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 HIBITORS FOR THE TREATMENT OF CANCER

Description

BACKGROUND

[0001] Glutaminyl cyclases belong to the family of metal-dependent aminoacyltransferases and catalyze the intramolecular cyclization of peptide or protein N-terminal glutamine or glutamate amino acid residues to pyroglutamate (pE). Glutaminyl cyclases utilize a zinc-dependent catalytic mechanism to form the pyroglutamate residue and liberate ammonia. The pyroglutamate modification is often important for biological activity as it may protect the protein from degradation by proteolytic enzymes or modulate the interactions of the protein with other proteins. (W. Busby et al., J Biol Chem. 262 (18), 8532 (1987); W. Fischer and J Spiess, Pro Natl Acad Sci U.S.A. 84, 3628 (1987); A. Stephan et al., FEBS J. 276, 6522 (2009).

[0002] 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 leads to its retention within the Golgi complex. QPCT and QPCTL share high sequence similarity and structure in the region of their active sites. However, they differ in their cellular distribution and thus convert different substrates leading to distinct physiological roles. QPCT is abundant in the hypothalamus, medulla, and hippocampus, and the majority of the glutaminyl cyclase activity in the brain is mediated by QPCT. QPCTL is more broadly expressed and acts on substrates, such as cytokines, in peripheral cells. (H. Cynis et al., J Mol Bio. 379 (5), 966 (2008); S. Schilling et al., J Biol Chem. 286 (16), 14199 (2011).

[0003] Both QPCT and QPCTL are strongly implicated in disease pathology. For example, QPCT modifies amyloid-beta (Aβ) peptides to yield pE-Aβ. The pE-modification alters the biophysical characteristics of Aβ peptides by increasing their aggregation behavior. pE-Aβ has been shown to be one of the major constituents of Aβ deposits in patients with Alzheimer's disease (AD) and has been reported to trigger neurotoxic events in the pathogenesis of AD (K. Liu et al., Acta Neuropathol. 112 (2), 163 (2006); J. Nussbaum et al., Nature. 485, 7400 (2012) 651). QPCTL catalyzes the formation of pE on the integrin-associated transmembrane protein, CD47, which enhances its interaction with the regulatory membrane glycoprotein, SIRPα. CD47 expression is increased on tumor cells and the CD47-SIRPα interaction provides cancer cells with a phagocytosis checkpoint that enables their escape from immune surveillance (M. Logtenberg et al., Nat Med. 25, 612 (2019); Z. Wu et al., Cell Res. 29, 502 (2019)). QPCTL also catalyzes pE formation on chemotactic cytokines such as CCL2 and related family members, which protect them from proteolytic degradation. CCL2 regulates migration and infiltration of monocytes with a pivotal role in inflammatory conditions. CCL2 also enables recruitment of monocytes to the tumor microenvironment where they become tumor associated macrophages (TAMs) that support the growth and survival of the associated tumor cells (H. Cynis et al., EMBO Mol Med. 3, 545 (2011); R. Barreira da Silva et al., Nat Immun. 23, 568 (2022)).

[0004] WO 2022 / 086920 A1 discloses glutaminyl-peptide cyclotransferase like (QPCTL) inhibitors for the treatment of cancer.

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

[0006] The present disclosure provides in various embodiments a compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof: W 1< is N or CR 1< , W 2< is N or CR 2< , and W 3< is N or CR 3< ; wherein no more than one of W 1< , W 2< , and W 3< is N; X 1< and X 2< are independently selected from CR 4< and N.

[0007] In some embodiments, Ring Y is of formula (a):

[0008] In formula (a), Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR 5< and N wherein Y 1< , Y 2< , Y 3< , and Y 4< are not simultaneously N.

[0009] In other embodiments, Ring Y is of formula (b):

[0010] In formula (b), Y 1< is CR 5< and Y 2< is NR 5'< .

[0011] In still other embodiments, Ring Y is of formula (c):

[0012] In formula (c), Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR 5< and N.

[0013] In some embodiments, either Y 1< and Y 2< , or Y 2< and Y 3< , or Y 3< and Y 4< represent a fused ring selected from a C 5 -C 8 -cycloalkyl, a C 6 -C 10 -aryl, a 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and a 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, B, O, and S), wherein the ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, C 1 -C 6 -haloalkyl, C 2 -C 6 -haloalkenyl, C 2 -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< (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).

[0014] A, B, and E are independently selected from C, N, O, and S, and D is C or N.

[0015] The symbol represents the presence of double bonds such that the ring A-B-D-EN is aromatic and is optionally substituted with one or two substituents independently selected from C 1 -C 3 -alkyl, C 3 -C 5 -cycloalkyl, OH, OMe, NH 2 , N(H)Me, NMe 2 . Further, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0016] R 1< , R 2< , and R 3< are independently selected from the group consisting of 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< (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 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), 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) optionally fused to 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S.

[0017] In some embodiments, R 1< and R 2< , or R 2< and R 3< , together with the carbon atoms to which they are bound, form a fused C 5 -C 8 -cycloalkyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0018] Any heteroaryl or heterocycloalkyl in R 1< , R 2< , and R 3< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy, C 3 -C 8 -cycloalkyl, heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and -R b< -N(R a< ) 2 .

[0019] R 4< in each instance is independently H, OH, halo, C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy.

[0020] R 5< in each instance is independently selected from the group consisting of 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 (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0021] R 5'< is selected from the group consisting of 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 (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0022] Any heteroaryl or heterocycloalkyl in R 5< and R 5'< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy, C 3 -C 8 -cycloalkyl, and -R b< -N(R a< ) 2 .

[0023] 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, NO 2 , OH, CN, -R b< -N(R a< ) 2 , -R b< -OH, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy.

[0024] 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.

[0025] 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 atoms to which they are bound, independently combine to form a fused ring selected from a C 3 -C 6 -cycloalkyl and C 3 -C 6 -heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0026] 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< represent a bond between the ring carbon members to which they are bound.

[0027] R a< in each instance is independently selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, -(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0028] R b< in each instance is independently selected from a direct bond, a straight or branched C 2 -C 6 -alkylene, and C 2 -C 6 -alkenylene chain.

[0029] Any heteroaryl or heterocycloalkyl in R a< and R b< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy,

[0030] R c< in each instance is independently selected from a straight or branched C 2 -C 6 -alkylene and C 2 -C 6 -alkenylene chain.

[0031] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein and a pharmaceutically acceptable carrier.

[0032] The present disclosure also provides, in additional embodiments, cormpounds for use in a method of treating a disease in a patient suffering therefrom, wherein the disease is associated with expression of glutaminyl-peptide cyclotransferase protein (QPCT) or glutaminyl-peptide cyclotransferase-like protein (QPCTL). The method comprises administering to the patient a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein.

[0033] In still another embodiment, the present disclosure provides cormpounds for use in method of inhibiting a glutaminyl-peptide cyclotransferase (QPCT) or glutaminyl-peptide cyclotransferase-like (QPCTL) enzyme. The method comprises contacting the enzyme with a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein.

[0034] In embodiments, the present disclosure provides a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein for use in the treatment of a cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease.

[0035] The present disclosure also provides a use of a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein in the manufacture of a medicament for the treatment of a cancer, neurodegenerative disease, inflammatory disease, or autoimmune disease.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] FIG. 1. X-ray crystal structure of reference compound SEN177 bound to QPCTL. FIG. 2. X-ray crystal structure of Example 1 bound to QPCTL. FIG. 3. Overlay of X-ray crystal structures of QPCTL with SEN177 and Example 1, respectively. DETAILED DESCRIPTION

[0037] The present disclosure provides compounds of formula (I) and formula (II) that are potent inhibitors of the QPCTL and QPCT enzymes. The compounds are useful in the treatment of diseases and conditions that are associated with the expression of QPCTL or QPCT, including various cancers and neurodegenerative diseases.Definitions

[0038] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of" or "consist essentially of" the described features.

[0039] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0040] "Amino" refers to the -NH 2 moiety.

[0041] "Cyano" refers to the -CN moiety.

[0042] "Nitro" refers to the -NO 2 moiety.

[0043] "Oxa" refers to the -O- moiety.

[0044] "Oxo" refers to the =O moiety.

[0045] "Thioxo" refers to the =S moiety.

[0046] "Imino" refers to the =N-H moiety.

[0047] "Oximo" refers to the =N-OH moiety.

[0048] "Hydrazino" refers to the =N-NH 2 moiety.

[0049] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C 1 -C 15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C 1 -C 8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C 1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C 5 -C 8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 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 (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. An alkyl group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF 3 group.

[0050] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0051] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. An alkenyl group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0052] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. An alkynyl group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0053] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C 1 -C 8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C 1 -C 5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C 1 -C 4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C 1 -C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C 1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkylene). An alkylene group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0054] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C 2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkenylene). An alkenylene group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0055] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C 2 -C 8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C 2 -C 5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C 2 -C 4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C 2 -C 3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C 2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., C 5 -C 8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C 3 -C 5 alkynylene). An alkynylene group may be optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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) where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0056] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. For example, aryl is a C 6 -C 10 ring system. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") may include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, 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< (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), where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), 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 where each of the R a< , R b< , or R c< substituents is unsubstituted unless otherwise indicated.

[0057] "Aralkyl" refers to a radical of the formula -R c< -aryl where R c< is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0058] "Aralkenyl" refers to a radical of the formula -R d< -aryl where R d< is an alkenylene chain as defined above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0059] "Aralkynyl" refers to a radical of the formula -R e< -aryl, where R e< is an alkynylene chain as defined above. The aryl part of the aralkynyl radical may be optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0060] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula - O-R c< -aryl where R c< is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical may be optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0061] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A carbocyclyl group may be optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally 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(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), where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), 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 where each of the R a< , R b< , and R c< substituents is unsubstituted unless otherwise indicated.

[0062] "Carbocyclylalkyl" refers to a radical of the formula -R c< -carbocyclyl where R c< is an alkylene chain as defined above. The alkynylene chain and the carbocyclyl radical may be optionally substituted as defined above.

[0063] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-R c< -carbocyclyl where R c< is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical may be optionally substituted as defined above.

[0064] "Halo" or "halogenn" refers to bromo, chloro, fluoro or iodo substituents.

[0065] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0066] "Heterocyclyl" or, equally, "heterocycloalkyl," refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. In embodiments, heterocycloalkyl is a 3- to 6-membered ring (wherein 1-4 ring members are independently selected from N, O, and S), wherein the ring is optionally substituted with 1 to 3 substituents. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest 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. A heterocyclyl group may be optionally substituted by one or more substituents selected from 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< (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), where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), 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 where each of the R a< , R b< , and R c< substituents is unsubstituted unless otherwise indicated.

[0067] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl includes a 5- to 10-membered ring wherein 1-4 heteroaryl members are independently selected from N, O, and S. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[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-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[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-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 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). A heteroaryl group may be optionally substituted by one or more substituents selected from 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< , -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< (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), where each R a< is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (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), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), 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 where each of the R a< , R b< , and R c< substituents is unsubstituted unless otherwise indicated.

[0068] "Heteroarylalkoxy" refers to a radical of the formula -R c< -heteroaryl, where R c< is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group. "Heteroarylalkoxy" alternatively refers to a radical bonded through an oxygen atom of the formula -O-R c< -heteroaryl, where R c< is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical may be optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0069] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, 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 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, such as ortho-, meta-, and para- isomers around a benzene ring.

[0070] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to, and the like.

[0071] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0072] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2< H, 3< H, 11< C, 13< C and / or 14< C. In one embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure 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 a compound, and thereby increase the duration of therapeutic action of the compound.

[0073] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13< C- or 14< C-enriched carbon are within the scope of the present disclosure.

[0074] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 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< I are all 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 encompassed within the scope of the present disclosure.

[0075] In some embodiments, the compounds disclosed herein have some or all of the 1< H atoms replaced with 2< H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0076] Deuterium substituted compounds are synthesized using various methods such as described in: 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.

[0077] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0078] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3 (CD 3 I), are readily available and may be employed to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD 3 I is illustrated, by way of example only, in the reaction schemes below.

[0079] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD 4 ), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD 4 is illustrated, by way of example only, in the reaction schemes below.

[0080] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0081] 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 compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 1< H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0082] With regard to the compounds provided herein, when a particular atom's position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, 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) at each designated deuterium atom. The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0083] The present disclosure describes compounds interchangeably by chemical name and chemical structure. Insofar as any discrepancy might exist between the given chemical name and chemical structure for a compound, the chemical structure controls.

[0084] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Examples of pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0085] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, 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, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0086] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and 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 basic ion exchange resins, for example, 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, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0087] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0088] 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, isotopologue, and / or tautomer thereof. Thus, for instance, 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 isotopologue of the compound.

[0089] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0090] As used herein, "treatment" or "treating," or "palliating" or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, 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 though a diagnosis of this disease has not been made.

[0091] The term "effective amount" refers to an amount of a compound as described herein or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to a compound as described herein means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. Used in connection with a compound as described herein, the term can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of or is synergistic with another therapeutic agent.COMPOUNDS

[0092] The present disclosure provides in various embodiments a compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof:

[0093] W 1< is N or CR 1< , W 2< is N or CR 2< , and W 3< is N or CR 3< ; wherein no more than one of W 1< , W 2< , and W 3< is N.

[0094] X 1< and X 2< are independently selected from CR 4< and N.

[0095] In some embodiments, Ring Y is of formula (a):

[0096] In formula (a), Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR 5< and N wherein Y 1< , Y 2< , Y 3< , and Y 4< are not simultaneously N.

[0097] In other embodiments, Ring Y is of formula (b):

[0098] In formula (b), Y 1< is CR 5< and Y 2< is NR 5'< .

[0099] In still other embodiments, Ring Y is of formula (c):

[0100] In formula (c), Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR 5< and N.

[0101] In some embodiments, either Y 1< and Y 2< , or Y 2< and Y 3< , or Y 3< and Y 4< represent a fused ring selected from a C 5 -C 8 -cycloalkyl, a C 6 -C 10 -aryl, a 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and a 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, B O, and S), wherein the ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, C 1 -C 6 -haloalkyl, C 2 -C 6 -haloalkenyl, C 2 -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< (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).

[0102] A, B, and E are independently selected from C, N, O, and S, and D is C or N.

[0103] The symbol represents the presence of double bonds such that the ring A-B-D-E-N is aromatic and is optionally substituted with one or two substituents independently selected from C 1 -C 3 -alkyl, C 3 -C 5 -cycloalkyl, OH, OMe, NH 2 , N(H)Me, NMe 2 . Further, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0104] R 1< , R 2< , and R 3< are independently selected from the group consisting of 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< (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 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), 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) optionally fused to 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S.

[0105] In some embodiments, R 1< and R 2< , or R 2< and R 3< , together with the carbon atoms to which they are bound, form a fused C 5 -C 8 -cycloalkyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0106] Any heteroaryl or heterocycloalkyl in R 1< , R 2< , and R 3< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy, C 3 -C 8 -cycloalkyl, heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and -R b< -N(R a< ) 2 .

[0107] R 4< in each instance is independently H, OH, halo, C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy.

