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

Abstract

Provided herein are compounds of Formula (II) and Formula (I), which are inhibitors of QPCTL and QPCT: (II) and (I). # imgabs0 # also provides a pharmaceutical composition comprising said compound, as well as said compound for use in a method of treating cancer, a neurodegenerative disease, an inflammatory disease, or an autoimmune disease. Exemplary compounds are, for example, 3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1, 2, 4-triazol-3-yl) piperidin-1-yl] benzonitrile (embodiment 1): (1). Pharmacological data is provided.

Description

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 391,630, filed on July 22, 2022, which is incorporated herein as if fully set forth. Background of the Invention

[0003] Glutaminyl cyclases belong to a family of metal-dependent aminoacyltransferases and catalyze the intramolecular cyclization of peptide or protein N-terminal glutamine or glutamic acid amino acid residues to pyroglutamate (pE). Glutaminyl cyclases utilize a zinc-dependent catalytic mechanism to form pyroglutamate residues and release ammonia. Pyroglutamate modification is generally important for biological activity because it protects proteins from degradation by proteolytic enzymes or regulates the interaction 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 USA 84, 3628 (1987); A. Stephan et al., FEBS J. 276, 6522 (2009).

[0004] 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 allows it to be retained within the Golgi complex. QPCT and QPCTL share high sequence similarity and structure in their active site regions. However, their cellular distribution is different, so different substrates are converted, resulting in different physiological effects. QPCT is abundant in the hypothalamus, medulla, and hippocampus, and most glutaminyl cyclase activity in the brain is mediated by QPCT. QPCTL is more widely expressed in peripheral cells and acts on substrates such as cytokines. (H. Cynis et al., J Mol Biol. 379(5), 966(2008); S. Schilling et al., J Biol Chem. 286(16), 14199(2011).

[0005] Both QPCT and QPCTL are closely related to disease pathology. For example, QPCT modifies amyloid β (Aβ) peptide to produce pE-Aβ. pE-modification changes the biophysical properties of Aβ peptide by increasing its aggregation behavior. It has been shown that pE-Aβ is one of the main components of Aβ deposition 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 Neuropat hol. 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 a phagocytic checkpoint for cancer cells, enabling them to evade 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 cytokines such as CCL2 and related family members, which protects them from proteolytic degradation. CCL2 regulates the migration and infiltration of monocytes that play a key role in inflammatory conditions. CCL2 is also able to recruit monocytes into the tumor microenvironment, where they become tumor-associated macrophages (TAMs) that support the growth and survival of associated tumor cells (H. Cynis et al., EMBO Mol Med. 3, 545 (2011); R. Barreira da Silva et al., Nat Immun. 23, 568 (2022)).

[0006] Thus, inhibition of either QPCT or QPCTL provides a therapeutic approach for treating disorders such as neurological diseases, cancer, and inflammation.Therefore, there is a need for compounds that can modulate or inhibit QPCT and QPCTL. Summary of the Invention

[0007] In various embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof:

[0008]

[0009] W 1 N or CR 1 , W 2 N or CR 2 , and W 3 N or CR3 ;W 1 、W 2 and W 3 No more than one of them is N;

[0010] X 1 and X 2 Independently selected from CR 4 and N.

[0011] In some embodiments, ring Y With formula (a):

[0012]

[0013] In formula (a), Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR 5 and N, where Y 1 、Y 2 、Y 3 and Y 4 Not N at the same time.

[0014] In other embodiments, ring Y With formula (b):

[0015]

[0016] In formula (b), Y 1 CR 5 , and Y 2 NR 5’ .

[0017] In yet other embodiments, Ring Y With formula (c):

[0018]

[0019] In formula (c), Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR 5 and N.

[0020] In some embodiments, Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 Any one of represents a fused ring selected from the following: C5-C8 cycloalkyl, C6-C 10alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -OR a (N(R a )2),-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR 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).

[0021] A, B and E are independently selected from C, N, O and S, and D is C or N.

[0022] symbol Indicates the presence of a double bond, such that the ring ABDEN 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. In addition, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0023] 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 -OR c -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O)t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, -(C1-C6 alkyl)(C6-C 10 aryl), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) optionally fused to 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0024] In some embodiments, R 1 and R 2 , or R 2 and R 3 Together with the carbon atoms to which they are attached, they form fused C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0025] R 1 、R 2 and R 3 Any heteroaryl or heterocycloalkyl in 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 to 4 ring members are independently selected from N, O and S) and -R b -N(R a )2.

[0026] R 4 Each occurrence is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0027] R 5 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -R b -OR a 、-R b -OR c -OR a 、-R b -OC(O)-Ra 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2、-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 (wherein t is 1 or 2), C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0028] R 5 'Selected from the group consisting of: hydrogen, -Rc -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 -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0029] R 5 and R5 Any heteroaryl or heterocycloalkyl in ' is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxy, C3-C8 cycloalkyl and -R b -N(R a )2.

[0030] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h independently selected from the group consisting of: H, halogen, NO2, OH, CN, -R b -N(R a )2. -R b -OH, C1-C6 alkyl and C1-C6 alkoxy.

[0031] 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 and independently represent oxo, thio, imino, or oxime.

[0032] 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 attached, they independently combine to form a fused ring selected from C3-C6 cycloalkyl and C3-C6-heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0033] In additional embodiments, optionally in combination with any other embodiment described herein, R 6c and R 6d One of them and R 6e and R 6f One of the together represents a bond between the ring carbon members to which it is bound.

[0034] R aEach occurrence is independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)(C3-C8 cycloalkyl), C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0035] R b is independently selected at each occurrence from a direct bond, a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain.

[0036] R a and R b Any heteroaryl or heterocycloalkyl in is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxy,

[0037] R c is independently selected at each occurrence from straight-chain or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0038] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable carrier.

[0039] In additional embodiments, the present disclosure also provides a method of treating a disease in a patient suffering from the disease, wherein the disease is associated with expression of glutamyl-peptide cyclotransferase protein (QPCT) or glutamyl-peptide cyclotransferase-like protein (QPCTL). The method comprises administering to the patient a compound as described herein or a pharmaceutically acceptable salt and / or solvate thereof.

[0040] In yet another embodiment, the present disclosure provides a method of inhibiting a glutaminyl-peptide cyclotransferase (QPCT) or glutaminyl-peptide cyclotransferase-like (QPCTL) enzyme, comprising contacting the enzyme with a compound or pharmaceutically acceptable salt and / or solvate as described herein.

[0041] In an embodiment, the present disclosure provides a compound as described herein, or a pharmaceutically acceptable salt and / or solvate thereof, for use in treating cancer, a neurodegenerative disease, an inflammatory disease, or an autoimmune disease.

[0042] The present disclosure also provides use of a compound as described herein, or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for treating cancer, a neurodegenerative disease, an inflammatory disease, or an autoimmune disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 X-ray crystal structure of the reference compound SEN177 bound to QPCTL.

[0044] Figure 2 . X-ray crystal structure of Example 1 bound to QPCTL.

[0045] Figure 3 . X-ray crystal structures of QPCTL covered with SEN177 and Example 1, respectively. DETAILED DESCRIPTION

[0046] The present disclosure provides compounds of Formula (I) and Formula (II), which are potent inhibitors of QPCTL and QPCT enzymes. The compounds can be used to treat diseases and conditions associated with the expression of QPCTL or QPCT, including various cancers and neurodegenerative diseases.

[0047] definition

[0048] 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 cells) and equivalents thereof known to those of ordinary skill 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 thereof, are intended to be included. When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is an approximation within the experimental variability (or within the statistical experimental error), such that in some cases the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," or "having," or "including") is not intended to exclude certain other embodiments, e.g., embodiments of any composition of matter, composition, method, or process, etc. described herein, that "consist of," or "consist essentially of" the described features.

[0049] As used in the specification and appended claims, the following terms have the meanings indicated below unless indicated otherwise.

[0050] "Amino" refers to a -NH2 moiety.

[0051] "Cyano" refers to a -CN moiety.

[0052] "Nitro" refers to the -NO2 moiety.

[0053] "Oxa" refers to the moiety -O-.

[0054] "Oxo" refers to the =0 moiety.

[0055] "Thioxo" refers to the =S moiety.

[0056] "Imino" refers to a =NH moiety.

[0057] "Oximo" refers to a =N-OH moiety.

[0058] "Hydrazino" refers to the moiety =N-NH2.

[0059] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, which is unsaturated and has one to fifteen carbon atoms (e.g., C1-C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C 15In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Unless specifically stated otherwise in this specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximino, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIn some embodiments, optionally substituted alkyl is a haloalkyl. In other embodiments, optionally substituted alkyl is a fluoroalkyl. In other embodiments, optionally substituted alkyl is a -CF3 group.

[0060] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above.

[0061] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is attached to the remainder of the molecule by a single bond (e.g., ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.). Unless otherwise specifically stated in this specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O)t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and 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).

[0062] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having two to twelve carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group comprises two to six carbon atoms. In other embodiments, the alkynyl group comprises two to four carbon atoms. The alkynyl group is attached to the remainder of the molecule via a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise in this specification, the alkynyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a(where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and 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).

[0063] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group, consisting solely of carbon and hydrogen, free of unsaturation, and having one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule and to the group through a single bond. The point of attachment of the alkylene chain to the rest of the molecule and the group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, the alkylene group comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in this specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximino, trimethylsilyl, -OR a、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and 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).

[0064] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule and to the radical by a single bond. In certain embodiments, the alkenylene group contains two to eight carbon atoms (e.g., C2-C8 alkenylene). In other embodiments, the alkenylene group contains two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, the alkenylene group contains two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, the alkenylene group contains two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, the alkenylene group contains two carbon atoms (e.g., C2 alkenylene). In other embodiments, the alkenylene group contains five to eight carbon atoms (e.g., C5-C8 alkenylene). In other embodiments, the alkenylene group comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless specifically stated otherwise in the specification, the alkenylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand 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).

[0065] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a radical, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule and to the radical by a single bond. In certain embodiments, the alkynylene group comprises two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene group comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene group comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene group comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene group comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, the alkynylene group comprises five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene group comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless specifically stated otherwise in the specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximino, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O)t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and 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).

[0066] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, wherein at least one of the rings in the ring system is fully unsaturated, that is, it contains a cyclic, delocalized (4n+2) π-electron system according to the Hückel theory. For example, an aryl group is C6-C 10 Ring systems. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically stated otherwise in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl groups optionally substituted with 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)Ra 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -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 R 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 are 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 wherein unless otherwise indicated, R a 、R b , or R c Each of the substituents is unsubstituted.

[0067] "Aralkyl" refers to a group of the formula -R c -aryl groups, where R cis an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for the aryl group.

[0068] "Aralkenyl" refers to a group of the formula -R d -aryl groups, where R d is an alkenylene chain as defined above. The aryl portion of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain portion of the aralkenyl group is optionally substituted as defined above for alkenylene.

[0069] "Aralkynyl" refers to a group of the formula -R e -aryl groups, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl group is optionally substituted as defined above for an alkynylene chain.

[0070] "Aralkoxy" refers to a group of the formula -OR c - a group bonded to the oxygen atom of an aromatic group, wherein R c is an alkenylene chain as defined above, for example, methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0071] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused rings or bridged ring systems, having three to fifteen carbon atoms. In certain embodiments, the carbocyclyl group comprises three to ten carbon atoms. In other embodiments, the carbocyclyl group comprises five to seven carbon atoms. The carbocyclyl group is attached to the remainder of the molecule by a single bond. The carbocyclyl group is saturated (that is, containing only a single C-C bond) or unsaturated (that is, containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also referred to as "cycloalkyl". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyl groups are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless specifically stated otherwise in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups that are optionally substituted with one or more substituents independently selected from the group consisting of 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 -OR 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 R 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 are 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 wherein unless otherwise indicated, R a 、R b and R c Each of the substituents is unsubstituted.

[0072] "Carbocyclylalkyl" refers to a group of the formula -R c -carbocyclic group, wherein R c is an alkylene chain as defined above. The alkynylene chain and the carbocyclyl group are optionally substituted as defined above.

[0073] "Carbocyclylalkoxy" refers to a group of the formula -OR c - a group bonded to the oxygen atom of a carbocyclic group, wherein R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0074] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0075] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0076] "Heterocyclyl" or equivalently "heterocycloalkyl" refers to a stable 3 to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. In an embodiment, heterocycloalkyl is a 3 to 6-membered ring (wherein 1 to 4 ring members are independently selected from N, O and S), wherein the ring is optionally substituted with 1 to 3 substituents. Unless otherwise specifically stated in this specification, a heterocyclyl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes a fused ring or a bridged ring system. The heteroatoms in the heterocyclyl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclyl group is partially or completely saturated. The heterocyclyl group is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl, [1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, which are optionally substituted with one or more substituents selected from the group consisting of 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 -OR 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 R 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 are 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 wherein unless otherwise indicated, R a 、R b and R c Each of the substituents is unsubstituted.

[0077] "Heteroaryl" refers to a group derived from a 3 to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl includes 5 to 10-membered rings, wherein 1 to 4 heteroaryl members are independently selected from N, O and S. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, that is, according to the Hückel theory, it contains a cyclic, delocalized (4n+2) π-electron system. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the (multiple) rings.Examples of heteroaryl groups include, but are not limited to, azathiophene, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepenyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzophenylthio), 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, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctane[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctane[d]pyridazinyl, 5,6,7,8,9 ,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolinyl, isodihydroindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methan-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazolinyl, 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 phenylthio (i.e., thienyl).Unless stated otherwise specifically in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with 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 -OR 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 aR 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 are 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 wherein unless otherwise indicated, R a 、R b and R c Each of the substituents is unsubstituted.

[0078] "Heteroarylalkoxy" refers to a group of the formula -R c -heteroaryl groups, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for a heteroaryl group. "Heteroarylalkoxy" alternatively refers to a heteroaryl group of the formula -OR c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for a heteroaryl group.

[0079] In some embodiments, compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise stated, the disclosure is intended to contemplate all stereoisomeric forms of compounds disclosed herein. When compounds as described herein contain olefin double bonds, and unless otherwise stated, the disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, and 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 olefin double bond. The term "positional isomer" refers to the structural isomers around the central ring, such as the ortho, meta and para isomers around the phenyl ring.

[0080] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits similar physical, biological, and / or chemical properties to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0081]

[0082] wait.

[0083] "Tautomers" refer to molecules in which a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. 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:

[0084]

[0085] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example, 2 H. 3 H. 11 C. 13 C and / or 14In one embodiment, the compound is deuterated in at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and efficacy of the compound and thereby increase the duration of the compound's therapeutic effect.

[0086] Unless otherwise stated, structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by an isotopically enriched 13 C- or 14 Compounds having the present structures except for carbon substitutions at C- are within the scope of this disclosure.

[0087] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the 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). 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 Isotopic substitutions are contemplated. In some embodiments, isotopic substitutions with 18 F are contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0088] In some embodiments, the compounds disclosed herein have some or all of 1 H atoms are 2H atom substitution. Methods for the synthesis of deuterium-containing compounds are known in the art and include the following by way of non-limiting example only.

[0089] Deuterium substituted compounds are synthesized using various methods, such as described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; 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.

[0090] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0091] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I) are readily available and can be employed to transfer a deuterium-substituted carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated in the following reaction schemes only by way of example.

