one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, and flavoring agents, in accordance with accepted practices of pharmaceutical formulation.

[0163] In one embodiment, the pharmaceutical composition comprises a compound selected from those exemplified in Tables 1-16, or a pharmaceutically acceptable salt, stereoisomer, isotope-substituted form, and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0164] The pharmaceutical compositions of the present disclosure are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site to which the agent is to be delivered, the method of administration, the scheduling of administration, and other factors known to the medical practitioner.

[0165] The "therapeutically effective amount" of the compound to be administered or a pharmaceutically acceptable salt, stereoisomer, isotope-substituted form, and / or tautomer thereof is governed by such considerations and is the minimum amount necessary to inhibit QPCTL, QPCT, or both. Such an amount may be less than an amount that is toxic to normal cells or to the subject as a whole. Generally, the initial therapeutically effective amount of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) to be administered ranges from about 0.01 to about 200 mg / kg of patient body weight per day, or from about 0.1 to about 20 mg / kg, and a typical initial range is from about 0.3 to about 15 mg / kg / day. Oral unit dosage forms such as tablets and capsules may contain from about 0.1 mg to about 1000 mg of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In still yet another embodiment, such dosage forms contain from about 10 mg to about 100 mg of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In a further embodiment, such dosage forms contain from about 5 mg to about 50 mg of the compounds of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form may be administered once or twice a day.

[0166] In certain embodiments, the compounds described herein or a pharmaceutically acceptable salt or solvate thereof are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other organic small molecules such as unreacted intermediates or synthetic by-products produced, for example, in one or more steps of the synthetic method.

[0167] The compositions of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. As used herein, the term "parenterally" includes subcutaneous injection, intravenous, intramuscular, or intracostal injection and infusion techniques.

[0168] Suitable oral compositions described herein include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0169] In another aspect, pharmaceutical compositions suitable for single unit dosages are also included, which comprise a compound of the present disclosure or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0170] Compositions of the present disclosure suitable for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. For example, liquid formulations of the compounds of the present disclosure contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide pharmaceutically preferred preparations of the compounds of the present disclosure.

[0171] For tablet compositions, the compounds of the present disclosure in a mixture with non-toxic pharmaceutically acceptable excipients are used in the manufacture of tablets. These excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid, or talc, but are not limited thereto. Tablets may or may not be coated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained therapeutic effect over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be employed.

[0172] Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient may be mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

[0173] For aqueous suspensions, the compounds of the present disclosure are mixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum.

[0174] Oral suspensions may also contain dispersing or wetting agents such as naturally occurring phosphatides, for example, lecithin, or condensates of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensates of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol, or partial esters derived from ethylene oxide and fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitol monooleate, or partial esters derived from ethylene oxide and fatty acids and hexitol, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0175] Oily suspensions may be formulated by suspending the compounds of the present disclosure in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin, or cetyl alcohol.

[0176] Sweeteners and flavoring agents such as those described above can be added to provide a palatable oral preparation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid.

[0177] By the addition of water, dispersible powders and granules suitable for the preparation of aqueous suspensions are obtained by mixing the compounds of the present disclosure with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents, and suspending agents are exemplified by those already mentioned above. Further excipients, such as sweeteners, flavoring agents, and coloring agents may also be present.

[0178] The pharmaceutical compositions of the present disclosure may also be in the form of a water-in-oil emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring esters or partial esters, anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavoring agents, and preservatives.

[0179] Syrups and elixirs can be formulated using sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may contain viscosity agents, preservatives, as well as flavoring and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable, an aqueous suspension or an oily suspension. This suspension may be formulated according to known techniques using these suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension as a solution in a non-toxic parenterally acceptable diluent or solvent, for example, in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil including synthetic mono- or diglycerides may be employed. In addition, fatty acids such as oleic acid have been found to be used in injectable preparations.

[0180] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration of drugs. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such substances are cocoa butter and polyethylene glycol.

[0181] Compositions for parenteral administration are administered in a sterile medium. Depending on the vehicle and concentration used, the concentration of the drug in the formulation, the parenteral formulation can be either a suspension or a solution containing the dissolved drug. Adjuvants such as local anesthetics, preservatives, and buffering agents can also be added to the parenteral composition.

[0182] Method of Use The compounds of the present disclosure are surprisingly potent inhibitors of glutaminyl - peptide cyclotransferase protein (QPCT) or glutaminyl - peptide cyclotransferase - like protein (QPCTL). The compounds are useful, in various embodiments, in methods of treating a patient afflicted with a disease, where the disease is associated with the expression of QPCT or QPCTL. The methods include administering to the patient a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof. The compound or its pharmaceutically acceptable salt is optionally administered in a pharmaceutical composition according to the present disclosure and by any of the administration routes described herein.

[0183] In some embodiments, the disease is a cancer such as leukemia or lymphoma. Examples of leukemia or lymphoma include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non - Hodgkin lymphoma (NHL), Burkitt lymphoma, hairy cell lymphoma (HCL), Waldenström macroglobulinemia, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B - cell lymphoma (DLBCL), B - cell chronic lymphocytic leukemia (B - CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and precursor B - cell acute lymphoblastic leukemia (pre - B ALL).

[0184] In additional embodiments, the cancer is selected from the group consisting of multiple myeloma (MM), ovarian cancer, glioma, colon cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, small cell lung cancer (SCLC), non - small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, mesothelioma, melanoma, glioblastoma, and pancreatic neuroendocrine tumor.

[0185] In still further embodiments, the cancer is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, invasive ductal carcinoma, adenocarcinoma, Merkel cell carcinoma, skin cancer, prostate cancer, colorectal cancer, soft tissue sarcoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, and myeloma.

[0186] The compounds of the present disclosure are potent inhibitors of QPCT, a druggable target in the therapy of various neurodegenerative diseases (M. Jimenez-Sanchez et al., Nat Chem Biol. 11(5)(2015)347-354). These include, for example, Alzheimer's disease (A. Becker et al., BMC Neurosci 14(2013)108; M. Morawski et al, J Alzheimers Dis 39(2)(2014)385-400), Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body dementia, and spinal muscular atrophy. In some embodiments, combination therapies are contemplated, and the compounds of the present disclosure are administered in combination with antibodies that remove amyloid beta (Aβ) plaques in the brain. Bapineuzumab, Solanezumab, Gantenerumab, Crenezumab, Ponezumab, BAN2401, and Aducanumab are mentioned, but not limited to these, and various monoclonal antibodies that bind to different epitopes and conformations of Aβ are known in the art and suitable for this purpose (see C.H. van Dyck Biol. Psych. 83(4)(2018)311-319).

[0187] In further embodiments, the disease is an inflammatory disease (see, for example, K. Bresser et al., Oncoimmunology 11(1)(2022)(https: / / doi.org / 10.1080 / 2162402X.2022.2049486)). In other embodiments, the disease is an autoimmune disease (see N. Kanemitsu et al., Naunyn Schmiedebergs Arch Pharmacol. 394(4), 751(2021)).

[0188] In a further embodiment, the disease is a cardiovascular disease. In an exemplary embodiment, the cardiovascular disease is atherosclerosis.

[0189] In some embodiments, optionally, in combination with any other embodiment described herein, the compound of formula (I) or (II) or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and LAG-3 inhibitors.

[0190] In a further embodiment, the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an opsonizing antibody. Opsonizing antibodies, including IgG and IgM, are known in the art.

[0191] In an additional embodiment, the present disclosure provides a method of inhibiting glutaminyl peptide cyclotransferase protein (QPCT) or glutaminyl peptide cyclotransferase-like (QPCTL) enzyme. The method includes contacting the enzyme with a compound described herein or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the contacting is performed in vitro. In another embodiment, the contacting is performed in vivo.

[0192] Also provided are the compounds described herein or pharmaceutically acceptable salts and / or solvates thereof for use in the treatment of cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease, or cardiovascular disease. The present disclosure also provides the use of the compounds described herein or pharmaceutically acceptable salts and / or solvates thereof in the manufacture of a medicament for the treatment of cancer, neurodegenerative disease, inflammatory disease, autoimmune disease, or cardiovascular disease.

[0193] Other embodiments and uses will be apparent to those skilled in the art upon consideration of the present disclosure. The following examples are provided to illustrate and provide various embodiments and are not to be construed as limiting the present disclosure in any way.

Example

[0194] Preparation of Compounds The compounds used in the synthetic chemical reactions described in this specification are prepared from commercially available chemical substances and / or compounds described in the chemical literature, according to organic synthesis techniques known to those skilled in the art. "Commercially available chemical substances" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (including Milwaukee, WI, Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0195] Suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described in this specification, or provide references to papers that describe the preparation, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described in this specification, or provide references to papers that describe the preparations, include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942 - 2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes can be mentioned.

[0196] Specific and similar reactants are indicators of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries, as well as optionally identified through online databases (for details, inquire with the American Chemical Society, Washington D.C.). Chemical substances that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard chemical supply houses (e.g., those listed above) offer custom synthesis services. A useful reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0197] General synthetic scheme The compounds disclosed herein are prepared by various synthetic routes including, but not limited to, the routes described below in Scheme I or II.

[0198] As shown below in Scheme I, suitably functionalized 2-fluoro-3-bromobenzonitrile can undergo a nucleophilic aromatic substitution reaction with a substituted piperidine to provide a piperidinyl-substituted bromoarene. One of ordinary skill in the art will understand that various organic synthesis methods can be applied to prepare substituted 2-fluoro-3-bromobenzonitrile.

[0199] The compounds of the present disclosure can be synthesized by various transition metal-mediated cross-coupling reactions (e.g., the Suzuki method or the Stille method). As shown below in Scheme II, a trialkylstannane arene, a heteroarylboronic acid, or a heteroarylboronic acid ester can undergo a cross-coupling reaction with an intermediate cyanobromoarene under a palladium catalyst to obtain the final compound. Scheme I TIFF2025524039000068.tif49148

[0200] Scheme II illustrates the use of tetrakis(triphosphine)palladium(0) for a Stille-type reaction with a stannane reagent and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) for a Suzuki-type coupling with a heteroarylboronic acid. One of ordinary skill in the art will understand that there are many palladium catalysts and reaction conditions that can be used for these types of cross-coupling reactions. Scheme II TIFF2025524039000069.tif68128

[0201] I. Chemical Synthesis As used below and throughout this disclosure, unless otherwise specified, the following abbreviations are to be understood to have the following meanings: ACN Acetonitrile AcOH Acetic acid AMPhos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) °C Degrees Celsius δ H 1 part per million downfield chemical shift from tetramethylsilane d Day(s) DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropylethylamine DMF Dimethylformamide DMF-DMA Dimethylformamide dimethylacetal DMSO Dimethyl sulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene dcypf 1,1'-Bis(di-cyclohexylphosphino)ferrocene EA Ethyl acetate EtOAc Ethyl acetate EtOH Ethanol ESI Electrospray ionization Et Ethyl g Gram(s) h (plural) hours hr (plural) hours HPLC High Performance Liquid Chromatography Hz Hertz J Coupling constant (in NMR spectroscopy) LCMS Liquid Chromatography - Mass Spectrometry μ micro m multiplicity (spectrum); meter (plural); milli M mole M + parent molecular ion Me methyl MeOH methanol mg (plural) milligrams MsCl methanesulfonyl chloride MHz megahertz min (plural) minutes mol mole (plural); molecular weight (in mol weight) mL milliliter MS Mass Spectrometry nm (plural) nanometers NMR Nuclear Magnetic Resonance pH hydrogen ion exponent; measure of acidity or basicity PE petroleum ether RT room temperature s singlet (spectrum) t triplet (spectrum) SFC Supercritical Fluid Chromatography T temperature TBAB tetrabutylammonium bromide TBDMS tert-butyldimethylsilyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TPP triphenylphosphine

[0202] Synthesis of Intermediate Intermediate 1: 3-Bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000070.tif38128

[0203] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine hydrochloride (2 g, 9.9 mmol) and 3-bromo-2-fluorobenzonitrile (2.2 g, 11 mmol) in DMSO (80 mL) was added DIEA (5.1 g, 4 mmol). The resulting mixture was stirred at 130 °C for 15 h. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to afford 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (0.8 g) as a white solid. LCMS (ESI) m / z: 346, 348 [M+H] + .

[0204] Intermediate 2: 3-bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile TIFF2025524039000071.tif64128

[0205] A solution of imidazole (2.4 g, 35.8 mmol) in DMF (120 mL) was treated with NaH (0.86 g, 35.8 mmol) at 0 °C for 25 min under a nitrogen atmosphere, and then tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (5 g, 17.8 mmol) was added at 0 °C. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (5:1) to give tert-butyl 4-(imidazol-1-yl)piperidine-1-carboxylate (1.5 g, 33%) as a yellow oil. LCMS (ESI) m / z: 252 [M+H] + .

[0206] A solution of tert-butyl 4-(imidazol-1-yl)piperidine-1-carboxylate (1.5 g, 5.9 mmol) in 4 M HCl in 1,4-dioxane (25 mL) was stirred at room temperature for 1 h. The reaction mixture was evaporated and partitioned between saturated aqueous K2CO3 solution and EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-(imidazol-1-yl)piperidine (600 mg, 66%) as a pale yellow oil. LCMS (ESI) m / z: 152 [M+H] + .

[0207] To a stirred solution of 4-(imidazol-1-yl)piperidine (600 mg, 3.96 mmol) in DMSO (150 mL) was added 3-bromo-2-fluorobenzonitrile (1190.4 mg, 5.95 mmol) and DIEA (2564.2 mg, 19.8 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 2 days under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (5:1) to give 3-bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile. LCMS (ESI) m / z: 331, 333 [M+H] + .

[0208] Intermediate 3: 1-bromo-3-cyano-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzene TIFF2025524039000072.tif103136

[0209] A stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5 g, 16.2 mmol) and 5-bromo-1,3-thiazole (2652 mg, 16.2 mmol) in H2O (12 mL) / dioxane (72 mL) was added with K2CO3 (6704 mg, 48.5 mmol) and Pd(dppf)Cl2 (1317 mg, 1.6 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h under nitrogen. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / CH2Cl2 (0% - 20%) to give tert-butyl 4-(1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.8 g, 88%) as a brown oil. LCMS(ESI) m / z: 267 [M+H] + .

[0210] A stirred solution of tert-butyl 4-(1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3 g, 11.3 mmol) in MeOH (20 mL) was added with Pd / C (1.5 g) portionwise at room temperature under a hydrogen atmosphere. The resulting mixture was stirred at room temperature for 26 h under a hydrogen atmosphere. The mixture was filtered and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(1,3-thiazol-5-yl)piperidine-1-carboxylate (1.9 g, 63%) as a yellow oil. LCMS(ESI) m / z: 269 [M+H] + .

[0211] A mixture of tert-butyl 4-(1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.9 g, 7.1 mmol) in HCl in 1,4-dioxane (20 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 4-(1,3-thiazol-5-yl)piperidine hydrochloride (1.43 g, 98%) as an off-white solid. LCMS (ESI) m / z: 169 [M+H] + .

[0212] A mixture of 4-(1,3-thiazol-5-yl)piperidine hydrochloride (500 mg, 2.44 mmol), 1-bromo-2-fluoro-3-cyanobenzene (488.5 mg, 2.4 mmol), and DIEA (1262.7 mg, 9.8 mmol) in DMSO (5 mL) was stirred at 120 °C for 16 h. The reaction was quenched with water (50 mL) at room temperature. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (40% - 60%) to give 1-bromo-3-cyano-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzene (143.2 mg, 17%) as a yellow oil. LCMS (ESI) m / z: 348, 350 [M+H] + .

[0213] Intermediate 4: 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile TIFF2025524039000073.tif43146

[0214] To a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5 g, 23.7 mmol) in TFA (120 mL), thiosemicarbazide (3.2 g, 35.6 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 65 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 1% to 10% in 20 minutes; detector, UV 254 nm to give 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (4 g, 91%) as a colorless oil. LCMS (ESI) m / z: 185 [M+H] + .

[0215] To a stirred solution of 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (3 g, 16.3 mmol) in DMSO (60 mL), DIEA (8.4 g, 65.1 mmol) and 3-bromo-2-fluorobenzonitrile (2.3 g, 11.4 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (5:1) to give 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile (450 mg, 8%) as a yellowish brown solid. LCMS (ESI) m / z: 364,366 [M+H] + .

[0216] Intermediate 5: 3-bromo-2-[4-(3-methyl-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile TIFF2025524039000074.tif85156

[0217] A mixture of acetohydrazide (5 g, 67.5 mmol) and DMF-DMA (8 g, 67.5 mmol) in ACN (70 mL) was stirred at 50 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS (ESI) m / z: 130 [M+H] + .

[0218] A mixture of N’-[(1E)-(dimethylamino)methylidene]acetohydrazide (2 g, 15.5 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (3.7 g, 18.6 mmol) in AcOH (40 mL) and ACN (10 mL) was stirred at 120 °C for 16 h. The reaction was quenched by adding water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (0 - 10%) to give tert-butyl 4-(3-methyl-1,2,4-triazol-4-yl)piperidine-1-carboxylate (1.99 g, 48%) as a yellow oil. LCMS (ESI) m / z: 267 [M+H] + .

[0219] A mixture of tert-butyl 4-(3-methyl-1,2,4-triazol-4-yl)piperidine-1-carboxylate (1.9 g, 7.13 mmol) in HCl in 1,4-dioxane (30 mL) was stirred at room temperature for 2 h. The reaction was quenched by adding saturated aqueous K2CO3 solution (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (20 - 30%) to give 4-(3-methyl-1,2,4-triazol-4-yl)piperidine (1 g, 84%) as a yellow oil.

[0220] To a stirred mixture of 4-(3-methyl-1,2,4-triazol-4-yl)piperidine (1 g, 6 mmol) and 3-bromo-2-fluorobenzonitrile (1.18 g, 5.9 mmol) in DMSO (60 mL), DIEA (3.2 g, 24.7 mmol) was added dropwise at room temperature. The resulting mixture was stirred at 120 °C for 16 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / CH2Cl2 (0 - 10%) to give 3-bromo-2-[4-(3-methyl-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile (200 mg, 10%) as a yellow oil. LCMS (ESI) m / z: 346, 348 [M+H] + .

[0221] Intermediate 6: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000075.tif35128

[0222] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (9 g, 54.1 mmol) in DMSO (150 mL) were added DIEA (48.9 g, 379 mmol) and 3-bromo-6-chloro-2-fluorobenzonitrile (8.9 g, 37.9 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (5:1) to give 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (2.7 g, 13%) as a dark red solid. LCMS (ESI) m / z: 380, 382 [M+H] + .

[0223] Intermediate 7: 3-bromo-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000076.tif28128

[0224] To a stirred solution of Intermediate 6 (500 mg, 1.3 mmol) in DMF (12 mL) were added K2CO3 (363 mg, 2.6 mmol) and CH3ONa (212.9 mg, 3.9 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 2 h. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give Intermediate 7 (350 mg, 71%). LCMS (ESI) m / z: 376, 378 [M+H] + .