[0108] R 5< in each instance is independently selected from the group consisting of 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 (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0109] R 5'< is selected from the group consisting of 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 (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0110] Any heteroaryl or heterocycloalkyl in R 5< and R 5'< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy, C 3 -C 8 -cycloalkyl, and -R b< -N(R a< ) 2 .

[0111] 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, NO 2 , OH, CN, -R d< -N(R a< ) 2 , -R b< -OH, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy;

[0112] 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.

[0113] 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 atoms to which they are bound, independently combine to form a fused ring selected from a C 3 -C 6 -cycloalkyl and C 3 -C 6 -heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0114] 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< represent a bond between the ring carbon members to which they are bound.

[0115] R a< in each instance is independently selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, -(C 1 -C 6 -alkyl)(C 3 -C 8 -cycloalkyl), C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0116] R b< in each instance is independently selected from a direct bond, a straight or branched C 2 -C 6 -alkylene, and C 2 -C 6 -alkenylene chain.

[0117] Any heteroaryl or heterocycloalkyl in R a< and R b< is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 -alkyl, halo, hydroxy,

[0118] R c< in each instance is independently selected from a straight or branched C 2 -C 6 -alkylene and C 2 -C 6 -alkenylene chain.

[0119] 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< , W 2< is CR 2< , and W 3< is N. In still further embodiments, W 1< is CR 1< , W 2< is CR 2< , and W 3< is CR 3< .

[0120] The present disclosure also provides in various embodiments a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof:

[0121] X 1< and X 2< are independently selected from CR 4< and N.

[0122] In some embodiments, Ring Y is of formula (a):

[0123] In formula (a), Y 1< , Y 2< , Y 3< , and Y 4< are independently selected from CR 5< and N wherein Y 1< , Y 2< , Y 3< , and Y 4< are not simultaneously N.

[0124] In other embodiments, the Ring Y is of formula (b):

[0125] In formula (b), Y 1< is CR 5< and Y 2< is NR 5'< .

[0126] In some embodiments, either Y 1< and Y 2< , or Y 2< and Y 3< , or Y 3< and Y 4< represent a fused ring selected from a C 5 -C 8 -cycloalkyl, a C 6 -C 10 -aryl, a 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and a 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), wherein the ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halo, C 1 -C 6 -haloalkyl, C 2 -C 6 -haloalkenyl, C 2 -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< (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),

[0127] A, B, and E are independently selected from C, N, O, and S, and D is C or N. represents the presence of double bonds such that the ring A-B-D-E-N is aromatic and is optionally substituted with one or two substituents independently selected from C 1 -C 3 -alkyl, C 3 -C 5 -cycloalkyl, OH, OMe, NH 2 , N(H)Me, NMe 2 . No more than two of A, B, D, and E are simultaneously N, O, or S.

[0128] R 1< , R 2< , and R 3< are independently selected from the group consisting of 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 (where 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), 5- to 10-membered heteroaryl or (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0129] In some embodiments, R 1< and R 2< , or R 2< and R 3< , together with the carbon atoms to which they are bound, form a fused C 5 -C 8 -cycloalkyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0130] R 4< in each instance is independently H, OH, halo, C 1 -C 6 -alkyl, or C 1 -C 6 -alkoxy.

[0131] R 5< in each instance is independently selected from the group consisting of 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), C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl or (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0132] R 5'< is selected from the group consisting of 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 (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0133] 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, NO 2 , OH, CN, -R b< -N(R a< ) 2 , -R b< -OH, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy.

[0134] 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.

[0135] 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 bound, independently combine to form a fused ring selected from a C 3 -C 6 -cycloalkyl and C 3 -C 6 -heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0136] R a< in each instance is independently selected from hydrogen, C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, -(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), 5-to 10-membered heteroaryl or (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl or -(C 1 -C 6 -alkyl)(3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0137] R b< in each instance is independently selected from a direct bond, a straight or branched C 2 -C 6 -alkylene, and C 2 -C 6 -alkenylene chain.

[0138] R c< in each instance is independently selected from a straight or branched C 2 -C 6 -alkylene and C 2 -C 6 -alkenylene chain.

[0139] In some embodiments, the 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 is N. Specific examples of the A-B-D-EN ring is an optionally substituted ring selected from the group consisting of:

[0140] In some embodiments, the optionally substituted A-B-D-E-N ring is one selected from the group consisting of:

[0141] In a specific embodiment, the optionally substituted A-B-D-E-N ring is

[0142] In some embodiments of the present disclosure, Ring Y is of formula (a). Examples of Ring Y include those in which one of Y 1< , Y 2< , Y 3< , and Y 4< is N and each of the remaining three is CR 5< . Thus, in embodiments, each of Y 1< , Y 2< , Y 3< is CR 5< and Y 4< is N. Illustrative embodiments of Ring Y are wherein each of Y 1< and Y 2< is CH and Y 3< is CF.

[0143] In other embodiments, two of Y 1< , Y 2< , Y 3< , and Y 4< are N and each of the remaining two is CR 5< . For example, each of Y 1< and Y 2< is CR 5< and each of Y 3< and Y 4< is N.

[0144] In some embodiments, wherein Ring Y is of formula (a) or formula (b), either Y 1< and Y 2< or Y 3< and Y 4< represent an optionally substituted fused ring. For example, the fused ring in various embodiments is an optionally substituted fused 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) or 5- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S).

[0145] In various embodiments, one or each of X 1< and X 2< 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 each of X 1< and X 2< is CR 4< , or each of X 1< and X 2< is N. Optionally in combination with these embodiments, R 4< is H.

[0146] In additional embodiments, R 1< is selected from the group consisting of H, halo, C 1 -C 6 -alkoxy, C 6 -C 10 -aryl, C 3 -C 8 -cycloalkyl,3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S).

[0147] In still further embodiments, each of R 2< and R 3< is independently H, halo, cyano, CH 3 or CF 3 .

[0148] Other embodiments provide for formula (I) compounds wherein 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, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy. Examples include compounds wherein each of R 6a< , R 6b< , R 6c< , R 6d< , R 6e< , R 6f< , R 6g< , and R 6h< is H.

[0149] The present disclosure also provides, in embodiments, a compound of formula (I) or (II) that is a compound of formula (IA):

[0150] Optionally in combination with any embodiment described herein, R 1< is selected from the group consisting of H, halo, C 1 -C 6 -alkoxy, C 6 -C 10 -aryl, C 3 -C 6 -cycloalkyl, 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); and each of R 2< and R 3< is independently H, F, cyano, CH 3 , or CF 3 .

[0151] The present disclosure also provides, in various embodiments, a compound of formula (I) or (II) that is a compound of formula (IB), (IC), or (ID):

[0152] In formulae (IB), (IC), and (ID), per some embodiments, R 1< is selected from the group consisting of H, halo, C 1 -C 6 -alkoxy, C 6 -C 10 -aryl, C 3 -C 6 -cycloalkyl, 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) and 3- to 6-membered heterocycloalkyl (wherein 1-4 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, CH 3 , or CF 3 .

[0153] In additional embodiments, optionally in reference 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.

[0154] 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< .

[0155] In still further embodiments, the ring containing Y 1< , Y 2< , Y 3< , and Y 4< is: In an exemplary embodiment, the ring containing Y 1< ,

[0156] In additional embodiments, the present disclosure provides a compound or pharmaceutically acceptable salt and / or solvate thereof wherein the compound is one selected from Table 1. Table 1. Exemplary Compounds of the Present Disclosure. 1 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile2 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridin-3-yl)benzonitrile3 3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile4 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]benzonitrile5 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyrazin-2-yl)benzonitrile6 3-[6-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile7 3-(4-hydroxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile8 3-{ 4-[2-(dimethylamino)ethoxy]pyridin-3-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile9 3-[4-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile10 3-(4-chloropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile11 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile12 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]benzonitrile13 2-[4-(1H-imidazol-1-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile14 3-(4-methoxypyridin-3-yl)-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzonitrile15 3-(1,3-benzoxazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile16 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]benzonitrile17 2-[4-(2-amino-1,3-thiazol-5-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile18 3-(4-methoxypyridin-3-yl)-2-[4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile19 3-(2,1,3-benzoxadiazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile20 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} benzonitrile21 2-(4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-3-(4-methoxypyridin-3-yl)benzonitrile22 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]benzonitrile23 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]benzonitrile24 3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile25 6-methoxy-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile26 6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile27 6-chloro-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile28 4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-2-carbonitrile29 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile30 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile31 3-(4-methoxypyridin-3-yl)-2-[4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl]benzonitrile32 4-(4-methoxypyridin-3-yl)-3-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-2-carbonitrile33 6-chloro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile34 3-(1-methyl-2-oxo-1,2-dihydropyrimidin-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile35 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]benzonitrile36 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)benzonitrile37 6-[2-(dimethylamino)ethoxy]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile38 4-fluoro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile39 4-fluoro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile40 3-(6-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile41 3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile42 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzonitrile43 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)benzonitrile44 6-(2-aminopyridin-4-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile45 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(1H-pyrazol-3-yl)benzonitrile46 2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile47 3-(6-fluoro-5-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile48 6-(1-methyl-1H-pyrazol-4-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile49 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile50 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)benzonitrile51 6-((2-(dimethylamino)ethyl)amino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile52 3-(6-hydroxypyridazin-4-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile53 4-fluoro-3-(6-fluoro-5-methylpyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile54 3-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile55 6-(1-methyl-1H-pyrazol-4-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridazin-4-yl)benzonitrile56 6-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile57 3-(6-fluoropyridin-3-yl)-6-(methoxy-d3)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile58 6-(2-(dimethylamino)ethoxy)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(pyridazin-4-yl)benzonitrile59 4-fluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile60 6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile61 6-(1-methyl-1H-pyrazol-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile62 6-(2-(dimethylamino)ethoxy)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile63 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile64 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)benzonitrile65 2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)-6-(1H-pyrazol-3-yl)benzonitrile66 3-(6-fluoropyridin-3-yl)-5-methyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile67 3-(6-fluoropyridin-3-yl)-6-methyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile68 6-cyclopropyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile69 5-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile70 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile71 6-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile72 2-(4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile73 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(1H-pyrazol-4-yl)benzonitrile74 2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)-6-(1H-pyrazol-4-yl)benzonitrile75 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)benzonitrile76 6-cyclopropoxy-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile77 6-(cyclopropylmethoxy)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile78 6-amino-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile79 2-cyano-4-(6-fluoropyridin-3-yl)-N,N-dimethyl-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzamide80 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(4-methylpiperazin-1-yl)benzonitrile81 6-(cyclopropylamino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile82 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(2-(methylamino)ethoxy)benzonitrile83 3-(6-fluoropyridin-3-yl)-6-(methyl(2-(methylamino)ethyl)amino)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile84 N-(2-cyano-4-(6-fluoropyridin-3-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)methanesulfonamide85 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(piperazin-1-yl)benzonitrile86 3-(6-fluoropyridin-3-yl)-6-(2-methoxyethoxy)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile87 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-morpholinobenzonitrile88 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)oxy)benzonitrileAbsolute stereochemistry not assigned (Isomer A)89 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-((tetrahydrofuran-3-yl)oxy)benzonitrileAbsolute stereochemistry not assigned (Isomer B)90 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)benzonitrileAbsolute stereochemistry not assigned (Isomer A)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)benzonitrileAbsolute stereochemistry not assigned (Isomer B)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)benzonitrile93 3-(imidazo[1,2-a]pyrimidin-6-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile94 3-(imidazo[1,2-a]pyrimidin-6-yl)-6-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile95 3-(6-fluoropyridin-3-yl)-6-(3-hydroxyazetidin-1-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile96 4'-fluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile97 6-acetyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile98 6-(1-cyclopropyl-1H-pyrazol-3-yl)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile99 3-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile100 5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)isophthalonitrile101 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(methylsulfonyl)benzonitrile102 3',4'-difluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile103 2',4'-difluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile104 3-(1-methyl-1H-1,2,3-triazol-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile105 5-(6-fluoropyridin-3-yl)-6-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-1H-indazole-7-carbonitrile106 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile107 4-fluoro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile108 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(oxetan-3-yl)benzonitrile109 3'-formyl-4'-hydroxy-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile110 3'-formyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile111 (3'-cyano-2'-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-4-yl)boronic acid112 (3'-cyano-2'-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)boronic acid113 3-(3-hydroxy-1H-indazol-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile114 3-(5-bromopyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile115 3-(5-chloropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile116 3-(6-hydroxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile117 (5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-yl)boronic acid118 5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-yl sulfurofluoridate119 5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-2-yl sulfurofluoridate120 3-(5-hydroxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile121 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)benzonitrile122 3-(6-fluoropyridin-3-yl)-6-(1-methyl-1H-pyrazol-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile123 3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile124 3'-formyl-4'-hydroxy-4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile125 2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)benzonitrile126 (5-(3-cyano-4-(1-methyl-1H-pyrazol-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-yl)boronic acid127 4-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile128 4'-ethynyl-3'-formyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-carbonitrile129 6-cyclopropyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile130 5-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile131 4-fluoro-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)benzonitrile132 6-fluoro-3'-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[3,4'-bipyridine]-2'-carbonitrile133 6'-fluoro-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[2,3'-bipyridine]-4-carbonitrile134 6'-fluoro-3-(4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl)-[2,3'-bipyridine]-4-carbonitrile135 6-cyclopropyl-4-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile136 6'-fluoro-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)-[2,3'-bipyridine]-4-carbonitrile137 6'-fluoro-5-methoxy-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[2,3'-bipyridine]-4-carbonitrile138 6'-fluoro-5-(1-methyl-1H-pyrazol-3-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[2,3'-bipyridine]-4-carbonitrile139 6'-fluoro-5-(1-methyl-1H-pyrazol-4-yl)-3-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-[2,3'-bipyridine]-4-carbonitrile

[0157] In additional embodiments, the present disclosure provides a compound or pharmaceutically acceptable salt and / or solvate thereof, wherein the compound is selected from Table 2. PHARMACEUTICAL COMPOSITION

[0158] The disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to Formula I or Formula II, or a pharmaceutically acceptable salt, stereoisomer, isotopologue, and / or tautomer thereof in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.

[0159] In one embodiment, the pharmaceutical composition comprises a compound selected from those illustrated in Tables 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, isotopologue, and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0160] The pharmaceutical composition of the present disclosure is formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration 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 of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0161] The "therapeutically effective amount" of a compound or a pharmaceutically acceptable salt, stereoisomer, isotopologue, and / or tautomer thereof that is administered is governed by such considerations, and is the minimum amount necessary to inhibit QPCTL, QPCT, or both. Such amount may be below the amount that is toxic to normal cells, or the subject as a whole. Generally, the initial therapeutically effective amount of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure that is administered is in the range of about 0.01 to about 200 mg / kg or about 0.1 to about 20 mg / kg of patient body weight per day, with the typical initial range being 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 a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In still another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In a further embodiment, such dosage forms contain from about 5 mg to about 50 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In any of the foregoing embodiments the dosage form can be administered once a day or twice per day.