[0092]

[0093] Deuterium transfer reagents, such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the following reaction schemes only by way of example.

[0094]

[0095] Deuterium gas and a palladium catalyst are employed to reduce unsaturated carbon-carbon bonds and to perform reductive substitutions of aryl carbon-halogen bonds as illustrated by way of example only in the following reaction schemes.

[0096]

[0097] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and do not contain non-interchangeable deuterium atoms. 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by a synthetic method in which deuterated synthetic building blocks are used as starting materials.

[0098] With respect to the compounds provided herein, when a particular atomic 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%. In certain embodiments, positions designated as having deuterium typically have 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 6000 (80% deuterium incorporation), at least 7000 (90% deuterium incorporation), at least 8000 (90% deuterium incorporation), at least 9000 (100% deuterium incorporation), at least 10000 (15% deuterium incorporation), at least 10000 (100% deuterium incorporation), at least 11000 (100% deuterium incorporation), at least 12000 (100% deuterium incorporation), at least 13000 (100% deuterium incorporation), at least 14000 (100% deuterium incorporation), at least 15000 (100% deuterium incorporation), at least 16000 (100% deuterium incorporation), at least 17000 (100% deuterium incorporation), at least 18000 (100% deuterium incorporation), at least 19000 (100% deuterium The isotopic enrichment factors of the compounds provided herein are preferably 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). The isotopic enrichment and isotopic enrichment factors of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0099] The present disclosure describes compounds by chemical name and chemical structure interchangeably. If there is any discrepancy between a given chemical name and chemical structure of a compound, the chemical structure shall prevail.

[0100] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any of the 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.

[0101] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and 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 formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, 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. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, etc. Salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those skilled in the art.

[0102] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise desirable. These salts are prepared by adding inorganic or organic bases to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are 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, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrazinoamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0103] "Pharmaceutically acceptable solvate" refers to a composition of matter in a solvent-added form. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during a process of preparation with a pharmaceutically acceptable solvent such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in unsolvated or solvated forms.

[0104] As used herein, and unless otherwise indicated to the contrary, the term "compound" is inclusive in that it encompasses a compound or a pharmaceutically acceptable salt, stereoisomer, isotopic conformer, and / or tautomer thereof. Thus, for example, a compound of formula (I) or formula (II) includes pharmaceutically acceptable salts of tautomers of the compound. Similarly, a compound of formula (I) or formula (II) includes pharmaceutically acceptable salts of isotopic conformers of the compound.

[0105] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0106] As used herein, "treatment" or "treating," or "palliating," or "ameliorating" are used interchangeably. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk for developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0107] The term "effective amount" refers to an amount of a compound or other active ingredient described herein that is sufficient to provide a therapeutic or preventive benefit in the treatment or prevention of a disease or to delay or minimize the symptoms associated with the disease. Additionally, a therapeutically effective amount with respect to a compound described herein means an amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. When used in combination with a compound described herein, the term can encompass an amount that improves overall therapy, alleviates or avoids symptoms or causes of a disease, or enhances the efficacy of another therapeutic agent or acts synergistically with another therapeutic agent.

[0108] Compound

[0109] In various embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof:

[0110]

[0111] W 1 N or CR 1 , W 2 N or CR 2 , and W 3 N or CR 3 ;W 1 、W2 and W 3 No more than one of them is N.

[0112] X 1 and X 2 Independently selected from CR 4 and N.

[0113] In some embodiments, ring Y With formula (a):

[0114]

[0115] In formula (a), Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR 5 and N, where Y 1 、Y 2 、Y 3 and Y 4 Not N at the same time.

[0116] In other embodiments, ring Y With formula (b):

[0117]

[0118] In formula (b), Y 1 CR 5 , and Y 2 NR 5’ .

[0119] In yet other embodiments, Ring Y With formula (c):

[0120]

[0121] In formula (c), Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR 5 and N.

[0122] In some embodiments, Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 Any one of represents a fused ring selected from the following: C5-C8 cycloalkyl, C6-C 10alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -OR a (N(R a )2),-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR 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).

[0123] A, B and E are independently selected from C, N, O and S, and D is C or N.

[0124] symbol Indicates the presence of a double bond, such that the ring ABDEN 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. In addition, no more than two of A, B, D, and E are simultaneously N, O, or S.

[0125] 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 -OR c -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O)t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, -(C1-C6 alkyl)(C6-C 10 aryl), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) optionally fused to 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0126] In some embodiments, R 1 and R 2 , or R 2 and R 3 Together with the carbon atoms to which they are attached, they form fused C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0127] R 1 、R 2 and R 3 Any heteroaryl or heterocycloalkyl in 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 to 4 ring members are independently selected from N, O and S) and -R b -N(R a )2.

[0128] R 4 Each occurrence is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0129] R 5 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -R b -OR a 、-R b -OR c -OR a 、-R b -OC(O)-Ra 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2、-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 (wherein t is 1 or 2), C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0130] R 5 'Selected from the group consisting of: hydrogen, -Rc -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 -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0131] R 5 and R5 Any heteroaryl or heterocycloalkyl in ' is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxy, C3-C8 cycloalkyl and -R b -N(R a )2.

[0132] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h independently selected from the group consisting of: H, halogen, NO2, OH, CN, -R b -N(R a )2. -R b -OH, C1-C6 alkyl and C1-C6 alkoxy;

[0133] 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 and independently represent oxo, thio, imino, or oxime.

[0134] 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 attached, they independently combine to form a fused ring selected from C3-C6 cycloalkyl and C3-C6-heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0135] In additional embodiments, optionally in combination with any other embodiment described herein, R 6c and R 6d One of them and R 6e and R 6f One of the together represents a bond between the ring carbon members to which it is bound.

[0136] R aEach occurrence is independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)(C3-C8 cycloalkyl), C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0137] R b is independently selected at each occurrence from a direct bond, a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain.

[0138] R a and R b Any heteroaryl or heterocycloalkyl in is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxy,

[0139] R c is independently selected at each occurrence from straight-chain or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0140] In some embodiments, W 1 N, W 2 CR 2 , and W 3 CR 3 In other embodiments, W 1 CR 1 , W 2 CR 2 , and W 3 is N. In still further embodiments, W 1 CR 1 , W 2 CR 2 , and W 3 CR 3 .

[0141] In various embodiments, the present disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof:

[0142]

[0143] X 1 and X 2 Independently selected from CR 4 and N.

[0144] In some embodiments, ring Y With formula (a):

[0145]

[0146] In formula (a), Y 1 、Y 2 、Y 3 and Y 4 Independently selected from CR 5 and N, where Y 1 、Y 2 、Y 3 and Y 4 Not N at the same time.

[0147] In other embodiments, ring Y With formula (b):

[0148]

[0149] In formula (b), Y 1 CR 5 , and Y 2 NR 5’ .

[0150] In some embodiments, Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 Any one of represents a fused ring selected from the following: C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S), and 5- to 8-membered heterocycloalkyl (wherein 1 to 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 to 4 ring members are independently selected from N, O, and S), C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -OR a (N(R a )2),-R b-C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR 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),

[0151] A, B and E are independently selected from C, N, O and S, and D is C or N. Symbol Indicates the presence of a double bond such that the ring ABDEN 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. No more than two of A, B, D, and E are simultaneously N, O, or S.

[0152] 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 -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. -Rb -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, -(C1-C6 alkyl)(C6-C 10 aryl), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0153] In some embodiments, R 1 and R 2 , or R 2 and R 3 Together with the carbon atoms to which they are attached, they form fused C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0154] R4 Each occurrence is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0155] R 5 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -R b -OR a 、-R b -OR c -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a)2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl or (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0156] R 5 '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 -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (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(Ra )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0157] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h independently selected from the group consisting of: H, halogen, NO2, OH, CN, -R b -N(R a )2. -R b -OH, C1-C6 alkyl and C1-C6 alkoxy.

[0158] 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 and independently represent oxo, thio, imino, or oxime.

[0159] In other embodiments, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h Together with the carbon atoms to which they are attached, they independently combine to form a fused ring selected from C3-C6 cycloalkyl and C3-C6-heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0160] R a Each occurrence is independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)(C3-C8 cycloalkyl), C6-C 10 Aryl, -(C1-C6 alkyl)(C6-C 10 aryl), 5- to 10-membered heteroaryl or (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl or -(C1-C6 alkyl)(3- to 6-membered heterocycloalkyl) (wherein 1 to 4 ring members are independently selected from N, O and S).

[0161] R b is independently selected at each occurrence from a direct bond, a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain.

[0162] R c is independently selected at each occurrence from straight-chain or branched C2-C6-alkylene and C2-C6-alkenylene chains.

[0163] In some embodiments, ring member D is C. In additional embodiments, A, B, and E are independently selected from C and N. For example, at least one of A, B, and E is N, or in some embodiments, two of A, B, and E are N. Specific examples of ABDEN rings are optionally substituted rings selected from the group consisting of:

[0164]

[0165] In some embodiments, the optionally substituted ABDEN ring is selected from one of the group consisting of:

[0166]

[0167] In a specific embodiment, the optionally substituted ABDEN ring is

[0168] In some embodiments of the present disclosure, ring Y has formula (a). Examples of ring Y include wherein Y 1 、Y 2 、Y 3 and Y 4 One of them is N, and each of the other three is CR 5 Therefore, in the embodiment, Y 1 、Y 2 、Y 3 Each of them is CR 5 , and Y 4 is N. An illustrative embodiment of ring Y is wherein Y 1 and Y 2 Each of them is CH and Y 3 For CF.

[0169] In other embodiments, Y 1 、Y 2 、Y 3 and Y 4 Two of them are N, and each of the other two is CR 5 For example, Y 1 and Y 2 Each of them is CR 5, and Y 3 and Y 4 Each of them is N.

[0170] In some embodiments, wherein ring Y is of formula (a) or formula (b), Y 1 and Y 2 or Y 3 and Y 4 Any of represents an optionally substituted fused ring. For example, in various embodiments, the fused ring is an optionally substituted fused 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O, and S) or a 5- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S).

[0171] In various embodiments, X 1 and X 2 One or each of is N. For example, X 1 is N, and X 2 CR 4 , or X 1 CR 4 And X 2 N, or X 1 and X 2 Each of them is CR 4 , or X 1 and X 2 Each of is N. Optionally in combination with these embodiments, R 4 For H.

[0172] In additional embodiments, R 1 Selected from the group consisting of: H, halogen, C1-C6 alkoxy, C6-C 10 aryl, C3-C8 cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S) and 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S).

[0173] In still further embodiments, R 2 and R 3 Each of the groups is independently H, halo, cyano, CH3 or CF3.

[0174] Other embodiments provide compounds of formula (I) wherein R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6hare independently selected from the group consisting of: H, halo, C1-C6 alkyl, and C1-C6 alkoxy. Examples include wherein R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h Wherein each is a compound of H.

[0175] In an embodiment, the present disclosure also provides a compound of formula (I) or (II), which is a compound of formula (IA):

[0176]

[0177] Optionally, in combination with any of the embodiments described herein, R 1 Selected from the group consisting of: H, halogen, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); and R 2 and R 3 Each of the groups is independently H, F, cyano, CH3, or CF3.

[0178] In various embodiments, the present disclosure also provides compounds of formula (I) or (II), which are compounds of formula (IB), (IC), or (ID):

[0179]

[0180] In Formulas (IB), (IC) and (ID) according to some embodiments, R 1 Selected from the group consisting of: H, halogen, C1-C6 alkoxy, C6-C 10 aryl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); and R 2 and R 3 Each of wherein, when present, is independently H, F, cyano, CH 3 , or CF 3 .

[0181] In additional embodiments, optionally with reference to any one of Formulas (IA), (B), (IC) and (ID), Y 1 、Y 2 、Y 3 and Y 4One of them is N, and each of the other three is CR 5 For example, Y 1 and Y 2 Each of them is CH, and Y 3 For CF.

[0182] In some embodiments, Y 1 、Y 2 、Y 3 and Y 4 Two of them are N, and each of the other two is CR 5 .

[0183] In still further embodiments, the compound containing Y 1 、Y 2 、Y 3 and Y 4 The ring is:

[0184] In an exemplary embodiment, the compound containing Y 1 、Y 2 、Y 3 and Y 4 The ring is:

[0185] In additional embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound is selected from one of Table 1.

[0186] Table 1. Exemplary compounds of the present disclosure.

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213] In additional embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound is selected from Table 2.

[0214] Table 2. Additional exemplary compounds of the present disclosure.

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] Pharmaceutical composition

[0221] The present 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, isotopic conformer and / or tautomer thereof, mixed with a pharmaceutically acceptable carrier. In some embodiments, according to accepted pharmaceutical formulation practices, the composition further contains one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents.

[0222] In one embodiment, the pharmaceutical composition comprises a compound selected from those described in Tables 1 to 16, or a pharmaceutically acceptable salt, stereoisomer, isotopic conformer and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0223] The pharmaceutical compositions of the present disclosure are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific condition being treated, the specific subject being treated, the subject's clinical condition, the cause of the condition, the site of delivery of the medicament, the method of administration, the schedule of administration, and other factors known to medical practitioners.

[0224] The "therapeutically effective amount" of the compound or its pharmaceutically acceptable salt, stereoisomer, isotopic conformer and / or tautomer administered is determined by such considerations and is the minimum amount required to inhibit QPCTL, QPCT, or both. Such an amount may be below an amount that is toxic to normal cells or the subject as a whole. Typically, the initial therapeutically effective amount of the compound of the present disclosure (or its pharmaceutically acceptable salt, stereoisomer, or tautomer) administered is in the range of about 0.01 mg / kg to about 200 mg / kg or about 0.1 mg / kg to about 20 mg / kg of patient body weight per day, with a typical initial range of about 0.3 mg / kg / day to about 15 mg / kg / day. Oral unit dosage forms such as tablets and capsules may contain about 0.1 mg to about 1000 mg of the compound of the present disclosure (or its pharmaceutically acceptable salt, stereoisomer, or tautomer). In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In a further embodiment, such dosage forms contain from about 5 mg to about 50 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form can be administered once a day or twice a day.

[0225] In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, are substantially pure in that they contain less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthesis by-products formed in one or more of the steps of the synthetic methods.

[0226] 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.

[0227] Suitable oral compositions described herein include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs.

[0228] In another aspect, pharmaceutical compositions suitable for use in single unit dosage form are also contemplated, comprising a compound of the present disclosure, or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0229] The compositions of the present disclosure suitable for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions. For example, liquid formulations of the compounds of the present disclosure contain one or more agents selected from the group consisting of sweeteners, flavorings, coloring agents, and preservatives to provide pharmaceutically palatable preparations of the compounds of the present disclosure.

[0230] For tablet compositions, the compounds of the present disclosure are mixed with non-toxic pharmaceutically acceptable excipients for the manufacture of tablets. Examples of such excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binding agents such as starch, gelatin, or gum arabic, and lubricants such as 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, thereby providing a sustained therapeutic effect over the desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0231] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0232] For aqueous suspensions, the compounds of the present disclosure are mixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth, and gum arabic.

[0233] Oral suspensions also can contain dispersants or wetting agents, such as naturally occurring phosphatide for example lecithin or the condensation product of alkylene oxide and fatty acid for example polyoxyethylene stearate or the condensation product of ethylene oxide and long chain fatty alcohol for example 17 ethyleneoxy hexadecanol or the condensation product of ethylene oxide and the partial ester derived from fatty acid and hexitol for example polyoxyethylene sorbitan monooleate or the condensation product of ethylene oxide and the partial ester derived from fatty acid and hexitol anhydride for example polyethylene sorbitan monooleate.Aqueous suspensions also can contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl ester, one or more coloring agents, one or more flavorings and one or more sweeteners, such as sucrose or saccharin.