[0225] Intermediate 8: 3-Bromo-2-[4-(3-methylimidazol-4-yl)piperidin-1-yl]benzonitrile TIFF2025524039000077.tif84132

[0226] To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5 g, 14.6 mmol) in anhydrous 1,4-dioxane (50 mL) and H2O (10 mL), K2CO3 (4 g, 29.1 mmol) and Pd(dppf)Cl2 (1.07 g, 1.5 mmol) were added, followed by 5-bromo-1-methylimidazole (2.3 g, 14.6 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 6 h. After completion of the reaction, the reaction mixture was quenched by adding water (40 mL). The separated aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using (10% - 50% MeOH / DCM) to afford the desired compound benzyl 4-(3-methylimidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3 g). LCMS(ESI) m / z: 298 [M+H] + .

[0227] A solution of 4-(3-methyl-1,2-dihydroimidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3 g, 10 mmol) and Pd / C (2.7 g) in MeOH (50 mL) was stirred at room temperature for 16 h under a hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (12:1) to give 4-(3-methyl-1,2-dihydroimidazol-4-yl)piperidine (2 g) as a brown solid. LCMS(ESI) m / z: 166 [M+H] + .

[0228] A solution of 4-(3-methylimidazol-4-yl)piperidine (400 mg, 2.4 mmol), 3-bromo-2-fluorobenzonitrile (581 mg, 2.9 mmol), and DIEA (938.6 mg, 7.26 mmol) in DMSO (20 mL) was stirred at 120 °C for 6 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (12:1) to give 3-bromo-2-[4-(3-methylimidazol-4-yl)piperidin-1-yl]benzonitrile (100 mg, 12%) as a yellow solid. LCMS (ESI) m / z: 345, 347 [M+H] + .

[0229] Intermediate 9: 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000078.tif70152

[0230] To a stirred solution of 3,4-dichloro-2-fluorobenzaldehyde (4 g, 20.7 mmol) in anhydrous DCM (50 mL), TEA (6.29 g, 62.2 mmol) and NH2OH.HCl (10.8 mg, 0.16 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After the reaction was complete, the reaction mixture was quenched by the addition of water (50 mL). The resulting mixture was extracted with CH2Cl2 (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (E)-N-[(3,4-dichloro-2-fluorophenyl)methylene]hydroxylamine (3.2 g) as a brown solid. LCMS (ESI) m / z: 209 [M+H] + .

[0231] To a stirred solution of (E)-N-[(3,4-dichloro-2-fluorophenyl)methylene]hydroxylamine (3.2 g, 15.38 mmol) in anhydrous toluene (50 mL), SOCl2 (2.75 g, 23.08 mmol) was added at 0 °C. The reaction mixture was stirred at 120 °C for 2 h. After completion of the reaction, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was further purified by column chromatography using 5 - 20% EtOAc in a PE gradient to afford the desired compound 3,4-dichloro-2-fluorobenzonitrile (2.3 g). LCMS(ESI) m / z: 191 [M + H] + .

[0232] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (700 mg, 4.21 mmol) in anhydrous DMSO (50 mL), 3,4-dichloro-2-fluorobenzonitrile (720.1 mg, 3.79 mmol) and DIEA (2.18 g, 16.8 mmol) were added at room temperature. The reaction mixture was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was quenched by addition of water (50 mL). The separated aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was further purified by column chromatography using 5 - 15% MeOH in a DCM gradient to afford the desired compound 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg). LCMS(ESI) m / z: 337 [M + H] + .

[0233] To a stirred solution of 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 1.49 mmol) in anhydrous DMSO (50 mL) were added tetrabutylammonium bromide (47.9 mg, 0.15 mmol) and CsF (2.26 g, 14.9 mmol) at room temperature. The reaction mixture was stirred at 150 °C for a period of 2 hours. After completion of the reaction, the reaction mixture was quenched by the addition of water (50 mL). The separated aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was further purified by column chromatography using 5 - 15% MeOH in a DCM gradient to afford compound 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg). LCMS(ESI) m / z: 320 [M+H] + .

[0234] Intermediate 10: 3-bromo-2-{4-[4-( 2 H3)methyl-1,2,4-triazol-3-yl]piperidin-1-yl)benzonitrile TIFF2025524039000079.tif79128

[0235] A solution of tert-butyl 4-(hydrazinecarbonyl)piperidine-1-carboxylate (10.5 g, 43.1 mmol) in THF (50 mL) and ACN (200 mL) was added dropwise with DMF-DMA (12.9 g, 107 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 2 h. To the above mixture, (2H3)methanamine hydrochloride (6.1 g, 86.3 mmol) and AcOH (25.9 g, 432 mmol) were added portionwise over 20 min at 50 °C. The resulting mixture was further stirred at 90 °C for 16 h. The resulting mixture was concentrated under reduced pressure and quenched by adding water (100 mL) at room temperature. The mixture was basified to pH 7 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH (10% - 15%) in CH2Cl2 to give tert-butyl 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate (7 g, 60%) as a yellow oil. LCMS (ESI) m / z: 270 [M+H] + .

[0236] To tert-butyl 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate (7 g, 25.9 mmol), HCl in 1,4-dioxane (100 mL) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine hydrochloride (5 g) as a white solid. The crude product was used in the next step without further purification. LCMS (ESI) m / z: 170 [M+H] + .

[0237] To a stirred mixture of 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine hydrochloride (3 g, 14.5 mmol) and 3-bromo-2-fluorobenzonitrile (3.2 g, 16.0 mmol) in DMSO (50 mL) was added DIEA (9.4 g, 72.9 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 16 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient from 40% to 50% in 10 min, detector, UV 254 nm to give 3-bromo-2-{4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidin-1-yl}benzonitrile (300 mg, 6%) as a black oil. LCMS (ESI) m / z: 349, 351 [M+H] + .

[0238] Intermediate 11: 3-bromo-2-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000080.tif77128

[0239] To a stirred solution of benzyl 4-cyanopiperidine-1-carboxylate (9.6 g, 39.3 mmol) and N-formylhydrazine (2.4 g, 40 mmol) in MeOH (20 mL) was added NaOMe (0.64 g) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 72 h under nitrogen. The resulting mixture was washed with acetic acid (3 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 4-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (2.4 g, 21%) as a white solid. LCMS (ESI) m / z: 287 [M+H] + .

[0240] A solution of benzyl 4-(4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (2.4 g, 8.4 mmol) in MeOH (10 mL) was added with Pd / C (10%, Pd / C (0.19 g)) under a nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad, and concentrated under reduced pressure. The resulting filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to obtain 4-(4H-1,2,4-triazol-3-yl)piperidine (640 mg, 46%) as a white solid. LCMS (ESI) m / z: 153 [M+H] + .

[0241] To a stirred solution of 4-(4H-1,2,4-triazol-3-yl)piperidine (640 mg, 4.2 mmol) and 3-bromo-2-fluorobenzonitrile (1093 mg, 5.5 mmol) in DMSO (5 mL), DIEA (1630 mg) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 12 hours. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to obtain 3-bromo-2-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (80 mg, 6%) as a white solid. LCMS (ESI) m / z: 332, 334 [M+H] + .

[0242] Intermediate 12: 3-Bromo-5-methyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000081.tif39128

[0243] A solution of 3-bromo-2-fluoro-5-methylbenzaldehyde (1 g, 4.6 mmol) and hydroxylamine-o-sulfonic acid (0.89 g, 7.8 mmol) in H2O (10 mL) was stirred at room temperature for 10 minutes and then stirred at 50 °C overnight under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give 3-bromo-2-fluoro-5-methylbenzonitrile (879 mg, 89%) as a white solid. LCMS (ESI) m / z: 214, 216 [M+H] + .

[0244] To a stirred solution of 3-bromo-2-fluoro-5-methylbenzonitrile (879 mg, 4.1 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (586.2 mg, 3.5 mmol) in DMSO (12 mL), DIEA (2681.1 mg, 20.7 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 140 °C for 16 hours. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 9:1) to give 3-bromo-5-methyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (156 mg, 10%) as a white solid. LCMS (ESI) m / z: 360, 362 [M+H] + .

[0245] Intermediate 13: 3-bromo-5-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000082.tif40128

[0246] A solution of 3-bromo-5-chloro-2-fluorobenzaldehyde (1 g, 4.2 mmol) and aminooxysulfonic acid (0.81 g, 7.2 mmol) in water (10 mL) was stirred at 50 °C for 1 h. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-bromo-5-chloro-2-fluorobenzonitrile (900 mg, 91%) as a yellow solid. LCMS (ESI) m / z: 234, 236 [M+H] + .

[0247] A solution of 3-bromo-5-chloro-2-fluorobenzonitrile (730 mg, 3.1 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (517.6 mg, 3.1 mmol) and K2CO3 (2151.6 mg, 15.6 mmol) in DMSO (5 mL) was stirred at 90 °C for 1 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA) with a gradient of 10% to 50% in 10 min; detector, UV 254 nm to give 3-bromo-5-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (160 mg, 13%) as a brown oil. LCMS (ESI) m / z: 380, 382 [M+H] + .

[0248] Intermediate 14: 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)benzonitrile TIFF2025524039000083.tif40128

[0249] A solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (500 mg, 1.8 mmol) and (aminooxy)sulfonic acid (354.7 mg, 3.1 mmol) in H2O (10 mL) was stirred at 50 °C for 2 h under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (0% - 10%) to give 3-bromo-2-fluoro-5-(trifluoromethyl)benzonitrile (200 mg) as a white solid. LCMS(ESI) m / z: 268, 270 [M+H] + .

[0250] To a stirred mixture of 3-bromo-2-fluoro-5-(trifluoromethyl)benzonitrile (500 mg, 1.87 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (465 mg, 2.79 mmol) in DMSO (10 mL), DIEA (1205 mg, 9.33 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 140 °C overnight. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)benzonitrile (180 mg) as a pink oil. LCMS(ESI) m / z: 414, 416 [M+H] + .

[0251] Intermediate 15: 3-bromo-2-[4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl]benzonitrile TIFF2025524039000084.tif78128

[0252] A solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (5 g, 19 mmol), N-formylhydrazine (1.48 g, 24.7 mmol), HATU (8.66 g, 22.8 mmol) and DIPEA (6.38 g, 49.4 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (5×100 mL). The combined organic layers were washed with brine (5×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 4-(N’-formylhydrazinecarbonyl)piperidine-1-carboxylate (4.5 g, 77%) as a white solid. LCMS (ESI) m / z: 306 [M+H] + .

[0253] A solution of 4-(N’-formylhydrazinecarbonyl)piperidine-1-carboxylate (4.50 g, 14.7 mmol) and Lawesson's reagent (6.56 g, 16.2 mmol) in dioxane (30 mL) was stirred at 100 °C for 3 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min; detector, UV 254 nm to give 4-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (210 mg, 5%) as a yellow oil. LCMS (ESI) m / z: 304 [M+H] + .

[0254] A solution of benzyl 4-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (210 mg, 0.69 mmol) in dioxane (1 mL) and HBr (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS (ESI) m / z: 170 [M+H] + .

[0255] A solution of 4-(1,3,4-thiadiazol-2-yl)piperidine (150 mg, 0.89 mmol), 3-bromo-2-fluorobenzonitrile (177 mg, 0.89 mmol), and DIEA (572.7 mg, 4.43 mmol) in DMSO (4 mL) was heated at 120 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), gradient of 10% - 50% in 10 minutes; detector, UV 254 nm to give 3-bromo-2-[4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl]benzonitrile (50 mg, 16%) as a yellow oil. LCMS (ESI) m / z: 349, 351 [M+H] + .

[0256] Intermediate 16: 3-bromo-2-[(1R,5S)-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]benzonitrile TIFF2025524039000085.tif79128

[0257] A solution of (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (3 g, 12.2 mmol) and NH2NH2·H2O (18.4 g, 366.9 mmol) in EtOH (30 mL) was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 10 min; detector, UV 254 nm to give (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.5 g, 88%) as a white solid. LCMS (ESI) m / z: 232 [M+H] + .

[0258] A solution of (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbohydrazide (1 g, 4.3 mmol), and DMF-DMA (1.29 g, 10.8 mmol) in MeCN (1.7 mL, 32.4 mmol), THF (5 mL) was stirred at 50 °C for 1 h. To the above mixture, CH3NH2·HCl (0.35 g, 5.2 mmol), HOAc (2.6 g, 43.2 mmol) were added dropwise at room temperature over 10 min. The resulting mixture was stirred at 90 °C for an additional 15 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give (1R,5S)-3-benzyl-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (1 g, 91%) as a pale yellow oil. LCMS (ESI) m / z: 255 [M+H] + .

[0259] A solution of (1R,5S)-3-benzyl-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (1 g, 3.9 mmol) and Pd / C (1 g, 9.4 mmol) in MeOH (50 mL) was stirred at 60 °C for 5 h under a hydrogen atmosphere (5 atm). The resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the desired product as a pale yellow oil (660 mg). The crude product was used in the next step without further purification. LCMS(ESI) m / z: 165 [M+H] + .

[0260] A solution of (1R,5S)-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (600 mg, 3.6 mmol), 3-bromo-2-fluorobenzonitrile (877 mg, 4.4 mmol), and DIEA (1416.7 mg, 10.9 mmol) in DMSO (10 mL) was stirred at 120 °C for 12 h. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-bromo-2-[(1R,5S)-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]benzonitrile (90 mg, 4%) as a pale yellow oil. LCMS(ESI) m / z: 344, 346 [M+H] + .

[0261] Intermediate 17: 5-chloro-4-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzene-1,3-dicarbonitrile TIFF2025524039000086.tif40128

[0262] To a stirred solution of 5-bromo-3-chloro-2-fluorobenzonitrile (3 g, 12.8 mmol) in DMSO (150 mL) were added TEA (10.8 g, 106.6 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (3.5 g, 21.3 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (8:1) to give 5-bromo-3-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (2.3 g, 28%) as a yellow solid.

[0263] A mixture of 5-bromo-3-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 1.31 mmol) and CuCN (176.5 mg, 1.97 mmol) in DMSO (10 mL) was stirred at 120 °C for 2 days under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 5-chloro-4-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzene-1,3-dicarbonitrile (160 mg, 37%) as a yellow solid. LCMS (ESI) m / z: 327 [M+H] + .

[0264] Intermediate 18: 3-chloro-5-methanesulfonyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000087.tif44128

[0265] To a stirred solution of 5-bromo-3-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg, 0.79 mmol) in DMSO (5 mL), methyl[2-(methylamino)ethyl]amine (55.6 mg, 0.63 mmol), sodium methanesulfinate (80.4 mg, 0.79 mmol), and copper(I) trifluoromethanesulfonate benzene complex (39.7 mg, 0.08 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 20% to 40% in 20 minutes; detector, UV 254 nm to give 3-chloro-5-methanesulfonyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (190 mg, 63%) as a yellow solid. LCMS (ESI) m / z: 380 [M+H] + .

[0266] Intermediate 19: 5-Bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile TIFF2025524039000088.tif83159

[0267] A solution of 6-amino-3-bromo-2-fluorobenzonitrile (5 g, 23.2 mmol), trifluoroacetic anhydride (5.9 g, 27.9 mmol), and TEA (7.1 g, 69.7 mmol) in DCM (25 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give N-(4-bromo-2-cyano-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 68%) as a pale yellow solid. LCMS (ESI) m / z: 311, 313 [M+H] + .

[0268] A solution of N-(4-bromo-2-cyano-3-fluorophenyl)-2,2,2-trifluoroacetamide (6 g, 19.3 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (6.4 g, 38.6 mmol), and CsF (8.8 g, 57.9 mmol) in DMSO (25 mL) was stirred at 140 °C for 16 h. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 6-amino-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 7%) as a pale yellow oil. LCMS (ESI) m / z: 361, 363 [M+H] + .

[0269] A solution of 6-amino-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 1.6 mmol) and NIS (373.7 mg, 1.6 mmol) in AcOH (15 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (8:1) to give 2-amino-5-bromo-3-iodo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (900 mg, 75%) as a light brown oil. LCMS (ESI) m / z: 487, 489 [M+H] + .

[0270] A solution of 2-amino-5-bromo-3-iodo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (900 mg, 1.84 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (278.3 mg, 2.22 mmol), K2CO3 (510.7 mg, 3.7 mmol), and Pd(dppf)Cl2 (135.2 mg, 0.18 mmol) in 1,4-dioxane (20 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (8:1) to give 2-amino-5-bromo-3-methyl-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 86%) as a pale yellow oil. LCMS(ESI) m / z: 375, 377 [M+H] + .

[0271] A solution of 2-amino-5-bromo-3-methyl-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 1.6 mmol) in CHCl3 (10 mL) was treated with Ac2O (359.1 mg, 3.5 mmol) at 0 °C for 10 min, followed by the addition of isoamyl nitrite (430.8 mg, 3.7 mmol) and AcOK (47.1 mg, 0.48 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (8:1) to give 5-bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile (50 mg, 8%) as a pale yellow oil. LCMS(ESI) m / z: 386, 388 [M+H] + .

[0272] Intermediate 20: 3-Bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile TIFF2025524039000089.tif36142

[0273] A mixture of 3-bromo-4-methyl-1,2,4-triazole (1 g, 6.2 mmol) in tert-butyl piperazine-1-carboxylate (5 g, 26.8 mmol) was stirred at 90 °C for 2 days. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%), and then by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B - 40% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 12.62) to obtain tert-butyl 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate (1.2 g) as a white oil. LCMS (ESI) m / z: 268 [M+H] + .

[0274] A mixture of tert-butyl 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate (1.2 g, 4.48 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the crude product was used in the next step without further purification. LCMS (ESI) m / z: 168 [M+H] + .

[0275] To a stirred mixture of 1-(4-methyl-1,2,4-triazol-3-yl)piperazine (100 mg, 0.6 mmol) and 3-bromo-2-fluorobenzonitrile (179.4 mg, 0.9 mmol) in DMSO (5 mL), TEA (302.6 mg, 3 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 90 °C overnight. Water (20 mL) was added to the reaction, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0% - 10%) to afford 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (70 mg) as a brown solid. LCMS (ESI) m / z: 347, 349 [M+H] + .

[0276] Intermediate 21: 3-Bromo-4-chloro-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000090.tif81128

[0277] To a stirred mixture of 4-chloro-2,6-difluorobenzonitrile (10 g, 57.6 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (14.4 g, 86.4 mmol) in DMSO (30 mL), TEA (17.5 g, 172.9 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 16 h. Water (500 mL) was added to the reaction, and the mixture was extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to afford 4-chloro-2-fluoro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (15 g) as a brown solid. LCMS (ESI) m / z: 320 [M+H] + .

[0278] To a stirred mixture of 4-chloro-2-fluoro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (15 g, 47 mmol) in H2SO4 (50 mL), NBS (16.7 g, 93.8 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 16 h. Water (600 mL) was added to the reaction mixture at 0 °C. The mixture was basified to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 1 L). The combined organic layers were washed with brine (2 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to afford 3-bromo-4-chloro-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (8 g) as a pale yellow solid. LCMS (ESI) m / z: 398, 400 [M+H] + .

[0279] A mixture of 3-bromo-4-chloro-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1 g, 2.5 mmol) and CH3ONa (203.3 mg, 3.8 mmol) in MeOH (15 mL) was stirred at room temperature for 8 h. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to give 3-bromo-4-chloro-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (750 mg) as an off-white solid. LCMS(ESI) m / z: 410, 412 [M+H] + .