[0162] In certain embodiments, the compound as described herein or a pharmaceutically acceptable salt or solvate thereof, is substantially pure, in that it contains 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 synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0163] The compositions of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0164] Suitable oral compositions as described herein include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs.

[0165] In another aspect, also encompassed are pharmaceutical compositions suitable for single unit dosages that comprise a compound of the disclosure or its pharmaceutically acceptable stereoisomer, salt, or tautomer and a pharmaceutically acceptable carrier.

[0166] The compositions of the present disclosure that are suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. For instance, 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 preserving agents in order to provide pharmaceutically palatable preparations of a compound of the present disclosure.

[0167] For tablet compositions, a compound of the present disclosure in admixture with non-toxic pharmaceutically acceptable excipients is used for the manufacture of tablets. Examples of such excipients include without limitation inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[0168] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0169] For aqueous suspensions, a compound of the present disclosure is admixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include without limitation are sodium carboxymethylcellulose, methylcellulose, hydroxpropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

[0170] Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The 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.

[0171] Oily suspensions may be formulated by suspending a compound 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.

[0172] Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0173] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide a compound of the present disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0174] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation reaction products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.

[0175] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable, an aqueous suspension or an oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution 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 may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.

[0176] A compound of the present disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0177] Compositions for parenteral administrations are administered in a sterile medium. Depending on the vehicle used and concentration the concentration of the drug in the formulation, the parenteral formulation can either be a suspension or a solution containing dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parenteral compositions.METHODS OF USE

[0178] 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 a method of treating a disease in a patient suffering therefrom, wherein the disease is associated with expression of QPCT or QPCTL. The method comprises administering to the patient a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein. The compound or pharmaceutically acceptable salt thereof is administered optionally in a pharmaceutical composition in accordance with the present disclosure, and by any of the routes of administration as described herein.

[0179] In some embodiments, the disease is a cancer, such as a leukemia or lymphoma. Examples of the leukemia or lymphoma include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL), Burkitt lymphoma, hairy cell lymphoma (HCL), Waldenstrom 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 pre-B acute lymphoblastic leukemia (pre-B ALL).

[0180] In additional embodiments, the cancer is selected from the group consisting of multiple myeloma (MM), ovarian cancer, gliomas, 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 cancer, mesothelioma, melanoma, glioma, glioblastoma, and pancreatic neuroendocrine tumors.

[0181] 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's sarcoma, chondrosarcoma, and myeloma.

[0182] The compounds of the present disclosure are potent inhibitors of QPCT, which is a druggable target in therapies for various neurogenerative 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 ataxia, Huntington's disease, Lewy body dementia, and spinal muscular atrophy. In some embodiments, combination therapy is contemplated, wherein the compound of the present disclosure is administered in combination with an antibody that clears amyloid-beta (Aβ) plaque in the brain. Various monoclonal antibodies that bind different epitopes and conformations of Aβ are known in the art and suitable for this purpose, including but not limited to Bapineuzumab, Solanezumab, Gantenerumab, Crenezumab, Ponezumab, BAN2401, and Aducanumab (See C. H. van Dyck Biol. Psych. 83(4) (2018) 311 - 319).

[0183] In further embodiments, the disease is an inflammatory disease (see, e.g., 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)

[0184] In further embodiments, the disease is a cardiovascular disease. In an illustrative embodiment, the cardiovascular disease is atherosclerosis.

[0185] In some embodiments, optionally in combination with any other embodiment described herein, the compound of formula (I) or (II) or 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.

[0186] In further embodiments, the compound or pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an opsonizing antibody. Opsonizing antibodies are well-known in the art, including IgG and IgM.

[0187] In additional embodiments, the present disclosure provides cormpounds for use in a method of inhibiting a glutaminyl-peptide cyclotransferase (QPCT) or glutaminyl-peptide cyclotransferase-like (QPCTL) enzyme. The method comprises contacting the enzyme with a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein. In one embodiment, the contacting occurs in vitro. In another embodiment, the contacting occurs in vivo.

[0188] Also provided is a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein for use in the treatment of a cancer, neurodegenerative disease, inflammatory disease, autoimmune disease, or a cardiovascular disease. The present disclosure also provides a use of a compound or pharmaceutically acceptable salt and / or solvate thereof as described herein in the manufacture of a medicament for the treatment of a cancer, neurodegenerative disease, inflammatory disease, autoimmune disease, or a cardiovascular disease.

[0189] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosure. The following examples are provided to illustrate and provide various embodiments and shall not be construed to limit the disclosure in any way.EXAMPLES Preparation of Compounds

[0190] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including 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).

[0191] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles 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 treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, 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.

[0192] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful 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.General Synthetic Schemes

[0193] The compounds disclosed herein are prepared by a variety of synthetic routes including, but not limited to, the routes described below in Scheme I or II.

[0194] As shown below in Scheme I, suitably functionalized 2-fluoro-3-bromobenzonitriles can undergo nucleophilic aromatic substitution reactions with a substituted piperidine to provide the piperidinyl-substituted bromoarenes. A person of ordinary skill in the art will understand that various organic synthesis methods can be applied to prepare the substituted 2-fluoro-3-bromobenzonitriles.

[0195] Compounds of the present disclosure can be synthesized by various transition metal-mediated cross coupling reactions (e.g. Suzuki or Stille methods). As shown below in Scheme II, trialkylstannane arenes, heteroarylboronic acids, or heteroarylboronate esters can undergo cross coupling reactions with the intermediate cyano-bromoarenes under palladium catalysis to give final compounds.

[0196] Scheme II illustrates the use of tetrakis(triphosphine)palladium(0) for the Stille-type reaction with the stannane reagent and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) for the Suzuki-type coupling with the heteroarylboronic acid. A person 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. I. Chemical Synthesis

[0197] As used below and throughout the present disclosure, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACNacetonitrile AcOHacetic acid AMPhosbis(di-tert-butyl(4-dimethylaminophenyl)phosphine) °Cdegrees Celsius δ H chemical shift in parts per million downfield from tetramethylsilane dday(s) DCMdichloromethane DIADdiisopropyl azodicarboxylate DIEAdiisopropylethylamine DMFdimethylformamide DMF-DMAdimethylformamide dimethyl acetal DMSOdimethylsulfoxide dppf1,1'-bis(diphenylphosphino)ferrocene dcypf1,1'-bis(di-cyclohexylphosphino)ferrocene EAethyl acetate EtOAcethyl acetate EtOHethanol ESIelectrospray ionization Etethyl ggram(s) hhour(s) hrhour(s) HPLChigh performance liquid chromatography Hzhertz Jcoupling constant (in NMR spectrometry) LCMSliquid chromatography mass spectrometry µmicro mmultiplet (spectral); meter(s); milli Mmolar M +< parent molecular ion Memethyl MeOHmethanol mgmilligram(s) MsClmethanesulfonyl chloride MHzmegahertz minminute(s) molmole(s); molecular (as in mol wt) mLmilliliter MSmass spectrometry nmnanometer(s) NMRnuclear magnetic resonance pHpotential of hydrogen; a measure of the acidity or basicity PEpetroleum ether RTroom temperature ssinglet (spectral) ttriplet (spectral) SFCsupercritical fluid chromatography Ttemperature TBABtetrabutylammonium bromide TBDMStert-butyldimethylsilyl TEAtriethylamine TFAtrifluoroacetic acid THFtetrahydrofuran TPPtriphenylphosphine Synthesis of Intermediates Intermediate 1: 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0198]

[0199] 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 for 15 h at 130 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . 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] +< .Intermediate 2: 3-bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile

[0200]

[0201] A solution of imidazole (2.4 g, 35.8 mmol) in DMF (120 mL) was treated with NaH (0.86 g, 35.8 mmol) for 25 min at 0 °C under nitrogen atmosphere followed by the addition of tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (5 g, 17.8 mmol) at 0 °C. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (5:1) to afford tert-butyl 4-(imidazol-1-yl)piperidine-1-carboxylate (1.5 g, 33%) as a yellow oil. LCMS (ESI) m / z: 252 [M+H] +< .

[0202] A solution of tert-butyl 4-(imidazol-1-yl)piperidine-1-carboxylate (1.5 g, 5.9 mmol) in 4M HCl in 1,4-dioxane (25 mL) was stirred for 1 h at room temperature. The reaction mixture was evaporated and partitioned between saturated aqueous K 2 CO 3 and EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and was concentrated under reduced pressure, to afford 4-(imidazol-1-yl)piperidine (600 mg, 66%) as a light yellow oil. LCMS (ESI) m / z: 152 [M+H] +< .

[0203] To a stirred solution of 4-(imidazol-1-yl)piperidine (600 mg, 3.96 mmol) in DMSO (150 mL) were added 3-bromo-2-fluorobenzonitrile (1190.4 mg, 5.95 mmol) and DIEA (2564.2 mg, 19.8 mmol) in portions at room temperature. The resulting mixture was stirred for 2 days at 120 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (5:1) to afford 3-bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile. LCMS (ESI) m / z: 331, 333 [M+H] +< .Intermediate 3: 1-bromo-3-cyano-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzene

[0204]

[0205] To 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 H 2 O (12 mL) / dioxane (72 mL) were added K 2 CO 3 (6704 mg, 48.5 mmol) and Pd(dppf)Cl 2 (1317 mg, 1.6 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (0%-20%) to afford 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] +< .

[0206] To 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 Pd / C (1.5 g) in portions at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 26 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure to afford 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] +< .

[0207] 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 for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-(1,3-thiazol-5-yl)piperidine hydrochloride (1.43 g, 98%) as an off-white solid. LCMS (ESI) m / z: 169 [M+H] +< .

[0208] 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 for 16 h at 120 ° C. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (40% - 60%) to afford 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] +< .Intermediate 4: 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile

[0209]

[0210] To a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5 g, 23.7 mmol) in TFA (120 mL) was added thiosemicarbazide (3.2 g, 35.6 mmol) in portions at room temperature under 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 with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 1% to 10% gradient in 20 min; detector, UV 254 nm. to afford 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (4 g, 91%) as a colorless oil. LCMS (ESI) m / z: 185 [M+H] +< .

[0211] To a stirred solution of 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (3 g, 16.3 mmol) in DMSO (60 mL) were added DIEA (8.4 g, 65.1 mmol) and 3-bromo-2-fluorobenzonitrile (2.3 g, 11.4 mmol) in portions at room temperature. The resulting mixture was stirred at 120 °C overnight. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (5:1) to afford 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile (450 mg, 8%) as a brown yellow solid. LCMS (ESI) m / z: 364, 366 [M+H] +< .Intermediate 5: 3-bromo-2-[4-(3-methyl-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile

[0212]

[0213] A mixture of acetohydrazide (5 g, 67.5 mmol) and DMF-DMA (8 g, 67.5 mmol) in ACN (70 mL) was stirred for 1 h at 50 ° C. The resulting mixture was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. LCMS (ESI) m / z: 130 [M+H] +< .

[0214] 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 for 16 h at 120° C .The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 . 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 afford 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] +< .

[0215] 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 1,4-dioxane (30 mL) was stirred for 2 h at room temperature The reaction was quenched by the addition of saturated aqueous K 2 CO 3 (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 . 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 afford 4-(3-methyl-1,2,4-triazol-4-yl)piperidine (1 g, 84%) as a yellow oil.

[0216] 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) was added DIEA (3.2 g, 24.7 mmol) dropwise at room temperature .The resulting mixture was stirred for 16 h at 120° C. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (0-10%) to afford 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] +< .Intermediate 6: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0217]

[0218] 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) in portions at room temperature. The resulting mixture was stirred for overnight at 120 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (5:1) to afford 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] +< .Intermediate 7: 3-bromo-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0219]

[0220] To a stirred solution of Intermediate 6 (500 mg, 1.3 mmol) in DMF (12 mL) were added K 2 CO 3 (363 mg, 2.6 mmol) and CH 3 ONa (212.9 mg, 3.9 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 120 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to obtain Intermediate 7 (350 mg, 71%). LCMS (ESI) m / z: 376, 378 [M+H] +< .Intermediate 8: 3-bromo-2-[4-(3-methylimidazol-4-yl) piperidin-1-yl] benzonitrile

[0221]

[0222] To a stirred solution of benzyl 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 H 2 O (10 mL) was added K 2 CO 3 (4 g, 29.1 mmol) and Pd(dppf)Cl 2 (1.07 g, 1.5 mmol) 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 reaction, the reaction mixture was quenched by addition of water (40 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was further purified by column chromatography using (10% to 50% MeOH / DCM) to afford desired compound benzyl 4-(3-methylimidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3 g). LCMS (ESI) m / z: 298 [M+H] +< .

[0223] A solution of benzyl 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 for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, 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 CH 2 Cl 2 / MeOH (12:1) to afford 4-(3-methyl-1,2-dihydroimidazol-4-yl) piperidine (2 g) as a brown solid. LCMS (ESI) m / z: 166 [M+H] +< .

[0224] 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 for 6 h at 120 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (3x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (12: 1) to afford 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] +< .Intermediate 9: 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl) piperidin-1-yl] benzonitrile

[0225]

[0226] To a stirred solution of 3,4-dichloro-2-fluorobenzaldehyde (4 g, 20.7 mmol) in anhydrous DCM (50 mL) was added TEA (6.29 g, 62.2 mmol) and NH 2 OH.HCl (10.8 mg, 0.16 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. After completion of reaction, the reaction mixture was quenched by addition of water (50 mL). The resulting mixture was extracted with CH 2 Cl 2 (300 mL) dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in (E)-N-[(3,4-dichloro-2-fluorophenyl) methylidene] hydroxylamine (3.2 g) as a brown solid. LCMS (ESI) m / z: 209 [M+H] +< .

[0227] To a stirred solution of (E)-N-[(3,4-dichloro-2-fluorophenyl) methylidene] hydroxylamine (3.2 g, 15.38 mmol) in anhydrous toluene (50 mL) was added SOCl 2 (2.75 g, 23.08 mmol) at 0 °C. The reaction mixture was stirred at 120 °C for 2 h. After completion of 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 give crude product which was further purified by column chromatography using 5 to 20% EtOAc in PE gradient to afford desired compound 3,4-dichloro-2-fluorobenzonitrile (2.3 g). LCMS (ESI) m / z: 191 [M+H] +< .

[0228] 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) was added 3,4-dichloro-2-fluorobenzonitrile (720.1 mg, 3.79 mmol) and DIEA (2.18 g, 16.8 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 12 h. After completion of reaction, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 5 to 15 % MeOH in DCM gradient to afford 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] +< .

[0229] 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) was 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 h. After completion of reaction, the reaction mixture was quenched by addition of water (50 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 5 to 15% MeOH in 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] +< .Intermediate 10: 3-bromo-2-{4-[4-( 2< H3)methyl-1,2,4-triazol-3-yl]piperidin-1-yl}benzonitrile

[0230]

[0231] To 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 DMF-DMA (12.9 g, 107 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 °C. To the above mixture was added (2H3)methanamine hydrochloride (6.1 g, 86.3 mmol) and AcOH (25.9 g, 432 mmol) in portions over 20 min at 50 °C. The resulting mixture was stirred for additional 16 h at 90 °C. The resulting mixture was concentrated under reduced pressure and quenched by the addition of water (100 mL) at room temperature. The mixture was basified to pH 7 with saturated Na 2 CO 3 (aq.). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in CH 2 Cl 2 (10%-15%) to afford 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] +< .