[0234] Oily suspensions can be formulated by suspending the disclosed compound in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol.

[0235] Sweetening agents such as those listed above, and flavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0236] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the compounds of the present disclosure mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0237] Pharmaceutical compositions of the present disclosure can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring gums (such as gum arabic or tragacanth), naturally occurring phosphatides (such as soybean, lecithin and ester or partial ester derived from fatty acid and hexitol), anhydrides (such as sorbitan monooleate) and the condensation reaction product of the partial ester and ethylene oxide (such as polyoxyethylene sorbitan monooleate). The emulsion can also contain sweeteners and flavorings.

[0238] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, preservative, and flavoring and coloring agents. Pharmaceutical compositions may be in the form of sterile injectables, aqueous suspensions, or oily suspensions. Such suspensions may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0239] The compounds 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 that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0240] Compositions for parenteral administration are administered in a sterile medium. Depending on the vehicle used and the concentration of the drug concentrated in the formulation, the parenteral formulation may be a suspension or a solution containing the dissolved drug. Adjuvants such as local anesthetics, preservatives, and buffers may also be added to the parenteral composition.

[0241] How to use

[0242] The compounds of the present disclosure are surprisingly potent inhibitors of glutaminyl-peptide cyclotransferase protein (QPCT) or glutaminyl-peptide cyclotransferase-like protein (QPCTL). In various embodiments, the compounds can be used in methods of treating a patient suffering from a disease, wherein the disease is associated with the expression of QPCT or QPCTL. The methods comprise administering to the patient a compound as described herein or a pharmaceutically acceptable salt and / or solvate thereof. The compound or a pharmaceutically acceptable salt thereof is optionally administered in a pharmaceutical composition according to the present disclosure and is administered by any of the routes of administration as described herein.

[0243] In some embodiments, the disease is cancer, such as leukemia or lymphoma. Examples of leukemias or lymphomas include acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), Burkitt's 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 (BCL), and leukemia. leukemia, B-CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and pre-B acute lymphoblastic leukemia (pre-B ALL).

[0244] In additional embodiments, the cancer is selected from the group consisting of multiple myeloma (MM), ovarian cancer, glioma, colon cancer, breast cancer, bladder cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, mesothelioma, melanoma, glioma, glioblastoma and pancreatic neuroendocrine tumor.

[0245] 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.

[0246] The compounds of the present disclosure are potent inhibitors of QPCT, which is a druggable target for the treatment of various neurodegenerative diseases (M. Jimenez-Sanchez et al., Nat Chem Biol. 11(5)(2015)347-354). These neurogenic diseases 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 therapies are contemplated in which the compounds of the present disclosure are administered in combination with antibodies that clear amyloid-β (Aβ) protein plaques in the brain. Various monoclonal antibodies that bind to different epitopes and conformations of Aβ are known in the art and are suitable for this purpose, including but not limited to Bapineuzumab, Solanezumab, Gantenerumab, Crenezumab, Ponezumab, BAN2401 and Aducanumab (see CH van Dyck Biol. Psych. 83(4) (2018) 311–319).

[0247] 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, e.g., N. Kanemitsu et al., Naunyn Schmiedebergs Arch Pharmacol. 394(4), 751(2021)).

[0248] In further embodiments, the disease is cardiovascular disease.In illustrative embodiments, the cardiovascular disease is atherosclerosis.

[0249] In some embodiments, optionally in combination with any other embodiment described herein, a compound of formula (I) or (II) or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and LAG-3 inhibitors.

[0250] In a further embodiment, the compound or a pharmaceutically acceptable salt and / or solvate thereof is administered in combination with an opsonic antibody.Osonic antibodies are well known in the art and include IgG and IgM.

[0251] In additional embodiments, the present disclosure provides 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 as described herein. In one embodiment, the contacting is performed in vitro. In another embodiment, the contacting is performed in vivo.

[0252] Also provided are compounds as described herein, or pharmaceutically acceptable salts and / or solvates thereof, for use in treating cancer, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, or cardiovascular diseases. The present disclosure also provides uses of compounds as described herein, or pharmaceutically acceptable salts and / or solvates thereof, in the manufacture of medicaments for treating cancer, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, or cardiovascular diseases.

[0253] Other embodiments and uses will be apparent to those of ordinary skill in the art in light of this disclosure.The following examples are provided to illustrate and provide various embodiments and should not be construed as limiting the present disclosure in any way.

[0254] Example

[0255] Preparation of compounds

[0256] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those of ordinary skill in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. “Commercially available chemicals” were 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, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), 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, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), 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).

[0257] Suitable reference books and treatises that detail the synthesis of reactants used to prepare the compounds described herein, or provide references to articles describing the preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd edition, W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants used to prepare the compounds described herein or provide references to articles describing the preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "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.(Ed.) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "IndustrialOrganic 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.

[0258] Specific and similar reactants are optionally identified by indexing known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which is available in most public and university libraries, as well as through online databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis companies, many of which standard chemical supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl & C.G. Wermuth, "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0259] General synthetic scheme

[0260] The compounds disclosed herein are prepared by a variety of synthetic routes, including but not limited to those depicted in Schemes I or II below.

[0261] As shown below in Scheme 1, appropriately functionalized 2-fluoro-3-bromobenzonitriles can undergo nucleophilic aromatic substitution reactions with substituted piperidines to provide piperidinyl-substituted bromoarenes. One of ordinary skill in the art will appreciate that various organic synthesis methods can be applied to prepare substituted 2-fluoro-3-bromobenzonitriles.

[0262] The compounds of the present disclosure can be synthesized by various transition metal-mediated cross-coupling reactions (e.g., Suzuki or Stille methods). As shown in Scheme II below, trialkylstannane arenes, heteroarylboronic acids, or heteroarylboronic esters can be cross-coupled with intermediate cyano-bromoarenes under palladium catalysis to provide the final compounds.

[0263] Plan I

[0264]

[0265] Scheme II illustrates the use of tetrakis(triphosphine)palladium(0) with a stannane reagent for a Stille-type reaction and the use of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with a heteroarylboronic acid for a Suzuki-type coupling. One of ordinary skill in the art will appreciate that there are many palladium catalysts and reaction conditions that can be used for these types of cross-coupling reactions.

[0266] Option II

[0267]

[0268] I. Chemical Synthesis

[0269] As used below and throughout this disclosure, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0270] ACN acetonitrile

[0271] AcOH acetic acid

[0272] AMPhos Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)

[0273] ℃ degrees Celsius

[0274] δ H Chemical shift of tetramethylsilane to the front field in parts per million

[0275] d day

[0276] DCM dichloromethane

[0277] DIAD Diisopropyl azodicarboxylate

[0278] DIEA Diisopropylethylamine

[0279] DMF dimethylformamide

[0280] DMF-DMA dimethylformamide dimethyl acetal

[0281] DMSO dimethyl sulfoxide

[0282] dppf 1,1'-bis(diphenylphosphino)ferrocene

[0283] dcypf 1,1'-Bis(di-cyclohexylphosphino)ferrocene

[0284] EA Ethyl acetate

[0285] EtOAc

[0286] EtOH

[0287] ESI electrospray ionization

[0288] Et ethyl

[0289] g grams

[0290] h hour

[0291] hr hours

[0292] HPLC high-performance liquid chromatography

[0293] Hz Hertz

[0294] J coupling constant (in NMR spectroscopy)

[0295] LCM S liquid chromatography mass spectrometry

[0296] μ micrometer

[0297] m multiplet (spectrum); meter; millimeter

[0298] M Moore

[0299] M + Parent molecular ion

[0300] Me methyl

[0301] MeOH methanol

[0302] mg milligrams

[0303] MsCl methanesulfonyl chloride

[0304] MHz Millihertz

[0305] min

[0306] mol mole; molecule (e.g., mol wt)

[0307] mL milliliters

[0308] MS

[0309] nm nanometer

[0310] NMR Nuclear Magnetic Resonance

[0311] pH Hydrogen index; a measure of acidity or alkalinity

[0312] PE petroleum ether

[0313] RT Room temperature

[0314] s singlet (spectrum)

[0315] t triplet state (spectrum)

[0316] SFC Supercritical Fluid Chromatography

[0317] T temperature

[0318] TBAB Tetrabutylammonium Bromide

[0319] TBDMS tert-butyldimethylsilyl

[0320] TEA triethylamine

[0321] TFA trifluoroacetic acid

[0322] THF Tetrahydrofuran

[0323] TPP Triphenylphosphine

[0324] Synthesis of intermediates

[0325] Intermediate 1: 3-Bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0326]

[0327] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine hydrochloride (2 g, 9.9 mmol) and 3-bromo-2-fluorobenzonitrile (2.2 g, 11 mmol) in DMSO (80 mL) was added DIEA (5.1 g, 4 mmol). The resulting mixture was stirred at 130 ° C for 15 h. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1: 1) to give 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] + .

[0328] Intermediate 2: 3-Bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile

[0329]

[0330] A solution of imidazole (2.4 g, 35.8 mmol) in DMF (120 mL) was treated with NaH (0.86 g, 35.8 mmol) at 0 ° C. under a nitrogen atmosphere for 25 min, 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 at 80 ° C. under a nitrogen atmosphere for 2 h. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5: 1) to give tert-butyl 4-(imidazol-1-yl)piperidine-1-carboxylate (1.5 g, 33%) as a yellow oil. LCMS (ESI) m / z: 252 [M + H] + .

[0331] 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 at room temperature for 1 h. The reaction mixture was evaporated and partitioned between saturated aqueous K2CO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 4-(imidazol-1-yl)piperidine (600 mg, 66%) as a light yellow oil. LCMS (ESI) m / z: 152 [M+H] + .

[0332] To a stirred solution of 4-(imidazol-1-yl)piperidine (600 mg, 3.96 mmol) in DMSO (150 mL) was added 3-bromo-2-fluorobenzonitrile (1190.4 mg, 5.95 mmol) and DIEA (2564.2 mg, 19.8 mmol) in batches at room temperature. The resulting mixture was stirred at 120 ° C. under a nitrogen atmosphere for 2 days. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (5: 1) to give 3-bromo-2-[4-(imidazol-1-yl)piperidin-1-yl]benzonitrile. LCMS (ESI) m / z: 331,333 [M + H] + .

[0333] Intermediate 3: 1-Bromo-3-cyano-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzene

[0334]

[0335] 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 H2O (12 mL) / dioxane (72 mL) was added K2CO3 (6704 mg, 48.5 mmol) and Pd(dppf)Cl2 (1317 mg, 1.6 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 3 h. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (0%-20%) to give tert-butyl 4-(1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.8 g, 88%) as a brown oil. LCMS (ESI) m / z: 267 [M+H] + .

[0336] 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) at room temperature under a hydrogen atmosphere was added Pd / C (1.5 g) in portions. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 26 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(1,3-thiazol-5-yl)piperidine-1-carboxylate (1.9 g, 63%) as a yellow oil. LCMS (ESI) m / z: 269 [M+H] + .

[0337] 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. The resulting mixture was concentrated under reduced pressure to give 4-(1,3-thiazol-5-yl)piperidine hydrochloride (1.43 g, 98%) as an off-white solid. LCMS (ESI) m / z: 169 [M+H] + .

[0338] A mixture of 4-(1,3-thiazol-5-yl)piperidine hydrochloride (500 mg, 2.44 mmol), 1-bromo-2-fluoro-3-cyanobenzene (488.5 mg, 2.4 mmol) and DIEA (1262.7 mg, 9.8 mmol) in DMSO (5 mL) was stirred at 120 ° C for 16 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (40%-60%) to give 1-bromo-3-cyano-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzene (143.2 mg, 17%) as a yellow oil. LCMS (ESI) m / z: 348, 350 [M+H] + .

[0339] Intermediate 4: 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile

[0340]

[0341] At room temperature under nitrogen atmosphere, to a stirred solution of tert-butyl 4-cyanopiperidine-1-carboxylate (5g, 23.7mmol) in TFA (120mL), thiosemicarbazide (3.2g, 35.6mmol) was added in batches. The resulting mixture was stirred at 65 ° C overnight. The resulting mixture was concentrated under reduced pressure. 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), 1% to 10% gradient in 20min; detector, UV 254nm. To obtain colorless oily 5- (piperidin-4-yl) -1,3,4- thiadiazole -2-amine (4g, 91%). LCMS (ESI) m / z: 185 [M + H] + .

[0342] To a stirred solution of 5-(piperidin-4-yl)-1,3,4-thiadiazol-2-amine (3 g, 16.3 mmol) in DMSO (60 mL) was 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 × 80 mL). The combined organic layers were washed with brine (3 × 60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (5: 1) to give 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-bromobenzonitrile (450 mg, 8%) as a brown solid. LCMS (ESI) m / z: 364, 366 [M+H] + .

[0343] Intermediate 5: 3-Bromo-2-[4-(3-methyl-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile

[0344]

[0345] A mixture of acetic hydrazide (5 g, 67.5 mmol) and DMF-DMA (8 g, 67.5 mmol) in ACN (70 mL) was stirred at 50 ° C for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification. LCMS (ESI) m / z: 130 [M+H] + .

[0346] A mixture of N'-[(1E)-(dimethylamino)methylene (methylidene)]acetohydrazide (2g, 15.5mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (3.7g, 18.6mmol) in AcOH (40mL) and ACN (10mL) was stirred at 120 ° C for 16h. The reaction was quenched by adding water (150mL) at room temperature. The resulting mixture was extracted with EtOAc (2×100mL). The combined organic layers were washed with brine (80mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (0-10%) to give tert-butyl 4-(3-methyl-1,2,4-triazol-4-yl)piperidine-1-carboxylate (1.99g, 48%) as a yellow oil. LCMS (ESI) m / z: 267 [M+H] + .

[0347] 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 at room temperature for 2 h. The reaction was quenched by adding saturated aqueous K2CO3 (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (20-30%) to give 4-(3-methyl-1,2,4-triazol-4-yl)piperidine (1 g, 84%) as a yellow oil.

[0348] 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 at 120 ° C for 16 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / CH2Cl2 (0-10%) to give 3-bromo-2-[4-(3-methyl-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile (200 mg, 10%) as a yellow oil. LCMS (ESI) m / z: 346, 348 [M+H] + .

[0349] Intermediate 6: 3-Bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0350]

[0351] To a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (9 g, 54.1 mmol) in DMSO (150 mL) was 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 at 120 ° C overnight. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (5: 1) to give 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (2.7 g, 13%) as a dark red solid. LCMS (ESI) m / z: 380, 382 [M+H] + .

[0352] Intermediate 7: 3-Bromo-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0353]

[0354] To a stirred solution of intermediate 6 (500 mg, 1.3 mmol) in DMF (12 mL) was added K2CO3 (363 mg, 2.6 mmol) and CH3ONa (212.9 mg, 3.9 mmol) in portions at room temperature. The resulting mixture was stirred at 120 ° C for 2 h. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to obtain intermediate 7 (350 mg, 71%). LCMS (ESI) m / z: 376,378 [M+H] + .