[0280] Intermediate 22: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile TIFF2025524039000091.tif35128

[0281] To a stirred mixture of 1-(4-methyl-1,2,4-triazol-3-yl)piperazine (500 mg, 3 mmol) and 3-bromo-6-chloro-2-fluorobenzonitrile (1051.5 mg, 4.48 mmol) in DMSO (10 mL), TEA (1512.9 mg, 14.9 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to give 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (150 mg) as a brown solid. LCMS(ESI) m / z: 381, 383 [M+H] + .

[0282] Intermediate 23: 3-Chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile TIFF2025524039000092.tif84137

[0283] A mixture of 3,4-dichloro-2-fluorobenzaldehyde (5 g, 25.9 mmol) and aminooxysulfonic acid (5.3 g, 46.6 mmol) in H2O (150 mL) was stirred at 50 °C overnight. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The residue was purified by silica gel column chromatography eluted with PE / EA (0% - 10%) to give 3,4-dichloro-2-fluorobenzonitrile (3.3 g, 67%) as an off-white solid. LCMS(ESI) m / z: 191 [M+H] + .

[0284] To a stirred mixture of 3,4-dichloro-2-fluorobenzonitrile (852.2 mg, 4.48 mmol) and 1-bromo-2-fluorobenzene (31.4 mg, 0.18 mmol) in DMSO (10 mL), TEA (1512.9 mg, 14.9 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 90 °C overnight. The reaction was quenched by adding water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 160 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to give 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (180 mg, 18%) as a light brown solid. LCMS(ESI) m / z: 338 [M+H] + .

[0285] To a stirred mixture of 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (80 mg, 0.24 mmol) and CsF (360.4 mg, 2.37 mmol) in DMSO (8 mL) was added TBAB (7.6 mg, 0.024 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 8 h. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 110 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to give 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (50 mg, 66%) as a pale yellow solid. LCMS (ESI) m / z: 321 [M+H] + .

[0286] Intermediate 24: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile TIFF2025524039000093.tif37128

[0287] To a stirred mixture of 1-(4-methyl-1,2,4-triazol-3-yl)piperazine (300 mg, 1.79 mmol) and 3-bromo-6-chloro-2-fluorobenzonitrile (630.9 mg, 2.69 mmol) in DMSO (10 mL), TEA (907.7 mg, 8.97 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 90 °C overnight. The reaction was quenched by adding water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 90 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to afford 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (120 mg, 17%) as a brown oil. LCMS (ESI) m / z: 381,383 [M+H] + .

[0288] Intermediate 25: 3-bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000094.tif40128

[0289] A solution of 3-bromo-2,5-difluorobenzonitrile (1 g, 4.6 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (0.9 g, 5.5 mmol), and TEA (1.4 g, 13.8 mmol) in DMSO (25 mL) was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 3-bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (140 mg, 7%) as a pale yellow oil. LCMS (ESI) m / z: 364,366 [M+H] + .

[0290] Intermediate 26: 6-Bromo-4-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000095.tif84136

[0291] A solution of 2-bromo-4-chloro-6-fluoroaniline (25 g, 111.4 mmol), KCN (14.5 g, 222.7 mmol), NOBF4 (13 g, 111.4 mmol), and CuSO4 (53.3 g, 334.1 mmol) in DCM (50 mL) was stirred at room temperature for 2 h. The reaction was quenched at room temperature with saturated iron(II) sulfate aqueous sodium bisulfite. The mixture was basified to pH 10 with saturated NaHCO3 (aqueous solution). The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 2-bromo-4-chloro-6-fluorobenzonitrile (10 g, 38%) as a pale yellow oil. LCMS (ESI) m / z: 234, 236 [M+H] + .

[0292] A solution of 2-bromo-4-chloro-6-difluorobenzonitrile (5 g, 21.3 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (4.2 g, 25.6 mmol), and TEA (6.5 g, 64 mmol) in DMSO (25 mL) was stirred at 80 °C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 2-bromo-4-chloro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1.1 g, 11%) as a pale yellow oil. LCMS (ESI) m / z: 380, 382 [M+H] + .

[0293] A solution of 2-bromo-4-chloro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1.1 g, 2.9 mmol) and NIS (0.65 g, 2.9 mmol) in H2SO4 (20 mL) was stirred at room temperature for 2 hours. The mixture was basified to pH 10 with NaOH. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 6-bromo-4-chloro-3-iodo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (400 mg, 23%) as a pale yellow solid. LCMS (ESI) m / z: 506,508 [M+H] + .

[0294] A solution of 6-bromo-4-chloro-3-iodo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (400 mg, 0.79 mmol), 6-fluoropyridin-3-ylboronic acid (0.09 g, 0.63 mmol), K2CO3 (0.33 g, 2.37 mmol) and Pd(dppf)Cl2 (0.06 g, 0.08 mmol) in 1,4-dioxane (16 mL) and H2O (2 mL) was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 6-bromo-4-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (270 mg, 68%) as a pale yellow oil. LCMS (ESI) m / z: 475,477 [M+H] + .

[0295] Intermediate 27: Iodo-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile TIFF2025524039000096.tif38128

[0296] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (2 g, 12 mmol) and 3-fluoro-4-iodopyridine-2-carbonitrile (3.6 g, 14.4 mmol) in DMSO (50 mL), TEA (6.1 g, 60.1 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 16 h. Water (10 mL) was added to the reaction mixture at room temperature and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in CH2Cl2 (0% - 10%) to afford 4-iodo-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile (200 mg, 4%) as a red solid. LCMS (ESI) m / z: 395 [M+H] + .

[0297] Intermediate 28: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile TIFF2025524039000097.tif38128

[0298] To a stirred mixture of 2-chloro-3-fluoropyridine-4-carbonitrile (2 g, 12.8 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (4.2 g, 25.5 mmol) in DMSO (40 mL) was added dropwise TEA (6.5 g, 63.9 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. Water was added at room temperature and the mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (0 - 10%) to give 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (1 g, 26%) as a red solid. LCMS (ESI) m / z: 303 [M+H] + .

[0299] Intermediate 29: 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidyl]isonicotinonitrile TIFF2025524039000098.tif91131

[0300] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (2 g, 5.83 mmol), 5-bromo-1-methylimidazole (985 mg, 6.12 mmol), K2CO3 (1.61 g, 11.7 mmol), Pd(dppf)Cl2.DCM (238 mg, 0.29 mmol) was dissolved in 1,4-dioxane (19.4 mL) and water (5 mL). The reaction was heated at 100 °C for 30 min. The reaction was quenched with water, extracted with EtOAc and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0 - 100% Hex:[25% EtOH in EtOAc]) to give benzyl 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.15 g, 66%) as a brown oil.

[0301] A solution of benzyl 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.15 g, 3.87 mmol) in MeOH (13 mL) was dissolved, and Pd / C (250 mg) was added. The reaction vessel was placed under a hydrogen atmosphere and stirred at room temperature over the weekend. The mixture was filtered through celite and washed with methanol. The solution was dried in vacuo to obtain an orange residue. The residue was dissolved in Et2O (50 mL) and MeOH (1 mL), and HCl gas was bubbled through the reaction mixture. The resulting precipitate was filtered and dried in vacuo to obtain 1-methyl-5-(4-piperidyl)imidazole-hydrochloride (658 mg, 84%) as a tan solid. LCMS (ESI) m / z: 166 [M+H] + .

[0302] DIEA (192 mg, 1.5 mmol) was added to a mixture of 1-methyl-5-(4-piperidyl)imidazole-hydrochloride (1 / 1) (0.1 g, 0.5 mmol) and 2-chloro-3-fluoroisonicotinonitrile (85.4 mg, 0.54 mmol) in DMSO (2.1 mL). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (0 - 100%, Hex: [EtOH 25% in EtOAc]) to obtain 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidyl]isonicotinonitrile (46 mg, 31%). LCMS (ESI) m / z: 302 [M+H] + .

[0303] Intermediate 30: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]pyridine-4-carbonitrile TIFF2025524039000099.tif38128

[0304] To a stirred mixture of 2-chloro-3-fluoropyridine-4-carbonitrile (200 mg, 1.28 mmol) and 1-(4-methyl-1,2,4-triazol-3-yl)piperazine (320.5 mg, 1.92 mmol) in DMSO (5 mL), TEA (646.4 mg, 6.39 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C overnight under a nitrogen atmosphere. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to afford 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]pyridine-4-carbonitrile (210 mg) as a green solid. LCMS (ESI) m / z: 304 [M+H] + .

[0305] Intermediate 31: 2-Chloro-5-methoxy-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile TIFF2025524039000100.tif38153

[0306] A solution of 3,5-difluoropyridine-4-carbonitrile (5 g, 35.7 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (5.93 g, 35.7 mmol), and TEA (18.1 g, 178.4 mmol) in DMSO (25 mL) was stirred at 80 °C for 3 hours. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 3-fluoro-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (2.5 g, 24%) as a pale yellow oil. LCMS (ESI) m / z: 287 [M+H] + .

[0307] A solution of 3-fluoro-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (1 g, 3.49 mmol) and sodium methoxide (0.23 g, 4.19 mmol) in MeOH (15 mL) was stirred at 50 °C for 30 minutes. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 3-methoxy-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (440 mg, 42%) as a pale yellow oil. LCMS (ESI) m / z: 299 [M+H] + .

[0308] A solution of 3-methoxy-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (440 mg, 1.47 mmol) and sodium hypochlorite (109.8 mg, 1.47 mmol) in DMF (10 mL) was stirred at room temperature for 16 h under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 2-chloro-5-methoxy-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (110 mg, 22%) as a pale yellow oil.

[0309] Synthesis of Example Compounds Example 1: 3-(6-Fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000101.tif39128

[0310] The title compound was prepared using the following procedure. TIFF2025524039000102.tif42128

[0311] To a stirred solution of Intermediate 1 (80 mg, 0.2 mmol) and K2CO3 (64 mg, 0.5 mmol) in 1,4-dioxane (3 mL), Pd(dppf)Cl2·CH2Cl2 (19 mg, 0.1 mmol) and 6-fluoropyridin-3-ylboronic acid (36 mg, 0.3 mmol) were added at room temperature under a nitrogen atmosphere. The final reaction mixture was heated at 100 °C for 4 hours. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 15% B to 35% B in 7 minutes, 35% B; wavelength: 220 nm) to obtain Example 1. LCMS (ESI) m / z: 363.05 [M+H] + .

[0312] Example 2: 2-[4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridin-3-yl)benzonitrile TIFF2025524039000103.tif41128

[0313] The title compound was prepared using the following procedure. TIFF2025524039000104.tif43128

[0314] To a stirred mixture of Intermediate 1 (20 mg, 0.06 mmol) and pyridin-3-ylboronic acid (8.5 mg, 0.07 mmol) in dioxane (3 mL) / H2O (0.5 mL), K2CO3 (24.0 mg, 0.2 mol) and Pd(dppf)Cl2.CH2Cl2 (4.7 mg, 0.006 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h under nitrogen. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 27% B to 42% B in 7 min, 42% B; wavelength: 220 nm, RT1 (min): 4.65) to give Example 2. LCMS (ESI) m / z: 345.15 [M+H] + .

[0315] Example 3: 3-(4-Methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000105.tif41128

[0316] The title compound was prepared using the following procedure. TIFF2025524039000106.tif43128

[0317] To a stirred mixture of Intermediate 1 (40 mg, 0.12 mmol) and 4-methoxypyridin-3-ylboronic acid (21.2 mg, 0.1 mmol) in dioxane (5 mL) / H2O (0.8 mL), K2CO3 (47.9 mg, 0.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (9.4 mg, 0.01 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 8 h under nitrogen. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 34% B to 58% B in 8 min, 58% B; wavelength: 220 nm, RT1 (min): 7.35) to give Example 3. LCMS (ESI) m / z: 375.10 [M+H] + .

[0318] Example 4: 3-{1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000107.tif48128

[0319] The title compound was prepared using the following procedure. TIFF2025524039000108.tif54128

[0320] To a stirred mixture of 1-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (20 mg, 0.07 mmol) and Intermediate 1 (25.7 mg, 0.08 mmol) in dioxane (5 mL) were added Pd(PPh3)4 (7.8 mg, 0.007 mmol), K2CO3 (28.0 mg, 0.2 mmol), CsF (10.3 mg, 0.07 mmol) and CuI (12.9 mg, 0.07 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen. The reaction was quenched with water (40 mL) at room temperature. The resulting reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: MeOH; flow rate: 60 mL / min, gradient: 34% B to 60% B in 9 min, 60% B; wavelength: 254 / 220 nm, RT1 (min): 6.73) to give Example 4. LCMS (ESI) m / z: 399.15 [M+H] + .

[0321] TIFF2025524039000109.tif22146

[0322] To a stirred DMF (20 mL) mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs2CO3 (2.1 g, 6.3 mmol) in DMF (20 mL), CH3I (394.2 mg, 2.8 mmol) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA / PE (60% - 90%) to afford 4-bromo-1-methylpyrazolo[3,4-c]pyridine (280 mg, 52%) as a pale yellow solid. LCMS (ESI) m / z: 212, 214 [M+H] + .

[0323] To a stirred mixture of 4-bromo-1-methylpyrazolo[3,4-c]pyridine (100.0 mg, 0.5 mmol) and hexamethyldistannane (185.4 mg, 0.6 mmol) in dioxane (10 mL), Pd(PPh3)4 (54.5 mg, 0.05 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h under nitrogen. The reaction was quenched with water (80 mL) at room temperature. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (0% - 12%) to afford 1-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (89 mg, 63.8%) as a brown solid. LCMS (ESI) m / z: 298.0 [M+H] + .

[0324] Example 5: 2-[4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyrazin-2-yl)benzonitrile TIFF2025524039000110.tif37128

[0325] The title compound was prepared using the following procedure. TIFF2025524039000111.tif41128

[0326] To a stirred solution of intermediate 1 (50 mg, 0.14 mmol) and 2-(tributylstannyl)pyrazine (53 mg, 0.15 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL), CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol) were added at room temperature, followed by a catalytic amount of Pd(PPh3)4 (16.7 mg, 0.014 mmol). The resulting mixture was stirred at 100 °C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 25% B to 60% B in 7 min, 60% B; wavelength: 220 nm, RT1 (min): 6.88) to obtain Example 5. LCMS (ESI) m / z: 346.05 [M+H] + .

[0327] Example 6: 3-[6-(2-Hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000112.tif40128

[0328] The title compound was prepared using the following procedure. TIFF2025524039000113.tif40130

[0329] A solution of ethylene glycol (11 mg, 0.18 mmol) and NaH (4 mg, 0.2 mmol) in THF (10 mL) was stirred at 0 °C for 30 minutes under a N2 atmosphere. To the above mixture, 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (60 mg, 0.2 mmol) was added at 0 °C for 5 minutes. The resulting mixture was stirred at 50 °C for an additional 4 hours. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 18% B to 45% B in 7 minutes, 45% B; wavelength: 220 nm, RT1 (min): 6.47) to obtain Example 6. LCMS (ESI) m / z: 405.10 [M+H] + .

[0330] Example 7: 3-(4-Hydroxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000114.tif41128

[0331] The title compound was prepared using the following procedure. TIFF2025524039000115.tif40128

[0332] A mixture of 3-(4-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (40 mg, 0.11 mmol) and TMSI (213.7 mg, 1.07 mmol) in acetonitrile (5 mL) was stirred at 80 °C overnight under a nitrogen atmosphere. The residue was basified to pH 10 with saturated aqueous Na2CO3 solution. The resulting reaction mixture was extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 20% B to 40% B in 7 minutes, 40% B; wavelength: 254 / 2220 nm, RT1 (min): 6.42) to obtain Example 7. LCMS (ESI) m / z: 361.10 [M+H] + .

[0333] Example 8: 3-{4-[2-(dimethylamino)ethoxy]pyridin-3-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000116.tif47128

[0334] The title compound was prepared using the following procedure. TIFF2025524039000117.tif40128

[0335] A solution of NaH (4 mg, 0.2 mmol) in dimethylaminoethanol (3 mL, 0.1 mmol) was stirred at 0 °C for 30 min under a nitrogen atmosphere. To the above mixture was added 3-(4-chloropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (25 mg, 0.1 mmol) at room temperature. The resulting mixture was stirred at 120 °C overnight. The reaction was quenched by adding water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 25% B to 45% B in 7 min, 45% B; wavelength: 254 / 220 nm, RT1 (min): 5.92) to obtain Example 8. LCMS (ESI) m / z: 432.10 [M+H] + .

[0336] Example 9: 3-[4-(2-Hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000118.tif46128

[0337] The title compound was prepared using the following procedure. TIFF2025524039000119.tif40128

[0338] A solution of NaH (4 mg, 0.2 mmol) in ethylene glycol (3 mL, 0.1 mmol) was stirred at 0 °C for 30 minutes under a nitrogen atmosphere. To the above mixture, 3-(4-chloropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (25 mg, 0.1 mmol) was added at room temperature over 2 minutes. The resulting mixture was stirred at 120 °C overnight. The reaction was quenched by adding water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X Bridge BEH130 Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 18% B to 30% B over 7 minutes, 30% B; wavelength: 220 nm, RT1 (min): 6.42) to obtain Example 9. LCMS (ESI) m / z: 405.05 [M+H] + .

[0339] Example 10: 3-(4-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000120.tif41128

[0340] The title compound was prepared using the following procedure. TIFF2025524039000121.tif46128

[0341] To a stirred solution of Intermediate 1 (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.5 mmol) in 1,4-dioxane (3 mL), Pd(dppf)Cl2·CH2Cl2 (16 mg, 0.1 mmol) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (40 mg, 0.3 mmol) were added at room temperature under a nitrogen atmosphere. The final reaction mixture was heated at 100 °C for 4 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 18% B to 45% B in 7 min, 45% B; wavelength: 220 nm, RT1 (min): 6.47) to give Example 10. LCMS (ESI) m / z: 379.00 [M+H] + .

[0342] Example 11: 2-[4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000122.tif41128

[0343] The title compound was prepared using the following procedure. TIFF2025524039000123.tif41128

[0344] A stirred solution of intermediate 1 (50 mg, 0.14 mmol) and 4-(tributylstannyl)pyridazine (63.9 mg, 0.17 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added with CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol), followed by a catalytic amount of Pd(PPh3)4 (16.7 mg, 0.014 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 25% B to 60% B in 7 min, 60% B; wavelength: 220 nm, RT1 (min): 6.88) to obtain Example 11. LCMS (ESI) m / z: 346.05 [M+H] + .

[0345] Example 12: 3-{1-Methyl-1H-pyrrolo[2,3-c]pyridin-4-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000124.tif50128

[0346] The title compound was prepared using the following procedure. TIFF2025524039000125.tif50128

[0347] A stirred solution of Intermediate 1 (100 mg, 0.29 mmol) and 1-methyl-4-(trimethylstannyl)pyrrolo[2,3-c]pyridine (102.2 mg, 0.35 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added with CuI (110 mg, 0.58 mmol) and CsF (87.8 mg, 0.58 mmol), followed by a catalytic amount of Pd(PPh3)4 (33.4 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X select CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 10% B to 33% B in 7 min, 33% B; wavelength: 220 nm, RT1 (min): 6.32) to give Example 12. LCMS (ESI) m / z: 398.10 [M+H] + .