[0232] To tert-butyl 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate (7 g, 25.9 mmol) was added HCl in 1,4-dioxane (100 mL) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine hydrochloride (5g) as a white solid. The crude product mixture was used in the next step directly without further purification. LCMS (ESI) m / z: 170 [M+H] +< .

[0233] 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) in portions at room temperature. The resulting mixture was stirred for 16 h at 120 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford 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] +< .Intermediate 11: 3-bromo-2-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0234]

[0235] 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) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 72 h at 60 °C under nitrogen atmosphere. 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 afford benzyl 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] +< .

[0236] To 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 Pd / C (10%, Pd / C (0.19 g)) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 2 h under 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 x 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 afford 4-(4H-1,2,4-triazol-3-yl)piperidine (640 mg, 46%) as a white solid. LCMS (ESI) m / z: 153 [M+H] +< .

[0237] 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) was added DIEA (1630 mg) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 120 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . 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-(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] +< .Intermediate 12: 3-bromo-5-methyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0238]

[0239] 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 H 2 O (10 mL) was stirred for 10 min at room temperature and then stirred at 50 °C overnight under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to afford 3-bromo-2-fluoro-5-methylbenzonitrile (879 mg, 89%) as a white solid. LCMS (ESI) m / z: 214, 216 [M+H] +< .

[0240] 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) was added DIEA (2681.1 mg, 20.7 mmol) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 140 °C. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / MeOH 9:1) to afford 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] +< .Intermediate 13: 3-bromo-5-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl) piperidin-1-yl] benzonitrile

[0241]

[0242] 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 for 1 h at 50 °C. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . 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-5-chloro-2-fluorobenzonitrile (900 mg, 91%) as a yellow solid. LCMS (ESI) m / z: 234, 236 [M+H] +< .

[0243] 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 K 2 CO 3 (2151.6 mg, 15.6 mmol) in DMSO (5 mL) was stirred for 1 h at 90 °C. The residue was purified by reverse-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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] +< .Intermediate 14: 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)benzonitrile

[0244]

[0245] A solution of 3-bromo-2-fluoro-5-(trifluoromethyl) benzaldehyde (500 mg, 1.8 mmol) and (aminooxy)sulfonic acid (354.7 mg, 3.1mmol) in H 2 O (10 mL) was stirred for 2 h at 50 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . 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 afford 3-bromo-2-fluoro-5-(trifluoromethyl) benzonitrile (200 mg) as a white solid. LCMS (ESI) m / z: 268, 270 [M+H] +< .

[0246] 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) was added DIEA (1205 mg, 9.33 mmol) in portions at room temperature. The resulting mixture was stirred at 140 °C overnight. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford 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] +< .Intermediate 15: 3-bromo-2-[4-(1,3,4-thiadiazol-2-yl) piperidin-1-yl] benzonitrile

[0247]

[0248] 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 for 2 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with brine (5 x 50 mL), dried over anhydrous Na 2 SO 4 . 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 benzyl 4-(N'-formylhydrazinecarbonyl) piperidine-1-carboxylate (4.5 g, 77%) as a white solid. LCMS (ESI) m / z: 306 [M+H] +< .

[0249] A solution of benzyl 4-(N'-formylhydrazinecarbonyl) piperidine-1-carboxylate (4.50 g, 14.7 mmol) and Lawesson Reagent (6.56 g, 16.2 mmol) in dioxane (30 mL) was stirred for 3 h at 100 °C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford benzyl 4-(1,3,4-thiadiazol-2-yl) piperidine-1-carboxylate (210 mg, 5%) as a yellow oil. LCMS (ESI) m / z: 304 [M+H] +< .

[0250] 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 for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used for the next step without further purification. LCMS (ESI) m / z: 170 [M+H] +< .

[0251] 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 reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH 3 .H 2 O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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] +< .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

[0252]

[0253] A solution of ethyl (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (3 g, 12.2 mmol) and NH 2 NH 2 .H 2 O (18.4 g, 366.9 mmol) in EtOH (30 mL) was stirred for 16 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbohydrazide (2.5 g, 88%) as a white solid. LCMS (ESI) m / z: 232 [M+H] +< .

[0254] 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 for 1 h at 50 °C. To the above mixture was added CH 3 NH 2 -HCl (0.35 g, 5.2 mmol), HOAc (2.6 g, 43.2 mmol) dropwise over 10 min at room temperature. The resulting mixture was stirred for additional 15 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford (1R,5S)-3-benzyl-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (1 g, 91%) as a light yellow oil. LCMS (ESI) m / z: 255 [M+H] +< .

[0255] 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 for 5 h at 60 °C under hydrogen atmosphere (5 atm). The resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford the desired product as a light yellow oil (660 mg). The crude product was used in the next step directly without further purification. LCMS (ESI) m / z: 165 [M+H] +< .

[0256] 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 for 12 h at 120 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . 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-[(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 light yellow oil. LCMS (ESI) m / z: 344, 346 [M+H] +< .Intermediate 17: 5-chloro-4-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzene-1,3-dicarbonitrile

[0257]

[0258] 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) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (8:1) to afford 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.

[0259] 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 for 2 days at 120 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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] +< .Intermediate 18: 3-chloro-5-methanesulfonyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0260]

[0261] 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) were added 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) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 20% to 40% gradient in 20 min; detector, UV 254 nm. to afford 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] +< .Intermediate 19: 5-bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile

[0262]

[0263] 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 for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-(4-bromo-2-cyano-3-fluorophenyl)-2,2,2-trifluoroacetamide (5 g, 68%) as a light yellow solid. LCMS (ESI) m / z: 311, 313 [M+H] +< .

[0264] 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 for 16 h at 140 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 6-amino-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 7%) as a light yellow oil. LCMS (ESI) m / z: 361, 363 [M+H] +< .

[0265] 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 for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (8:1) to afford 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] +< .

[0266] 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), K 2 CO 3 (510.7 mg, 3.7 mmol) and Pd(dppf)Cl 2 (135.2 mg, 0.18 mmol) in 1,4-dioxane (20 mL) was stirred for 16 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (8:1) to afford 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 light yellow oil. LCMS (ESI) m / z: 375, 377 [M+H] +< .

[0267] 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 CHCl 3 (10 mL) was treated with Ac 2 O (359.1 mg, 3.5 mmol) for 10 min at 0 °C followed by the addition of isoamyl nitrite (430.8 mg, 3.7 mmol), AcOK (47.1 mg, 0.48 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (8:1) to afford 5-bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile (50 mg, 8%) as a light yellow oil. LCMS (ESI) m / z: 386, 388 [M+H] +< .Intermediate 20: 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0268]

[0269] 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 for 2 days at 90 °C. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) and then by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 28% B to 40% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.62) to afford 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] +< .

[0270] 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 for 4 h at room temperature. The mixture was concentrated under reduced pressure and the crude product was used in the next step directly without further purification. LCMS (ESI) m / z: 168 [M+H] +< .

[0271] 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) was added TEA (302.6 mg, 3 mmol) in portions at room temperature. The resulting mixture was stirred for overnight at 90 °C. To the reaction water (20 mL) was added and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .Intermediate 21: 3-bromo-4-chloro-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0272]

[0273] 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) was added TEA (17.5 g, 172.9 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at 80 °C. To the reaction water (500 mL) was added and extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (2 x100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .

[0274] 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 H 2 SO 4 (50 mL) was added NBS (16.7 g, 93.8 mmol) at 0 °C. The resulting mixture was stirred for 16h at room temperature. To the reaction mixture water (600 mL) was added at 0 °C. The mixture was basified to pH 8 with saturated Na 2 CO 3 (aq.). The resulting mixture was extracted with EtOAc (3 x 1L). The combined organic layers were washed with brine (2 x150 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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 light yellow solid. LCMS (ESI) m / z: 398, 400 [M+H] +< .

[0275] 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 CH 3 ONa (203.3 mg, 3.8 mmol) in MeOH (15 mL) was stirred for 8 h at room temperature. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford 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] +< .Intermediate 22: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0276]

[0277] 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) was added TEA (1512.9 mg, 14.9 mmol) in portions at room temperature. The resulting mixture was stirred over night at 80 °C. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford 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] +< .Intermediate 23: 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0278]

[0279] A mixture of 3,4-dichloro-2-fluorobenzaldehyde (5 g, 25.9 mmol) and aminooxysulfonic acid (5.3 g, 46.6 mmol) in H 2 O (150 mL) was stirred overnight at 50 °C. The precipitated solids were collected by filtration and washed with water (3 x 100 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (0%-10%) to afford 3,4-dichloro-2-fluorobenzonitrile (3.3 g, 67%) as an off-white solid. LCMS (ESI) m / z: 191 [M+H] +< .

[0280] 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) was added TEA (1512.9 mg, 14.9 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 90 °C. The reaction was quenched by the addition of water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 160 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford 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] +< .

[0281] 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) in portions at room temperature. The resulting mixture was stirred for 8 h at 120 °C. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 110 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (50 mg, 66%) as a light yellow solid. LCMS (ESI) m / z: 321 [M+H] +< .Intermediate 24: 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0282]

[0283] 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) was added TEA (907.7 mg, 8.97 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 90 °C. The reaction was quenched by the addition of water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 90 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .Intermediate 25: 3-bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0284]

[0285] 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 for 16 h at 80 °C. The resulting mixture was diluted with water (100 mL) and was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 3-bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (140 mg, 7%) as a light yellow oil. LCMS (ESI) m / z: 364, 366 [M+H] +< .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

[0286]

[0287] A solution of 2-bromo-4-chloro-6-fluoroaniline (25 g, 111.4 mmol), KCN (14.5 g, 222.7 mmol), NOBF 4 (13 g, 111.4 mmol) and CuSO 4 (53.3 g, 334.1 mmol) in DCM (50 mL) was stirred for 2 h at room temperature. The reaction was quenched with Fe 2 SO 4 sat. sodium hyposulfite (aq.) at room temperature. The mixture was basified to pH 10 with saturated NaHCO 3 (aq.). The resulting mixture was diluted with water (200 mL) and extracted with CH 2 Cl 2 (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . 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 2-bromo-4-chloro-6-fluorobenzonitrile (10 g, 38%) as a light yellow oil. LCMS (ESI) m / z: 234, 236 [M+H] +< .

[0288] A solution of 2-bromo-4-chloro-6-fluorobenzonitrile (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 for 16 h at 80 °C. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 2-bromo-4-chloro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1.1 g, 11%) as a light yellow oil. LCMS (ESI) m / z: 380, 382 [M+H] +< .

[0289] 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 H 2 SO 4 (20 mL) was stirred for 2 h at room temperature. The mixture was basified to pH 10 with NaOH. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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 light yellow solid. LCMS (ESI) m / z: 506, 508 [M+H] +< .

[0290] 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), K 2 CO 3 (0.33 g, 2.37 mmol) and Pd(dppf)Cl 2 (0.06 g, 0.08 mmol) in 1,4-dioxane (16 mL), H 2 O (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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 light yellow oil. LCMS (ESI) m / z: 475, 477 [M+H] +< .Intermediate 27: iodo-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile

[0291]

[0292] 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) was added TEA (6.1 g, 60.1 mmol) in portions at room temperature. The resulting mixture was stirred for 16 h at 80 °C. To the reaction mixture of water (10 mL) was added at room temperature and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in CH 2 Cl 2 (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] +< .Intermediate 28: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile

[0293]

[0294] 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 TEA (6.5 g, 63.9 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 h at 80 C. Water was added at room temperature and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (0-10%) to afford 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] +< .Intermediate 29: 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidyl]isonicotinonitrile

[0295]

[0296] A mixture of benzyl 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), K 2 CO 3 (1.61 g, 11.7 mmol), Pd(dppf)Cl 2. DCM (238 mg, 0.29 mmol) were dissolved in 1,4 dioxane (19.4 mL) and water (5 mL). The reaction was heated at 100 °C for 30 minutes. Reaction was quenched with water, extracted with EtOAc, dried with anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% Hex : [25% EtOH in EtOAc]) to afford benzyl 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.15 g, 66%) as a brown oil.

[0297] A solution of benzyl 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.15 g, 3.87 mmol) was dissolved in MeOH (13 mL) and added Pd / C (250 mg). The reaction vessel was placed under a hydrogen atmosphere and stirred at room temperature over the weekend. The mixture was filtered over celite, washed with methanol. The solution was dried in vacuo to afford and orange residue. The residue was dissolved in Et 2 O (50 mL) and MeOH (1 mL) and HCl gas was bubbled through the reaction mixture. The resultant precipitate was filtered and dried in vacuo to afford 1-methyl-5-(4-piperidyl)imidazole-hydrogen chloride (658 mg, 84%) as a tan solid. LCMS (ESI) m / z: 166 [M+H] +< .

[0298] To a mixture of 1-methyl-5-(4-piperidyl)imidazole-hydrogen chloride (1 / 1) (0.1 g, 0.5 mmol), 2-chloro-3-fluoroisonicotinonitrile (85.4 mg, 0.54 mmol) in DMSO (2.1 mL) was added DIEA (192 mg, 1.5 mmol). The reaction was stirred at room temperature overnight. Solvent was removed in vacuo and the residue was purified by silica gel column chromatography (0-100%, Hex : [25% EtOH in EtOAc] to afford 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidyl]isonicotinonitrile_(46 mg, 31%). LCMS (ESI) m / z: 302 [M+H] +< .Intermediate 30: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]pyridine-4-carbonitrile

[0299]

[0300] 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) was added TEA (646.4 mg, 6.39 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .Intermediate 31: 2-chloro-5-methoxy-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile

[0301]

[0302] 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 for 3 h at 80 °C. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 3-fluoro-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (2.5 g, 24%) as a light yellow oil. LCMS (ESI) m / z: 287 [M+H] +< .

[0303] 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 for 30 min at 50 °C. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 3-methoxy-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (440 mg, 42%) as a light yellow oil. LCMS (ESI) m / z: 299 [M+H] +< .