[0355] Intermediate 8: 3-Bromo-2-[4-(3-methylimidazol-4-yl)piperidin-1-yl]benzonitrile

[0356]

[0357] At room temperature, to a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (5 g, 14.6 mmol) in anhydrous 1,4-dioxane (50 mL) and H2O (10 mL), K2CO3 (4 g, 29.1 mmol) and Pd(dppf)Cl2 (1.07 g, 1.5 mmol) were added followed by 5-bromo-1-methylimidazole (2.3 g, 14.6 mmol). The reaction mixture was stirred at 100 ° C for 6 h. After completion of the reaction, the reaction mixture was quenched by adding water (40 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using (10% to 50% MeOH / DCM) to give the desired compound, 4-(3-methylimidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (3 g). LCMS (ESI) m / z: 298 [M+H] + .

[0358] A solution of 4- (3- methyl -1,2- dihydroimidazol-4-yl) -3,6- dihydro -2H- pyridine -1- carboxylic acid benzyl ester (3g, 10mmol) and Pd / C (2.7g) in MeOH (50mL) was stirred at room temperature under a hydrogen atmosphere for 16h. The resulting mixture was filtered and the filter cake was washed with MeOH (100mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (12: 1) to give 4- (3- methyl -1,2- dihydroimidazol-4-yl) piperidine (2g) as a brown solid. LCMS (ESI) m / z: 166 [M + H] + .

[0359] A solution of 4-(3-methylimidazol-4-yl)piperidine (400 mg, 2.4 mmol), 3-bromo-2-fluorobenzonitrile (581 mg, 2.9 mmol) and DIEA (938.6 mg, 7.26 mmol) in DMSO (20 mL) was stirred at 120 ° C for 6 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layer was washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12: 1) to give 3-bromo-2-[4-(3-methylimidazol-4-yl)piperidin-1-yl]benzonitrile (100 mg, 12%) as a yellow solid. LCMS (ESI) m / z: 345,347 [M+H]+ .

[0360] Intermediate 9: 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0361]

[0362] To a stirred solution of 3,4-dichloro-2-fluorobenzaldehyde (4g, 20.7mmol) in anhydrous DCM (50mL) at 0°C, TEA (6.29g, 62.2mmol) and NH2OH.HCl (10.8mg, 0.16mmol) were added. The reaction mixture was stirred at room temperature for 12h. After completion of the reaction, the reaction mixture was quenched by adding water (50mL). The resulting mixture was extracted with CH2Cl2 (300mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (E)-N-[(3,4-dichloro-2-fluorophenyl)methylene]hydroxylamine (3.2g) as a brown solid. LCMS (ESI) m / z: 209[M+H] + .

[0363] To a stirred solution of (E)-N-[(3,4-dichloro-2-fluorophenyl)methylene]hydroxylamine (3.2 g, 15.38 mmol) in anhydrous toluene (50 mL) was added SOCl2 (2.75 g, 23.08 mmol) at 0 ° C. The reaction mixture was stirred at 120 ° C for 2 h. After completion of the reaction, the reaction mixture was quenched by adding 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 a crude product, which was further purified by column chromatography using a gradient of 5% to 20% EtOAc in PE to give the desired compound 3,4-dichloro-2-fluorobenzonitrile (2.3 g). LCMS (ESI) m / z: 191 [M + H] + .

[0364] At room temperature, to a stirred solution of 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (700 mg, 4.21 mmol) in anhydrous DMSO (50 mL), 3,4-dichloro-2-fluorobenzonitrile (720.1 mg, 3.79 mmol) and DIEA (2.18 g, 16.8 mmol) were added. The reaction mixture was stirred at 120 ° C for 12 h. After completion of the reaction, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using a gradient of 5% to 15% MeOH in DCM to give the desired compound 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg). LCMS (ESI) m / z: 337 [M+H] + .

[0365] 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 2 h. After completion of the reaction, the reaction mixture was quenched by adding water (50 mL). The aqueous layer was extracted with ethyl acetate (300 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was further purified by column chromatography using a gradient of 5% to 15% MeOH in DCM to give 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] + .

[0366] Intermediate 10: 3-bromo-2-{4-[4-( 2 H3) methyl-1,2,4-triazol-3-yl]piperidin-1-yl}benzonitrile

[0367]

[0368] 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) at room temperature. The resulting mixture was stirred at 50 ° C for 2 h. (2H ) methylamine hydrochloride (6.1 g, 86.3 mmol) and AcOH (25.9 g, 432 mmol) were added in batches at 50 ° C for 20 min. The resulting mixture was stirred at 90 ° C for an additional 16 h. The resulting mixture was concentrated under reduced pressure and quenched by adding water (100 mL) at room temperature. The mixture was alkalized to pH 7 with saturated Na CO (aqueous). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layer was washed with water (2 × 200 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in CH2Cl2 (10%-15%) to give tert-butyl 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate (7 g, 60%) as a yellow oil. LCMS (ESI) m / z: 270 [M+H] + .

[0369] At room temperature, HCl in 1,4-dioxane (100 mL) was added portionwise to tert-butyl 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate (7 g, 25.9 mmol). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give 4-[4-(2H3)methyl-1,2,4-triazol-3-yl]piperidine hydrochloride (5 g) as a white solid. The crude product mixture was used directly in the next step without further purification. LCMS (ESI) m / z: 170 [M+H] + .

[0370] 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) at room temperature was added DIEA (9.4 g, 72.9 mmol) in portions. The resulting mixture was stirred at 120°C for 16 h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 40% to 50% gradient over 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] + .

[0371] Intermediate 11: 3-Bromo-2-[4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0372]

[0373] At room temperature under a nitrogen atmosphere, to a stirred solution of 4-cyanopiperidine-1-carboxylic acid benzyl ester (9.6 g, 39.3 mmol) and N-formyl hydrazide (2.4 g, 40 mmol) in MeOH (20 mL), NaOMe (0.64 g) was added in batches. The resulting mixture was stirred at 60 ° C under a nitrogen atmosphere for 72 h. 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 and eluted with PE / EA (1: 1) to give 4- (4H-1,2,4-triazol-3-yl) piperidine-1-carboxylic acid benzyl ester (2.4 g, 21%) as a white solid. LCMS (ESI) m / z: 287 [M + H] + .

[0374] Under a nitrogen atmosphere, Pd / C (10%, Pd / C (0.19 g)) was added 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). The mixture was hydrogenated using a hydrogen balloon at room temperature for 2 h under a hydrogen atmosphere, filtered through a celite pad and concentrated under reduced pressure. The resulting filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give 4-(4H-1,2,4-triazol-3-yl)piperidine (640 mg, 46%) as a white solid. LCMS (ESI) m / z: 153 [M+H] +.

[0375] Under a nitrogen atmosphere, DIEA (1630 mg) was added dropwise 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). The resulting mixture was stirred at 120 ° C for 12 h. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give 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] + .

[0376] Intermediate 12: 3-Bromo-5-methyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0377]

[0378] A solution of 3-bromo-2-fluoro-5-methylbenzaldehyde (1 g, 4.6 mmol) and hydroxylamine-o-sulfonic acid (0.89 g, 7.8 mmol) in H2O (10 mL) was stirred at room temperature for 10 min, then stirred at 50 ° C under a nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to give 3-bromo-2-fluoro-5-methylbenzonitrile (879 mg, 89%) as a white solid. LCMS (ESI) m / z: 214,216 [M + H] + .

[0379] 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 a nitrogen atmosphere. The resulting mixture was stirred at 140 ° C for 16 h. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 9:1) to give 3-bromo-5-methyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (156 mg, 10%) as a white solid. LCMS (ESI) m / z: 360, 362 [M+H] + .

[0380] Intermediate 13: 3-Bromo-5-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0381]

[0382] A solution of 3-bromo-5-chloro-2-fluorobenzaldehyde (1 g, 4.2 mmol) and aminooxysulfonic acid (0.81 g, 7.2 mmol) in water (10 mL) was stirred at 50 ° C for 1 h. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to give 3-bromo-5-chloro-2-fluorobenzonitrile (900 mg, 91%) as a yellow solid. LCMS (ESI) m / z: 234,236 [M + H] + .

[0383] 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 KCO (2151.6 mg, 15.6 mmol) in DMSO (5 mL) was stirred at 90° C. for 1 h. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient over 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] + .

[0384] Intermediate 14: 3-Bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)benzonitrile

[0385]

[0386] A solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (500 mg, 1.8 mmol) and (aminooxy)sulfonic acid (354.7 mg, 3.1 mmol) in H2O (10 mL) was stirred at 50 ° C under a nitrogen atmosphere for 2 h. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0%-10%) to give 3-bromo-2-fluoro-5-(trifluoromethyl)benzonitrile (200 mg) as a white solid. LCMS (ESI) m / z: 268,270 [M+H] + .

[0387] 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 × 150 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-5-(trifluoromethyl)benzonitrile (180 mg) as a pink oil. LCMS (ESI) m / z: 414, 416 [M+H] + .

[0388] Intermediate 15: 3-Bromo-2-[4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl]benzonitrile

[0389]

[0390] A solution of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (5 g, 19 mmol), N-formylhydrazide (1.48 g, 24.7 mmol), HATU (8.66 g, 22.8 mmol) and DIPEA (6.38 g, 49.4 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (5 × 100 mL). The combined organic layers were washed with brine (5 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give benzyl 4-(N'-formylhydrazidecarbonyl)piperidine-1-carboxylate (4.5 g, 77%) as a white solid. LCMS (ESI) m / z: 306 [M+H] + .

[0391] A solution of benzyl 4-(N'-formylhydrazidecarbonyl)piperidine-1-carboxylate (4.50 g, 14.7 mmol) and Lawesson's reagent (6.56 g, 16.2 mmol) in dioxane (30 mL) was stirred at 100 ° C for 3 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layer was washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 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] + .

[0392] A solution of benzyl 4-(1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (210 mg, 0.69 mmol) in dioxane (1 mL) and HBr (2 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. LCMS (ESI) m / z: 170 [M+H] + .

[0393] A solution of 4-(1,3,4-thiadiazol-2-yl)piperidine (150 mg, 0.89 mmol), 3-bromo-2-fluorobenzonitrile (177 mg, 0.89 mmol) and DIEA (572.7 mg, 4.43 mmol) in DMSO (4 mL) was heated at 120 ° C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm, to give 3-bromo-2-[4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl]benzonitrile (50 mg, 16%) as a yellow oil. LCMS (ESI) m / z: 349,351 [M+H] + .

[0394] 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

[0395]

[0396] A solution of (1R, 5S)-3-benzyl-3-azabicyclo[3.1.0]hexane-6-carbohydrazide (3 g, 12.2 mmol) and NH2NH2.H2O (18.4 g, 366.9 mmol) in EtOH (30 mL) was stirred at 80 ° C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to obtain (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] + .

[0397] 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) and THF (5 mL) was stirred at 50 ° C for 1 h. CH 3 NH 2 -HCl (0.35 g, 5.2 mmol) and HOAc (2.6 g, 43.2 mmol) were added dropwise to the above mixture at room temperature over 10 min. The resulting mixture was stirred at 90 ° C for an additional 15 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give (1R,5S)-3-benzyl-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (1 g, 91%) as a light yellow oil. LCMS (ESI) m / z: 255 [M+H] + .

[0398] A solution of (1R, 5S) -3-benzyl -6- (4- methyl -1,2,4- triazol -3- yl) -3- azabicyclo [3.1.0] hexane (1 g, 3.9 mmol) and Pd / C (1 g, 9.4 mmol) in MeOH (50 mL) was stirred at 60 ° C under a hydrogen atmosphere (5 atm) for 5 h. The resulting mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the desired product (660 mg) as a light yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 165 [M + H] + .

[0399] A solution of (1R,5S)-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexane (600 mg, 3.6 mmol), 3-bromo-2-fluorobenzonitrile (877 mg, 4.4 mmol) and DIEA (1416.7 mg, 10.9 mmol) in DMSO (10 mL) was stirred at 120 ° C for 12 h. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were extracted with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-bromo-2-[(1R,5S)-6-(4-methyl-1,2,4-triazol-3-yl)-3-azabicyclo[3.1.0]hexan-3-yl]benzonitrile (90 mg, 4%) as a pale yellow oil. LCMS (ESI) m / z: 344, 346 [M+H] + .

[0400] Intermediate 17: 5-chloro-4-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzene-1,3-dicarbonitrile

[0401]

[0402] At room temperature under a nitrogen atmosphere, to a stirred solution of 5-bromo-3-chloro-2-fluorobenzonitrile (3 g, 12.8 mmol) in DMSO (150 mL), TEA (10.8 g, 106.6 mmol) and 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (3.5 g, 21.3 mmol) were added in batches. The resulting mixture was stirred at 80 ° C overnight. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8:1) to give 5-bromo-3-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (2.3 g, 28%) as a yellow solid.

[0403] A mixture of 5-bromo-3-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 1.31 mmol) and CuCN (176.5 mg, 1.97 mmol) in DMSO (10 mL) was stirred at 120 ° C. under a nitrogen atmosphere for 2 days. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (9: 1) to give 5-chloro-4-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzene-1,3-dicarbonitrile (160 mg, 37%) as a yellow solid. LCMS (ESI) m / z: 327 [M+H] + .

[0404] Intermediate 18: 3-chloro-5-methanesulfonyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0405]

[0406] 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) was added methyl[2-(methylamino)ethyl]amine (55.6 mg, 0.63 mmol), sodium methanesulfonate (80.4 mg, 0.79 mmol), and trifluoromethanesulfonate copper(I) benzene complex (39.7 mg, 0.08 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 20% to 40% over 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 oil. LCMS (ESI) m / z: 380 [M+H] + .

[0407] Intermediate 19: 5-Bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile

[0408]

[0409] A solution of 6-amino-3-bromo-2-fluorobenzonitrile (5 g, 23.2 mmol), trifluoroacetic anhydride (5.9 g, 27.9 mmol) and TEA (7.1 g, 69.7 mmol) in DCM (25 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give 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] + .

[0410] A solution of N-(4-bromo-2-cyano-3-fluorophenyl)-2,2,2-trifluoroacetamide (6 g, 19.3 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (6.4 g, 38.6 mmol) and CsF (8.8 g, 57.9 mmol) in DMSO (25 mL) was stirred at 140 ° C for 16 h. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 6-amino-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 7%) as a light yellow oil. LCMS (ESI) m / z: 361, 363 [M+H] + .

[0411] A solution of 6-amino-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 1.6 mmol) and NIS (373.7 mg, 1.6 mmol) in AcOH (15 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (8: 1) to give 2-amino-5-bromo-3-iodo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (900 mg, 75%) as a light brown oil. LCMS (ESI) m / z: 487,489 [M+H] + .

[0412] 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), KCO (510.7 mg, 3.7 mmol) and Pd(dppf)Cl (135.2 mg, 0.18 mmol) in 1,4-dioxane (20 mL) was stirred at 80° C. under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8:1) to give 2-amino-5-bromo-3-methyl-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 86%) as a light yellow oil. LCMS (ESI) m / z: 375, 377 [M+H] + .

[0413] A solution of 2-amino-5-bromo-3-methyl-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (600 mg, 1.6 mmol) in CHCl3 (10 mL) was treated with Ac2O (359.1 mg, 3.5 mmol) at 0 ° C for 10 min, and then isoamyl nitrite (430.8 mg, 3.7 mmol) and AcOK (47.1 mg, 0.48 mmol) were added in batches at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (8: 1) to give 5-bromo-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-1H-indazole-7-carbonitrile (50 mg, 8%) as a light yellow oil. LCMS (ESI) m / z: 386, 388 [M+H] + .