[0348] TIFF2025524039000126.tif23128

[0349] A solution of hexamethyldistannane (372 mg, 1 mmol) in 1,4-dioxane (10 mL) was treated with Pd(dppf)Cl2 (77 mg, 0.1 mmol) for 5 minutes at room temperature under a nitrogen atmosphere, followed by the addition of 4-bromo-1-methylpyrrolo[2,3-c]pyridine (200 mg, 1 mmol) at room temperature. The reaction mixture was stirred at 100 °C for a period of 4 hours. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography eluted with CH3CN / H2O (8:1) to afford 4-(trimethylstannyl)-1H-pyrrolo[2,3-c]pyridine (110 mg) as a brown oil.

[0350] Example 13: 2-[4-(1H-imidazol-1-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile TIFF2025524039000127.tif40128

[0351] The title compound was prepared using the following procedure. TIFF2025524039000128.tif45128

[0352] To a stirred solution of Intermediate 2 (300 mg, 0.91 mmol) in dioxane (12 mL) and H2O (2 mL), 4-methoxypyridin-3-ylboronic acid (277 mg, 1.81 mmol), K2CO3 (250.4 mg, 1.81 mmol), and Pd(dppf)Cl2 (66.3 mg, 0.091 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (6:1) to give a dark red solid as the crude product. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 25% B to 50% B in 7 minutes, 50% B; wavelength: 220 nm, RT1 (min): 5.98) to give Example 13. LCMS (ESI) m / z: 360.05 [M+H] + .

[0353] Example 14: 3-(4-Methoxypyridin-3-yl)-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzonitrile TIFF2025524039000129.tif38128

[0354] The title compound was prepared using the following procedure. TIFF2025524039000130.tif46128

[0355] To a stirred solution of Intermediate 3 (133 mg, 0.39 mmol) and 4-methoxypyridin-3-ylboronic acid (63.9 mg, 0.39 mmol) in dioxane (6 mL) / H2O (1 mL), Pd(dppf)Cl2 (28.0 mg, 0.04 mmol) and K2CO3 (157.8 mg, 1.15 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 30% B to 55% B in 8 min, 55% B; wavelength: 220 nm, RT1 (min): 8.10) to give Example 14. LCMS (ESI) m / z: 377.05 [M+H] + .

[0356] Example 15: 3-(1,3-Benzoxazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000131.tif45128

[0357] The title compound was prepared using the following procedure. TIFF2025524039000132.tif46128

[0358] A mixture of intermediate 1 (60.0 mg, 0.17 mmol), K2CO3 (71.8 mg, 0.5 mmol), Pd(dppf)Cl2 (14.1 mg, 0.02 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (46.7 mg, 0.2 mmol) in 1,4-dioxane (3.0 mL) / H2O (0.5 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. The reaction was quenched with water (25 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (45 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 27% B to 53% B in 7 min, 53% B; wavelength: 220 nm, RT1 (min): 5.84) to obtain Example 15. LCMS (ESI) m / z: 385.05 [M+H] + .

[0359] Example 16: 3-{2-Methyl-2H-pyrazolo[3,4-c]pyridin-4-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000133.tif48128

[0360] The title compound was prepared using the following procedure. TIFF2025524039000134.tif50128

[0361] To a stirred mixture of 2-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (50 mg, 0.17 mmol) and Intermediate 1 (58.5 mg, 0.17 mmol) in dioxane (3 mL), Pd(PPh3)4 (19.6 mg, 0.017 mmol), CsF (25.7 mg, 0.17 mmol) and CuI (32.2 mg, 0.17 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under nitrogen. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (12 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 15% B to 40% B in 7 min, 40% B; wavelength: 254 / 220 nm, RT1 (min): 6.08) to give Example 16. LCMS (ESI) m / z: 399.05 [M+H] + .

[0362] TIFF2025524039000135.tif29141

[0363] To a stirred mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs2CO3 (2.1 g, 6.3 mmol) in DMF (20 mL), CH3I (394.2 mg, 2.8 mmol) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (60% - 90%) to give 4-bromo-2-methylpyrazolo[3,4-c]pyridine (130 mg, 24%) as a pale yellow solid.

[0364] To a stirred mixture of 4-bromo-2-methyl-1H,7aH-pyrazolo[3,4-c]pyridine (80 mg, 0.4 mmol) and hexamethyldistannane (148.3 mg, 0.45 mmol) in dioxane (4 mL), Pd(PPh3)4 (43.6 mg, 0.04 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h under nitrogen. The reaction was quenched with water (40 mL) at room temperature. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / CH2Cl2 (2%-10%) to afford 2-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (50 mg, 45%) as a yellow solid.

[0365] Example 17: 2-[4-(2-Amino-1,3-thiazol-5-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile TIFF2025524039000136.tif43128

[0366] The title compound was prepared using the following procedure. TIFF2025524039000137.tif144164

[0367] A solution of N-(5-bromo-1,3-thiazol-2-yl)acetamide (2 g, 9.05 mmol), Pd(dppf)Cl2 (0.66 g, 0.91 mmol), K2CO3 (3.75 g, 27.14 mmol), and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.36 g, 10.86 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1 g, 34%) as a black solid. LCMS (ESI) m / z: 324 [M+H] + .

[0368] A solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (560 mg, 1.73 mmol) and Pd / C (200 mg) in MeOH (50 mL) was stirred at room temperature overnight under hydrogen. The mixture was filtered and the filter cake was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate (440 mg, 78%) as a pale yellow solid. LCMS (ESI) m / z: 326 [M+H] + .

[0369] A solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate (440 mg, 1.35 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0370] A solution of N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (300 mg, 1.33 mmol), DIEA (860.5 mg, 6.66 mmol), and 3-bromo-2-fluorobenzonitrile (319.6 mg, 1.60 mmol) in DMSO (10 mL) was stirred at 120 °C for 2 days. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give N-{5-[1-(2-bromo-6-cyanophenyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (150 mg, 28%) as a black solid. LCMS (ESI) m / z: 405, 407 [M+H] + .

[0371] A solution of N-{5-[1-(2-bromo-6-cyanophenyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (20 mg, 0.05 mmol), Pd(dppf)Cl2 (3.61 mg, 0.005 mmol), K2CO3 (20.5 mg, 0.15 mmol) and 4-methoxypyridin-3-ylboronic acid (9.1 mg, 0.06 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 11% B to 19% B in 7 minutes, 19% B; wavelength: 254 / 220 nm, RT1 (min): 4.82) to give N-(5-{1-[2-cyano-6-(4-methoxypyridin-3-yl)phenyl]piperidin-4-yl}-1,3-thiazol-2-yl)acetamide (1.9 mg, 8.9%) as a pale yellow solid. LCMS (ESI) m / z: 434 [M+H] + .

[0372] A solution of N-(5-{1-[2-cyano-6-(4-methoxypyridin-3-yl)phenyl]piperidin-4-yl}-1,3-thiazol-2-yl)acetamide (20 mg, 0.046 mmol), concentrated HCl (3 mL), and EtOH (5 mL) was stirred at 80 °C overnight. The mixture was basified to pH 8 with saturated Na2CO3 (aqueous solution). The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (9 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 30% B to 45% B over 7 minutes, 45% B; wavelength: 254 / 220 nm, RT1 (min): 6.43) to obtain Example 17. LCMS (ESI) m / z: 392.05 [M+H] + .

[0373] Example 18: 3-(4-Methoxypyridin-3-yl)-2-[4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile TIFF2025524039000138.tif41128

[0374] The title compound was prepared using the following procedure. TIFF2025524039000139.tif42128

[0375] A stirred mixture of intermediate 5 (200 mg, 0.58 mmol) and 4-methoxypyridin-3-ylboronic acid (132.5 mg, 0.87 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was added with K2CO3 (239.5 mg, 1.73 mmol) and Pd(dppf)Cl2 (42.3 mg, 0.058 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 3 h under nitrogen. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 12% B to 40% B in 9 min, 40% B; wavelength: 220 / 254 nm, RT1 (min): 6.10) to give Example 18. LCMS (ESI) m / z: 375.05 [M+H] + .

[0376] Example 19: 3-(2,1,3-Benzoxadiazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000140.tif41128

[0377] The title compound was prepared using the following procedure. TIFF2025524039000141.tif43128

[0378] To a stirred mixture of Intermediate 1 (60 mg, 0.17 mmol) and 2,1,3-benzoxadiazol-5-ylboronic acid (42.6 mg, 0.26 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (71.8 mg, 0.52 mmol) and Pd(dppf)Cl2 (12.7 mg, 0.017 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 h under nitrogen. The resulting mixture was extracted with EtOAc (2 × 60 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. The crude product (50 mg) was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 28% B to 50% B in 8 min, 50% B; wavelength: 254 / 220 nm, RT1 (min): 6.95) to give Example 19. LCMS (ESI) m / z: 386.05 [M+H] + .

[0379] Example 20: 2-[4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-{2H,3H,4H-pyrido[4,3-b][1,4]oxazin-8-yl}benzonitrile TIFF2025524039000142.tif50128

[0380] The title compound was prepared using the following procedure. TIFF2025524039000143.tif54132

[0381] To a stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H,3H,4H-pyrido[4,3-b][1,4]oxazine (40 mg, 0.15 mmol) and K2CO3 (38 mg, 0.29 mmol) in 1,4-dioxane / H2O (10:1), Pd(dppf)Cl2CH2Cl2 (11 mg, 0.1 mmol) and Intermediate 1 (48 mg, 0.14 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched at room temperature by the addition of water (5 mL). The crude product was purified by reverse-phase flash using the following conditions (column: X select CSH F-Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 2% B to 22% B in 9 min, 22% B; wavelength: 220 nm, RT1 (min): 7.20) to give Example 20. LCMS (ESI) m / z: 402.05 [M+H] + .

[0382] TIFF2025524039000144.tif26128

[0383] To a stirred solution of 8-bromo-2H,3H,4H-pyrido[4,3-b][1,4]oxazine (900 mg, 4.18 mmol) in 1,4-dioxane (50 mL) were added Pd(dppf)Cl2 (342 mg, 0.42 mmol), AcOK (1232 mg, 12.6 mmol), and bis(pinacolato)diboron (218 mg, 0.84 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water (0.1% FA) in MeCN, gradient from 10% to 50% in 10 min; detector, UV 254 nm to give the desired compound (600 mg) as a brown solid. LCMS (ESI) m / z: 263 [M+H] + .

[0384] Example 21: 2-[4-(5-Amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile TIFF2025524039000145.tif46128

[0385] The title compound was prepared using the following procedure. TIFF2025524039000146.tif47128

[0386] To a stirred solution of intermediate 4 (200 mg, 0.55 mmol) in dioxane (15 mL) and H2O (2 mL), K2CO3 (151.7 mg, 1.1 mmol), 4-methoxypyridin-3-ylboronic acid (167.9 mg, 1.01 mmol) and Pd(dppf)Cl2 (40.2 mg, 0.06 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to afford a dark red solid as the crude product. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 24% B to 48% B in 7 min, 48% B; wavelength: 220 nm, RT1 (min): 6.27) to give Example 21. LCMS (ESI) m / z: 393.00 [M+H] + .

[0387] Example 22: 3-{4-methyl-2H,3H,4H-pyrido[4,3-b][1,4]oxazin-8-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000147.tif50128

[0388] The title compound was prepared using the following procedure. TIFF2025524039000148.tif49131

[0389] A stirred solution of 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-{2H,3H,4H-pyrido[4,3-b][1,4]oxazin-8-yl}benzonitrile (25 mg, 0.06 mmol) in anhydrous MeOH (5 mL) was treated with HCHO (4 mg, 0.13 mmol) and NaBH3CN (12 mg, 0.19 mmol), followed by a catalytic amount of HCOOH (3 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for a period of 4 h. After completion of the reaction, the reaction mixture was quenched by the addition of water (5 mL) and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The crude product was purified by reverse-phase flash using the following conditions (column: X select CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 10% B to 40% B in 7 min, 40% B; wavelength: 220 nm, RT1 (min): 5.62) to give Example 22. LCMS (ESI) m / z: 416.10 [M+H] + .

[0390] Example 23: 3-[4-(2-Hydroxyethyl)-2H,3H,4H-pyrido[4,3-b][1,4]oxazin-8-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000149.tif57128

[0391] The title compound was prepared using the following procedure. TIFF2025524039000150.tif106128

[0392] To a stirred solution of Intermediate 1 (20 mg, 0.058 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (15.9 mg, 0.12 mmol) and 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-ylboronic acid (21.5 mg, 0.064 mmol), followed by a catalytic amount of Pd(dppf)Cl2 (4.71 mg, 0.006 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for a period of 4 h. After completion of the reaction, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using 5% - 20% MeOH in a DCM gradient to afford the desired compound 3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (10 mg).

[0393] Under a nitrogen atmosphere, HCOOH (1.6 mg, 0.036 mmol) and H2O (5 mL) were added to a stirred solution of 3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (10 mg, 0.018 mmol) at room temperature. The final reaction mixture was stirred at room temperature for 1 h. The crude product was purified by reverse phase flash using the following conditions (column: X select CSH F-phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 2% B to 22% B in 9 min, 22% B; wavelength: 220 nm, RT1 (min): 7.20) to afford Example 23. LCMS (ESI) m / z: 446.05 [M+H] + .

[0394] TIFF2025524039000151.tif86160

[0395] A solution of 3-amino-5-bromopyridin-4-ol (6 g, 31.7 mmol) in acetone (100 mL) was treated with NaOAc (5.2 g, 63.4 mmol) at 0 °C for 5 minutes under a nitrogen atmosphere, and then chloroacetyl chloride (4.3 g, 38 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave N-(5-bromo-4-hydroxypyridin-3-yl)-2-chloroacetamide (4 g) as a brown solid. LCMS (ESI) m / z: 265 [M+H] + .

[0396] A solution of N-(5-bromo-4-hydroxypyridin-3-yl)-2-chloroacetamide (4 g, 15.1 mmol) in DMF (10 mL) was treated with K2CO3 (4.2 g, 30.1 mmol) at 0 °C for 5 minutes. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 8-bromo-2H,4H,4aH,8aH-pyrido[4,3-b][1,4]oxazin-3-one (3 g) as a brown solid. LCMS (ESI) m / z: 229, 231 [M+H] + .

[0397] A solution of 8-bromo-2H,4H,4aH,8aH-pyrido[4,3-b][1,4]oxazin-3-one (4 g, 17.3 mmol) in borane-THF (70 mL) was stirred at 0 °C for 5 minutes under a nitrogen atmosphere. The resulting mixture was stirred at 35 °C for an additional 16 hours. The reaction was quenched with MeOH (7 mL) at 60 °C for 30 minutes. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 8-bromo-2H,3H,4H-pyrido[4,3-b][1,4]oxazine (2.5 g) as a brown solid. LCMS (ESI) m / z: 215, 217 [M+H] + .

[0398] To a stirred solution of 8-bromo-2H,3H,4H-pyrido[4,3-b][1,4]oxazine (30 mg, 0.14 mmol) in anhydrous THF (5 mL) was added NaH (6.7 mg, 0.28 mmol) over a period of 30 minutes at 0 °C. A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (50.1 mg, 0.21 mmol) was stirred at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched by the addition of water (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using 5% - 40% EtOAc in a PE gradient to afford the desired compound 8-bromo-4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazine (40 mg). LCMS (ESI) m / z: 373, 375 [M+H] + .

[0399] A stirred solution of 8-bromo-4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazine (40 mg, 0.11 mmol) in anhydrous 1,4-dioxane (5 mL) was added with AcOK (19.3 mg, 0.32 mmol) and bis(pinacolato)diboron (54.4 mg, 0.21 mmol), followed by the addition of a catalytic amount of Pd(dppf)Cl2 (8.7 mg, 0.01 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for a period of 16 h. After the reaction was completed, the reaction mixture was quenched by adding water (5 mL). The aqueous layer was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was further purified by column chromatography using 1% - 10% MeOH in a DCM gradient to give the desired compound 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-ylboronic acid (20 mg). LCMS(ESI) m / z: 339 [M+H] + .

[0400] Example 24: 3-(6-Fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000152.tif40128

[0401] The title compound was prepared using the following procedure. TIFF2025524039000153.tif39143

[0402] To a stirred solution of intermediate 7 (100 mg, 0.27 mmol) in dioxane (8 mL) and H2O (1 mL), K2CO3 (73.5 mg, 0.53 mmol), 6-fluoropyridin-3-ylboronic acid (74.9 mg, 0.53 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.03 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (7:1) to give a brown solid as the crude product. The crude product (80 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 26% B to 43% B in 7 min, 43% B; wavelength: 254 / 220 nm, RT1 (min): 6.38) to give Example 24. LCMS (ESI) m / z: 393.05 [M+H] + .

[0403] Example 25: 6-Methoxy-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000154.tif41128

[0404] The title compound was prepared using the following procedure. TIFF2025524039000155.tif43145

[0405] To a stirred solution of Intermediate 7 (100 mg, 0.27 mmol) in dioxane (7 mL) and H2O (1 mL), K2CO3 (73.5 mg, 0.53 mmol), 4-methoxypyridin-3-ylboronic acid (81.3 mg, 0.53 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (6:1) to afford a yellowish brown solid as the crude product. The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 9% B to 18% B in 8 min, 18% B; wavelength: 254 / 220 nm, RT1 (min): 5.73) to give Example 25. LCMS (ESI) m / z: 405.10 [M+H] + .

[0406] Example 26: 6-Methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000156.tif39128

[0407] The title compound was prepared using the following procedure. TIFF2025524039000157.tif47141

[0408] To a stirred solution of intermediate 7 (50 mg, 0.133 mmol) in dioxane (2 mL) and H2O (1 mL), K2CO3 (36.7 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (54.8 mg, 0.27 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (5:1) to afford a white solid as the crude product. The crude product (40 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 39% B to 69% B in 7 min, 69% B; wavelength: 254 / 220 nm, RT1 (min): 7.13) to give Example 26. LCMS (ESI) m / z: 376.05 [M+H] + .

[0409] Example 27: 6-Chloro-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000158.tif39128

[0410] The title compound was prepared using the following procedure. TIFF2025524039000159.tif43140

[0411] To a stirred mixture of intermediate 6 (0.5 g, 1.31 mmol), K2CO3 (0.36 g, 2.63 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL), (4-methoxypyridin-3-yl)boronic acid (0.16 g, 1.05 mmol) and Pd(dppf)Cl2 (0.10 g, 0.13 mmol) were added at room temperature under N2 atmosphere. The mixture was stirred at 90 °C for 20 h under nitrogen atmosphere. The crude product (10 mg) was purified by preparative HPLC using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 5% B to 28% B in 8 min, 28% B; wavelength: 254 / 220 nm, RT1 (min): 7.00) to give Example 27. LCMS(ESI) m / z: 409.00 [M+H] + .

[0412] Example 28: 4-(6-Fluoropyridin-3-yl)-3-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-2-carbonitrile TIFF2025524039000160.tif38128

[0413] The title compound was prepared using the following procedure. TIFF2025524039000161.tif79128

[0414] To a stirred mixture of intermediate 6 (200 mg, 0.52 mmol), K2CO3 (145 mg, 1.05 mmol) in dioxane (5 mL) and H2O (0.5 mL), (6-fluoropyridin-3-yl)boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl2 (115.3 mg, 0.16 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 20 h under nitrogen. The crude product (150 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 48% B to 69% B in 10 min, 69% B; wavelength: 220 nm, RT1 (min): 8.50) to give 6-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile. LCMS (ESI) m / z: 409 [M+H] + .