[0304] 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 for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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 light yellow oil.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

[0305]

[0306] The title compound was prepared using the following procedure:

[0307] To a stirred solution of Intermediate 1 (80 mg, 0.2 mmol) and K 2 CO 3 (64 mg, 0.5 mmol) in 1,4-dioxane (3 mL) were added Pd(dppf)Cl 2 .CH 2 Cl 2 (19 mg, 0.1 mmol) and 6-fluoropyridin-3-ylboronic acid (36 mg, 0.3 mmol) at room temperature under nitrogen atmosphere. The final reaction mixture was heated for 4 h at 100 °C. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X Bridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 15% B to 35% B in 7 min, 35% B; Wavelength: 220 nm; to afford Example 1. LCMS (ESI) m / z: 363.05 [M+H] +< .Example 2: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridin-3-yl)benzonitrile

[0308]

[0309] The title compound was prepared using the following procedure:

[0310] 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) / H 2 O (0.5 mL) were added K 2 CO 3 (24.0 mg, 0.2 mol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (4.7 mg, 0.006 mmol,) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 42% B in 7 min, 42% B; Wavelength: 220 nm; RT1(min): 4.65; to afford Example 2. LCMS (ESI) m / z: 345.15 [M+H] +< .Example 3: 3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0311]

[0312] The title compound was prepared using the following procedure:

[0313] 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) / H 2 O (0.8 mL) were added K 2 CO 3 (47.9 mg, 0.3 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (9.4 mg, 0.01 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 34% B to 58% B in 8 min, 58% B; Wavelength: 220 nm; RT1(min): 7.35; to afford Example 3. LCMS (ESI) m / z: 375.10 [M+H] +< .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

[0314]

[0315] The title compound was prepared using the following procedure:

[0316] 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(PPh 3 ) 4 (7.8 mg, 0.007 mmol), K 2 CO 3 (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 nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90° C under nitrogen atmosphere. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with water (2 x 15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150mm 5µm, 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 afford Example 4. LCMS (ESI) m / z: 399.15 [M+H] +< .

[0317] To a stirred mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs 2 CO 3 (2.1 g, 6.3 mmol) in DMF (20 mL) was added CH 3 I (394.2 mg, 2.8 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . 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 light yellow solid. LCMS (ESI) m / z: 212, 214 [M+H] +< .

[0318] 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) was added Pd(PPh 3 ) 4 (54.5 mg, 0.05 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 ° C under nitrogen atmosphere. The reaction was quenched with water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . 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] +< .Example 5: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyrazin-2-yl)benzonitrile

[0319]

[0320] The title compound was prepared using the following procedure:

[0321] 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 H 2 O (1 mL) was added CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol) followed by catalytic amount of Pd(PPh 3 ) 4 (16.7 mg, 0.014 mmol) at room temperature. The resulting mixture was stirred for 12 h at 100 °C. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 5. LCMS (ESI) m / z: 346.05 [M+H] +< .Example 6: 3-[6-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0322]

[0323] The title compound was prepared using the following procedure:

[0324] A solution of ethylene glycol (11 mg, 0.18 mmol) and NaH (4 mg, 0.2 mmol) in THF (10 mL) was stirred for 30 min at 0 °C under N 2 atmosphere. To the above mixture was added 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (60 mg, 0.2 mmol) over 5 min at 0 °C. The resulting mixture was stirred for additional 4 h at 50 °C. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X Bridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 18% B to 45% B in 7 min, 45% B; Wavelength: 220 nm; RT1(min): 6.47; to afford Example 6. LCMS (ESI) m / z: 405.10 [M+H] +< .Example 7: 3-(4-hydroxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0325]

[0326] The title compound was prepared using the following procedure:

[0327] 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 overnight at 80 °C under nitrogen atmosphere. The residue was basified to pH 10 with saturated aqueous Na 2 CO 3 . The resulting mixture was extracted with CH 2 Cl 2 (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 40% B in 7 min, 40% B; Wavelength: 254 / 2220 nm; RT1(min): 6.42; to afford Example 7. LCMS (ESI) m / z: 361.10 [M+H] +< .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

[0328]

[0329] The title compound was prepared using the following procedure:

[0330] A solution of NaH (4 mg, 0.2 mmol) in dimethylaminoethanol (3 mL, 0.1 mmol) was stirred for 30 min at 0 °C under 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 the addition of water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5µm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 7 min, 45% B; Wavelength: 254 / 220 nm; RT1(min): 5.92; to afford Example 8. LCMS (ESI) m / z: 432.10 [M+H] +< .Example 9: 3-[4-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0331]

[0332] The title compound was prepared using the following procedure:

[0333] A solution of NaH (4 mg, 0.2 mmol) in ethylene glycol (3 mL, 0.1 mmol) was stirred for 30 min at 0 °C under 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) over 2 min at room temperature. The resulting mixture was stirred at 120 °C overnight. The reaction was quenched by the addition of water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X Bridge BEH130 Prep C18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (0.05% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 18% B to 30% B in 7 min, 30% B; Wavelength: 220 nm; RT1(min): 6.42; to afford Example 9. LCMS (ESI) m / z: 405.05 [M+H] +< .Example 10: 3-(4-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0334]

[0335] The title compound was prepared using the following procedure:

[0336] To a stirred solution of Intermediate 1 (50 mg, 0.14 mmol) and K 2 CO 3 (40 mg, 0.5 mmol) in 1,4-dioxane (3 mL) were added Pd(dppf)Cl 2 .CH 2 Cl 2 (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) at room temperature under nitrogen atmosphere. The final reaction mixture was heated at 100 °C for 4 h. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X Bridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 18% B to 45% B in 7 min, 45% B; Wavelength: 220 nm; RT1(min): 6.47; to afford Example 10. LCMS (ESI) m / z: 379.00 [M+H] +< .Example 11: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0337]

[0338] The title compound was prepared using the following procedure:

[0339] To 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 H 2 O (1 mL) was added CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol) followed by catalytic amount of Pd(PPh 3 ) 4 (16.7 mg, 0.014 mmol) at room temperature. The resulting mixture was stirred for 12 h at 100 °C. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 11. LCMS (ESI) m / z: 346.05 [M+H] +< .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

[0340]

[0341] The title compound was prepared using the following procedure:

[0342] To a stirred solution 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 H 2 O (1 mL) was added CuI (110 mg, 0.58 mmol) and CsF (87.8 mg, 0.58 mmol) followed by catalytic amount of Pd(PPh 3 ) 4 (33.4 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred for 12 h at 100 °C. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X select CSH C18 OBD Column 30*150mm 5µm, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 33% B in 7 min, 33% B; Wavelength: 220 nm; RT1(min): 6.32) to afford Example 12. LCMS (ESI) m / z: 398.10 [M+H] +< .

[0343] A solution of hexamethyldistannane (372 mg, 1 mmol) in 1,4-dioxane (10 mL) was treated with Pd(dppf)Cl 2 (77 mg, 0.1 mmol) for 5 min at room temperature under 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 h. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . The residue was purified by silica gel column chromatography, eluted with CH 3 CN / H 2 O (8:1) to afford 4-(trimethylstannyl)-1H-pyrrolo[2,3-c] pyridine (110 mg) as a brown oil.Example 13: 2-[4-(1H-imidazol-1-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0344]

[0345] The title compound was prepared using the following procedure:

[0346] To a stirred solution of Intermediate 2 (300 mg, 0.91 mmol) in dioxane (12 mL) and H 2 O (2 mL) were added 4-methoxypyridin-3-yl boronic acid (277 mg, 1.81 mmol), K 2 CO 3 (250.4 mg, 1.81 mmol) and Pd(dppf)Cl 2 (66.3 mg, 0.091 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (6: 1) to afford a dark red solid as a crude product. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 50% B in 7 min, 50% B; Wavelength: 220 nm; RT1(min): 5.98; to afford Example 13. LCMS (ESI) m / z: 360.05 [M+H] +< .Example 14: 3-(4-methoxypyridin-3-yl)-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzonitrile

[0347]

[0348] The title compound was prepared using the following procedure:

[0349] 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) / H 2 O (1 mL) were added Pd(dppf)Cl 2 (28.0 mg, 0.04 mmol) and K 2 CO 3 (157.8 mg, 1.15 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 ° C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 8 min, 55% B; Wavelength: 220 nm; RT1(min): 8.10; to afford Example 14. LCMS (ESI) m / z: 377.05 [M+H] +< .Example 15: 3-(1,3-benzoxazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0350]

[0351] The title compound was prepared using the following procedure:

[0352] A mixture of Intermediate 1 (60.0 mg, 0.17 mmol), K 2 CO 3 (71.8 mg, 0.5 mmol), Pd(dppf)Cl 2 (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) / H 2 O (0.5 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (25 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (45 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 27% B to 53% B in 7 min, 53% B; Wavelength: 220 nm; RT1(min): 5.84; to afford Example 15. LCMS (ESI) m / z: 385.05 [M+H] +< .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

[0353]

[0354] The title compound was prepared using the following procedure:

[0355] 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) were added Pd(PPh 3 ) 4 (19.6 mg, 0.017 mmol), CsF (25.7 mg, 0.17 mmol) and CuI (32.2 mg, 0.17 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (12 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 40% B in 7 min, 40% B; Wavelength: 254 / 220 nm; RT1(min): 6.08; to afford Example 16. LCMS (ESI) m / z: 399.05 [M+H] +< .

[0356] To a stirred mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs 2 CO 3 (2.1 g, 6.3 mmol) in DMF (20 mL) was added CH 3 I (394.2 mg, 2.8 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . 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 afford 4-bromo-2-methylpyrazolo[3,4-c]pyridine (130 mg, 24%) as a light yellow solid.

[0357] 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) was added Pd(PPh 3 ) 4 (43.6 mg, 0.04 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (2%-10%) to afford 2-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (50 mg, 45%) as a yellow solid.Example 17: 2-[4-(2-amino-1,3-thiazol-5-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0358]

[0359] The title compound was prepared using the following procedure:

[0360] A solution of N-(5-bromo-1,3-thiazol-2-yl)acetamide (2 g, 9.05 mmol), Pd(dppf)Cl 2 (0.66 g, 0.91 mmol) , K 2 CO 3 (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 for overnight at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na 2 SO 4 . 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 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] +< .

[0361] 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 for overnight at room temperature under hydrogen. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 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 afford tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl) piperidine-1-carboxylate (440 mg, 78%) as a light yellow solid. LCMS (ESI) m / z: 326 [M+H] +< .

[0362] 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 for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0363] 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 for 2 days at 120 °C. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to afford 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] +< .

[0364] 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)Cl 2 (3.61 mg, 0.005 mmol), K 2 CO 3 (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 for 1 h at 90 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B to 19% B in 7 min, 19% B; Wavelength: 254 / 220 nm; RT1(min): 4.82) to afford 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 light yellow solid. LCMS (ESI) m / z: 434 [M+H] +< .

[0365] 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), conc HCl (3 mL) and EtOH (5 mL) was stirred overnight at 80 °C. The mixture was basified to pH 8 with saturated Na 2 CO 3 (aq.). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (9 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 45% B in 7 min, 45% B; Wavelength: 254 / 220 nm; RT1(min): 6.43) to afford Example 17. LCMS (ESI) m / z: 392.05 [M+H] +< .Example 18: 3-(4-methoxypyridin-3-yl)-2-[4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile

[0366]

[0367] The title compound was prepared using the following procedure:

[0368] To 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 H 2 O (1 mL) were added K 2 CO 3 (239.5 mg, 1.73 mmol) and Pd(dppf)Cl 2 (42.3 mg, 0.058 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90° C under nitrogen atmosphere. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and evaporated to dryness. The crude product (50 mg) was purified by Prep-HPLC with 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 afford Example 18. LCMS (ESI) m / z: 375.05 [M+H] +< .Example 19: 3-(2,1,3-benzoxadiazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0369]

[0370] The title compound was prepared using the following procedure:

[0371] 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 H 2 O (1 mL) were added K 2 CO 3 (71.8 mg, 0.52 mmol) and Pd(dppf)Cl 2 (12.7 mg, 0.017 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 100° C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 60 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na 2 SO 4 . The crude product (50 mg) was purified by Prep-HPLC with 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: 28% B to 50% B in 8 min, 50% B; Wavelength: 254 / 220 nm; RT1(min): 6.95; to afford Example 19. LCMS (ESI) m / z: 386.05 [M+H] +< .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

[0372]

[0373] The title compound was prepared using the following procedure:

[0374] 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 K 2 CO 3 (38 mg, 0.29 mmol) in 1,4-dioxane / H 2 O (10:1) were added Pd(dppf)Cl 2 CH 2 Cl 2 (11 mg, 0.1 mmol) and Intermediate 1 (48 mg, 0.14 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The reaction was quenched by the addition of water (5 mL) at room temperature. The crude product was purified by reverse phase flash with the following conditions (Column: X select CSH F-Phenyl OBD column, 19*250 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 2% B to 22% B in 9 min, 22% B; Wavelength: 220 nm; RT1(min): 7.20; to afford Example 20. LCMS (ESI) m / z: 402.05 [M+H] +< .

[0375] 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) was added Pd(dppf)Cl 2 (342 mg, 0.42 mmol), AcOK (1232 mg, 12.6 mmol) and bis(pinacolato)diboron (218 mg, 0.84 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford desired compound (600 mg) as a brown solid. LCMS (ESI) m / z: 263 [M+H] +< .Example 21: 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0376]

[0377] The title compound was prepared using the following procedure:

[0378] To a stirred solution of Intermediate 4 (200 mg, 0.55 mmol) in dioxane (15 mL) and H 2 O (2 mL) were added K 2 CO 3 (151.7 mg, 1.1 mmol), 4-methoxypyridin-3-ylboronic acid (167.9 mg, 1.01 mmol) and Pd(dppf)Cl 2 (40.2 mg, 0.06 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford a dark red solid as a crude product. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 24% B to 48% B in 7 min, 48% B; Wavelength: 220 nm; RT1(min): 6.27; to afford Example 21. LCMS (ESI) m / z: 393.00 [M+H] +< .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

[0379]

[0380] The title compound was prepared using the following procedure:

[0381] To 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 added HCHO (4 mg, 0.13 mmol) and NaBH 3 CN (12 mg, 0.19 mmol) followed by 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 reaction, the reaction mixture was quenched by addition of water (5 mL) and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 , and evaporated to dryness. The crude product was purified by reverse phase flash with the following conditions (Column: X select CSH C18 OBD Column 30*150mm 5µm, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B in 7 min, 40% B; Wavelength: 220 nm; RT1(min): 5.62; to afford Example 22. LCMS (ESI) m / z: 416.10 [M+H] +< .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

[0382]

[0383] The title compound was prepared using the following procedure:

[0384] To a stirred solution of Intermediate 1 (20 mg, 0.058 mmol) in anhydrous 1,4-dioxane (5 mL) and H 2 O (0.5 mL) was added K 2 CO 3 (15.9 mg, 0.12 mmol) and 4-{2-[(tertbutyldimethylsilyl) oxy] ethyl}-2H,3H-pyrido[4,3-b] [1,4] oxazin-8-ylboronic acid (21.5 mg, 0.064 mmol) followed by catalytic amount of Pd(dppf)Cl 2 (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 reaction, the reaction mixture was quenched by addition of 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 crude product which was further purified by column chromatography using 5% to 20% MeOH in DCM gradient to afford 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).

[0385] 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) added HCOOH (1.6 mg, 0.036 mmol) and H 2 O (5 mL) at room temperature under nitrogen atmosphere. The final reaction mixture was stirred at room temperature for 1 h. The crude product was purified by reverse phase flash with the following conditions (Column: X select CSH F-Phenyl OBD column, 19*250 mm, 5µm;Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 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] +< .