[0414] Intermediate 20: 3-Bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0415]

[0416] A mixture of 3-bromo-4-methyl-1,2,4-triazole (1 g, 6.2 mmol) in tert-butyl piperazine-1-carboxylate (5 g, 26.8 mmol) was stirred at 90° C. for 2 days. The residue was purified by silica gel column chromatography eluting with CH 2 Cl 2 / MeOH (0%-10%) and then purified by preparative HPLC under the following conditions (column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 28% B to 40% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.62) to give 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] + .

[0417] A mixture of tert-butyl 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate (1.2 g, 4.48 mmol) in TFA (2 mL) and DCM (10 mL) was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure, and the crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 168 [M+H] + .

[0418] 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) at room temperature, TEA (302.6 mg, 3 mmol) was added in portions. The resulting mixture was stirred at 90 ° C overnight. Water (20 mL) was added to the reaction and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (0%-10%) to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-yl]benzonitrile (70 mg) as a brown solid. LCMS (ESI) m / z: 347, 349 [M+H] + .

[0419] Intermediate 21: 3-Bromo-4-chloro-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0420]

[0421] 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 at 80 ° C for 16 h. Water (500 mL) was added to the reaction and extracted with EtOAc (3×800 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 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] + .

[0422] To a stirred mixture of 4-chloro-2-fluoro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (15 g, 47 mmol) in H2SO4 (50 mL) at 0 ° C was added NBS (16.7 g, 93.8 mmol). The resulting mixture was stirred at room temperature for 16 h. Water (600 ml) was added to the reaction mixture at 0 ° C. The mixture was basified to pH 8 with saturated Na2CO3 (aqueous). The resulting mixture was extracted with EtOAc (3×1 L). The combined organic layers were washed with brine (2×150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 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] + .

[0423] A mixture of 3-bromo-4-chloro-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1 g, 2.5 mmol) and CH3ONa (203.3 mg, 3.8 mmol) in MeOH (15 mL) was stirred at room temperature for 8 h. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3-bromo-4-chloro-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (750 mg) as an off-white solid. LCMS (ESI) m / z: 410, 412 [M+H] + .

[0424] Intermediate 22: 3-Bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0425]

[0426] 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 at 80 ° C overnight. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (150 mg) as a brown solid. LCMS (ESI) m / z: 381, 383 [M+H] + .

[0427] Intermediate 23: 3-Chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0428]

[0429] A mixture of 3,4-dichloro-2-fluorobenzaldehyde (5 g, 25.9 mmol) and aminooxysulfonic acid (5.3 g, 46.6 mmol) in H2O (150 mL) was stirred at 50 ° C overnight. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The residue was purified by silica gel column chromatography and eluted with PE / EA (0%-10%) to give 3,4-dichloro-2-fluorobenzonitrile (3.3 g, 67%) as an off-white solid. LCMS (ESI) m / z: 191 [M + H] + .

[0430] 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 at 90 ° C overnight. The reaction was quenched by adding water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 160 mL). The combined organic layer was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3,4-dichloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (180 mg, 18%) as a light brown solid. LCMS (ESI) m / z: 338 [M+H] + .

[0431] 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 at 120 ° C for 8 h. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×110 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3-chloro-4-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (50 mg, 66%) as a light yellow solid. LCMS (ESI) m / z: 321 [M+H] + .

[0432] Intermediate 24: 3-Bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile

[0433]

[0434] 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 at 90 ° C overnight. The reaction was quenched by adding water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 90 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 3-bromo-6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (120 mg, 17%) as a brown oil. LCMS (ESI) m / z: 381, 383 [M+H] + .

[0435] Intermediate 25: 3-Bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0436]

[0437] A solution of 3-bromo-2,5-difluorobenzonitrile (1 g, 4.6 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (0.9 g, 5.5 mmol) and TEA (1.4 g, 13.8 mmol) in DMSO (25 mL) was stirred at 80 ° C for 16 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to give 3-bromo-5-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (140 mg, 7%) as a light yellow oil. LCMS (ESI) m / z: 364, 366 [M+H] + .

[0438] 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

[0439]

[0440] A solution of 2-bromo-4-chloro-6-fluoroaniline (25 g, 111.4 mmol), KCN (14.5 g, 222.7 mmol), NOBF4 (13 g, 111.4 mmol) and CuSO4 (53.3 g, 334.1 mmol) in DCM (50 mL) was stirred at room temperature for 2 h. The reaction was quenched with Fe2SO4 saturated sodium thiosulfate (aqueous) at room temperature. The mixture was basified to pH 10 with saturated NaHCO3 (aqueous). The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to give 2-bromo-4-chloro-6-fluorobenzonitrile (10 g, 38%) as a light yellow oil. LCMS (ESI) m / z: 234, 236 [M+H] + .

[0441] 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 at 80 ° C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to give 2-bromo-4-chloro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1.1 g, 11%) as a light yellow oil. LCMS (ESI) m / z: 380, 382 [M+H] + .

[0442] A solution of 2-bromo-4-chloro-6-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (1.1 g, 2.9 mmol) and NIS (0.65 g, 2.9 mmol) in H2SO4 (20 mL) was stirred at room temperature for 2 h. The mixture was basified to pH 10 with NaOH. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 6-bromo-4-chloro-3-iodo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (400 mg, 23%) as a light yellow solid. LCMS (ESI) m / z: 506, 508 [M+H] + .

[0443] 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), KCO (0.33 g, 2.37 mmol) and Pd(dppf)Cl (0.06 g, 0.08 mmol) in 1,4-dioxane (16 mL) and HO (2 mL) was stirred at 90° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 6-bromo-4-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (270 mg, 68%) as a light yellow oil. LCMS (ESI) m / z: 475, 477 [M+H] + .

[0444] Intermediate 27: Iodo-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile

[0445]

[0446] 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 at 80 ° C for 16 h. Water (10 mL) was added to the reaction mixture at room temperature and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in CH2Cl2 (0%-10%) to give 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] + .

[0447] Intermediate 28: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile

[0448]

[0449] 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 at 80 ° C for 2 h. Water was added at room temperature and extracted with EtOAc (2 × 150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / CH2Cl2 (0-10%) to give 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (1 g, 26%) as a red solid. LCMS (ESI) m / z: 303 [M+H] + .

[0450] Intermediate 29: 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidinyl]isonicotinonitrile

[0451]

[0452] 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), KCO (1.61 g, 11.7 mmol), and Pd(dppf)Cl.DCM (238 mg, 0.29 mmol) was dissolved in 1,4-dioxane (19.4 mL) and water (5 mL). The reaction was heated at 100° C. for 30 minutes. The reaction was quenched with water, extracted with EtOAc, and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% Hex: [25% EtOH in EtOAc]) to give benzyl 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylate (1.15 g, 66%) as a brown oil.

[0453] A solution of 4-(1-methyl-5-imidazolyl)-1,2,3,6-tetrahydro-1-pyridinecarboxylic acid benzyl ester (1.15 g, 3.87 mmol) was dissolved in MeOH (13 mL) and Pd / C (250 mg) was added. The reaction vessel was placed under a hydrogen atmosphere and stirred at room temperature over the weekend. The mixture was filtered through celite and washed with methanol. The solution was dried under vacuum to obtain an orange residue. The residue was dissolved in Et2O (50 mL) and MeOH (1 mL), and HCl gas was bubbled through the reaction mixture. The resulting precipitate was filtered and dried under vacuum to give 1-methyl-5-(4-piperidinyl)imidazole-hydrochloride (658 mg, 84%) as a tan solid. LCMS (ESI) m / z: 166 [M+H] + .

[0454] To a mixture of 1-methyl-5-(4-piperidinyl)imidazole-hydrochloride (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. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (0% to 100%, Hex: [25% EtOH in EtOAc]) to give 2-chloro-3-[4-(1-methyl-5-imidazolyl)-1-piperidinyl]isonicotinonitrile (46 mg, 31%). LCMS (ESI) m / z: 302 [M+H] + .

[0455] Intermediate 30: 2-chloro-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]pyridine-4-carbonitrile

[0456]

[0457] 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 at 80 ° C under a nitrogen atmosphere overnight. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0%-10%) to give 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] + .

[0458] Intermediate 31: 2-chloro-5-methoxy-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile

[0459]

[0460] A solution of 3,5-difluoropyridine-4-carbonitrile (5 g, 35.7 mmol), 4-(4-methyl-1,2,4-triazol-3-yl)piperidine (5.93 g, 35.7 mmol) and TEA (18.1 g, 178.4 mmol) in DMSO (25 mL) was stirred at 80 ° C for 3 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to give 3-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] + .

[0461] A solution of 3-fluoro-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (1 g, 3.49 mmol) and sodium methoxide (0.23 g, 4.19 mmol) in MeOH (15 mL) was stirred at 50 ° C for 30 min. The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (2×80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to give 3-methoxy-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (440 mg, 42%) as a light yellow oil. LCMS (ESI) m / z: 299 [M+H] + .

[0462] A solution of 3-methoxy-5-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (440 mg, 1.47 mmol) and sodium hypochlorite (109.8 mg, 1.47 mmol) in DMF (10 mL) was stirred at room temperature under a nitrogen atmosphere for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (9: 1) to give 2-chloro-5-methoxy-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]pyridine-4-carbonitrile (110 mg, 22%) as a light yellow oil.

[0463] Synthesis of Example Compounds

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

[0465]

[0466] The title compound was prepared using the following procedure:

[0467]

[0468] To a stirred solution of intermediate 1 (80 mg, 0.2 mmol) and K2CO3 (64 mg, 0.5 mmol) in 1,4-dioxane (3 mL) at room temperature under a nitrogen atmosphere, Pd(dppf)Cl2.CH2Cl2 (19 mg, 0.1 mmol) and 6-fluoropyridin-3-ylboronic acid (36 mg, 0.3 mmol) were added. The final reaction mixture was heated at 100 ° C for 4 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15% B to 35% B, 35% B in 7 min; wavelength: 220 nm; to obtain Example 1. LCMS (ESI) m / z: 363.05 [M+H] + .

[0469] Example 2: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridin-3-yl)benzonitrile

[0470]

[0471] The title compound was prepared using the following procedure:

[0472]

[0473] At room temperature under a nitrogen atmosphere, to a stirred mixture of intermediate 1 (20 mg, 0.06 mmol) and pyridin-3-ylboronic acid (8.5 mg, 0.07 mmol) in dioxane (3 mL) / H2O (0.5 mL), K2CO3 (24.0 mg, 0.2 mol) and Pd(dppf)Cl2.CH2Cl2 (4.7 mg, 0.006 mmol) were added in batches. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 42% B, 42% B in 7 min; wavelength: 220 nm; RT1 (min): 4.65; to give Example 2. LCMS (ESI) m / z: 345.15 [M+H] + .

[0474] Example 3: 3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0475]

[0476] The title compound was prepared using the following procedure:

[0477]

[0478] At room temperature under a nitrogen atmosphere, to a stirred mixture of intermediate 1 (40 mg, 0.12 mmol) and 4-methoxypyridin-3-ylboronic acid (21.2 mg, 0.1 mmol) in dioxane (5 mL) / H2O (0.8 mL), K2CO3 (47.9 mg, 0.3 mmol) and Pd(dppf)Cl2.CH2Cl2 (9.4 mg, 0.01 mmol) were added. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 8 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 34% B to 58% B, 58% B in 8 min; wavelength: 220 nm; RT1 (min): 7.35; to give Example 3. LCMS (ESI) m / z: 375.10 [M+H] + .

[0479] 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

[0480]

[0481] The title compound was prepared using the following procedure:

[0482]

[0483] 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) at room temperature under a nitrogen atmosphere, Pd(PPh3)4 (7.8 mg, 0.007 mmol), K2CO3 (28.0 mg, 0.2 mmol), CsF (10.3 mg, 0.07 mmol) and CuI (12.9 mg, 0.07 mmol) were added. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×15 mL). The combined organic layers were washed with water (2×15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 34% B to 60% B, 60% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 6.73; to give Example 4. LCMS (ESI) m / z: 399.15 [M+H] + .

[0484]

[0485] To a stirred mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs2CO3 (2.1 g, 6.3 mmol) in DMF (20 mL) was added CH3I (394.2 mg, 2.8 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (60%-90%) to give 4-bromo-1-methylpyrazolo[3,4-c]pyridine (280 mg, 52%) as a light yellow solid. LCMS (ESI) m / z: 212,214 [M+H] + .

[0486] To a stirred mixture of 4-bromo-1-methylpyrazolo[3,4-c]pyridine (100.0 mg, 0.5 mmol) and hexamethyldistanane (185.4 mg, 0.6 mmol) in dioxane (10 mL) at room temperature under a nitrogen atmosphere, Pd(PPh3)4 (54.5 mg, 0.05 mmol) was added in portions. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched with water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0%-12%) to give 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] + .

[0487] Example 5: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyrazin-2-yl)benzonitrile

[0488]

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

[0490]

[0491] To a stirred solution of intermediate 1 (50 mg, 0.14 mmol) and 2-(tributyltinyl)pyrazine (53 mg, 0.15 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol) at room temperature, followed by a catalytic amount of Pd(PPh3)4 (16.7 mg, 0.014 mmol). The resulting mixture was stirred at 100 ° C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 60% B, 60% B in 7 min; wavelength: 220 nm; RT1 (min): 6.88) to give Example 5. LCMS (ESI) m / z: 346.05 [M+H] + .

[0492] Example 6: 3-[6-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0493]

[0494] The title compound was prepared using the following procedure:

[0495]

[0496] A solution of ethylene glycol (11 mg, 0.18 mmol) and NaH (4 mg, 0.2 mmol) in THF (10 mL) was stirred at 0 ° C under N2 atmosphere for 30 min. 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) at 0 ° C over 5 min. The resulting mixture was stirred at 50 ° C for an additional 4 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18% B to 45% B, 45% B in 7 min; wavelength: 220 nm; RT1 (min): 6.47; to give Example 6. LCMS (ESI) m / z: 405.10 [M+H] + .

[0497] Example 7: 3-(4-hydroxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0498]

[0499] The title compound was prepared using the following procedure:

[0500]

[0501] A mixture of 3-(4-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile (40 mg, 0.11 mmol) and TMSI (213.7 mg, 1.07 mmol) in acetonitrile (5 mL) was stirred at 80 ° C. under a nitrogen atmosphere overnight. The residue was basified to pH 10 with saturated aqueous Na2CO3. The resulting mixture was extracted with CHCl (3×100 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 mg) was purified by preparative HPLC 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: 20% B to 40% B, 40% B in 7 min; wavelength: 254 / 2220 nm; RT1 (min): 6.42; to give Example 7. LCMS (ESI) m / z: 361.10 [M+H] + .

[0502] 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

[0503]

[0504] The title compound was prepared using the following procedure:

[0505]

[0506] A solution of NaH (4 mg, 0.2 mmol) in dimethylaminoethanol (3 mL, 0.1 mmol) was stirred at 0 ° C under a nitrogen atmosphere for 30 min. At room temperature, 3- (4-chloropyridin-3-yl) -2- [4- (4-methyl -1,2,4- triazole -3- yl) piperidin-1-yl] benzonitrile (25 mg, 0.1 mmol) was added to the above mixture. The resulting mixture was stirred at 120 ° C overnight. The reaction was quenched by adding water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation 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: 25% B to 45% B, 45% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 5.92; to give Example 8. LCMS (ESI) m / z: 432.10 [M+H] + .