[0415] A stirred solution of 6-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (100 mg, 0.25 mmol) and K2CO3 (69.6 mg, 0.5 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added with phenylboronic acid (61.4 mg, 0.5 mmol) and Pd(dppf)Cl2 (55.3 mg, 0.076 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 20 h. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 25% B to 55% B in 7 min, 55% B; wavelength: 254 / 220 nm, RT1 (min): 6.52) to obtain Example 28. LCMS (ESI) m / z: 439.05 [M+H] + .

[0416] Example 29: 2-[4-(4-Methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile TIFF2025524039000162.tif41128

[0417] The title compound was prepared using the following procedure. TIFF2025524039000163.tif45128

[0418] To a stirred solution of Intermediate 1 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane / H2O (10:1), K2CO3 (80 mg, 0.58 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (87 mg, 0.32 mmol) were added, followed by Pd(dppf)Cl2 (24 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. After the reaction was complete, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse-phase flash using the following conditions (column: X Bridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 16% B to 37% B in 10 min, 37% B; wavelength: 220 nm, RT1 (min): 8.62) to obtain Example 29. LCMS (ESI) m / z: 413.05 [M+H] + .

[0419] Example 30: 6-Chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000164.tif39128

[0420] The title compound was prepared using the following procedure. TIFF2025524039000165.tif36129

[0421] To a stirred mixture of intermediate 6 (200 mg, 0.52 mmol), K2CO3 (145.2 mg, 1.05 mmol) in dioxane (5 mL) and H2O (0.5 mL), (6-fluoropyridin-3-yl)boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl2 (115.3 mg, 0.16 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 10 h. The crude product (150 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 48% B to 69% B in 10 min, 69% B; wavelength: 220 nm, RT1 (min): 8.50) to give Example 30. LCMS (ESI) m / z: 397.00 [M+H] + .

[0422] Example 31: 3-(4-Methoxypyridin-3-yl)-2-[4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl]benzonitrile TIFF2025524039000166.tif39128

[0423] The title compound was prepared using the following procedure. TIFF2025524039000167.tif45128

[0424] To a stirred solution of intermediate 8 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) were added K2CO3 (80 mg, 0.58 mmol) and Pd(dppf)Cl2 (1.07 g, 1.5 mmol), followed by 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 0.29 mmol) at room temperature. The reaction mixture was stirred at 100 °C for a period of 6 hours. After completion of the reaction, the reaction mixture was quenched by the addition of water (5 mL). The crude product was purified by reverse-phase flash using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 15% B to 50% B in 7 minutes, 50% B; wavelength: 254 / 220 nm, RT1 (min): 3.88) to give Example 31. LCMS (ESI) m / z: 374.35 [M+H] + .

[0425] Example 32: 4-(4-Methoxypyridin-3-yl)-3-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-2-carbonitrile TIFF2025524039000168.tif38128

[0426] The title compound was prepared using the following procedure. TIFF2025524039000169.tif85128

[0427] To a stirred mixture of intermediate 6 (0.5 g, 1.31 mmol), K2CO3 (0.36 g, 2.62 mmol) in 1,4 - dioxane (5 mL) and H2O (0.5 mL), (4 - methoxypyridin - 3 - yl)boronic acid (0.16 g, 1 mmol) and Pd(dppf)Cl2 (0.10 g, 0.13 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was stirred at 90 °C for 20 h. The crude product (10 mg) was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 5% B to 28% B in 8 min, 28% B; wavelength: 254 / 220 nm, RT1 (min): 7.00) to give 6 - chloro - 3 - (4 - methoxypyridin - 3 - yl)-2-(4-(4 - methyl - 4H - 1,2,4 - triazol - 3 - yl)piperidin - 1 - yl)benzonitrile. LCMS(ESI) m / z: 409[M + H] + .

[0428] To a stirred solution of 6 - chloro - 3 - (4 - methoxypyridin - 3 - yl)-2-(4-(4 - methyl - 4H - 1,2,4 - triazol - 3 - yl)piperidin - 1 - yl)benzonitrile (50 mg, 0.12 mmol) and K2CO3 (33.8 mg, 0.24 mmol) in dioxane (0.7 mL), phenylboronic acid (14.9 mg, 0.12 mmol) and Pd(dppf)Cl2 (26.8 mg, 0.04 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was stirred at 90 °C for 20 h. The crude product (5 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 31% B to 52% B in 8 min, 52% B; wavelength: 220 nm, RT1 (min): 7.70) to give Example 32. LCMS(ESI) m / z: 451.10[M + H] + .

[0429] Example 33: 6-Chloro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000170.tif39128

[0430] The title compound was prepared using the following procedure. TIFF2025524039000171.tif47140

[0431] To a stirred solution of Intermediate 6 (100 mg, 0.26 mmol) in dioxane (2 mL) and H2O (0.5 mL) were added K2CO3 (72.6 mg, 0.53 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (64.9 mg, 0.32 mmol) and Pd(dppf)Cl2 (38.4 mg, 0.053 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (6:1) to give a red solid as the crude product. The crude product (20 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: from 39% B to 69% B in 7 minutes, 69% B; wavelength: 254 / 220 nm, RT1 (min): 7.13) to give Example 33. LCMS (ESI) m / z: 380.00 [M+H] + .

[0432] Example 34: 3-(1-Methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000172.tif43128

[0433] The title compound was prepared using the following procedure. TIFF2025524039000173.tif27128

[0434] To a stirred solution of 5-bromo-1-methylpyrimidin-2-one (2 g, 10.6 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.4 g, 21.2 mmol) in dioxane (30 mL) were added AcOK (3.1 g, 31.7 mmol), dicyclohexyl[3,6-dimethoxy-2’,4’,6’-tris(propan-2-yl)-[1,1’-biphenyl]-2-yl]phosphane (1.1 g, 2.1 mmol) and Pd(dppf)Cl2·CH2Cl2 (43.1 mg, 0.01 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EtOAc / petroleum ether (70% - 90%) to give 1-methyl-2-oxopyrimidin-5-ylboronic acid (400 mg, 25%) as a pale yellow solid.

[0435] TIFF2025524039000174.tif52137

[0436] To a stirred solution of 1-methyl-2-oxopyrimidin-5-ylboronic acid (88.9 mg, 0.6 mmol) and Intermediate 1 (100 mg, 0.3 mmol) in dioxane (5 mL) / H2O (0.5 mL) were added K2CO3 (119.8 mg, 0.9 mmol) and Pd(dppf)Cl 2.CH2Cl2 (23.5 mg, 0.03 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 30 mL). The crude product (50 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 5% B to 25% B in 9 minutes, 25% B; wavelength: 254 / 220 nm, RT1 (min): 10.80) to obtain Example 34. LCMS (ESI) m / z: 376.05 [M + H] + .

[0437] Example 35: 3-(6-Fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000175.tif42128

[0438] The title compound was prepared using the following procedure. TIFF2025524039000176.tif91135

[0439] To a stirred solution of intermediate 6 (300 mg, 0.79 mmol) in dioxane (3 mL) and H2O (1 mL), K2CO3 (218 mg, 1.58 mmol), 6-fluoropyridin-3-ylboronic acid (88.8 mg, 0.63 mmol) and Pd(dppf)Cl2 (115.3 mg, 0.16 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (6:1) to afford 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (200 mg, 64%) as a red solid. LCMS (ESI) m / z: 397 [M+H] + .

[0440] To a stirred solution of 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (150 mg, 0.38 mmol) in dioxane (3 mL) and H2O (1 mL) were added K2CO3 (104.5 mg, 0.76 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (157.3 mg, 0.76 mmol) and Pd(dppf)Cl2 (55.3 mg, 0.076 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 10% - 50% in 10 min; detector, UV 254 nm to give a light brown solid as the crude product. The crude product (25 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*100 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15% B to 35% B in 8 min, 35% B; wavelength: 254 / 220 nm, RT1 (min): 9.88) to give Example 35. LCMS: (ES, m / z): 443.10 [M+H] + .

[0441] Example 36: 6-(1-Methyl-1H-pyrazol-4-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000177.tif39128

[0442] The title compound was prepared using the following procedure. TIFF2025524039000178.tif97130

[0443] To a stirred solution of intermediate 6 (100 mg, 0.26 mmol) in dioxane (3 mL) and H2O (1 mL), K2CO3 (72.6 mg, 0.53 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (64.9 mg, 0.32 mmol) and Pd(dppf)Cl2 (38.4 mg, 0.053 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (6:1) to afford 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile (50 mg, 50%) as a red solid. LCMS (ESI) m / z: 380 [M+H] + .

[0444] To a stirred solution of 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile (50 mg, 0.13 mmol) in dioxane (2 mL) and H2O (0.5 mL), K2CO3 (36.4 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (54.8 mg, 0.26 mmol) and Pd(dppf)Cl2 (19.3 mg, 0.026 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient 15% - 40% over 20 min; detector, UV 254 nm to give a black solid as the crude product. The crude product (60 mg) was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 50 mL / min, gradient: 31% B to 41% B over 8 min, 41% B; wavelength: 254 / 220 nm, RT1 (min): 5.00) to give Example 36. LCMS (ESI) m / z: 426.05 [M+H] + .

[0445] Example 37: 6-[2-(dimethylamino)ethoxy]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000179.tif38128

[0446] The title compound was prepared using the following procedure. TIFF2025524039000180.tif86144

[0447] To a stirred solution of Intermediate 6 (1.4 g, 3.7 mmol) in dimethylaminoethanol (393.4 mg, 4.4 mmol) was added NaH (189 mg, 7.9 mmol) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C overnight under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 minutes; detector, UV 254 nm. 3-Bromo-6-[2-(dimethylamino)ethoxy]-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (430 mg, 26.4%) was obtained as a brown viscous oil.

[0448] To a stirred solution of 3-bromo-6-[2-(dimethylamino)ethoxy]-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (250 mg, 0.6 mmol) and 6-fluoropyridin-3-ylboronic acid (89.4 mg, 0.6 mmol) in dioxane (5 mL) / H2O (0.5 mL) were added Pd(dppf)Cl2CH2Cl2 (47 mg, 0.06 mmol) and K2CO3 (239.2 mg, 1.7 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeCN (3 × 20 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 12% B to 32% B in 9 minutes, 32% B; wavelength: 254 / 220 nm, RT1 (min): 11.82) to obtain Example 37. LCMS (ESI) m / z: 450.10 [M+H] + .

[0449] Example 38: 4-Fluoro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000181.tif40128

[0450] The title compound was prepared using the following procedure. TIFF2025524039000182.tif49128

[0451] To a stirred solution of Intermediate 9 (150 mg, 0.47 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (2 mL) were added K2CO3 (129.7 mg, 0.94 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (115.1 mg, 0.52 mmol), followed by the addition of a catalytic amount of Pd(AMPhos)2Cl2 (33.2 mg, 0.05 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash using the following conditions (column: X Bridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 25% B to 40% B in 8 min, 40% B; wavelength: 254 / 220 nm, RT1 (min): 6.93) to obtain Example 38. LCMS (ESI) m / z) 381.05 [M+H] + .

[0452] Example 39: 4-Fluoro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000183.tif38128

[0453] The title compound was prepared using the following procedure. TIFF2025524039000184.tif49128

[0454] To a stirred solution of intermediate 9 (50 mg, 0.156 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (1 mL) were added K2CO3 (129.7 mg, 0.94 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (35.4 mg, 0.17 mmol), followed by a catalytic amount of PdCl2(dcypf) (11.8 mg, 0.016 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse-phase flash using the following conditions (column: X Select CSH Fluoro Phenyl, 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: MeOH-HPLC; flow rate: 60 mL / min, gradient: 20% B to 38% B in 10 min, 38% B; wavelength: 254 / 220 nm; RT1 (min)) to give Example 39. LCMS(ESI) m / z: 364.05 [M+H] + .

[0455] Example 40: 3-(6-Chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile TIFF2025524039000185.tif40128

[0456] The title compound was prepared using the following procedure. TIFF2025524039000186.tif40128

[0457] To a stirred solution of intermediate 1 (50 mg, 0.14 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (0.5 mL) were added K2CO3 (39.9 mg, 0.29 mmol) and 6-chloropyridin-3-ylboronic acid (25 mg, 0.16 mmol), followed by a catalytic amount of Pd(dppf)Cl2 (11.8 mg, 0.014 mmol) at room temperature. The reaction mixture was stirred at 100 °C for a period of 2 h. After completion of the reaction, the reaction mixture was quenched by the addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse-phase flash using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 21% B to 40% B in 9 min, 40% B; wavelength: 254 / 220 nm, RT1 (min): 10.48) to give Example 40. LCMS (ESI) m / z: 379.00 [M+H] + .

[0458] Example 41: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000187.tif40128

[0459] The title compound was prepared using the following procedure. TIFF2025524039000188.tif50128

[0460] To a stirred solution of Intermediate 10 (100 mg, 0.29 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (76.6 mg, 0.34 mmol) in dioxane (20 mL), Pd(dppf)Cl2·CH2Cl2 (23.3 mg, 0.03 mmol) and K2CO3 (79 mg, 0.57 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen. The reaction was quenched at room temperature by the addition of water (5 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 16% B to 34% B in 9 min, 34% B; wavelength: 254 / 220 nm, RT1 (min): 9.38) to give Example 41 (48.4 mg, 44%). LCMS (ESI) m / z: 366.05 [M+H] + .

[0461] Example 43: 3-(6-Fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000189.tif51128

[0462] The title compound was prepared using the following procedure. TIFF2025524039000190.tif51128

[0463] To a stirred solution of Example 30 (150 mg, 0.38 mmol) in dioxane (5 mL) and H2O (1 mL), K2CO3 (104.5 mg, 0.76 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (118 mg, 0.57 mmol) and Pd(dppf)Cl2 (27.7 mg, 0.038 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give a red solid as the crude product. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 20% B to 36% B in 10 min, 36% B; wavelength: 220 / 254 nm, RT1 (min): 11.22) to give Example 43 (22.8 mg, 13%). LCMS (ESI) m / z: 443.05 [M+H] + .

[0464] Example 49: 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile TIFF2025524039000191.tif34128

[0465] The title compound was prepared using the following procedure. TIFF2025524039000192.tif39128

[0466] To a stirred solution of Intermediate 11 (51 mg, 0.15 mmol) and 6-fluoropyridin-3-ylboronic acid (28.1 mg, 0.2 mmol) in 1,4-dioxane (5 mL) and water (1 mg), Cs2CO3 (100 mg) and Pd(dppf)Cl2.CH2Cl2 (12.5 mg) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 50 mL / min, gradient: from 56% B to 72% B in 8 minutes, 72% B; wavelength: 254 / 220 nm, RT1 (min): 6.47) to give Example 49 (2.7 mg, 4%). LCMS (ESI) m / z: 349.00 [M+H] + .

[0467] Example 50: 3-(6-Fluoropyridin-3-yl)-6-(3-methyl-1H-1,2,4-triazol-1-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000193.tif43128

[0468] The title compound was prepared using the following procedure. TIFF2025524039000194.tif46153

[0469] To a stirred solution of Intermediate 6 (300 mg, 0.7 mmol) and 3-methyl-1H-1,2,4-triazole (85.1 mg) in DMF (10 mL), NaH (28.4 mg) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The reaction was quenched by adding water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 3-bromo-6-(3-methyl-1,2,4-triazol-1-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (117 mg) as a yellow solid. LCMS (ESI) m / z: 427, 429 [M+H] + .

[0470] To a stirred solution of 3-bromo-6-(3-methyl-1,2,4-triazol-1-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (100 mg, 0.23 mmol) and 6-fluoropyridin-3-ylboronic acid (42.9 mg, 0.3 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (64.7 mg) and Pd(dppf)Cl2.CH2Cl2 (19.1 mg) were added portionwise under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give Example 50 (32.7 mg, 31%). LCMS (ESI) m / z: 444.05 [M+H] + .

[0471] Example 51: 6-((2-(Dimethylamino)ethyl)amino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000195.tif38128

[0472] The title compound was prepared using the following procedure. TIFF2025524039000196.tif38130

[0473] A solution of Example 30 (50 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL) was treated with Cs2CO3 (82.1 mg, 0.25 mmol) for 5 minutes at room temperature under a nitrogen atmosphere. To the above mixture, Pd-PEPPSI-IHeptCl 3-chloropyridine (12.3 mg, 0.013 mmol) and (2-aminoethyl)dimethylamine (22.2 mg, 0.25 mmol) were added for 5 minutes at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 9:1), and then by preparative HPLC using the following conditions (column: YMC-Actus Triart C 18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 20% B to 45% B in 7 minutes, 45% B; wavelength: 254 / 220 nm, RT1 (min): 6.72 to give Example 51 (6.8 mg, 12%). LCMS (ESI) m / z: 449.20 [M+H] + .

[0474] Example 57: 3-(6-fluoropyridin-3-yl)-6-(methoxy-d3)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000197.tif44128

[0475] The title compound was prepared using the following procedure. TIFF2025524039000198.tif40159

[0476] ( 2 A mixture of sodium (2 g, 87 mmol) in methanol (20 mL) was stirred at 50 °C for 4 hours under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. Thereby, 2 sodium methoxide (3.5 g, 70%) was obtained as a white solid.

[0477] To a stirred solution of intermediate 6 (150 mg, 0.39 mmol) and K2CO3 (109 mg, 0.79 mmol) in DMF (5 mL), sodium 2 (H3)methanolate (27 mg, 0.47 mmol) was added portionwise at room temperature. The resulting mixture was stirred at 120 °C for 4 hours. The resulting mixture was extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give 3-bromo-6-(2H3)methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 47%) as a pale yellow oil. LCMS (ESI) m / z: 379, 381 [M+H] + .

[0478] A stirred mixture of 3-bromo-6-(2H3)methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 0.18 mmol) and 6-fluoropyridin-3-ylboronic acid (33.8 mg, 0.24 mmol) in dioxane (10 mL) and H2O (1 mL) was added portionwise with K2CO3 (51 mg, 0.37 mmol) and Pd(dppf)Cl2 (13.5 mg, 0.02 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h, filtered, and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 20% B to 45% B in 7 min, 45% B; wavelength: 254 / 220 nm, RT1 (min): 6.72) to give Example 57 (26.5 mg, 36%). LCMS (ESI) m / z: 396.05 [M+H] + .

[0479] Example 58: 6-(2-(dimethylamino)ethoxy)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridazin-4-yl)benzonitrile TIFF2025524039000199.tif36128

[0480] The title compound was prepared using the following procedure. TIFF2025524039000200.tif37158

[0481] A solution of intermediate 6 (2.3 g, 6.0 mmol), 4-(tributylstannyl)pyridazine (2.23 g, 6.04 mmol), Pd(PPh3)4 (0.70 g, 0.60 mmol), CuI (1.15 g, 6.04 mmol), and CsF (0.92 g, 6.04 mmol) in dioxane (10 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to obtain 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile (240 mg, 10%) as a brown solid. LCMS (ESI) m / z: 380 [M+H] + .