[0386] 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) for 5 min at 0 °C under nitrogen atmosphere followed by the addition of chloroacetyl chloride (4.3 g, 38 mmol) dropwise at 0 °C. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in N-(5-bromo-4-hydroxypyridin-3-yl)-2-chloroacetamide (4 g) as a brown solid. LCMS (ESI) m / z: 265 [M+H] +< .

[0387] A solution of N-(5-bromo-4-hydroxypyridin-3-yl)-2-chloroacetamide (4 g, 15.1 mmol) in DMF (10 mL) was treated with K 2 CO 3 (4.2 g, 30.1 mmol) for 5 min at 0 °C. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 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] +< .

[0388] 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 for 5 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 16 h at 35 °C. The reaction was quenched with MeOH (7 mL) for 30 min at 60 °C. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to obtain 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] +< .

[0389] 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) at 0 °C for a period of 30 min. A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (50.1 mg, 0.21 mmol) was stirred for 3 h at room temperature under nitrogen atmosphere. After completion of reaction, the reaction mixture was quenched by addition of water (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude product which was further purified by column chromatography using 5% to 40% EtOAc in PE gradient to afford 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] +< .

[0390] To 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 AcOK (19.3 mg, 0.32 mmol) and bis(pinacolato)diboron (54.4 mg, 0.21 mmol) followed by catalytic amount of Pd(dppf)Cl 2 (8.7 mg, 0.01 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for a period of 16 h. After completion of reaction, the reaction mixture was quenched by addition of 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 crude product which was further purified by column chromatography using 1% to 10% MeOH in DCM gradient to afford desired compound 4-{2-[(tertbutyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-ylboronic acid (20 mg). LCMS (ESI) m / z: 339 [M+H] +< .Example 24: 3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0391]

[0392] The title compound was prepared using the following procedure:

[0393] To a stirred solution of Intermediate 7 (100 mg, 0.27 mmol) in dioxane (8 mL) and H 2 O (1 mL) were added K 2 CO 3 (73.5 mg, 0.53 mmol), 6-fluoropyridin-3-ylboronic acid (74.9 mg, 0.53 mmol) and Pd(dppf)Cl 2 (19.4 mg, 0.03 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (7: 1) to afford a brown solid as a crude product. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm;Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 43% B in 7 min, 43% B; Wavelength: 254 / 220 nm; RT1(min): 6.38; to afford Example 24. LCMS (ESI) m / z: 393.05 [M+H] +< .Example 25: 6-methoxy-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0394]

[0395] The title compound was prepared using the following procedure:

[0396] To a stirred solution of Intermediate 7 (100 mg, 0.27 mmol) in dioxane (7 mL) and H 2 O (1 mL) were added K 2 CO 3 (73.5 mg, 0.53 mmol) 4-methoxypyridin-3-ylboronic acid (81.3 mg, 0.53 mmol) and Pd(dppf)Cl 2 (19.4 mg, 0.027 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (6: 1) to afford a tan solid as a crude product. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm;Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9% B to 18% B in 8 min, 18% B; Wavelength: 254 / 220 nm; RT1(min): 5.73; to afford Example 25. LCMS (ESI) m / z: 405.10 [M+H] +< .Example 26: 6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0397]

[0398] The title compound was prepared using the following procedure:

[0399] To a stirred solution of Intermediate 7 (50 mg, 0.133 mmol) in dioxane (2 mL) and H 2 O (1 mL) were added K 2 CO 3 (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)Cl 2 (19.4 mg, 0.027 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (5:1) to afford a white solid as a crude product. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm;Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 26. LCMS (ESI) m / z: 376.05 [M+H] +< .Example 27: 6-chloro-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0400]

[0401] The title compound was prepared using the following procedure:

[0402] To a stirred mixture of Intermediate 6 (0.5 g, 1.31 mmol), K 2 CO 3 (0.36 g, 2.63 mmol) in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) were added (4-methoxypyridin-3-yl)boronic acid (0.16 g, 1.05 mmol) and Pd(dppf)Cl 2 (0.10 g, 0.13 mmol) at room temperature under N 2 atmosphere. The mixture was stirred for 20 h at 90 °C under nitrogen atmosphere. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 28% B in 8 min, 28% B; Wavelength: 254 / 220 nm; RT1(min): 7.00; to afford Example 27. LCMS (ESI) m / z: 409.00 [M+H] +< .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

[0403]

[0404] The title compound was prepared using the following procedure:

[0405] To a stirred solution of Intermediate 6 (200 mg, 0.52 mmol), K 2 CO 3 (145 mg, 1.05 mmol) in dioxane (5 mL) and H 2 O (0.5 mL) were added (6-fluoropyridin-3-yl) boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl 2 (115.3 mg, 0.16 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 20 h at 90 °C under nitrogen atmosphere. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford 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] +< .

[0406] To 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 K 2 CO 3 (69.6 mg, 0.5 mmol) in dioxane (5 mL) and H 2 O (0.5 mL) were added phenylboronic acid (61.4 mg, 0.5 mmol) and Pd(dppf)Cl 2 (55.3 mg, 0.076 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 20 h at 90 °C. The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 25% B to 55% B in 7 min, 55% B; Wavelength: 254 / 220 nm; RT1(min): 6.52; to afford Example 28. LCMS (ESI) m / z: 439.05 [M+H] +< .Example 29: 2-[4-(4-methyl-4H-1,24-triazol-3-yl)piperidin-1-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile

[0407]

[0408] The title compound was prepared using the following procedure:

[0409] To a stirred solution of Intermediate 1 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane / H 2 O (10:1) was added K 2 CO 3 (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) followed by Pd(dppf)Cl 2 (24 mg, 0.03 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Column: X Bridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (0.05% NH 3 .H 2 O), 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 afford Example 29. LCMS (ESI) m / z: 413.05 [M+H] +< .Example 30: 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0410]

[0411] The title compound was prepared using the following procedure:

[0412] To a stirred solution of Intermediate 6 (200 mg, 0.52 mmol), K 2 CO 3 (145.2 mg, 1.05 mmol) in dioxane (5 mL) and H 2 O (0.5 mL) were added (6-fluoropyridin-3-yl)boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl 2 (115.3 mg, 0.16 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 10 h at 90 °C. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 30. LCMS (ESI) m / z: 397.00 [M+H] +< .Example 31: 3-(4-methoxypyridin-3-yl)-2-[4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl]benzonitrile

[0413]

[0414] The title compound was prepared using the following procedure:

[0415] To a stirred solution of Intermediate 8 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane (10 mL) and H 2 O (1 mL) was added K 2 CO 3 (80 mg, 0.58 mmol) and Pd(dppf)Cl 2 (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 h. After completion of reaction, the reaction mixture was quenched by addition of water (5 mL). The crude product was purified by reverse phase flash with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 50% B in 7 min, 50% B; Wavelength: 254 / 220 nm; RT1(min): 3.88; to afford Example 31. LCMS (ESI) m / z: 374.35 [M+H] +< .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

[0416]

[0417] The title compound was prepared using the following procedure:

[0418] To a stirred mixture of Intermediate 6 (0.5 g, 1.31 mmol) and K 2 CO 3 (0.36 g, 2.62 mmol) in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) were added (4-methoxypyridin-3-yl)boronic acid (0.16 g, 1 mmol) and Pd(dppf)Cl 2 (0.10 g, 0.13 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 20 h at 90 °C. The crude product (10 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 28% B in 8 min, 28% B; Wavelength: 254 / 220 nm; RT1(min): 7.00; to afford 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] +< .

[0419] 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 K 2 CO 3 (33.8 mg, 0.24 mmol) in dioxane (0.7 mL) were added phenyl boronic acid (14.9 mg, 0.12 mmol) and Pd(dppf)Cl 2 (26.8 mg, 0.04 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred for 20 h at 90 °C. The crude product (5 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 31% B to 52% B in 8 min, 52% B; Wavelength: 220 nm; RT1(min): 7.70; to afford Example 32. LCMS (ESI) m / z: 451.10 [M+H] +< .Example 33: 6-chloro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0420]

[0421] The title compound was prepared using the following procedure:

[0422] To a stirred solution of Intermediate 6 (100 mg, 0.26 mmol) in dioxane (2 mL) and H 2 O (0.5 mL) were added K 2 CO 3 (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)Cl 2 (38.4 mg, 0.053 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (6:1) to afford a red solid as a crude product. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 33. LCMS (ESI) m / z: 380.00 [M+H] +< .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

[0423]

[0424] The title compound was prepared using the following procedure.

[0425] 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)Cl 2 .CH 2 Cl 2 (43.1 mg, 0.01 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . 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 afford 1-methyl-2-oxopyrimidin-5-ylboronic acid (400 mg, 25%) as a light yellow solid.

[0426] 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) / H 2 O (0.5 mL) were added K 2 CO 3 (119.8 mg, 0.9 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (23.5 mg, 0.03 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 x 30 mL). The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 25% B in 9 min, 25% B; Wavelength: 254 / 220 nm; RT1(min): 10.80; to afford Example 34. LCMS (ESI) m / z: 376.05 [M+H] +< .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

[0427]

[0428] The title compound was prepared using the following procedure:

[0429] To a stirred solution of Intermediate 6 (300 mg, 0.79 mmol) in dioxane (3 mL) and H 2 O (1 mL) were added K 2 CO 3 (218 mg, 1.58 mmol) 6-fluoropyridin-3-ylboronic acid (88.8 mg, 0.63 mmol) and Pd(dppf)Cl 2 (115.3 mg, 0.16 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .

[0430] 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 H 2 O (1 mL) were added K 2 CO 3 (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)Cl 2 (55.3 mg, 0.076 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm, to afford a light brown solid as a crude product. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*100 mm, 5 µ m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), 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 afford Example 35. LCMS: (ES, m / z): 443.10 [M+H] +< .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

[0431]

[0432] The title compound was prepared using the following procedure:

[0433] To a stirred solution of Intermediate 6 (100 mg, 0.26 mmol) in dioxane (3 mL) and H 2 O (1 mL) were added K 2 CO 3 (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)Cl 2 (38.4 mg, 0.053 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / 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] +< .

[0434] 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 H 2 O (0.5 mL) were added K 2 CO 3 (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)Cl 2 (19.3 mg, 0.026 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 15% to 40% gradient in 20 min; detector, UV 254 nm, to afford a black solid as a crude product. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: Water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: MeOH--HPLC; Flow rate: 50 mL / min; Gradient: 31% B to 41% B in 8 min, 41% B; Wavelength: 254 / 220 nm; RT1(min): 5.00) to afford Example 36. LCMS (ESI) m / z: 426.05 [M+H] +< .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

[0435]

[0436] The title compound was prepared using the following procedure:

[0437] 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) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm. To afford 3-bromo-6-[2-(dimethylamino)ethoxy]-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (430 mg, 26.4%) as a brown viscous oil.

[0438] 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) / H 2 O (0.5 mL) were added Pd(dppf)Cl 2 CH 2 Cl 2 (47 mg, 0.06 mmol) and K 2 CO 3 (239.2 mg, 1.7 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 +0.1%NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 32% B in 9 min, 32% B; Wavelength: 254 / 220 nm; RT1(min): 11.82) to afford Example 37. LCMS (ESI) m / z: 450.10 [M+H] +< .Example 38: 4-fluoro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0439]

[0440] The title compound was prepared using the following procedure:

[0441] To a stirred solution of Intermediate 9 (150 mg, 0.47 mmol) in anhydrous 1,4-dioxane (10 mL) and H 2 O (2mL) was added K 2 CO 3 (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 catalytic amount of Pd(AMPhos) 2 Cl 2 (33.2 mg, 0.05 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Column: X Bridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 25% B to 40% B in 8 min, 40% B; Wavelength: 254 / 220 nm; RT1(min): 6.93) to afford Example 38. LCMS (ESI) m / z) 381.05 [M+H] +< .Example 39: 4-fluoro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0442]

[0443] The title compound was prepared using the following procedure:

[0444] To a stirred solution of Intermediate 9 (50 mg, 0.156 mmol) in anhydrous 1,4-dioxane (5 mL) and H 2 O (1 mL) was added K 2 CO 3 (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 catalytic amount of PdCl 2 (dcypf) (11.8 mg, 0.016 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After completion of reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Column: X Select CSH Fluoro Phenyl, 30*250 mm, 5µm; 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 afford Example 39. LCMS (ESI) m / z: 364.05 [M+H] +< .Example 40: 3-(6-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0445]

[0446] The title compound was prepared using the following procedure:

[0447] To a stirred solution of Intermediate 1 (50 mg, 0.14 mmol) in anhydrous 1,4-dioxane (5 mL) and H 2 O (0.5 mL) was added K 2 CO 3 (39.9 mg, 0.29 mmol) and 6-chloropyridin-3-ylboronic acid (25 mg, 0.16 mmol) followed by catalytic amount of Pd(dppf)Cl 2 (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 reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21% B to 40% B in 9 min, 40% B; Wavelength: 254 / 220 nm; RT1(min): 10.48) to afford Example 40. LCMS (ESI) m / z: 379.00 [M+H] +< .Example 41: 3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0448]

[0449] The title compound was prepared using the following procedure:

[0450] 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) were added Pd(dppf)Cl 2 .CH 2 Cl 2 (23.3 mg, 0.03 mmol) and K 2 CO 3 (79 mg, 0.57 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5 µ m, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B to 34% B in 9 min, 34% B; Wave Length: 254 / 220 nm; RT1(min): 9.38; to afford Example 41 (48.4 mg, 44%). LCMS (ESI) m / z: 366.05 [M+H] +< .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

[0451]

[0452] The title compound was prepared using the following procedure:

[0453] To a stirred solution of Example 30 (150 mg, 0.38 mmol) in dioxane (5 mL) and H 2 O (1 mL) were added K 2 CO 3 (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)Cl 2 (27.7 mg, 0.038 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford a red solid as a crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 36% B in 10 min, 36% B; Wave Length: 220 / 254 nm; RT1(min): 11.22; to afford Example 43 (22.8 mg, 13%). LCMS (ESI) m / z: 443.05 [M+H] +< .Example 49: 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0454]

[0455] The title compound was prepared using the following procedure:

[0456] 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) were added Cs 2 CO 3 (100 mg) and Pd(dppf)Cl 2 .CH 2 Cl 2 (12.5 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: MeOH-HPLC; Flow rate: 50 mL / min; Gradient: 56% B to 72% B in 8 min, 72% B; Wave Length: 254 / 220 nm; RT1(min): 6.47; to afford Example 49 (2.7 mg, 4%). LCMS (ESI) m / z: 349.00 [M+H] +< .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

[0457]

[0458] The title compound was prepared using the following procedure:

[0459] 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) was added NaH (28.4 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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] +< .