[0507] Example 9: 3-[4-(2-hydroxyethoxy)pyridin-3-yl]-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0508]

[0509] The title compound was prepared using the following procedure:

[0510]

[0511] A solution of NaH (4 mg, 0.2 mmol) in ethylene glycol (3 mL, 0.1 mmol) was stirred at 0 ° C for 30 min under a nitrogen atmosphere. To the above mixture, 3- (4-chloropyridin-3-yl) -2- [4- (4-methyl-1,2,4-triazol-3-yl) piperidin-1-yl] benzonitrile (25 mg, 0.1 mmol) was added over 2 min at room temperature. The resulting mixture was stirred at 120 ° C overnight. The reaction was quenched by adding water (2 mL) at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X Bridge BEH130 Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 18% B to 30% B, 30% B in 7 min; wavelength: 220 nm; RT1 (min): 6.42; to give Example 9. LCMS (ESI) m / z: 405.05 [M+H]+ .

[0512] Example 10: 3-(4-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0513]

[0514] The title compound was prepared using the following procedure:

[0515]

[0516] To a stirred solution of intermediate 1 (50 mg, 0.14 mmol) and K2CO3 (40 mg, 0.5 mmol) in 1,4-dioxane (3 mL) at room temperature under a nitrogen atmosphere, Pd(dppf)Cl2.CH2Cl2 (16 mg, 0.1 mmol) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (40 mg, 0.3 mmol) were added. The final reaction mixture was heated at 100 ° C for 4 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 18% B to 45% B, 45% B in 7 min; wavelength: 220 nm; RT1 (min): 6.47; to give Example 10. LCMS (ESI) m / z: 379.00 [M+H] + .

[0517] Example 11: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0518]

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

[0520]

[0521] To a stirred solution of intermediate 1 (50 mg, 0.14 mmol) and 4-(tributyltinyl)pyridazine (63.9 mg, 0.17 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added CuI (55 mg, 0.29 mmol) and CsF (43.9 mg, 0.29 mmol) at room temperature, followed by a catalytic amount of Pd(PPh3)4 (16.7 mg, 0.014 mmol). The resulting mixture was stirred at 100 ° C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 60% B, 60% B in 7 min; wavelength: 220 nm; RT1 (min): 6.88;) to give Example 11. LCMS (ESI) m / z: 346.05 [M+H] + .

[0522] 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

[0523]

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

[0525]

[0526] To a stirred solution of intermediate 1 (100 mg, 0.29 mmol) and 1-methyl-4-(trimethylstannyl)pyrrolo[2,3-c]pyridine (102.2 mg, 0.35 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added CuI (110 mg, 0.58 mmol) and CsF (87.8 mg, 0.58 mmol) at room temperature, followed by a catalytic amount of Pd(PPh3)4 (33.4 mg, 0.03 mmol). The resulting mixture was stirred at 100 ° C for 12 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X select CSH C18 OBD column 30×150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 33% B, 33% B in 7 min; wavelength: 220 nm; RT1 (min): 6.32) to give Example 12. LCMS (ESI) m / z: 398.10 [M+H] + .

[0527]

[0528] A solution of hexamethyldistannane (372 mg, 1 mmol) in 1,4-dioxane (10 mL) was treated with Pd(dppf)Cl2 (77 mg, 0.1 mmol) at room temperature under a nitrogen atmosphere for 5 min, and then 4-bromo-1-methylpyrrolo[2,3-c]pyridine (200 mg, 1 mmol) was added 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 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with CH3CN / H2O (8: 1) to give 4-(trimethyltinyl)-1H-pyrrolo[2,3-c]pyridine (110 mg) as a brown oil.

[0529] Example 13: 2-[4-(1H-imidazol-1-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0530]

[0531] The title compound was prepared using the following procedure:

[0532]

[0533] At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 2 (300 mg, 0.91 mmol) in dioxane (12 mL) and H2O (2 mL), 4-methoxypyridin-3-ylboronic acid (277 mg, 1.81 mmol), K2CO3 (250.4 mg, 1.81 mmol) and Pd(dppf)Cl2 (66.3 mg, 0.091 mmol) were added in batches. The resulting mixture was stirred at 90 ° C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (6: 1) to obtain a dark red solid as a crude product. The crude product (100 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 50% B, 50% B in 7 min; wavelength: 220 nm; RT1 (min): 5.98; to give Example 13. LCMS (ESI) m / z: 360.05 [M+H] + .

[0534] Example 14: 3-(4-methoxypyridin-3-yl)-2-[4-(1,3-thiazol-5-yl)piperidin-1-yl]benzonitrile

[0535]

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

[0537]

[0538] To a stirred solution of intermediate 3 (133 mg, 0.39 mmol) and 4-methoxypyridin-3-ylboronic acid (63.9 mg, 0.39 mmol) in dioxane (6 mL) / H2O (1 mL) at room temperature under a nitrogen atmosphere, Pd(dppf)Cl2 (28.0 mg, 0.04 mmol) and K2CO3 (157.8 mg, 1.15 mmol) were added in portions. The resulting mixture was stirred at 90 ° C for 3 h. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 55% B, 55% B in 8 min; wavelength: 220 nm; RT1 (min): 8.10; to give Example 14. LCMS (ESI) m / z: 377.05 [M+H] + .

[0539] Example 15: 3-(1,3-Benzoxazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0540]

[0541] The title compound was prepared using the following procedure:

[0542]

[0543] A mixture of intermediate 1 (60.0 mg, 0.17 mmol), K2CO3 (71.8 mg, 0.5 mmol), Pd(dppf)Cl2 (14.1 mg, 0.02 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (46.7 mg, 0.2 mmol) in 1,4-dioxane (3.0 mL) / H2O (0.5 mL) was stirred at 100 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched with water (25 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (45 mg) was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 27% B to 53% B, 53% B in 7 min; wavelength: 220 nm; RT1 (min): 5.84; to give Example 15. LCMS (ESI) m / z: 385.05 [M+H] + .

[0544] 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

[0545]

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

[0547]

[0548] 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) at room temperature under a nitrogen atmosphere, Pd(PPh3)4 (19.6 mg, 0.017 mmol), CsF (25.7 mg, 0.17 mmol) and CuI (32.2 mg, 0.17 mmol) were added in batches. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (12 mg) was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 40% B, 40% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.08; to give Example 16. LCMS (ESI) m / z: 399.05 [M+H] + .

[0549]

[0550] To a stirred mixture of 4-bromo-1H-pyrazolo[3,4-c]pyridine (500 mg, 2.5 mmol) and Cs2CO3 (2.1 g, 6.3 mmol) in DMF (20 mL) was added CH3I (394.2 mg, 2.8 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water (80 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc / PE (60%-90%) to give 4-bromo-2-methylpyrazolo[3,4-c]pyridine (130 mg, 24%) as a light yellow solid.

[0551] To a stirred mixture of 4-bromo-2-methyl-1H,7aH-pyrazolo[3,4-c]pyridine (80 mg, 0.4 mmol) and hexamethyldistanane (148.3 mg, 0.45 mmol) in dioxane (4 mL) at room temperature under a nitrogen atmosphere was added Pd(PPh3)4 (43.6 mg, 0.04 mmol) in portions. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The reaction was quenched with water (40 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (2%-10%) to give 2-methyl-4-(trimethylstannyl)pyrazolo[3,4-c]pyridine (50 mg, 45%) as a yellow solid.

[0552] Example 17: 2-[4-(2-amino-1,3-thiazol-5-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0553]

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

[0555]

[0556] A solution of N-(5-bromo-1,3-thiazol-2-yl)acetamide (2 g, 9.05 mmol), Pd(dppf)Cl2 (0.66 g, 0.91 mmol), K2CO3 (3.75 g, 27.14 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.36 g, 10.86 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 100 ° C. under a nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1 g, 34%) as a black solid. LCMS (ESI) m / z: 324 [M+H] + .

[0557] A solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (560 mg, 1.73 mmol) and Pd / C (200 mg) in MeOH (50 mL) was stirred at room temperature under hydrogen overnight. The resulting mixture was filtered and the filter cake was washed with MeOH (2 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate (440 mg, 78%) as a light yellow solid. LCMS (ESI) m / z: 326 [M+H] + .

[0558] A solution of tert-butyl 4-(2-acetamido-1,3-thiazol-5-yl)piperidine-1-carboxylate (440 mg, 1.35 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0559] A solution of N-[5-(piperidin-4-yl)-1,3-thiazol-2-yl]acetamide hydrochloride (300 mg, 1.33 mmol), DIEA (860.5 mg, 6.66 mmol) and 3-bromo-2-fluorobenzonitrile (319.6 mg, 1.60 mmol) in DMSO (10 mL) was stirred at 120 ° C for 2 days. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10: 1) to give N-{5-[1-(2-bromo-6-cyanophenyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (150 mg, 28%). LCMS (ESI) m / z: 405, 407 [M+H] + .

[0560] A solution of N-{5-[1-(2-bromo-6-cyanophenyl)piperidin-4-yl]-1,3-thiazol-2-yl}acetamide (20 mg, 0.05 mmol), Pd(dppf)Cl2 (3.61 mg, 0.005 mmol), K2CO3 (20.5 mg, 0.15 mmol) and 4-methoxypyridin-3-ylboronic acid (9.1 mg, 0.06 mmol) in dioxane (5 mL) and water (0.5 mL) was stirred at 90 ° C under a nitrogen atmosphere for 1 h. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (10 mg) was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B to 19% B, 19% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 4.82) to give N-(5-{1-[2-cyano-6-(4-methoxypyridin-3-yl)phenyl]piperidin-4-yl}-1,3-thiazol-2-yl)acetamide (1.9 mg, 8.9%) as a light yellow solid. LCMS (ESI) m / z: 434 [M+H] + .

[0561] A solution of N-(5-{1-[2-cyano-6-(4-methoxypyridin-3-yl)phenyl]piperidin-4-yl}-1,3-thiazol-2-yl)acetamide (20 mg, 0.046 mmol), concentrated HCl (3 mL) and EtOH (5 mL) was stirred at 80 ° C overnight. The mixture was basified to pH 8 with saturated Na2CO3 (aqueous). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (9 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 45% B, 45% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.43) to give Example 17. LCMS (ESI) m / z: 392.05 [M+H] + .

[0562] Example 18: 3-(4-methoxypyridin-3-yl)-2-[4-(3-methyl-4H-1,2,4-triazol-4-yl)piperidin-1-yl]benzonitrile

[0563]

[0564] The title compound was prepared using the following procedure:

[0565]

[0566] At room temperature under a nitrogen atmosphere, 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 H2O (1 mL), K2CO3 (239.5 mg, 1.73 mmol) and Pd(dppf)Cl2 (42.3 mg, 0.058 mmol) were added in batches. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 3 h. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated to dryness. The crude product (50 mg) was purified by preparative 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, 40% B in 9 min; wavelength: 220 / 254 nm; RT1 (min): 6.10; to give Example 18. LCMS (ESI) m / z: 375.05 [M+H] + .

[0567] Example 19: 3-(2,1,3-Benzoxadiazol-5-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0568]

[0569] The title compound was prepared using the following procedure:

[0570]

[0571] To a stirred mixture of intermediate 1 (60 mg, 0.17 mmol) and 2,1,3-benzoxadiazole-5-ylboronic acid (42.6 mg, 0.26 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) at room temperature under a nitrogen atmosphere, K2CO3 (71.8 mg, 0.52 mmol) and Pd(dppf)Cl2 (12.7 mg, 0.017 mmol) were added in portions. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere for 4 h. The resulting mixture was extracted with EtOAc (2×60 mL). The combined organic layers were washed with brine (1×20 mL) and dried over anhydrous Na2SO4. The crude product (50 mg) was purified by preparative HPLC 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, 50% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 6.95; to give Example 19. LCMS (ESI) m / z: 386.05 [M+H] + .

[0572] 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

[0573]

[0574] The title compound was prepared using the following procedure:

[0575]

[0576] 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 KCO (38 mg, 0.29 mmol) in 1,4-dioxane / HO (10:1) was added Pd(dppf)ClCHCl (11 mg, 0.1 mmol) and Intermediate 1 (48 mg, 0.14 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 h. The reaction was quenched by the addition of water (5 mL) at room temperature. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X select CSH F-Phenyl OBD column 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 2% B to 22% B, 22% B in 9 min; wavelength: 220 nm; RT1 (min): 7.20; to give Example 20. LCMS (ESI) m / z: 402.05 [M+H] + .

[0577]

[0578] 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) at room temperature under a nitrogen atmosphere was added Pd (dppf) Cl2 (342 mg, 0.42 mmol), AcOK (1232 mg, 12.6 mmol) and bis (pinacolato) diboron (218 mg, 0.84 mmol). The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 16 h. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% over 10 min; detector, UV 254 nm to afford the desired compound (600 mg) as a brown solid. LCMS (ESI) m / z: 263 [M+H] + .

[0579] Example 21: 2-[4-(5-amino-1,3,4-thiadiazol-2-yl)piperidin-1-yl]-3-(4-methoxypyridin-3-yl)benzonitrile

[0580]

[0581] The title compound was prepared using the following procedure:

[0582]

[0583] At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 4 (200 mg, 0.55 mmol) in dioxane (15 mL) and H2O (2 mL), K2CO3 (151.7 mg, 1.1 mmol), 4-methoxypyridin-3-ylboronic acid (167.9 mg, 1.01 mmol) and Pd(dppf)Cl2 (40.2 mg, 0.06 mmol) were added in batches. The resulting mixture was stirred at 100 ° C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9: 1) to obtain a dark red solid as a crude product. The crude product (100 mg) was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 24% B to 48% B, 48% B in 7 min; wavelength: 220 nm; RT1 (min): 6.27; to give Example 21. LCMS (ESI) m / z: 393.00 [M+H] + .

[0584] 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

[0585]

[0586] The title compound was prepared using the following procedure:

[0587]

[0588] 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 NaBHCN (12 mg, 0.19 mmol) followed by a catalytic amount of HCOOH (3 mg, 0.07 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was quenched by adding water (5 mL) and extracted with EtOAc. The extract was washed with brine, dried over NaSO, and evaporated to dryness. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X select CSH C18 OBD column 30×150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 40% B, 40% B in 7 min; wavelength: 220 nm; RT1 (min): 5.62; to give Example 22. LCMS (ESI) m / z: 416.10 [M+H] + .

[0589] 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

[0590]

[0591] The title compound was prepared using the following procedure:

[0592]

[0593] To a stirred solution of intermediate 1 (20 mg, 0.058 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (0.5 mL) was added K2CO3 (15.9 mg, 0.12 mmol) and 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-ylboronic acid (21.5 mg, 0.064 mmol), followed by a catalytic amount of Pd(dppf)Cl2 (4.71 mg, 0.006 mmol) at 0°C. The reaction mixture was stirred at 100°C for a period of 4 h. After completion of the reaction, the reaction mixture was quenched by the 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 the crude product, which was further purified by column chromatography using a gradient of 5% to 20% MeOH in DCM to afford the desired compound 3-(4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (10 mg).