[0482] A solution of 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile (100 mg, 0.26 mmol) and NaH (12.6 mg, 0.53 mmol) in dimethylaminoethanol (2 mL) was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 17% B to 42% B in 10 minutes, 42% B; wavelength: 220 / 254 nm, RT1 (min): 9.82) to obtain Example 58 (2.8 mg, 4%). LCMS (ESI) m / z: 433.35 [M+H] + .

[0483] Example 59: 4-Fluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile TIFF2025524039000201.tif35128

[0484] The title compound was prepared using the following procedure. TIFF2025524039000202.tif47128

[0485] To a stirred solution of intermediate 9 (50 mg, 0.16 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (1 mL) were added K2CO3 (43.2 mg, 0.31 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (41.3 mg, 0.19 mmol), followed by catalytic amounts of Sphos Pd G3 (24.7 mg, 0.016 mmol) and Sphos (12.6 mg, 0.016 mmol) at room temperature. The reaction mixture was stirred at 80 °C for a period of 16 h. After completion of the reaction, the reaction mixture was quenched by the addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (100 mL) and the resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: X Bridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min, gradient: from 18% B to 34% B in 8 min, 34% B; wavelength: 254 / 220 nm, RT1 (min): 7.75) to give Example 59 (3.2 mg, 5%). LCMS (ESI) m / z: 378.00 [M+H] + .

[0486] Example 64: 6-(6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000203.tif47128

[0487] The title compound was prepared using the following procedure. TIFF2025524039000204.tif50128

[0488] A mixture of Example 30 (70 mg, 0.18 mmol) and K2CO3 (48.8 mg, 0.35 mmol) in dioxane (1.6 mL) and H2O (0.4 mL) was stirred at room temperature for 5 minutes under a nitrogen atmosphere. To the above mixture, SPhos Pd G3 (13.8 mg, 0.018 mmol), Sphos (7.2 mg, 0.018 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine (52.9 mg, 0.21 mmol) were added at room temperature. The resulting mixture was heated at 90 °C overnight. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1), and this was further purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 . H2O), mobile phase B: ACN; flow rate: 50 mL / min, gradient: from 26% B to 43% B in 8 minutes, 43% B; wavelength: 254 / 220 nm, RT1 (min): 8.12 to obtain Example 64 (2.1 mg, 2%). LCMS (ESI) m / z: 485.25 [M+H] + .

[0489] Example 66: 3-(6-Fluoropyridin-3-yl)-5-methyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000205.tif39128

[0490] The title compound was prepared using the following procedure. TIFF2025524039000206.tif44128

[0491] To a stirred solution of Intermediate 12 (50 mg, 0.14 mmol) and 6-fluoropyridin-3-ylboronic acid (25.4 mg, 0.18 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL), K2CO3 (38.4 mg, 0.28 mmol) and Pd(dppf)Cl2CH2Cl2 (11.3 mg, 0.014 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water (5 mL). The resulting reaction mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) and further purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 29% B to 46% B in 10 minutes; wavelength: 254 / 220 nm, RT1 (min): 8.50) to give Example 66 (1 mg, 2%). LCMS (ESI) m / z: 377.05 [M+H] + .

[0492] Example 69: 5-Chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000207.tif40128

[0493] The title compound was prepared using the following procedure. TIFF2025524039000208.tif44128

[0494] A solution of intermediate 13 (160 mg, 0.42 mmol), K2CO3 (174.3 mg, 1.26 mmol) and Pd(dppf)Cl2CH2Cl2 (34.2 mg, 0.042 mmol) in dioxane (5 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.10% FA) in MeCN, gradient of 10% to 50% in 10 min; detector, UV 254 nm, and then the following conditions (column: Xselect CSH F-Phenyl OBD column, 30 * 250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 5% to 18% of B in 10 min, 18% of B; wavelength: 254 / 220 nm, RT1 (min): 10.68) to obtain Example 69 (6.4 mg, 4%). LCMS (ESI) m / z: 397.05 [M+H] + .

[0495] Example 70: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile TIFF2025524039000209.tif40128

[0496] The title compound was prepared using the following procedure. TIFF2025524039000210.tif44128

[0497] A stirred mixture of intermediate 14 (50 mg, 0.12 mmol), 6-fluoropyridin-3-ylboronic acid (20.4 mg, 0.14 mmol) in H2O (1 mL) and 1,4-dioxane (4 mL) was added portionwise with K2CO3 (33.4 mg, 0.24 mmol) and Pd(dppf)Cl2.CH2Cl2 (10 mg) at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The residue was purified by preparative TLC (10% MeOH / CH2Cl2). The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 25% B to 45% B in 10 min; wavelength: 254 / 220 nm, RT1 (min): 12.27) to give Example 70 (6 mg, 12%). LCMS (ESI) m / z: 431.15 [M+H] + .

[0498] Example 71: 6-Fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000211.tif35128

[0499] The title compound was prepared using the following procedure. TIFF2025524039000212.tif36128

[0500] A solution of Example 30 (60 mg, 0.15 mmol), CsF (229.6 mg, 1.51 mmol) and TBAB (4.87 mg, 0.015 mmol) in DMSO (3 mL) was stirred at 120 °C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. The residue was purified by preparative HPLC using the following conditions: column, C18 silica gel; mobile phase, water (0.1% FA) in MeCN, gradient from 10% to 50% in 10 min; detector, UV 254 nm, followed by the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 5% of B to 18% of B in 10 min, 18% of B; wavelength: 254 / 220 nm, RT1 (min): 10.68) to give Example 71 (2.2 mg, 4%). LCMS (ESI) m / z: 381.05 [M+H] + .

[0501] Example 72: 2-(4-(1,3,4-Thiadiazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile TIFF2025524039000213.tif34128

[0502] The title compound was prepared using the following procedure. TIFF2025524039000214.tif44128

[0503] A solution of 3 intermediates 15 (160 mg, 0.46 mmol), 6-fluoropyridin-3-ylboronic acid (71 mg, 0.50 mmol), K2CO3 (126.6 mg, 0.92 mmol) and Pd(dppf)Cl2 (33.5 mg, 0.05 mmol) in dioxane (2 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (2×5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 5% B to 18% B in 10 min, 18% B; wavelength: 254 / 220 nm, RT1 (min): 10.68) to obtain Example 72 (3 mg, 2%). LCMS (ESI) m / z: 366.00 [M+H] + .

[0504] Example 75: 3-(6-Fluoropyridin-3-yl)-2-((1R,5S)-6-(4-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl)benzonitrile TIFF2025524039000215.tif37128

[0505] The title compound was prepared using the following procedure. TIFF2025524039000216.tif41128

[0506] A solution of intermediate 16 (90 mg, 0.26 mmol), 6-fluoropyridin-3-ylboronic acid (44.2 mg, 0.31 mmol), K2CO3 (108.4 mg, 0.78 mmol), and Pd(dppf)Cl2 (19.1 mg, 0.026 mmol) in 1,4-dioxane (12 mL) and H2O (1.2 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH3.H2O), mobile phase B: ACN; flow rate: 50 mL / min, gradient: from 13% B to 30% B in 8 min; wavelength: 254 / 220 nm, RT1 (min): 9.32) to give Example 75 (10.8 mg, 11%). LCMS (ESI) m / z: 361.10 [M+H] + .

[0507] Example 76: 6-Cyclopropoxy-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000217.tif42128

[0508] The title compound was prepared using the following procedure. TIFF2025524039000218.tif96136

[0509] A solution of intermediate 6 (1 g, 2.63 mmol), TBAB (0.08 g, 0.26 mmol), and CsF (3.99 g, 26.3 mmol) in DMSO (5 mL) was stirred at 120 °C overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 10 minutes; detector, UV 254 nm to give 3-bromo-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 52%) as a yellow oil. LCMS (ESI) m / z: 364,366 [M+H] + .

[0510] A solution of 3-bromo-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (150 mg, 0.41 mmol), cyclopropanol (35.9 mg, 0.62 mmol), and Cs2CO3 (201.3 mg, 0.62 mmol) in DMF (4 mL) was stirred at 120 °C for 2 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 10 minutes; detector, UV 254 nm to give 3-bromo-6-cyclopropoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (60 mg, 36%) as a yellow oil. LCMS (ESI) m / z: 402,404 [M+H] + .

[0511] A solution of 3-bromo-6-cyclopropoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (50 mg, 0.12 mmol), K2CO3 (34.3 mg, 0.25 mmol) and Pd(dppf)Cl2CH2Cl2 (10.1 mg, 0.01 mmol) in dioxane (2 mL) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min; detector, UV 254 nm. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH F-Phenyl OBD column, 30 * 250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 5% B to 18% B in 10 min, 18% B; wavelength: 254 / 220 nm, RT1 (min): 10.68) to give Example 76 (4.4 mg, 8%). LCMS (ESI) m / z: 419.25 [M + H] + .

[0512] Example 78: 6-Amino-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000219.tif35128

[0513] The title compound was prepared using the following procedure. TIFF2025524039000220.tif46159

[0514] A mixture of Example 30 (130 mg, 0.33 mmol), Pd2(dba)3 (45 mg, 0.049 mmol), BINAP (61.2 mg, 0.098 mmol), and t-BuONa (47.2 mg, 0.49 mmol) in toluene (6 mL) was stirred at 110 °C for 12 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (12:1) to give 6-[(diphenylmethylene)amino]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 39%) as an orange oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z: 542 [M+H] + .

[0515] To a round-bottom flask were added 6-[(diphenylmethylene)amino]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (60 mg, 0.11 mmol), HCl (1 mL), DCM (6 mL), and H2O (6 mL) at room temperature. The mixture was stirred at room temperature for 0.5 h. The mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) and further purified by preparative HPLC using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 25% B to 42% B in 9 min, 42% B; wavelength: 254 / 220 nm, RT1 (min): 8.97) to give Example 78 (5.1 mg, 12%). LCMS (ESI) m / z: 378.25 [M+H] + .

[0516] Example 79: 2-Cyano-4-(6-fluoropyridin-3-yl)-N,N-dimethyl-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzamide TIFF2025524039000221.tif41128

[0517] The title compound was prepared using the following procedure. TIFF2025524039000222.tif90159

[0518] To a solution of Example 30 (150 mg, 0.38 mmol) in MeOH (5 mL) were added Pd(dppf)Cl2 (27.7 mg, 0.038 mmol) and TEA (114.8 mg, 1.13 mmol) in a pressure tank. The mixture was purged with nitrogen for 10 minutes and then pressurized to 20 atm with carbon monoxide at 140 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / CH2Cl2 (0% - 10%) to give methyl 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoate (104 mg) as a red solid. LCMS (ESI) m / z: 421 [M+H] + .

[0519] A mixture of methyl 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoate (90 mg, 0.21 mmol) and NaOH (17.1 mg, 0.43 mmol) in H2O (3 mL) and MeOH (3 mL) was stirred at room temperature for 2 h. The residue was purified by preparative TLC (10% MeOH / CH2Cl2) to give 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoic acid (40 mg) as a pink solid. LCMS (ESI) m / z: 407 [M+H] + .

[0520] To a stirred mixture of 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoic acid (40 mg, 0.098 mmol) and dimethylamine (5.3 mg, 0.19 mmol) in DMF (3 mL), HATU (44.9 mg, 0.12 mmol) and DIEA (50.9 mg, 0.39 mmol) were added portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc (2×80 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 50 mL / min, gradient: from 15% B to 32% B in 8 min, 32% B; wavelength: 254 / 220 nm, RT1 (min): 6.75) to give Example 79 (10 mg, 23%). LCMS (ESI) m / z: 434.00 [M+H] + .

[0521] Example 80: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(4-methylpiperazin-1-yl)benzonitrile TIFF2025524039000223.tif41128

[0522] The title compound was prepared using the following procedure. TIFF2025524039000224.tif45157

[0523] To a solution of intermediate 6 (300 mg, 0.79 mmol) in 1-methylpiperazine (10 mL) was added K2CO3 (327 mg, 2.37 mmol) portionwise at room temperature. The resulting mixture was stirred at 100 °C for 2 days. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (0% - 10%) in CH2Cl2 to afford 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)benzonitrile (100 mg, 28%) as a yellow solid. LCMS (ESI) m / z: 444, 446 [M+H] + .

[0524] To a stirred solution of 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)benzonitrile (100 mg, 0.22 mmol) and 6-fluoropyridin-3-ylboronic acid (63.4 mg, 0.45 mmol) in dioxane (10 mL) and H2O (1 mL) were added Pd(dppf)Cl2CH2Cl2 (18.3 mg, 0.023 mmol) and K2CO3 (93.3 mg, 0.68 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen. The reaction was quenched by adding water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Aeris PEPTIDE 10um XB-C18 Axia, 50 mm × 250 mm, 10 μm; mobile phase A: water 0.1% NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min, gradient: from 5% B to 35% B in 30 min, 20% B; wavelength: 220 / 254 nm, RT1 (min): 13.97 to give Example 80 (10.5 mg, 10%). LCMS (ESI) m / z: 461.25 [M+H] + .

[0525] Example 81: 6-(Cyclopropylamino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000225.tif42128

[0526] The title compound was prepared using the following procedure. TIFF2025524039000226.tif42128

[0527] To a stirred solution of Example 30 (200 mg, 0.5 mmol) and aminocyclopropane (43.2 mg, 0.76 mmol) in dioxane (20 mL), Cs2CO3 (494 mg, 1.51 mmol) and Brettphos Pd G3 (45.7 mg, 0.05 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 16 h under nitrogen. The reaction was quenched at room temperature by the addition of water (5 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Aeris PEPTIDE 5um XB-C18 Axia, 21.2 mm × 250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 22% B to 40% B in 10 min, 40% B; wavelength: 220 / 254 nm, RT1 (min): 13.97) to give Example 81 (1.2 mg, 0.6%). LCMS (ESI) m / z: 418.30 [M+H] + .

[0528] Example 82: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(2-(methylamino)ethoxy)benzonitrile TIFF2025524039000227.tif47128

[0529] The title compound was prepared using the following procedure. TIFF2025524039000228.tif105146

[0530] A mixture of 2-[benzyl(methyl)amino]ethanol (138.9 mg, 0.84 mmol) and NaH (30.3 mg, 1.26 mmol) in DMF (8 mL) was stirred at 0 °C for 30 min under a nitrogen atmosphere. Intermediate 6 (400 mg, 1.05 mmol) was added to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water (0.1% FA) in MeCN with a gradient of 10% - 30% over 15 min; detector, UV 254 nm to give 6-{2-[benzyl(methyl)amino]ethoxy}-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (370 mg, 69%). LCMS (ESI) m / z: 509, 511 [M+H] + .

[0531] To a stirred solution of 6-{2-[benzyl(methyl)amino]ethoxy}-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (200 mg, 0.39 mmol) in dioxane (4 mL) and H2O (1 mL) were added K2CO3 (162.8 mg, 1.18 mmol), 6-fluoropyridin-3-ylboronic acid (83 mg, 0.59 mmol) and Pd(dppf)Cl2 (28.7 mg, 0.039 mmol). The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The crude mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, water (0.1% FA) in MeCN with a gradient of 20% - 40% over 20 min; detector, UV 254 nm to give 6-{2-[benzyl(methyl)amino]ethoxy}-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (160 mg, 77%) as a yellow oil. LCMS (ESI) m / z: 526 [M+H] + .

[0532] A stirred solution of 6-{2-[benzyl(methyl)amino]ethoxy}-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (100 mg, 0.19 mmol) in MeOH (10 mL) was added portionwise with Pd / C (50.6 mg, 0.47 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a hydrogen atmosphere. The mixture was filtered and the filter cake was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 6% B to 23% B over 10 min, 23% B; wavelength: 200 / 220 nm, RT1 (min): 12.73) to give Example 82 (12.3 mg, 14%). LCMS (ESI) m / z: 436.10 [M+H] + .

[0533] Example 84: N-(2-Cyano-4-(6-fluoropyridin-3-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide TIFF2025524039000229.tif43128

[0534] The title compound was prepared using the following procedure. TIFF2025524039000230.tif43128

[0535] A mixture of Example 30 (100 mg, 0.25 mmol), methanesulfonamide (47.9 mg, 0.50 mmol), BINAP (15.7 mg, 0.025 mmol), t-BuONa (36.3 mg, 0.38 mmol), and BrettPhos Pd G3 (22.8 mg, 0.025 mmol) in 1,4-dioxane was stirred at 110 °C for 12 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 25% B to 42% B in 9 min, 42% B; wavelength: 254 / 220 nm, RT1 (min): 8.97) to give Example 84 (12.5 mg, 11%). LCMS (ESI) m / z: 456.00 [M+H] + .

[0536] Example 85: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(piperazin-1-yl)benzonitrile TIFF2025524039000231.tif41128

[0537] The title compound was prepared using the following procedure. TIFF2025524039000232.tif45158

[0538] To a stirred solution of Intermediate 6 (300 mg, 0.79 mmol) in DMSO (10 mL) were added CsF (838 mg, 5.52 mmol), TBAB (25.4 mg, 0.079 mmol), and piperazine (135.7 mg, 1.58 mmol) portionwise at room temperature. The resulting mixture was stirred at 120 °C for 2 h under nitrogen. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% - 40% in 20 min; detector, UV 254 nm to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(piperazin-1-yl)benzonitrile (240 mg, 71%) as a yellowish brown solid.

[0539] To a stirred solution of 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(piperazin-1-yl)benzonitrile (200 mg, 0.46 mmol) in dioxane (4 mL) and H2O (1 mL) were added K2CO3 (192.7 mg, 1.39 mmol), 6-fluoropyridin-3-ylboronic acid (98.2 mg, 0.7 mmol), and Pd(dppf)Cl2 (34 mg, 0.047 mmol) portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 30% - 50% in 25 min; detector, UV 254 nm to give a brown oil as the crude product. The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 6% B to 23% B in 9 min, 23% B; wavelength: 254 / 220 nm, RT1 (min): 15.72) to give Example 85 (56.3 mg, 27%). LCMS (ESI) m / z: 447.35 [M+H] + .

[0540] Examples 90 and 91: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-((1-methylpyrrolidin-3-yl)oxy)benzonitrile (isomers A and B) TIFF2025524039000233.tif57128

[0541] The title compound was prepared using the following procedure. TIFF2025524039000234.tif113137

[0542] A solution of intermediate 6 (1 g, 2.63 mmol), TBAB (0.08 g, 0.26 mmol), and CsF (3.99 g, 26.3 mmol) in DMSO (5 mL) was stirred at 120 °C overnight. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 10 minutes; detector, UV 254 nm to give 3-bromo-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 52%) as a yellow oil.

[0543] A solution of 5-bromo-2-fluorobenzonitrile (200 mg, 1 mmol), 1-methylpyrrolidin-3-ol (61.1 mg, 0.6 mmol) and NaH (26.4 mg, 1.1 mmol) in THF (6 mL) was stirred at 0 °C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was filtered and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient of 10% - 50% in 10 min, detector, UV 254 nm to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]benzonitrile (190 mg, 78%) as a yellow solid.