[0460] 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 H 2 O (1 mL) were added K 2 CO 3 (64.7 mg,) and Pd(dppf)Cl 2 .CH 2 Cl 2 (19.1 mg) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to afford Example 50 (32.7 mg, 31%). LCMS (ESI) m / z: 444.05 [M+H] +< .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

[0461]

[0462] The title compound was prepared using the following procedure:

[0463] A solution of Example 30 (50 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL) was treated with Cs 2 CO 3 (82.1 mg, 0.25 mmol) for 5 min at room temperature under nitrogen atmosphere. To the above mixture were added Pd-PEPPSI-IHeptCl 3-chloropyridine (12.3 mg, 0.013 mmol) and (2-aminoethyl)dimethylamine (22.2 mg, 0.25 mmol) for 5 min at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH 2 Cl 2 / MeOH 9: 1) and then re-purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C 18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 45% B in 7 min, 45% B; Wave Length: 254 / 220 nm; RT1(min): 6.72; to afford Example 51 (6.8 mg, 12%). LCMS (ESI) m / z: 449.20 [M+H] +< .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

[0464]

[0465] The title compound was prepared using the following procedure:

[0466] A mixture of sodium (2 g, 87 mmol) in ( 2< H3)methanol (20 mL) was stirred for 4 h at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. This resulted in ( 2< H3)methoxysodium (3.5 g, 70%) as a white solid.

[0467] To a stirred solution of Intermediate 6 (150 mg, 0.39 mmol) and K 2 CO 3 (109 mg, 0.79 mmol) in DMF (5 mL) were added sodium ( 2< H3)methanolate (27 mg, 0.47 mmol) in portions at room temperature. The resulting mixture was stirred for 4 h at 120 °C. The resulting mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na 2 SO 4 . 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-6-(2H3)methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 47%) as a light yellow oil. LCMS (ESI) m / z: 379, 381 [M+H] +< .

[0468] To 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 H 2 O (1 mL) were added K 2 CO 3 (51 mg, 0.37 mmol) and Pd(dppf)Cl 2 (13.5 mg, 0.02 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C, filtered, the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 45% B in 7 min, 45% B; Wave Length: 254 / 220 nm; RT1(min): 6.72; to afford Example 57 (26.5 mg, 36%). LCMS (ESI) m / z: 396.05 [M+H] +< .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

[0469]

[0470] The title compound was prepared using the following procedure:

[0471] A solution of Intermediate 6 (2.3 g, 6.0 mmol), 4-(tributylstannyl)pyridazine (2.23 g, 6.04 mmol), Pd(PPh 3 ) 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 overnight at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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] +< .

[0472] 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 overnight at 80 °C. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*250 mm, 10µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 42% B in 10 min, 42% B; Wave Length: 220 / 254 nm; RT1(min): 9.82; to afford Example 58 (2.8 mg, 4%). LCMS (ESI) m / z: 433.35 [M+H] +< .Example 59: 4-fluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile

[0473]

[0474] The title compound was prepared using the following procedure:

[0475] To a stirred solution of Intermediate 9 (50 mg, 0.16 mmol) in anhydrous 1,4-dioxane (5 mL) and H 2 O (1 mL) was added K 2 CO 3 (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 amount of Sphos Pd G 3 (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 reaction, the reaction mixture was quenched by addition of water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: X Bridge Prep Phenyl OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 18% B to 34% B in 8 min, 34% B; Wave Length: 254 / 220 nm; RT1(min): 7.75; to afford Example 59 (3.2 mg, 5%). LCMS (ESI) m / z: 378.00 [M+H] +< .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

[0476]

[0477] The title compound was prepared using the following procedure:

[0478] A mixture of Example 30 (70 mg, 0.18 mmol) and K 2 CO 3 (48.8 mg, 0.35 mmol) in dioxane (1.6 mL), H 2 O (0.4 mL) was stirred for 5 min at room temperature under nitrogen atmosphere. To the above mixture were added SPhos Pd G3 (13.8 mg, 0.018 mmol), Sphos (7.2 mg, 0.018 mmol), 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) at room temperature. The resulting mixture was heated at 90 ° C overnight. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) which was further purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5 µ m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 ·H 2 O), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 26% B to 43% B in 8 min, 43% B; Wave Length: 254 / 220 nm; RT1(min): 8.12; to afford Example 64 (2.1 mg, 2%). LCMS (ESI) m / z: 485.25 [M+H] +< .Example 66: 3-(6-fluoropyridin-3-yl)-5-methyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0479]

[0480] The title compound was prepared using the following procedure:

[0481] 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 H 2 O (0.5 mL) were added K 2 CO 3 (38.4 mg, 0.28 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (11.3 mg, 0.014 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) and then further purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 29% B to 46% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 8.50) to afford Example 66 (1 mg, 2%). LCMS (ESI) m / z: 377.05 [M+H] +< .Example 69: 5-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0482]

[0483] The title compound was prepared using the following procedure:

[0484] A solution of Intermediate 13 (160 mg, 0.42 mmol), K 2 CO 3 (174.3 mg, 1.26 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (34.2 mg, 0.042 mmol) in dioxane (5 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.10% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm and then by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5µm; 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; Wave Length: 254 / 220 nm; RT1(min): 10.68; to afford Example 69 (6.4 mg, 4%). LCMS (ESI) m / z: 397.05 [M+H] +< .Example 70: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile

[0485]

[0486] The title compound was prepared using the following procedure:

[0487] To a stirred mixture of Intermediate 14 (50 mg, 0.12 mmol), 6-fluoropyridin-3-ylboronic acid (20.4 mg, 0.14 mmol) in H 2 O (1 mL) and 1,4-dioxane (4 mL) were added K 2 CO 3 (33.4 mg, 0.24 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (10 mg) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The residue was purified by Prep-TLC (10% MeOH / CH 2 Cl 2 ). The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 45% B in 10 min; Wave Length: 254 / 220 nm; RT1(min): 12.27) to afford Example 70 (6 mg, 12%). LCMS (ESI) m / z: 431.15 [M+H] +< .Example 71: 6-fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0488]

[0489] The title compound was prepared using the following procedure:

[0490] 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 for 1 h at 120 °C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 . The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm followed by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5µm; 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; Wave Length: 254 / 220 nm; RT1(min): 10.68; to afford Example 71 (2.2 mg, 4%). LCMS (ESI) m / z: 381.05 [M+H] +< .Example 72: 2-(4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0491]

[0492] The title compound was prepared using the following procedure:

[0493] A solution of 3 Intermediate 15 (160 mg, 0.46 mmol), 6-fluoropyridin-3-ylboronic acid (71 mg, 0.50 mmol), K 2 CO 3 (126.6 mg, 0.92 mmol) and Pd(dppf)Cl 2 (33.5 mg, 0.05 mmol) in dioxane (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5µm; 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; Wave Length: 254 / 220 nm; RT1(min): 10.68; to afford Example 72 (3 mg, 2%). LCMS (ESI) m / z: 366.00 [M+H] +< .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

[0494]

[0495] The title compound was prepared using the following procedure:

[0496] A solution of Intermediate 16 (90 mg, 0.26 mmol), 6-fluoropyridin-3-ylboronic acid (44.2 mg, 0.31 mmol), K 2 CO 3 (108.4 mg, 0.78 mmol) and Pd(dppf)Cl 2 (19.1 mg, 0.026 mmol) in 1,4-dioxane (12 mL) and H 2 O (1.2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 13% B to 30% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 9.32; to afford Example 75 (10.8 mg, 11%). LCMS (ESI) m / z: 361.10 [M+H] +< .Example 76: 6-cyclopropoxy-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0497]

[0498] The title compound was prepared using the following procedure:

[0499] 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 overnight at 120 °C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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] +< .

[0500] 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 Cs 2 CO 3 (201.3 mg, 0.62 mmol) in DMF (4 mL) was stirred for 2 h at 120 °C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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] +< .

[0501] 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), K 2 CO 3 (34.3 mg, 0.25 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (10.1 mg, 0.01 mmol) in dioxane (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5µm; 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; Wave Length: 254 / 220 nm; RT1(min): 10.68; to afford Example 76 (4.4 mg, 8%). LCMS (ESI) m / z: 419.25 [M+H] +< .Example 78: 6-amino-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0502]

[0503] The title compound was prepared using the following procedure:

[0504] A mixture of Example 30 (130 mg, 0.33 mmol), Pd 2 (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 for 12 h at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (12:1) to afford 6-[(diphenylmethylidene)amino]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 39%) as orange oil. The crude product was used in the next step directly without further purification. LCMS (ESI) m / z: 542 [M+H] +< .

[0505] Into a round-bottom flask were added 6-[(diphenylmethylidene)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 H 2 O (6 mL) at room temperature. The mixture was stirred for 0.5 h at room temperature. The mixture was basified to pH 8 with saturated NaHCO 3 (aq.). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) and then repurified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1% NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 42% B in 9 min, 42% B; Wave Length: 254 / 220 nm; RT1(min): 8.97 ) to afford Example 78 (5.1 mg, 12%). LCMS (ESI) m / z: 378.25 [M+H] +< .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

[0506]

[0507] The title compound was prepared using the following procedure:

[0508] To a solution of Example 30 (150 mg, 0.38 mmol) in MeOH (5 mL) was added Pd(dppf)Cl 2 (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 min and then was 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 x 80 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (0%-10%) to afford 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] +< .

[0509] 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 H 2 O (3 mL) and MeOH (3 mL) was stirred for 2 h at room temperature. The residue was purified by Prep-TLC (10% MeOH / CH 2 Cl 2 ) to afford 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] +< .

[0510] 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) were added HATU (44.9 mg, 0.12 mmol) and DIEA (50.9 mg, 0.39 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was extracted with EtOAc (2 x 80 mL). The combined organic layers were washed with brine (2 x10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19*250 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 15% B to 32% B in 8 min, 32% B; Wave Length: 254 / 220 nm; RT1(min): 6.75; to afford Example 79 (10 mg, 23%). LCMS (ESI) m / z: 434.00 [M+H] +< .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

[0511]

[0512] The title compound was prepared using the following procedure:

[0513] To a solution of Intermediate 6 (300 mg, 0.79 mmol) in 1-methylpiperazine (10 mL) was added K 2 CO 3 (327 mg, 2.37 mmol) in portions at room temperature. The resulting mixture was stirred for 2 days at 100 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in CH 2 Cl 2 (0%-10%) 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] +< .

[0514] 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 H 2 O (1 mL) were added Pd(dppf)Cl 2 CH 2 Cl 2 (18.3 mg, 0.023 mmol) and K 2 CO 3 (93.3 mg, 0.68 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Aeris PEPTIDE 10 um XB-C18 Axia, 50 mm X 250 mm, 10 µ m; Mobile Phase A: water 0.1% NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 5% B to 35% B in 30 min, 20% B; Wave Length: 220 / 254 nm; RT1(min): 13.97; to afford Example 80 (10.5 mg, 10%). LCMS (ESI) m / z: 461.25 [M+H] +< .Example 81: 6-(cyclopropylamino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0515]

[0516] The title compound was prepared using the following procedure:

[0517] To a stirred solution Example 30 (200 mg, 0.5 mmol) and aminocyclopropane (43.2 mg, 0.76 mmol) in dioxane (20 mL) were added Cs 2 CO 3 (494 mg, 1.51 mmol) and Brettphos Pd G3 (45.7 mg, 0.05 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Aeris PEPTIDE 5um XB-C18 Axia, 21.2 mm X 250 mm, 5 µ m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 40% B in 10 min, 40% B; Wave Length: 220 / 254 nm; RT1(min): 13.97; to afford Example 81 (1.2 mg, 0.6%). LCMS (ESI) m / z: 418.30 [M+H] +< .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

[0518]

[0519] The title compound was prepared using the following procedure:

[0520] 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 for 30 min at 0 °C under nitrogen atmosphere. To the above mixture added Intermediate 6 (400 mg, 1.05 mmol) at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 30% gradient in 15 min; detector, UV 254 nm, to afford 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] +< .

[0521] 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 H 2 O (1 mL) were added K 2 CO 3 (162.8 mg, 1.18 mmol) 6-fluoropyridin-3-ylboronic acid (83 mg, 0.59 mmol) and Pd(dppf)Cl 2 (28.7 mg, 0.039 mmol). The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The crude mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 20% to 40% gradient in 20 min; detector, UV 254 nm. to afford 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] +< .

[0522] To 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) were added Pd / C (50.6 mg, 0.47 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under hydrogen atmosphere. The mixture was filtered, the filter cake was washed with MeOH (2 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 23% B in 10 min, 23% B; Wave Length: 200 / 220 nm; RT1(min): 12.73; to afford Example 82 (12.3 mg, 14%). LCMS (ESI) m / z: 436.10 [M+H] +< .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

[0523]

[0524] The title compound was prepared using the following procedure:

[0525] 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 for 12 h at 110 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5µm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 42% B in 9 min, 42% B; Wave Length: 254 / 220 nm; RT1(min): 8.97.) to afford Example 84 (12.5 mg, 11%). LCMS (ESI) m / z: 456.00 [M+H] +< .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

[0526]

[0527] The title compound was prepared using the following procedure:

[0528] 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) in portions at room temperature. The resulting mixture was stirred for 2 h at 120 °C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 40% gradient in 20 min; detector, UV 254 nm. to afford 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 brown yellow oil.

[0529] 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 H 2 O (1 mL) were added K 2 CO 3 (192.7 mg, 1.39 mmol) 6-fluoropyridin-3-ylboronic acid (98.2 mg, 0.7 mmol) and Pd(dppf)Cl 2 (34 mg, 0.047 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 50% gradient in 25 min; detector, UV 254 nm. to afford a brown oil as a crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 23% B in 9 min, 23% B; Wave Length: 254 / 220 nm; RT1(min): 15.72; to afford Example 85 (56.3 mg, 27%). LCMS (ESI) m / z: 447.35 [M+H] +< .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)

[0530]

[0531] The title compounds were prepared using the following procedure:

[0532] 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 overnight at 120 °C. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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.

[0533] 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 for 1 h at 0 °C. The reaction was quenched with water at room temperature. The resulting mixture was filtered, the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 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.

[0534] 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)Cl 2 CH 2 Cl 2 (18.9 mg, 0.023 mmol) in dioxane (10 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH 3 .H 2 O), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 19*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 30% B in 10 min; Wave Length: 220 nm; RT1(min): 12.55) to afford 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 with the following conditions (Column: CHIRAL ART Cellulose-SZ, 4.6*50mm, 3µm; Mobile Phase A: Hex (0.1% DEA): EtOH=50: 50; Flow rate: 1 mL / min; Gradient: isocratic; Injection Volume: 5ul mL) to afford Example 90 (6.4 mg, 7%) and Example 91 (7.4 mg, 7%). LCMS (ESI) m / z: 462.40 [M+H] +< .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

[0535]

[0536] The title compound was prepared using the following procedure:

[0537] 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) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (0%-10%) to afford tert-butyl 3-amino-4-bromopyrazole-1-carboxylate (500 mg) as a white solid.

[0538] 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) was added AcOK (224.7 mg, 2.3 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (62.2 mg, 0.076 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (10% MeOH / CH 2 Cl 2 ) to afford 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.

[0539] 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 H 2 O (1 mL) were added K 2 CO 3 (295 mg, 2.14 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (52.2 mg, 0.064 mmol) in portions at room temperature. The resulting mixture was stirred for 1.5 h at 90 °C under nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluted with MeOH / CH 2 Cl 2 (0%-10%) to afford 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.