[0594] 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) was added HCOOH (1.6 mg, 0.036 mmol) and H 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 evaporation with the following conditions (column: Xs elect CSHF-Phenyl OBD column 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 2% B to 22% B, 22% B in 9 min; wavelength: 220 nm; RT1 (min): 7.20; to give Example 23. LCMS (ESI) m / z: 446.05 [M+H] + .

[0595]

[0596] A solution of 3-amino-5-bromopyridin-4-ol (6 g, 31.7 mmol) in acetone (100 mL) was treated with NaOAc (5.2 g, 63.4 mmol) at 0 ° C for 5 min, and then chloroacetyl chloride (4.3 g, 38 mmol) was added dropwise at 0 ° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave N- (5-bromo-4-hydroxypyridin-3-yl) -2-chloroacetamide (4 g) as a brown solid. LCMS (ESI) m / z: 265 [M + H] + .

[0597] A solution of N-(5-bromo-4-hydroxypyridin-3-yl)-2-chloroacetamide (4 g, 15.1 mmol) in DMF (10 mL) was treated with K2CO3 (4.2 g, 30.1 mmol) at 0 ° C for 5 min. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 8-bromo-2H, 4H, 4aH, 8aH-pyrido [4, 3-b] [1, 4] oxazine-3-one (3 g) as a brown solid. LCMS (ESI) m / z: 229, 231 [M + H] + .

[0598] A solution of 8-bromo-2H, 4H, 4aH, 8aH-pyrido [4, 3-b] [1, 4] oxazine-3-one (4 g, 17.3 mmol) in borane-THF (70 mL) was stirred at 0 ° C. under a nitrogen atmosphere for 5 min. The resulting mixture was stirred at 35 ° C. for an additional 16 h. The reaction was quenched with MeOH (7 mL) at 60 ° C. for 30 min. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to 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] + .

[0599] 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 over a period of 30 min. A mixture of (2-bromoethoxy)(tert-butyl)dimethylsilane (50.1 mg, 0.21 mmol) was stirred at room temperature under a nitrogen atmosphere for 3 h. After completion of the reaction, the reaction mixture was quenched by the addition of water (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was further purified by column chromatography using a gradient of 5% to 40% EtOAc in PE to provide the desired compound, 8-bromo-4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazine (40 mg). LCMS (ESI) m / z: 373, 375 [M+H] + .

[0600] 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 a catalytic amount of Pd(dppf)Cl2 (8.7 mg, 0.01 mmol) at 0°C. The reaction mixture was stirred at 100°C for 16 h. After completion of the reaction, the reaction mixture was quenched by the 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 a crude product, which was further purified by column chromatography using a gradient of 1% to 10% MeOH in DCM to give the desired compound 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2H,3H-pyrido[4,3-b][1,4]oxazin-8-ylboronic acid (20 mg). LCMS (ESI) m / z: 339 [M+H] + .

[0601] Example 24: 3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0602]

[0603] The title compound was prepared using the following procedure:

[0604]

[0605] At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 7 (100 mg, 0.27 mmol) in dioxane (8 mL) and H2O (1 mL), K2CO3 (73.5 mg, 0.53 mmol), 6-fluoropyridin-3-ylboronic acid (74.9 mg, 0.53 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.03 mmol) were added in batches. The resulting mixture was stirred at 90 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (7: 1) to obtain a brown solid as a crude product. The crude product (80 mg) was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 43% B, 43% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.38; to give Example 24. LCMS (ESI) m / z: 393.05 [M+H] + .

[0606] Example 25: 6-methoxy-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0607]

[0608] The title compound was prepared using the following procedure:

[0609]

[0610] At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 7 (100 mg, 0.27 mmol) in dioxane (7 mL) and H2O (1 mL), K2CO3 (73.5 mg, 0.53 mmol), 4-methoxypyridin-3-ylboronic acid (81.3 mg, 0.53 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) were added in batches. The resulting mixture was stirred at 90 ° C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (6: 1) to obtain a tan solid as a crude product. The crude product (50 mg) was purified by preparative HPLC with the following conditions (column: Sunfireprep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9% B to 18% B, 18% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 5.73; to give Example 25. LCMS (ESI) m / z: 405.10 [M+H] + .

[0611] Example 26: 6-Methoxy-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0612]

[0613] The title compound was prepared using the following procedure:

[0614]

[0615] To a stirred solution of intermediate 7 (50 mg, 0.133 mmol) in dioxane (2 mL) and H2O (1 mL) at room temperature under a nitrogen atmosphere, K2CO3 (36.7 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (54.8 mg, 0.27 mmol) and Pd(dppf)Cl2 (19.4 mg, 0.027 mmol) were added in batches. The resulting mixture was stirred at 90 ° C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (5: 1) to give a white solid as a crude product. The crude product (40 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 39% B to 69% B, 69% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.13; to give Example 26. LCMS (ESI) m / z: 376.05 [M+H] + .

[0616] Example 27: 6-Chloro-3-(4-methoxypyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0617]

[0618] The title compound was prepared using the following procedure:

[0619]

[0620] To a stirred mixture of intermediate 6 (0.5 g, 1.31 mmol), KCO (0.36 g, 2.63 mmol) in 1,4-dioxane (5 mL) and H0 (0.5 mL) was added (4-methoxypyridin-3-yl)boronic acid (0.16 g, 1.05 mmol) and Pd(dppf)Cl (0.10 g, 0.13 mmol) at room temperature under N2 atmosphere. The mixture was stirred at 90 ° C. under nitrogen atmosphere for 20 h. The crude product (10 mg) was purified by preparative 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: 5% B to 28% B, 28% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.00; to give Example 27. LCMS (ESI) m / z: 409.00 [M+H] + .

[0621] 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

[0622]

[0623] The title compound was prepared using the following procedure:

[0624]

[0625] To a stirred solution of intermediate 6 (200 mg, 0.52 mmol), KCO (145 mg, 1.05 mmol) in dioxane (5 mL) and H0 (0.5 mL) was added (6-fluoropyridin-3-yl)boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl (115.3 mg, 0.16 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C under nitrogen atmosphere for 20 h. The crude product (150 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 48% B to 69% B, 69% B in 10 min; wavelength: 220 nm; RT1 (min): 8.50; to give 6-chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile. LCMS (ESI) m / z: 409 [M+H] + .

[0626] 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 KCO (69.6 mg, 0.5 mmol) in dioxane (5 mL) and H0 (0.5 mL) was added phenylboronic acid (61.4 mg, 0.5 mmol) and Pd(dppf)Cl (55.3 mg, 0.076 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C for 20 h. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 55% B, 55% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.52; to give Example 28. LCMS (ESI) m / z: 439.05 [M+H] + .

[0627] Example 29: 2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-[6-(trifluoromethyl)pyridin-3-yl]benzonitrile

[0628]

[0629] The title compound was prepared using the following procedure:

[0630]

[0631] At room temperature, to a stirred solution of intermediate 1 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane / HO (10: 1), KCO (80 mg, 0.58 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (87 mg, 0.32 mmol) were added, followed by the addition of Pd(dppf)Cl (24 mg, 0.03 mmol). The reaction mixture was stirred at 100 ° C for 2 h. After completion of the reaction, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL) and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% NH3.H2O), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 16% B to 37% B, 37% B in 10 min; wavelength: 220 nm; RT1 (min): 8.62; to give Example 29. LCMS (ESI) m / z: 413.05 [M+H] + .

[0632] Example 30: 6-Chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0633]

[0634] The title compound was prepared using the following procedure:

[0635]

[0636] To a stirred solution of intermediate 6 (200 mg, 0.52 mmol), K2CO3 (145.2 mg, 1.05 mmol) in dioxane (5 mL) and H2O (0.5 mL) at room temperature under nitrogen atmosphere, (6-fluoropyridin-3-yl)boronic acid (74 mg, 0.52 mmol) and Pd(dppf)Cl2 (115.3 mg, 0.16 mmol) were added. The resulting mixture was stirred at 90°C for 10 h. The crude product (150 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 48% B to 69% B, 69% B in 10 min; wavelength: 220 nm; RT1 (min): 8.50; to give Example 30. LCMS (ESI) m / z: 397.00 [M+H] + .

[0637] Example 31: 3-(4-methoxypyridin-3-yl)-2-[4-(1-methyl-1H-imidazol-5-yl)piperidin-1-yl]benzonitrile

[0638]

[0639] The title compound was prepared using the following procedure:

[0640]

[0641] To a stirred solution of intermediate 8 (100 mg, 0.29 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (1 mL) was added K2CO3 (80 mg, 0.58 mmol) and Pd(dppf)Cl2 (1.07 g, 1.5 mmol) followed by 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 0.29 mmol) at room temperature. The reaction mixture was stirred at 100 ° C for 6 h. After completion of the reaction, the reaction mixture was quenched by adding water (5 mL). The crude product was purified by reverse phase flash evaporation 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: 15% B to 50% B, 50% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 3.88; to give Example 31. LCMS (ESI) m / z: 374.35 [M+H]+ .

[0642] 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

[0643]

[0644] The title compound was prepared using the following procedure:

[0645]

[0646] To a stirred mixture of intermediate 6 (0.5 g, 1.31 mmol) and K2CO3 (0.36 g, 2.62 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added (4-methoxypyridin-3-yl)boronic acid (0.16 g, 1 mmol) and Pd(dppf)Cl2 (0.10 g, 0.13 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 90°C for 20 h. The crude product (10 mg) was purified by preparative 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: 5% B to 28% B, 28% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.00; to give 6-chloro-3-(4-methoxypyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile. LCMS (ESI) m / z: 409 [M+H] + .

[0647] 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 KCO (33.8 mg, 0.24 mmol) in dioxane (0.7 mL) was added phenylboronic acid (14.9 mg, 0.12 mmol) and Pd(dppf)Cl (26.8 mg, 0.04 mmol) at room temperature under nitrogen atmosphere. The mixture was stirred at 90° C. for 20 h. The crude product (5 mg) was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 31% B to 52% B, 52% B in 8 min; wavelength: 220 nm; RT1 (min): 7.70; to give Example 32. LCMS (ESI) m / z: 451.10 [M+H] + .

[0648] Example 33: 6-Chloro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0649]

[0650] The title compound was prepared using the following procedure:

[0651]

[0652] To a stirred solution of intermediate 6 (100 mg, 0.26 mmol) in dioxane (2 mL) and H2O (0.5 mL) at room temperature under a nitrogen atmosphere, K2CO3 (72.6 mg, 0.53 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (64.9 mg, 0.32 mmol) and Pd(dppf)Cl2 (38.4 mg, 0.053 mmol) were added in batches. The resulting mixture was stirred at 90 ° C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (6: 1) to obtain a red solid as a crude product. The crude product (20 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 39% B to 69% B, 69% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 7.13; to give Example 33. LCMS (ESI) m / z: 380.00 [M+H] + .

[0653] 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

[0654]

[0655] The title compound was prepared using the following procedure.

[0656]

[0657] 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-dioxaborolan (5.4 g, 21.2 mmol) in dioxane (30 mL) at room temperature under a nitrogen atmosphere, AcOK (3.1 g, 31.7 mmol), dicyclohexyl[3,6-dimethoxy-2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (1.1 g, 2.1 mmol) and Pd(dppf)Cl2.CH2Cl2 (43.1 mg, 0.01 mmol) were added portionwise. The resulting mixture was stirred at 100 ° C for 2 h. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (70%-90%) to afford 1-methyl-2-oxopyrimidin-5-ylboronic acid (400 mg, 25%) as a light yellow solid.

[0658]

[0659] At room temperature under a nitrogen atmosphere, to a stirred solution of 1-methyl-2-oxopyrimidin-5-ylboronic acid (88.9 mg, 0.6 mmol) and intermediate 1 (100 mg, 0.3 mmol) in dioxane (5 mL) / H2O (0.5 mL), K2CO3 (119.8 mg, 0.9 mmol) and Pd(dppf)Cl2CH2Cl2 (23.5 mg, 0.03 mmol) were added in batches. The resulting mixture was stirred at 100 ° C under a nitrogen atmosphere overnight. The reaction was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EtOAc (3×30 mL). The crude product (50 mg) was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 25% B, 25% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 10.80; to give Example 34. LCMS (ESI) m / z: 376.05 [M+H] + .

[0660] 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

[0661]

[0662] The title compound was prepared using the following procedure:

[0663]

[0664] At room temperature under nitrogen atmosphere, to a stirred solution of intermediate 6 (300 mg, 0.79 mmol) in dioxane (3 mL) and H2O (1 mL), K2CO3 (218 mg, 1.58 mmol), 6-fluoropyridin-3-ylboronic acid (88.8 mg, 0.63 mmol) and Pd(dppf)Cl2 (115.3 mg, 0.16 mmol) were added in batches. The resulting mixture was stirred at 90 ° C under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (6: 1) to give 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] + .

[0665] 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 O (1 mL) was added K CO (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 (55.3 mg, 0.076 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to give a light brown solid as a crude product. The crude product (25 mg) was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*100 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15% B to 35% B, 35% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 9.88) to give Example 35. LCMS: (ES, m / z): 443.10 [M+H] + .

[0666] 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

[0667]

[0668] The title compound was prepared using the following procedure:

[0669]

[0670] To a stirred solution of intermediate 6 (100 mg, 0.26 mmol) in dioxane (3 mL) and H O (1 mL) was added K CO (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 (38.4 mg, 0.053 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (6:1) to give 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] + .

[0671] 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 O (0.5 mL) was added K CO (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 (19.3 mg, 0.026 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 15% to 40% gradient in 20 min; detector, UV 254 nm to give a black solid as a crude product. The crude product (60 mg) was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH--HPLC; flow rate: 50 mL / min; gradient: 31% B to 41% B, 41% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 5.00) to give Example 36. LCMS (ESI) m / z: 426.05 [M+H] + .

[0672] 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

[0673]

[0674] The title compound was prepared using the following procedure:

[0675]

[0676] To a stirred solution of intermediate 6 (1.4 g, 3.7 mmol) in dimethylaminoethanol (393.4 mg, 4.4 mmol) at 0 ° C under a nitrogen atmosphere, NaH (189 mg, 7.9 mmol) was added in portions. The resulting mixture was stirred at 70 ° C under a nitrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeCN (3×20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. To obtain 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.

[0677] To a stirred solution of 3-bromo-6-[2-(dimethylamino)ethoxy]-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (250 mg, 0.6 mmol) and 6-fluoropyridin-3-ylboronic acid (89.4 mg, 0.6 mmol) in dioxane (5 mL) / H2O (0.5 mL) at room temperature under a nitrogen atmosphere, Pd(dppf)Cl2CH2Cl2 (47 mg, 0.06 mmol) and K2CO3 (239.2 mg, 1.7 mmol) were added portionwise. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere overnight. The resulting mixture was filtered and the filter cake was washed with MeCN (3×20 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 32% B, 32% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 11.82) to give Example 37. LCMS (ESI) m / z: 450.10 [M+H] + .

[0678] Example 38: 4-Fluoro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0679]

[0680] The title compound was prepared using the following procedure:

[0681]

[0682] To a stirred solution of intermediate 9 (150 mg, 0.47 mmol) in anhydrous 1,4-dioxane (10 mL) and H2O (2 mL) was added K2CO3 (129.7 mg, 0.94 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (115.1 mg, 0.52 mmol) at room temperature, followed by a catalytic amount of Pd(AMPhos)2Cl2 (33.2 mg, 0.05 mmol). The reaction mixture was stirred at 80 ° C for 16 h. After completion of the reaction, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL) and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Prep PhenylOBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 25% B to 40% B, 40% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 6.93) to give Example 38. LCMS (ESI) m / z) 381.05 [M+H] + .