[0544] A solution of 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(pyrrolidin-3-yloxy)benzonitrile (100 mg, 0.23 mmol) and Pd(dppf)Cl2CH2Cl2 (18.9 mg, 0.023 mmol) in dioxane (10 mL) was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), gradient from 10% to 50% in 10 minutes; detector, UV 254 nm. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: from 12% B to 30% B in 10 minutes; wavelength: 220 nm, RT1 (min): 12.55) to obtain 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-[(1-methylpyrrolidin)-3-yl)oxy]benzonitrile (30 mg) as a white solid. The product was purified by chiral resolution using the following conditions (column: CHIRAL ART Cellulose-SZ, 4.6*50 mm, 3 μm; mobile phase A: Hex(0.1% DEA):EtOH = 50:50; flow rate: 1 mL / min; gradient: uniform concentration; injection volume: 5 ul mL) to obtain Example 90 (6.4 mg, 7%) and Example 91 (7.4 mg, 7%). LCMS(ESI) m / z: 462.40 [M+H] + .

[0545] Example 92: 6-(3-Amino-1H-pyrazol-4-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000235.tif40128

[0546] The title compound was prepared using the following procedure. TIFF2025524039000236.tif76159

[0547] To a stirred mixture of 4-bromo-1H-pyrazol-3-amine (500 mg, 3.09 mmol) and di-tert-butyl dicarbonate (1347.3 mg, 6.17 mmol) in THF (15 mL) was added DMAP (37.7 mg, 0.31 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by adding water (50 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (0% - 10%) to afford tert-butyl 3-amino-4-bromopyrazole-1-carboxylate (500 mg) as a white solid.

[0548] To a stirred mixture of tert-butyl 3-amino-4-bromopyrazole-1-carboxylate (200 mg, 0.76 mmol) and bis(pinacolato)diboron (775.1 mg, 3.05 mmol) in 1,4-dioxane (10 mL), AcOK (224.7 mg, 2.3 mmol) and Pd(dppf)Cl2CH2Cl2 (62.2 mg, 0.076 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOH / CH2Cl2) to give tert-butyl 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (220 mg) as an off-white solid.

[0549] To a stirred mixture of tert-butyl 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (220 mg, 0.71 mmol) and Example 30 (225.9 mg, 0.57 mmol) in dioxane (5 mL) and H2O (1 mL), K2CO3 (295 mg, 2.14 mmol) and Pd(dppf)Cl2CH2Cl2 (52.2 mg, 0.064 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 90 °C for 1.5 h under nitrogen. The residue was purified by silica gel column chromatography eluted with MeOH / CH2Cl2 (0% - 10%) to give tert-butyl 3-amino-4-[2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl]pyrazole-1-carboxylate (317 mg) as a brown solid.

[0550] A mixture of tert-butyl 3-amino-4-[2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl]pyrazole-1-carboxylate (300 mg, 0.55 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 0.5 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 50% in 10 min; detector, UV 254 nm. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient from 4% B to 24% B in 8 min, 24% B; wavelength: 254 / 220 nm, RT1 (min): 11.58; to give Example 92 (25 mg, 6%). LCMS (ESI) m / z: 444.30 [M + H] + .

[0551] Example 93: 3-(Imidazo[1,2-a]pyrimidin-6-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000237.tif37128

[0552] The title compound was prepared using the following procedure. TIFF2025524039000238.tif77128

[0553] To a stirred solution of 6-bromoimidazo[1,2-a]pyrimidine (50 mg, 0.25 mmol) in 1,4-dioxane (5 mL) were added bis(pinacolato)diboron (96.2 mg, 0.38 mmol), Pd(dppf)Cl2CH2Cl2 (20.6 mg, 0.025 mmol), and AcOK (74.3 mg, 0.76 mmol) portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The resulting mixture was evaporated under vacuum and used directly in the next step without further purification.

[0554] To a stirred mixture of Intermediate 1 (50 mg, 0.14 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyrimidine (35.5 mg, 0.14 mmol) in H2O (0.5 mL) were added K2CO3 (60 mg, 0.42 mmol) and Pd(dppf)Cl2CH2Cl2 (11.8 mg, 0.014 mmol) portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 4% B to 24% B in 8 min; wavelength: 254 / 220 nm, RT1 (min): 11.58) to give Example 93 (43 mg, 77%). LCMS (ESI) m / z: 385.10 [M + H] + .

[0555] Example 95: 3-(6-Fluoropyridin-3-yl)-6-(3-hydroxyazetidin-1-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000239.tif41128

[0556] The title compound was prepared using the following procedure. TIFF2025524039000240.tif31159

[0557] A mixture of Example 30 (200 mg, 0.5 mmol) and Cs2CO3 (328.4 mg, 1 mmol) in dioxane (5 mL) was stirred at room temperature for 5 minutes. To the above mixture, Pd-PEPPSI-IPentCl 3-chloropyridine (49 mg, 0.05 mmol) and 3-[(tert-butyldimethylsilyl)oxy]azetidine (188.8 mg, 1 mmol) were added. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (400 mL). The combined organic layers were washed with brine (400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (196 mg, 71%) as a brown solid. LCMS (ESI) m / z: 548 [M+H] + .

[0558] To a vial were added 6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (160 mg, 0.29 mmol) and tetrabutylammonium fluoride trihydrate (184.3 mg, 0.58 mmol) in THF (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (300 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B - 28% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 12.62) to obtain Example 95 (14.7 mg, 11%). LCMS (ESI) m / z: 434.05 [M+H] + .

[0559] Example 97: 6-Acetyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000241.tif40128

[0560] The title compound was prepared using the following procedure. TIFF2025524039000242.tif39159

[0561] To a vial were added Example 30 (320 mg, 0.81 mmol), DMF (5 mL), PdAMPHOS (57.1 mg, 0.081 mmol), and tributyl(1-ethoxyethenyl)stannane (436.8 mg, 1.21 mmol). The resulting mixture was stirred at 130 °C for 2 h. The reaction was quenched with water and extracted with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 6-(1-ethoxyethenyl)-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg, 92%) as a brown solid. LCMS (ESI) m / z: 433 [M+H] + .

[0562] To a vial were added 6-(1-ethoxyethenyl)-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg, 0.69 mmol), TFA (1.2 mL), and DCM (12 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 10% B to 30% B in 7 min; wavelength: 254 / 220 nm, RT1 (min): 6.92) to give Example 97 (85.5 mg, 30%). LCMS (ESI) m / z: 405.20 [M+H] + .

[0563] Example 100: 5-(6-Fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)isophthalonitrile TIFF2025524039000243.tif40128

[0564] The title compound was prepared using the following procedure. TIFF2025524039000244.tif43128

[0565] To a stirred solution of intermediate 17 (200 mg, 0.61 mmol) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (253.7 mg, 1.84 mmol), 6-fluoropyridin-3-ylboronic acid (172.5 mg, 1.22 mmol) and Pd(dppf)Cl2 (44.8 mg, 0.061 mmol) portionwise at room temperature under an atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (8:1) and then repurified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9% B to 25% B in 10 min; wavelength: 254 nm / 220 nm, RT1 (min): 12.78) to give Example 100 (19.3 mg, 8%). LCMS (ESI) m / z: 388.25 [M+H] + .

[0566] Example 101: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(methylsulfonyl)benzonitrile TIFF2025524039000245.tif43128

[0567] The title compound was prepared using the following procedure. TIFF2025524039000246.tif43128

[0568] To a stirred solution of Intermediate 18 (160 mg, 0.42 mmol) in dioxane (6 mL) and H2O (1.5 mL), K2CO3 (174.6 mg, 1.26 mmol), 6-fluoropyridin-3-ylboronic acid (71.2 mg, 0.5 mmol) and Pd(dppf)Cl2 (30.8 mg, 0.042 mmol) were added portionwise at room temperature under an atmosphere. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) and further purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 9% B to 25% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 12.78) to give Example 101 (69.6 mg, 37%). LCMS (ESI) m / z: 441.00 [M+H] + .

[0569] Example 105: 5-(6-Fluoropyridin-3-yl)-6-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-1H-indazole-7-carbonitrile TIFF2025524039000247.tif40128

[0570] The title compound was prepared using the following procedure. TIFF2025524039000248.tif42128

[0571] In 1,4-dioxane (8 mL) and H2O (2 mL), a solution of intermediate 19 (50 mg, 0.13 mmol), 6-fluoropyridin-3-ylboronic acid (21.9 mg, 0.15 mmol), K2CO3 (53.7 mg, 0.39 mmol), and Pd(dppf)Cl2 (9.5 mg, 0.013 mmol) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 11% B to 28% B in 10 min; wavelength: 254 nm / 220 nm, RT1 (min): 12.65) to obtain Example 105 (0.9 mg, 2%). LCMS (ESI) m / z: 403.50 [M+H] + .

[0572] Example 106: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile TIFF2025524039000249.tif34128

[0573] The title compound was prepared using the following procedure. TIFF2025524039000250.tif43128

[0574] To a stirred mixture of intermediate 20 (60 mg, 0.17 mmol) and 6-fluoropyridin-3-ylboronic acid (29.2 mg, 0.21 mmol) in H2O (1 mL) and 1,4-dioxane (4 mL), K2CO3 (47.8 mg, 0.35 mmol) and Pd(dppf)Cl2CH2Cl2 (14.1 mg, 0.017 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 90 °C for 2 h under nitrogen. The residue was purified by preparative TLC (10% MeOH / CH2Cl2) and further purified by preparative HPLC using the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 10% B to 30% B in 10 min; wavelength: 254 nm / 220 nm, RT1 (min): 11.68) to give Example 106 (10 mg, 16%). LCMS (ESI) m / z: 364.05 [M+H] + .

[0575] Example 107: 4-Fluoro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000251.tif35128

[0576] The title compound was prepared using the following procedure. TIFF2025524039000252.tif42158

[0577] To a stirred mixture of intermediate 21 (200 mg, 0.49 mmol) and 6-fluoropyridin-3-ylboronic acid (102.9 mg, 0.73 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL), K2CO3 (135 mg, 0.97 mmol) and Pd(dppf)Cl2 (35.6 mg, 0.049 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was quenched by adding water (30 mL) at room temperature and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, water (10 mmol / L NH4HCO3) in MeCN, gradient from 10% to 50% in 10 minutes; detector, UV 254 nm, and then purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: from 15% B to 45% B in 8 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 9.77) to obtain 4-chloro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile as a white solid.

[0578] A stirred mixture of 4-chloro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (25 mg, 0.059 mmol) and CsF (89 mg, 0.59 mmol) in DMSO (10 mL) was added portionwise with TBAB (2 mg, 0.006 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 4 h. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: from 15% B to 35% B in 10 min; wavelength: 254 nm / 220 nm, RT1 (min): 12.1) to give Example 107 (5 mg, 20%). LCMS (ESI) m / z: 411.25 [M+H] + .

[0579] Example 108: 3-(6-Fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(oxetan-3-yl)benzonitrile TIFF2025524039000253.tif38128

[0580] The title compound was prepared using the following procedure. TIFF2025524039000254.tif35159

[0581] To a stirred mixture of Example 30 (70 mg, 0.18 mmol) and 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2-dioxaborolane (64.9 mg, 0.35 mmol) in DMF (3 mL), 4,4'-di-tert-butyl-2,2'-bipyridine; bis[3,5-difluoro-2-(5-methylpyridin-2-yl)phenyl]iridium(III) hexafluorophosphate(V) (3.6 mg, 0.004 mmol), 1-methoxy-2-(2-methoxyethoxy)ethane, dibromonickel(II) (3.1 mg, 0.009 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.4 mg, 0.009 mmol) and morpholine (30.7 mg, 0.35 mmol) were added portionwise at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere under blue-ray conditions. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: YMC-Actus Triart C18 ExRS, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 17% B to 34% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 11.63) to give Example 108 (2.4 mg, 3%). LCMS (ESI) m / z: 419.20 [M + H] + .

[0582] Example 113: 3-(3-Hydroxy-1H-indazol-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000255.tif38128

[0583] The title compound was prepared using the following procedure. TIFF2025524039000256.tif71159

[0584] To a stirred mixture of 5-bromo-1,2-dihydro-3H-indazol-3-one (2.0 g, 9.4 mmol), K2CO3 (3.9 g, 28.2 mmol), and 4-methoxybenzyl chloride (2.9 g, 18.8 mmol) in DME (20 mL) and DMF (20 mL), lithium bromide (2.5 g, 28.2 mmol) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (2:3) to give 5-bromo-1,2-bis(4-methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (1.5 g, 48%) as a white solid.

[0585] To a stirred mixture of 5-bromo-1,2-bis(4-methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (1.5 g, 3.3 mmol) and bis(pinacolato)diboron (1.3 g, 5.0 mmol) in dioxane (15 mL), Pd(dppf)Cl2 (0.2 g, 0.3 mmol) and KOAc (1.0 g, 10.0 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under nitrogen. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel, mobile phase, 10% MeCN in water (10 mmol / L NH4HCO3) to give (1,2-bis(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl)boronic acid (492 mg, 29%) as a brown viscous oil.

[0586] To a stirred mixture of Intermediate 1 (291 mg, 0.8 mmol) and (1,2-bis(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl)boronic acid (490.1 mg, 1.0 mmol) in dioxane (15 mL) and H2O (1.7 mL), Pd(dppf)Cl2 (61.5 mg, 0.1 mmol) and K2CO3 (348.5 mg, 2.5 mmol) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeOH in water (0.1% FA), gradient of 10% to 50% in 10 minutes, detector, UV 254 nm to give 3-{1,2-bis[(p-methoxyphenyl)methyl]-3-oxo-1,2-dihydro-3H-indazol-5-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1-piperidyl]benzonitrile (225 mg, 42%) as a pale yellow solid.

[0587] A solution of 3-{1,2-bis[(p-methoxyphenyl)methyl]-3-oxo-1,2-dihydro-3H-indazol-5-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1-piperidyl]benzonitrile (225 mg, 0.4 mmol) in TFA (10 mL) was stirred at 70 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 13% B to 31% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 6.81) to give Example 113 (14.3 mg, 6%). LCMS (ESI) m / z: 400.20 [M+H] + .

[0588] Example 117: (5-(3-Cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-yl)boronic acid TIFF2025524039000257.tif37128

[0589] The title compound was prepared using the following procedure. TIFF2025524039000258.tif39128

[0590] To a stirred mixture of Example 115 (90 mg, 0.24 mmol) and bis(pinacolato)diboron (72.4 mg, 0.28 mmol) in dioxane (2 mL), XPhos Pd G3 (20.1 mg, 0.02 mmol) and KOAc (69.9 mg, 0.71 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C for 4 hours under nitrogen. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 2% B to 17% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 13.8) to give Example 117 (11.2 mg, 12%). LCMS (ESI) m / z: 389.15 [M+H] + .

[0591] Example 118: 5-(3-Cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-ylsulfurofluoridate TIFF2025524039000259.tif35128

[0592] The title compound was prepared using the following procedure. TIFF2025524039000260.tif36128

[0593] To a stirred solution of Example 120 (50 mg, 0.14 mmol) in anhydrous ACN (5 mL), DIEA (35.9 mg, 0.28 mmol) was added at room temperature under a sulfonyl fluoride atmosphere. The reaction mixture was stirred at room temperature for a period of 2 hours. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 19% B to 37% B in 10 minutes; wavelength: 254 nm / 220 nm, RT1 (min): 12.63) to obtain Example 118 (3.1 mg, 5%). LCMS (ESI) m / z: 443.20 [M+H] + .

[0594] Example 121: 3-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile TIFF2025524039000261.tif35128

[0595] The title compound was prepared using the following procedure. TIFF2025524039000262.tif86159

[0596] To a stirred mixture of intermediate 1 (200 mg, 0.58 mmol) and 3-chloro-4-formylboronic acid (127.8 mg, 0.69 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (159.7 mg, 1.16 mmol) and Pd(dppf)Cl2CH2Cl2 (47.1 mg, 0.058 mmol) were added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 2 h under nitrogen. The reaction was quenched by adding water (2 mL) at room temperature and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 3'-chloro-4'-formyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-carbonitrile (120 mg, 51%) as a brown solid.

[0597] To a stirred solution of 3'-chloro-4'-formyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-carbonitrile (100 mg, 0.25 mmol) in anhydrous 1,4-dioxane (5 mL) were added bis(pinacolato)diboron (75.1 mg, 0.3 mmol) and potassium trifluoroacetate (15 mg, 0.098 mmol), followed by the addition of a catalytic amount of SPhos Pd Gen.3 (19.2 mg, 0.025 mmol) and SPhos (10.1 mg, 0.025 mmol) at room temperature. The reaction mixture was stirred at 65 °C overnight. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give 3'-cyano-4-formyl-2'-[4-(4-methyl-1,2,4-triazo...

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof: Wherein, W １ is N or CR １ where W ２ is N or CR ２ where W ３ is N or CR ３ where W １ W ２ and W ３ at most one of which is N X １ and X ２ are each independently selected from CR ４ and N, Ring Y is of formula (a): or Ring Y wherein Y １ , Y ２ , Y ３ , and Y ４ are independently selected from CR ５ and N, and Y １ , Y ２ , Y ３ , and Y ４ are not simultaneously N, is of formula (b): or Ring Y is of formula (c): wherein, Y １ is CR ５ and Y ２ is NR ５’ and or Ring Y is of formula (c): wherein A, B, and E are independently selected from C, N, O, and S, D is C or N, wherein, Y １ , Y ２ , Y ３ , and Y ４ are each independently selected from CR ５ and N, Optionally, Y １ and Y ２ or Y ２ and Y ３ or Y ３ and Y ４ any one of which represents a fused ring selected from C ５ to C ８ -cycloalkyl, C ６ to C １０ -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, B, O, and S), and the ring is C １ to C ６ -alkyl, C ３ to C ８ -cycloalkyl, 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), C ２ to C ６ -alkenyl, C ２ to C ６ -alkynyl, halo, C １ to C ６ -haloalkyl, C ２ to C ６ -haloalkenyl, C ２ to C ６ -haloalkynyl, oxo, thioxo, cyano, nitro, -R ｂ -OR ａ , -R ｂ -OC(O)-R ａ , -R ｂ -OC(O)-OR ａ , -R ｂ -OC(O)-N(R ａ ) ２ , -R ｂ -N(R ａ ) ２ , -R ｂ -OR ａ (N(R ａ ) ２ ), -R ｂ -C(O)R ａ , -R ｂ -C(O)OR ａ , -R ｂ -C(O)N(R ａ ) ２ , -R ｂ -O-R ｃ -C(O)N(R ａ ) ２ , -R ｂ -N(R ａ ) C(O)OR ａ , -R ｂ -N(R ａ ) C(O)R ａ , -R ｂ -N(R ａ ) S (O) ｔ R ａ (wherein t is 1 or 2); -R ｂ -S (O) ｔ R ａ (wherein t is 1 or 2); -R ｂ -S (O) ｔ OR ａ (wherein t is 1 or 2) and -R ｂ -S (O) ｔ N (R ａ ) ２ wherein t is 1 or 2; here, here, no more than two of A, B, D, and E are simultaneously N, O, or S. wherein the ring A-B-D-E-N is aromatic and C １ ~C ３ -alkyl, C ３ ~C ５ -cycloalkyl, OH, OMe, NH ２ , N(H)Me, NMe ２ and may be substituted with one or two substituents independently selected therefrom, representing the presence of a double bond,