[0540] 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 for 0.5 h at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 4% B to 24% B in 8 min, 24% B; Wave Length: 254 / 220 nm; RT1(min): 11.58; to afford Example 92 (25 mg, 6%). LCMS (ESI) m / z: 444.30 [M+H] +< .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

[0541]

[0542] The title compound was prepared using the following procedure:

[0543] To a stirred solution of 6-bromoimidazo[1,2-a]pyrimidine (50 mg, 0.25 mmol) in 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (96.2 mg, 0.38 mmol), Pd(dppf)Cl 2 CH 2 Cl 2 (20.6 mg, 0.025 mmol) and AcOK (74.3 mg, 0.76 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was evaporated in vacuo and used in the next step directly without further purification.

[0544] 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 H 2 O (0.5 mL) was added K 2 CO 3 (60 mg, 0.42 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (11.8 mg, 0.014 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5 µ m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 4% B to 24% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 11.58) to afford Example 93 (43 mg, 77%). LCMS (ESI) m / z: 385.10 [M+H] +< .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

[0545]

[0546] The title compound was prepared using the following procedure:

[0547] A mixture of Example 30 (200 mg, 0.5 mmol) and Cs 2 CO 3 (328.4 mg, 1 mmol) in dioxane (5 mL) was stirred for 5 min at room temperature. To the above mixture were added Pd-PEPPSI-IPentCl 3-chloropyridine (49 mg, 0.05 mmol) and 3- [(tertbutyldimethylsilyl) oxy] azetidine (188.8 mg, 1 mmol). The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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] +< .

[0548] Into 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 for 1 h at room temperature under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (300 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5 µ m; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: isocratic 10% B -28% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.62) to afford Example 95 (14.7 mg, 11%). LCMS (ESI) m / z: 434.05 [M+H] +< .Example 97: 6-acetyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0549]

[0550] The title compound was prepared using the following procedure:

[0551] Into a vial were added Example 30 (320 mg, 0.81 mmol) and 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 for 2 h at 130 °C. The reaction was quenched with water and extracted with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (9:1) to afford 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] +< .

[0552] Into 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 for 1h at room temperature. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30* 150mm 5µm; 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; Wave Length: 254 / 220 nm; RT1(min): 6.92) to afford Example 97 (85.5 mg, 30%). LCMS (ESI) m / z: 405.20 [M+H] +< .Example 100: 5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)isophthalonitrile

[0553]

[0554] The title compound was prepared using the following procedure:

[0555] To a stirred solution of Intermediate 17 (200 mg, 0.61 mmol) in dioxane (5 mL) and H 2 O (1 mL) were added K 2 CO 3 (253.7 mg, 1.84 mmol), 6-fluoropyridin-3-ylboronic acid (172.5 mg, 1.22 mmol) and Pd(dppf)Cl 2 (44.8 mg, 0.061 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (8:1) to afford a brown solid which was repurified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 9% B to25% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.78) to afford Example 100 (19.3 mg, 8%). LCMS (ESI) m / z: 388.25 [M+H] +< .Example 101: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(methylsulfonyl)benzonitrile

[0556]

[0557] The title compound was prepared using the following procedure:

[0558] To a stirred solution of Intermediate 18 (160 mg, 0.42 mmol) in dioxane (6 mL) and H 2 O (1.5 mL) were added K 2 CO 3 (174.6 mg, 1.26 mmol), 6-fluoropyridin-3-ylboronic acid (71.2 mg, 0.5 mmol) and Pd(dppf)Cl 2 (30.8 mg, 0.042 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2 Cl 2 / MeOH (10:1) to afford a brown solid which was further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 + 0.1% NH 3 .H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 9% B to 25% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.78) to afford Example 101 (69.6 mg, 37%). LCMS (ESI) m / z: 441.00 [M+H] +< .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

[0559]

[0560] The title compound was prepared using the following procedure:

[0561] A solution of Intermediate 19 (50 mg, 0.13 mmol), 6-fluoropyridin-3-ylboronic acid (21.9 mg, 0.15 mmol), K 2 CO 3 (53.7 mg, 0.39 mmol) and Pd(dppf)Cl 2 (9.5 mg, 0.013 mmol) in 1,4-dioxane (8 mL), H 2 O (2 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5 µm; Mobile Phase A: water (10 mmol / L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 11% B to 28% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 12.65) to afford Example 105 (0.9 mg, 2%). LCMS (ESI) m / z: 403.50 [M+H] +< .Example 106: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile

[0562]

[0563] The title compound was prepared using the following procedure:

[0564] 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 H 2 O (1 mL) and 1,4-dioxane (4 mL) were added K 2 CO 3 (47.8 mg, 0.35 mmol) and Pd(dppf)Cl 2 CH 2 Cl 2 (14.1 mg, 0.017 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The residue was purified by Prep-TLC (10% MeOH / CH 2 Cl 2 ). and was further purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: isocratic 10% B - 30% B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 11.68) to afford Example 106 (10 mg, 16%). LCMS (ESI) m / z: 364.05 [M+H] +< .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

[0565]

[0566] The title compound was prepared using the following procedure:

[0567] 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 H 2 O (0.4 mL) were added K 2 CO 3 (135 mg, 0.97 mmol) and Pd(dppf)Cl 2 (35.6 mg, 0.049 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (30 mL) at room temperature and was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 x15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH 4 HCO 3 ), 10% to 50% gradient in 10 min; detector, UV 254 nm. and then by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5µm, n; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 15% B to 45% B i...

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof: wherein W1 is N or CR1, W2 is N or CR2, and W3 is N or CR3, wherein no more than one of W1, W2, and W3 is N; X1 and X2 are independently selected from CR4 and N; Ring Y is of formula (a): wherein Y1, Y2, Y3, and Y4 are independently selected from CR5 and N wherein Y1, Y2, Y3, and Y4 are not simultaneously N, or Ring Y is of formula (b): wherein Y1 is CR5 and Y2 is NR5'; or Ring Y is of formula (c): wherein Y1, Y2, Y3, and Y4 are independently selected from CR5 and N; optionally, either Y1 and Y2, or Y2 and Y3, or Y3 and Y4 represent a fused ring selected from a C5-C8-cycloalkyl, a C6-C10-aryl, a 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and a 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, B, O, and S), wherein the ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-ORa(N(Ra)2), -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), A, B, and E are independently selected from C, N, O, and S, and D is C or N, wherein represents the presence of double bonds such that the ring A-B-D-E-N is aromatic and is optionally substituted with one or two substituents independently selected from C1-C3-alkyl, C3-C5-cycloalkyl, OH, OMe, NH2, N(H)Me, NMe2; wherein no more than two of A, B, D, and E are simultaneously N, O, or S; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halo, cyano, nitro, -Rb-ORa, -Rb-O-Rc-O-Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-O-Rc-N(Ra)2, -Rb-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C6-C10-aryl, -(C1-C6-alkyl)(C6-C10-aryl), 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S) optionally fused to 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), or R1 and R2, or R2 and R3, together with the carbon atoms to which they are bound, form a fused C5-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); wherein any heteroaryl or heterocycloalkyl in R1, R2, and R3 is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and -Rb-N(Ra)2; R4 in each instance is independently H, OH, halo, C1-C6-alkyl, or C1-C6-alkoxy; R5 in each instance is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -Rb-ORa, -Rb-O-Rc-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-O-Rc-N(Ra)2, -B(ORa)2, -Rb-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, - Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-OS(O)tF (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); R5' is selected from the group consisting of hydrogen, -Rc-Ra, -Rc-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rc-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-O-Rc-N(Ra)2, -Rb-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); wherein any heteroaryl or heterocycloalkyl in R5 and R5' is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, hydroxy, C3-C8-cycloalkyl, and -Rb-N(Ra)2; R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are independently selected from the group consisting of H, halo, NO2, OH, CN, -Rb-N(Ra)2, -Rb-OH, C1-C6-alkyl, and C1-C6-alkoxy; and / or, optionally, R6a and R6b, or R6c and R6d, or R6e and R6f, or R6g and R6h independently represent oxo, thioxo, imino, or oximo; and / or, optionally, R6a and R6b, or R6c and R6d, or R6e and R6f, or R6g and R6h, together with the carbon atoms to which they are bound, independently combine to form a fused ring selected from a C3-C6-cycloalkyl and C3-C6-heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); and / or, optionally, one of R6c and R6d together with one of R6e and R6f represent a bond between the ring carbon members to which they are bound; Ra in each instance is independently selected from hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, - (C1-C6-alkyl)(C3-C8-cycloalkyl), C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); Rb in each instance is independently selected from a direct bond, a straight or branched C2-C6-alkylene, and C2-C6-alkenylene chain;wherein any heteroaryl or heterocycloalkyl in Ra and Rb is optionally and independently substituted with 1 to 3 substituents selected from the group consisting of C1-C6-alkyl, halo, hydroxy, Rc in each instance is independently selected from a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain.

2. The compound or a pharmaceutically acceptable salt and / or solvate thereof according to claim 1, wherein the compound is of formula (I): wherein each of X1 and X2 is N; Ring Y is of formula (a): wherein Y1, Y2, Y3, and Y4 are independently selected from CR5 and N wherein Y1, Y2, Y3, and Y4 are not simultaneously N, or Ring Y is of formula (b): wherein Y1 is CR5 and Y2 is NR5'; optionally, either Y1 and Y2, or Y2 and Y3, or Y3 and Y4 represent a fused ring selected from a C5-C8-cycloalkyl, a C6-C10-aryl, a 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and a 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), wherein the ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-C6-alkyl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-ORa(N(Ra)2), -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), A, B, and E are independently selected from C, N, O, and S, and D is C or N, wherein represents the presence of double bonds such that the ring A-B-D-E-N is aromatic and is optionally substituted with one or two substituents independently selected from C1-C3-alkyl, C3-C5-cycloalkyl, OH, OMe, NH2, N(H)Me, NMe2; wherein no more than two of A, B, D, and E are simultaneously N, O, or S; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halo, cyano, nitro, -Rb-ORa, -Rb-O-Ra, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, - Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-O-Rc-N(Ra)2, -Rb-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C10-aryl, -(C1-C6-alkyl)(C6-C10-aryl), 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), or R1 and R2, or R2 and R3, together with the carbon atoms to which they are bound, form a fused C5-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); R4 in each instance is independently H, OH, halo, C1-C6-alkyl, or C1-C6-alkoxy; R5 in each instance is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -Rb-ORa, -Rb-O-Rc-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-O-Rc-N(Ra)2, -W-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C10-aryl, 5-to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); R5' is selected from the group consisting of hydrogen, -Rc-Ra, -Rc-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rc-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-O-Rc-N(Ra)2, -Rb-N(Ra)-Rc-N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is 1 or 2), -Rb-S(O)tN(Ra)2 (where t is 1 or 2), C1-C6-alkyl, C3-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); R6a, R6b, R6c, R6d, R6e, R6f, R6g, and R6h are independently selected from the group consisting of H, halo, NO2, OH, CN, -Rb-N(Ra)2, -Rb-OH, C1-C6-alkyl, and C1-C6-alkoxy; or, optionally, R6a and R6b, or R6c and R6d, or R6e and R6f, or R6g and R6h independently represent oxo, thioxo, imino, or oximo; or, optionally, R6a and R6b, or R6c and R6d, or R6e and R6f, or R6g and R6h, together with the carbon atoms to which they are bound, independently combine to form a fused ring selected from a C3-C6-cycloalkyl and C3-C6-heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); Ra in each instance is independently selected from hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, C6-C10-aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); Rb in each instance is independently selected from a direct bond, a straight or branched C2-C6-alkylene, and C2-C6-alkenylene chain; Rc in each instance is independently selected from a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain.

3. The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1, wherein W1 is N, W2 is CR2, and W3 is CR3; or W1 is CR1, W2 is CR2, and W3 is N; or W2 is CR2, and W3 is CR3.

4. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 3, wherein D is C, and wherein A, B, and E are independently selected from C and N, or at least one of A, B, and E is N, or two of A, B, and E are N.

5. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 3, wherein the A-B-D-E-N ring is an optionally substituted ring selected from the group consisting of:

6. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 5, wherein Ring Y is of formula (a), and wherein one of Y1, Y2, Y3, and Y4 is N and each of the remaining three is CR5, or wherein two of Y1, Y2, Y3, and Y4 are N and each of the remaining two is CR5, or wherein either Y1 and Y2 or Y3 and Y4 represent an optionally substituted fused ring.

7. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 6, wherein R1 is selected from the group consisting of H, halo, C1-C6-alkyl, -Rb-ORa (wherein Rb is a direct bond and Ra is C1-C6-alkyl), C6-C10-aryl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and each of R2 and R3 is independently H, halo, cyano, C1-C6-alkyl, C3-C8-cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl ring members are independently selected from N, O, and S), -Rb-ORa (wherein Rb is a direct bond and Ra is C1-C6-alkyl), or CF3.

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

9. The compound, or pharmaceutically acceptable salt and / or solvate thereof, according to claim 8, wherein: R1 is selected from the group consisting of H, halo, C1-C6-alkoxy, C6-C10-aryl, C1-C6-alkyl, C3-C6-cycloalkyl, 5- to 6-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S); each of R2 is H, halo, cyano, -Rb-S(O)tRa (where t is 1 or 2), C1-C6-alkyl, C3-C6-cycloalkyl, or CF3, and R3, when present, is halo, cyano, -Rb-S(O)tRa (where t is 1 or 2), C1-C6-alkyl, C3-C6-cycloalkyl, or CF3; and wherein one of Y1, Y2, Y3, and Y4 is N and each of the remaining three is CR5, or two of Y1, Y2, Y3, and Y4 are N and each of the remaining two is CR5.

10. The compound, or pharmaceutically acceptable salt and / or solvate thereof, according to claim 8 or 9, wherein the ring containing Y1, Y2, Y3, and Y4 is:

11. The compound, or pharmaceutically acceptable salt and / or solvate thereof, according to any of claims 8 to 10, wherein the ring containing Y1, Y2, Y3, and Y4 is:

12. A compound or pharmaceutically acceptable salt and / or solvate thereof selected from the following table: 4 5 6 7 8 9 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 134 135 136 137 138 139 or a compound or pharmaceutically acceptable salt and / or solvate thereof selected from the following table:

13. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt and / or solvate thereof according to any of claims 1 to 12 and a pharmaceutically acceptable carrier.

14. A compound according to any of claims 1 - 12 for use in a method for treating a disease in a patient suffering therefrom, wherein the disease is a cancer, a neurodegenerative disease, an inflammatory or autoimmune disease, or cardiovascular disease.

15. The compound for use according to claim 14, wherein the cancer is a leukemia or lymphoma selected from the group consisting of acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL), Burkitt lymphoma, hairy cell lymphoma (HCL), Waldenstrom 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), pre-B acute lymphoblastic leukemia (pre-B ALL), multiple myeloma (MM), ovarian cancer, gliomas, 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 cancer, mesothelioma, melanoma, glioma, glioblastoma, pancreatic neuroendocrine tumors, 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's sarcoma, chondrosarcoma, and myeloma; the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Friedreich ataxia, Huntington's disease, Lewy body dementia, and spinal muscular atrophy; and the cardiovascular disease is atherosclerosis.