2. R １ 、R ２ 、and R ３ are each, independently, hydrogen, halo, cyano, nitro, -R ｂ -OR ａ 、-R ｂ -O-R ｃ -O-R ａ 、-R ｂ -OC(O)-R ａ 、-R ｂ -OC(O)-OR ａ 、-R ｂ -OC(O)-N(R ａ ) ２ 、-R ｂ -N(R ａ ) ２ 、-R ｂ -C(O)R ａ 、-R ｂ -C(O)OR ａ 、-R ｂ -C(O)N(R ａ ) ２ 、-R ｂ -O-R ｃ -C(O)N(R ａ ) ２ 、-R ｂ -O-R ｃ -N(R ａ ) ２ 、-R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ 、-R ｂ -N(R ａ )C(O)OR ａ 、-R ｂ -N(R ａ )C(O)R ａ 、-R ｂ -N(R ａ )S(O) ｔ R ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ R ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (wherein t is 1 or 2), C １ ~C ６ -alkyl, C １ ~C ６ -haloalkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C ３ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, -(C １ ~C ６ -alkyl)(C ６ ~C １０ -aryl), optionally a 5- to 10-membered heteroaryl fused to a 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S) (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and a 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), selected from the group consisting of or R １ and R ２ or R ２ and R ３ is, together with the carbon atom to which they are attached, fused C ５ to C ８ -cycloalkyl, C ６ to C １０ -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S) to form, R １ 、 R ２ 、 and R ３ any heteroaryl or heterocycloalkyl in is, independently, C １ ~C ６ -alkyl, halo, hydroxy, C ３ ~C ８ -cycloalkyl, heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and -R ｂ -N(R ａ ) ２ and may be substituted with 1 to 3 substituents selected from the group consisting of: R in each case ４ is independently H, OH, halo, C １ ~C ６ -alkyl, or C １ ~C ６ -alkoxy, and R in each case ５ independently is hydrogen, halo, cyano, nitro, -R ｂ -OR ａ -R ｂ -O-R ｃ -OR ａ -R ｂ -OC(O)-R ａ -R ｂ -OC(O)-OR ａ -R ｂ -OC(O)-N(R ａ ) ２ -R ｂ -N(R ａ ) ２ -R ｂ -C(O)R ａ -R ｂ -C(O)OR ａ -R ｂ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -N(R ａ ) ２ -B(OR ａ ) ２ -R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )C(O)OR ａ -R ｂ -N(R ａ )C(O)R ａ -R ｂ -N(R ａ )S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (where t is 1 or 2), -R ｂ -OS(O) ｔ F (where t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (where t is 1 or 2), C １ ~C ６ -alkyl, C ２ ~C ６ -alkynyl, C ３ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), selected from the group consisting of R ５’ is hydrogen, -R ｃ -R ａ -R ｃ -OR ａ -R ｂ -OC(O)-R ａ -R ｂ -OC(O)-OR ａ -R ｂ -OC(O)-N(R ａ ) ２ -R ｃ -N(R ａ ) ２ -R ｂ -C(O)R ａ -R ｂ -C(O)OR ａ -R ｂ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )C(O)OR ａ -R ｂ -N(R ａ )C(O)R ａ -R ｂ -N(R ａ )S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (where t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (where t is 1 or 2), C １ ~C ６ -alkyl, C ３ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, 5- to 10-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), selected from the group consisting of R ５ and R ５’ wherein any heteroaryl or heterocycloalkyl in R １ to C ６ -alkyl, halo, hydroxy, C ３ to C ８ -cycloalkyl, and -R ｂ -N(R ａ ) ２ may be substituted with 1 to 3 substituents selected from the group consisting of R ６ａ 、 R ６ｂ 、 R ６ｃ 、 R ６ｄ 、 R ６ｅ 、 R ６ｆ 、 R ６ｇ 、 and R ６ｈ are, independently, H, halo, NO ２ 、 OH, CN, -R ｂ -N(R ａ ) ２ 、 -R ｂ -OH, C １ ~C ６ -alkyl, and C １ ~C ６ -alkoxy, and are selected from the group consisting of and / or, optionally, R ６ａ and R ６ｂ or R ６ｃ and R ６ｄ or R ６ｅ and R ６ｆ or R ６ｇ and R ６ｈ are each independently oxo, thioxo, imino, or oximo, and / or, optionally, R ６ａ and R ６ｂ or R ６ｃ and R ６ｄ or R ６ｅ and R ６ｆ or R ６ｇ and R ６ｈ and, together with the carbon atoms to which they are attached, independently bond to form a fused ring selected from C ３ to C ６ -cycloalkyl and C ３ to C ６ -heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and / or, optionally, R ６ｃ and R ６ｄ one of which is R ６ｅ and R ６ｆ together with one of them represents the bond between the ring carbon members to which they are attached, R in each case ａ is independently selected from hydrogen, C １ to C ６ -alkyl, C ３ to C ８ -cycloalkyl, -(C １ to C ６ -alkyl)(C ３ to C ８ -cycloalkyl), C ６ to C １０ -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S). R in each example ｂ is independently selected from direct bond, linear or branched C ２ to C ６ -alkylene, and C ２ to C ６ -alkenylene chain, and any heteroaryl or heterocycloalkyl in R ａ and R ｂ may be independently substituted with 1 to 3 substituents selected from the group consisting of C １ to C ６ -alkyl, halo, and hydroxy, R in each case ｃ is independently selected from linear or branched C ２ to C ６ -alkylene and C ２ to C ６ -alkenylene chains. The compound is of formula (I): wherein, Ring Y is of formula (a): X １ and X ２ are each independently selected from CR ４ and N, or Ring Y is of formula (b): wherein A, B, and E are independently selected from C, N, O, and S, D is C or N, wherein Y １ , Y ２ , Y ３ , and Y ４ are, independently, selected from CR ５ and N, and Y １ , Y ２ , Y ３ , and Y ４ are not simultaneously N here, here, no more than two of A, B, D, and E are simultaneously N, O, or S. The compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof. In the formula, Y １ is CR ５ and Y ２ is NR ５’ and Optionally, Y １ and Y ２ or Y ２ and Y ３ or Y ３ and Y ４ any one of which represents a fused ring selected from C ５ to C ８ -cycloalkyl, C ６ to C １０ -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and the ring is C １ to C ６ -alkyl, C ３ to C ８ -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), C ２ to C ６ -alkenyl, C ２ to C ６ -alkynyl, halo, C １ to C ６ -haloalkyl, C ２ to C ６ -haloalkenyl, C ２ to C ６ -haloalkynyl, oxo, thioxo, cyano, nitro, -R ｂ -OR ａ , -R ｂ -OC(O)-R ａ , -R ｂ -OC(O)-OR ａ , -R ｂ -OC(O)-N(R ａ ) ２ , -R ｂ -N(R ａ ) ２ , -R ｂ -OR ａ (N(R ａ ) ２ ), -R ｂ -C(O)R ａ , -R ｂ -C(O)OR ａ , -R ｂ -C(O)N(R ａ ), -R ２ -O-R ｂ -C(O)N(R ｃ ), -R ａ ), -R ２ -N(R ｂ )(C(O)OR ａ ), -R ａ -N(R ｂ )(C(O)R ａ ), -R ａ -N(R ｂ )(S(O) ａ )R ｔ (where t is 1 or 2), -R ａ -S(O) ｂ )R ｔ (where t is 1 or 2), -R ａ -S(O) ｂ )OR ｔ (where t is 1 or 2), and -R ａ -S(O) ｂ )N(R ｔ )( ａ ) ２ (where t is 1 or 2), and may be substituted with 1 to 3 substituents independently selected from the group consisting of:

3.

4. wherein the ring A-B-D-E-N is aromatic and C １ to C ３ -alkyl, C ３ to C ５ -cycloalkyl, OH, OMe, NH ２ , N(H)Me, NMe ２ and which may be substituted with one or two substituents independently selected from, representing the presence of a double bond

5. R １ 、R ２ 、and R ３ are each independently hydrogen, halo, cyano, nitro, -R ｂ -OR ａ 、-R ｂ -O-R ａ 、-R ｂ -OC(O)-R ａ 、-R ｂ -OC(O)-OR ａ 、-R ｂ -OC(O)-N(R ａ ) ２ 、-R ｂ -N(R ａ ) ２ 、-R ｂ -C(O)R ａ 、-R ｂ -C(O)OR ａ 、-R ｂ -C(O)N(R ａ ) ２ 、-R ｂ -O-R ｃ -C(O)N(R ａ ) ２ 、-R ｂ -O-R ｃ -N(R ａ ) ２ 、-R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ 、-R ｂ -N(R ａ )C(O)OR ａ 、-R ｂ -N(R ａ )C(O)R ａ 、-R ｂ -N(R ａ )S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (where t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (wherein t is 1 or 2), C １ ~C ６ -alkyl, C ３ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, -(C １ ~C ６ -alkyl)(C ６ ~C １０ -aryl), a 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and a 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and is selected from the group consisting of or R １ and R ２ , or R ２ and R ３ is, together with the carbon atom to which they are attached, fused C ５ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S) to form, R in each case ４ is, independently, H, -OH, halo, C １ ~C ６ -alkyl, or C １ ~C ６ -alkoxy, and R in each case ５ is independently hydrogen, halo, cyano, nitro, -R ｂ -OR ａ -R ｂ -O-R ｃ -OR ａ -R ｂ -OC(O)-R ａ -R ｂ -OC(O)-OR ａ -R ｂ -OC(O)-N(R ａ ) ２ -R ｂ -N(R ａ ) ２ -R ｂ -C(O)R ａ -R ｂ -C(O)OR ａ -R ｂ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )C(O)OR ａ -R ｂ -N(R ａ )C(O)R ａ -R ｂ -N(R ａ )S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ R ａ (where t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (where t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (wherein t is 1 or 2), C １ ~ C ６ - alkyl, C ３ ~ C ８ - cycloalkyl, C ６ ~ C １０ - aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and is selected from the group consisting of R ５’ is hydrogen, -R ｃ -R ａ -R ｃ -OR ａ -R ｂ -OC(O)-R ａ -R ｂ -OC(O)-OR ａ -R ｂ -OC(O)-N(R ａ ) ２ -R ｃ -N(R ａ ) ２ -R ｂ -C(O)R ａ -R ｂ -C(O)OR ａ -R ｂ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -C(O)N(R ａ ) ２ -R ｂ -O-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )-R ｃ -N(R ａ ) ２ -R ｂ -N(R ａ )C(O)OR ａ -R ｂ -N(R ａ )C(O)R ａ -R ｂ -N(R ａ )S(O) ｔ R ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ R ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ OR ａ (wherein t is 1 or 2), -R ｂ -S(O) ｔ N(R ａ ) ２ (wherein t is 1 or 2), C １ ~C ６ -alkyl, C ３ ~C ８ -cycloalkyl, C ６ ~C １０ -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), selected from the group consisting of R ６ａ 、 R ６ｂ 、 R ６ｃ 、 R ６ｄ 、 R ６ｅ 、 R ６ｆ 、 R ６ｇ 、 and R ６ｈ are, independently, H, halo, NO ２ 、 OH, CN, -R ｂ -N(R ａ ) ２ 、 -R ｂ -OH, C １ ~C ６ -alkyl, and C １ ~C ６ -alkoxy, and are selected from the group consisting of or, optionally, R ６ａ and R ６ｂ or R ６ｃ and R ６ｄ or R ６ｅ and R ６ｆ or R ６ｇ and R ６ｈ are each independently oxo, thioxo, imino, or oximo, Or, optionally, R ６ａ and R ６ｂ or R ６ｃ and R ６ｄ or R ６ｅ and R ６ｆ or R ６ｇ and R ６ｈ together with the carbon atom to which they are attached independently form a fused ring selected from C ３ to C ６ -cycloalkyl and C ３ to C ６ -heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), R in each case ａ is independently hydrogen, C １ to C ６ -alkyl, C ３ to C ８ -cycloalkyl, C ６ to C １０ -aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), and is selected from R in each case ｂ is independently selected from direct bond, linear or branched C ２ ~C ６ -alkylene, and C ２ ~C ６ -alkenylene chains, R in each case ｃ is independently a linear or branched C ２ to C ６ -alkylene and C ２ to C ６ -alkenylene chain selected from,

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt and / or solvate thereof, wherein D is C. W １ is N, and W ２ is CR ２ and W ３ is CR ３ is a compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof.

7. W １ is CR １ and W ２ is CR ２ and W ３ is N, the compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt and / or solvate thereof, wherein A, B, and E are independently selected from C and N. W １ is CR １ and W ２ is CR ２ and W ３ is CR ３ is the compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt and / or solvate thereof, wherein at least one of A, B, and E is N.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt and / or solvate thereof, wherein two of A, B, and E are N.

10. The A-B-D-E-N ring is The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt and / or solvate thereof, which is an optionally substituted ring selected from the group consisting of

11. The optionally substituted A-B-D-E-N ring is The compound according to any one of claims 1 to 5 or 10, or a pharmaceutically acceptable salt and / or solvate thereof, which is selected from the group consisting of

12. The optionally substituted A-B-D-E-N ring is The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt and / or solvate thereof, which is

13. ​ ​ ​ ​ The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 12, wherein the ring Y is of formula (a).

14. Y １ , Y ２ , Y ３ , and Y ４ One of the three is N and each of the remaining three is CR ５ 14. The compound according to any one of claims 1 to 13, wherein:

15. Y １ 、 Y ２ 、 Y ３ each of which is CR ５ and Y ４ is N, the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt and / or solvate thereof.

16. Y １ and Y ２ each of which is CH, and Y ３ is CF, the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt and / or solvate thereof.

17. Y １ 、Y ２ 、Y ３ 、and Y ４ where two of Y, Y, Y, and Y are N and each of the remaining two is CR ５ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or solvate thereof.

18. Y １ and Y ２ each of which is CR ５ where Y ３ and Y ４ each of which is N, a compound according to any one of claims 1 to 13 and 17 or a pharmaceutically acceptable salt and / or solvate thereof.

19. Y １ and Y ２ or Y ３ and Y ４ The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 13, wherein any one of them represents a condensed ring which may be substituted.

20. Y １ and Y ２ or Y ３ and Y ４ wherein any one of and Y is an optionally substituted fused 5- or 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S) or 5- or 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), a compound according to any one of claims 1 to 13 and 19, or a pharmaceutically acceptable salt and / or solvate thereof.

21. X １ and X ２ The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt and / or solvate thereof, wherein one or each of １ and ２ is N.

22. X １ and X ２ each of which is N, a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt and / or solvate thereof.

23. X １ is N, and X ２ is CR ４ is a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt and / or solvate thereof.

24. R ４ The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 23, wherein R is H.

25. R １ is H, halo, C １ to C ６ -alkoxy, C ６ to C １０ -aryl, C ３ to C ８ -cycloalkyl, 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and 5- to 6-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and the compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 24.

26. R ２ and R ３ each independently is H, halo, cyano, CH ３ or CF ３ and the compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 25.

27. R ６ａ 、 R ６ｂ 、 R ６ｃ 、 R ６ｄ 、 R ６ｅ 、 R ６ｆ 、 R ６ｇ 、 and R ６ｈ are, independently, H, halo, C １ ~C ６ -alkyl and C １ ~C ６ -alkoxy, and the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt and / or solvate thereof.

28. R ６ａ 、R ６ｂ 、R ６ｃ 、R ６ｄ 、R ６ｅ 、R ６ｆ 、R ６ｇ 、and R ６ｈ each of which is H, a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt and / or solvate thereof.

29. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 or 2, wherein the compound is a compound of formula (IA):

30. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1 or 2, wherein the compound is a compound of formula (IB):

31. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1, wherein the compound is a compound of formula (IC):

32. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1, wherein the compound is a compound of formula (ID):

33. R １ is H, halo, C １ ~C ６ -alkoxy, C ６ ~C １０ -aryl, C ３ ~C ６ -cycloalkyl, 5- to 6-membered heteroaryl (where 1 to 4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (where 1 to 4 ring members are independently selected from N, O, and S), and is selected from the group consisting of R ２ and R ３ each, if present, independently is H, F, cyano, CH ３ , or CF ３ is The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 29 to 32.

34. Y １ 、Y ２ 、Y ３ 、and Y ４ wherein one of them is N and each of the remaining three is CR ５ The compound according to any one of claims 29 to 33, or a pharmaceutically acceptable salt and / or solvate thereof.

35. Y １ and Y ２ each of which is CH, and Y ３ is CF, the compound according to any one of claims 29 to 34, or a pharmaceutically acceptable salt and / or solvate thereof.

36. Y １ 、Y ２ 、Y ３ 、and Y ４ wherein two of Y ５ are N and each of the remaining two is CR and a pharmaceutically acceptable salt and / or solvate thereof, according to any one of claims 29 to 33.

37. Y １ 、Y ２ 、Y ３ 、and Y ４ The ring containing Y, The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 29 to 33.

38. Y １ , Y ２ , Y ３ , and Y ４ the said ring containing The compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 29 to 33 and 37.

39. The following table: A compound selected therefrom or a pharmaceutically acceptable salt and / or solvate thereof.

40. The following table: A compound selected therefrom or a pharmaceutically acceptable salt and / or solvate thereof.

41. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier.

42. A method of treating a patient suffering from a disease, wherein the disease is associated with the expression of glutaminylpeptide cyclotransferase protein (QPCT) or glutaminylpeptide cyclotransferase-like protein (QPCTL), and the method comprises administering to the patient a compound or a pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 40, said method.

43. The method according to claim 42, wherein the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an opsonizing antibody.

44. The method according to claim 42, wherein the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an immune checkpoint inhibitor.

45. The method according to claim 42, wherein the disease is cancer.

46. The method according to claim 45, wherein the cancer is leukemia or lymphoma.

47. The method according to claim 46, wherein the leukemia or the lymphoma is selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL), Burkitt lymphoma, hairy cell leukemia (HCL), Waldenström macroglobulinemia, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), diffuse large B-cell lymphoma (DLBCL), B-cell chronic lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and precursor B-cell acute lymphoblastic leukemia (pre-B ALL).

48. The method according to claim 45, wherein the cancer is selected from the group consisting of multiple myeloma (MM), ovarian cancer, glioma, colon cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, mesothelioma, melanoma, glioma, glioblastoma, and pancreatic neuroendocrine tumor.

49. The method according to claim 45, wherein the cancer is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, invasive ductal carcinoma, adenocarcinoma, Merkel cell carcinoma, skin cancer, prostate cancer, colorectal cancer, soft tissue sarcoma, osteosarcoma, Ewing sarcoma, chondrosarcoma, and myeloma.

50. The method according to claim 42, wherein the disease is a neurodegenerative disease.

51. The method according to claim 50, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body dementia, and spinal muscular atrophy.

52. The method according to claim 51, wherein the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an antibody that removes amyloid plaques in the brain.

53. The method according to claim 42, wherein the disease is an inflammatory disease or an autoimmune disease.

54. The method according to claim 42, wherein the disease is a cardiovascular disease.

55. The method according to claim 54, wherein the cardiovascular disease is atherosclerosis.

56. A method for inhibiting glutaminyl peptide cyclotransferase (QPCT) or glutaminyl peptide cyclotransferase-like (QPCTL) enzyme, the method comprising contacting the enzyme with a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt and / or solvate thereof.

57. The method according to claim 56, wherein the contact occurs in vitro.

58. The method according to claim 56, wherein the contact occurs in vivo.

59. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt and / or solvate thereof for use in the treatment of cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease.

60. Use of a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt and / or solvate thereof in the manufacture of a medicament for the treatment of cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease.

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