[0683] Example 39: 4-Fluoro-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile

[0684]

[0685] The title compound was prepared using the following procedure:

[0686]

[0687] At room temperature, to a stirred solution of intermediate 9 (50 mg, 0.156 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (1 mL), K2CO3 (129.7 mg, 0.94 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (35.4 mg, 0.17 mmol) were added, followed by a catalytic amount of PdCl2(dcypf) (11.8 mg, 0.016 mmol). The reaction mixture was stirred at 80 ° C for 16 h. After the reaction was completed, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash evaporation with the following conditions (column: X Select CSH Fluoro Phenyl, 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: MeOH-HPLC; flow rate: 60 mL / min; gradient: 20% B to 38% B, 38% B in 10 min; wavelength: 254 / 220 nm; RT1 (min) to give Example 39. LCMS (ESI) m / z: 364.05 [M+H] + .

[0688] Example 40: 3-(6-chloropyridin-3-yl)-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile

[0689]

[0690] The title compound was prepared using the following procedure:

[0691]

[0692] At room temperature, to a stirred solution of intermediate 1 (50 mg, 0.14 mmol) in anhydrous 1,4-dioxane (5 mL) and H2O (0.5 mL), K2CO3 (39.9 mg, 0.29 mmol) and 6-chloropyridin-3-ylboronic acid (25 mg, 0.16 mmol) were added, followed by a catalytic amount of Pd(dppf)Cl2 (11.8 mg, 0.014 mmol). The reaction mixture was stirred at 100 ° C for 2 h. After the reaction was complete, the reaction mixture was quenched by adding water (20 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phase was washed with brine (100 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash evaporation with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 21% B to 40% B, 40% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 10.48) to give Example 40. LCMS (ESI) m / z: 379.00 [M+H] + .

[0693] Example 41: 3-(6-fluoropyridin-3-yl)-2-(4-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0694]

[0695] The title compound was prepared using the following procedure:

[0696]

[0697] At room temperature under a nitrogen atmosphere, 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) was added Pd(dppf)Cl2.CH2Cl2 (23.3 mg, 0.03 mmol) and K2CO3 (79 mg, 0.57 mmol) in batches. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layer was washed with water (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSHC18 OBD column 30*150mm 5μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60mL / min; gradient: 16% B to 34% B, 34% B in 9min; wavelength: 254 / 220nm; RT1 (min): 9.38; to give Example 41 (48.4mg, 44%). LCMS (ESI) m / z: 366.05[M+H] + .

[0698] 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

[0699]

[0700] The title compound was prepared using the following procedure:

[0701]

[0702] To a stirred solution of Example 30 (150 mg, 0.38 mmol) in dioxane (5 mL) and H2O (1 mL) at room temperature under a nitrogen atmosphere, K2CO3 (104.5 mg, 0.76 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (118 mg, 0.57 mmol) and Pd(dppf)Cl2 (27.7 mg, 0.038 mmol) were added portionwise. The resulting mixture was stirred at 90 ° C for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (9:1) to give a red solid as a crude product. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 36% B, 36% B in 10 min; wavelength: 220 / 254 nm; RT1 (min): 11.22; to give Example 43 (22.8 mg, 13%). LCMS (ESI) m / z: 443.05 [M+H] + .

[0703] Example 49: 2-(4-(4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0704]

[0705] The title compound was prepared using the following procedure:

[0706]

[0707] 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) was added Cs2CO3 (100 mg) and Pd(dppf)Cl2.CH2Cl2 (12.5 mg) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C for 2 h. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep PhenylOBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 50 mL / min; gradient: 56% B to 72% B, 72% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 6.47; to give Example 49 (2.7 mg, 4%). LCMS (ESI) m / z: 349.00 [M+H] + .

[0708] 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

[0709]

[0710] The title compound was prepared using the following procedure:

[0711]

[0712] At room temperature under a nitrogen atmosphere, 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 batches. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched by adding water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 3-bromo-6-(3-methyl-1,2,4-triazol-1-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (117 mg) as a yellow solid. LCMS (ESI) m / z: 427, 429 [M+H] + .

[0713] To a stirred solution of 3-bromo-6-(3-methyl-1,2,4-triazol-1-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (100 mg, 0.23 mmol) and 6-fluoropyridin-3-ylboronic acid (42.9 mg, 0.3 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was added K2CO3 (64.7 mg) and Pd(dppf)Cl2.CH2Cl2 (19.1 mg) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere overnight. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give Example 50 (32.7 mg, 31%). LCMS (ESI) m / z: 444.05 [M+H] + .

[0714] 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

[0715]

[0716] The title compound was prepared using the following procedure:

[0717]

[0718] A solution of Example 30 (50 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL) was treated with Cs2CO3 (82.1 mg, 0.25 mmol) for 5 min at room temperature under a nitrogen atmosphere. To the above mixture was added Pd-PEPPSI-1HeptCl 3-chloropyridine (12.3 mg, 0.013 mmol) and (2-aminoethyl)dimethylamine (22.2 mg, 0.25 mmol) over 5 min at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2 / MeOH 9:1) and then repurified by preparative HPLC with the following conditions (column: YMC-Actus Triart C 18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B, 45% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.72; to obtain Example 51 (6.8 mg, 12%). LCMS (ESI) m / z: 449.20 [M+H] + .

[0719] 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

[0720]

[0721] The title compound was prepared using the following procedure:

[0722]

[0723] Sodium (2 g, 87 mmol) was added to 2 The mixture was stirred at 50 °C under nitrogen atmosphere for 4 h. The resulting mixture was concentrated in vacuo. This gave a white solid ( 2 H3) Sodium methoxide (3.5 g, 70%).

[0724] To a stirred solution of intermediate 6 (150 mg, 0.39 mmol) and K2CO3 (109 mg, 0.79 mmol) in DMF (5 mL) was added portionwise at room temperature ( 2H3) sodium methoxide (27 mg, 0.47 mmol). The resulting mixture was stirred at 120 ° C for 4 h. The resulting mixture was extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to give 3-bromo-6-(2H3)methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 47%) as a light yellow oil.

[0725] LCMS (ESI) m / z: 379, 381 [M+H] + .

[0726] 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 H2O (1 mL) at room temperature under a nitrogen atmosphere were added K2CO3 (51 mg, 0.37 mmol) and Pd(dppf)Cl2 (13.5 mg, 0.02 mmol) in portions. The resulting mixture was stirred at 100°C for 2 h, filtered, and the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 45% B, 45% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.72; to give Example 57 (26.5 mg, 36%). LCMS (ESI) m / z: 396.05 [M+H] + .

[0727] 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

[0728]

[0729] The title compound was prepared using the following procedure:

[0730]

[0731] A solution of intermediate 6 (2.3 g, 6.0 mmol), 4- (tributyltin alkyl) 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 a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (9: 1) to give 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazine-4-yl)benzonitrile (240 mg, 10%) as a brown solid. LCMS (ESI) m / z: 380 [M + H] + .

[0732] A solution of 6-chloro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-3-(pyridazin-4-yl)benzonitrile (100 mg, 0.26 mmol) and NaH (12.6 mg, 0.53 mmol) in dimethylaminoethanol (2 mL) was stirred at 80 ° C overnight. The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 42% B, 42% B in 10 min; wavelength: 220 / 254 nm; RT1 (min): 9.82; to give Example 58 (2.8 mg, 4%). LCMS (ESI) m / z: 433.35 [M+H] + .

[0733] Example 59: 4-Fluoro-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(6-methylpyridazin-4-yl)benzonitrile

[0734]

[0735] The title compound was prepared using the following procedure:

[0736]

[0737] At room temperature, to intermediate 9 (50mg, 0.16mmol) in anhydrous 1,4-dioxane (5mL) and H in a stirred solution in o (1mL), KCO (43.2mg, 0.31mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridazine (41.3mg, 0.19mmol) were added, followed by a catalytic amount of Sphos Pd G3 (24.7mg, 0.016mmol) and Sphos (12.6mg, 0.016mmol). The reaction mixture was stirred at 80°C for 16h. After the reaction was completed, the reaction mixture was quenched by adding water (20mL). The water layer was extracted with ethyl acetate (100mL). The combined organic phase was washed with saline (100mL), and the resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: X Bridge Prep Phenyl OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 18% B to 34% B, 34% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 7.75; to give Example 59 (3.2 mg, 5%). LCMS (ESI) m / z: 378.00 [M+H] + .

[0738] 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

[0739]

[0740] The title compound was prepared using the following procedure:

[0741]

[0742] A mixture of Example 30 (70 mg, 0.18 mmol) and KCO (48.8 mg, 0.35 mmol) in dioxane (1.6 mL) and H0 (0.4 mL) was stirred at room temperature under a nitrogen atmosphere for 5 min. To this mixture was added SPhosPdG (13.8 mg, 0.018 mmol), Sphos (7.2 mg, 0.018 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[3,2-b][1,3]oxazine (52.9 mg, 0.21 mmol) at room temperature. The resulting mixture was heated at 90°C overnight. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1), which was further purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 . H2O), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 26% B to 43% B, 43% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 8.12; to obtain Example 64 (2.1 mg, 2%). LCMS (ESI) m / z: 485.25 [M+H] + .

[0743] Example 66: 3-(6-fluoropyridin-3-yl)-5-methyl-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0744]

[0745] The title compound was prepared using the following procedure:

[0746]

[0747] To a stirred solution of intermediate 12 (50 mg, 0.14 mmol) and 6-fluoropyridin-3-ylboronic acid (25.4 mg, 0.18 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) at room temperature under a nitrogen atmosphere, K2CO3 (38.4 mg, 0.28 mmol) and Pd(dppf)Cl2CH2Cl2 (11.3 mg, 0.014 mmol) were added in portions. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere overnight. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) and then further purified by preparative HPLC with the following conditions (column: XBridge Shield RP18OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 29% B to 46% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 8.50) to give Example 66 (1 mg, 2%). LCMS (ESI) m / z: 377.05 [M+H] + .

[0748] Example 69: 5-Chloro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0749]

[0750] The title compound was prepared using the following procedure:

[0751]

[0752] A solution of intermediate 13 (160 mg, 0.42 mmol), K2CO3 (174.3 mg, 1.26 mmol) and Pd(dppf)Cl2CH2Cl2 (34.2 mg, 0.042 mmol) in dioxane (5 mL) was stirred at 90° C. under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.10% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm, and then purified by preparative HPLC with the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 18% B, 18% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 10.68; to give Example 69 (6.4 mg, 4%). LCMS (ESI) m / z: 397.05 [M+H] + .

[0753] Example 70: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(trifluoromethyl)benzonitrile

[0754]

[0755] The title compound was prepared using the following procedure:

[0756]

[0757] 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 O (1 mL) and 1,4-dioxane (4 mL) was added K CO (33.4 mg, 0.24 mmol) and Pd (dppf) Cl. CHCl (10 mg) in portions at room temperature. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The residue was purified by preparative TLC (10% MeOH / CHCl). The crude product was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 45% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 12.27) to give Example 70 (6 mg, 12%). LCMS (ESI) m / z: 431.15 [M+H] + .

[0758] Example 71: 6-Fluoro-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0759]

[0760] The title compound was prepared using the following procedure:

[0761]

[0762] A solution of Example 30 (60 mg, 0.15 mmol), CsF (229.6 mg, 1.51 mmol) and TBAB (4.87 mg, 0.015 mmol) in DMSO (3 mL) was stirred at 120 ° C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous Na2SO4. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 50% in 10 min; detector, UV 254 nm, and then purified by preparative HPLC with the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 18% B, 18% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 10.68; to give Example 71 (2.2 mg, 4%). LCMS (ESI) m / z: 381.05 [M+H] + .

[0763] Example 72: 2-(4-(1,3,4-thiadiazol-2-yl)piperidin-1-yl)-3-(6-fluoropyridin-3-yl)benzonitrile

[0764]

[0765] The title compound was prepared using the following procedure:

[0766]

[0767] A solution of 3 intermediate 15 (160 mg, 0.46 mmol), 6-fluoropyridin-3-ylboronic acid (71 mg, 0.50 mmol), K2CO3 (126.6 mg, 0.92 mmol) and Pd(dppf)Cl2 (33.5 mg, 0.05 mmol) in dioxane (2 mL) was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layer was washed with brine (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 18% B, 18% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 10.68; to give Example 72 (3 mg, 2%). LCMS (ESI) m / z: 366.00 [M+H] + .

[0768] 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

[0769]

[0770] The title compound was prepared using the following procedure:

[0771]

[0772] A solution of intermediate 16 (90 mg, 0.26 mmol), 6-fluoropyridin-3-ylboronic acid (44.2 mg, 0.31 mmol), K2CO3 (108.4 mg, 0.78 mmol) and Pd(dppf)Cl2 (19.1 mg, 0.026 mmol) in 1,4-dioxane (12 mL) and H2O (1.2 mL) was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridgePrep Phenyl OBD column, 19*250 mm, 5 μm; 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; wavelength: 254 / 220 nm; RT1 (min): 9.32; to give Example 75 (10.8 mg, 11%). LCMS (ESI) m / z: 361.10 [M+H] + .

[0773] Example 76: 6-Cyclopropyloxy-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0774]

[0775] The title compound was prepared using the following procedure:

[0776]

[0777] A solution of intermediate 6 (1 g, 2.63 mmol), TBAB (0.08 g, 0.26 mmol) and CsF (3.99 g, 26.3 mmol) in DMSO (5 mL) was stirred at 120 ° C overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layer was washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 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] + .

[0778] A solution of 3-bromo-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (150 mg, 0.41 mmol), cyclopropanol (35.9 mg, 0.62 mmol) and Cs2CO3 (201.3 mg, 0.62 mmol) in DMF (4 mL) was stirred at 120 ° C for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% over 10 min; detector, UV 254 nm to afford 3-bromo-6-cyclopropyloxy-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] + .

[0779] A solution of 3-bromo-6-cyclopropyloxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (50 mg, 0.12 mmol), KCO (34.3 mg, 0.25 mmol), and Pd(dppf)ClCHCl (10.1 mg, 0.01 mmol) in dioxane (2 mL) was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient over 10 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 18% B, 18% B in 10 min; wavelength: 254 / 220 nm; RT1 (min): 10.68; to give Example 76 (4.4 mg, 8%). LCMS (ESI) m / z: 419.25 [M+H] + .

[0780] Example 78: 6-amino-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0781]

[0782] The title compound was prepared using the following procedure:

[0783]

[0784] A mixture of Example 30 (130 mg, 0.33 mmol), Pd2(dba)3 (45 mg, 0.049 mmol), BINAP (61.2 mg, 0.098 mmol) and t-BuONa (47.2 mg, 0.49 mmol) in toluene (6 mL) was stirred at 110 ° C under a nitrogen atmosphere for 12 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CHCl / MeOH (12: 1) to give an orange oily 6-[(diphenylmethylene)amino]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (70 mg, 39%). The crude product was used directly in the next step without further purification. LCMS (ESI) m / z: 542 [M+H]+ .

[0785] To a round-bottom flask at room temperature, 6-[(diphenylmethylene)amino]-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (60 mg, 0.11 mmol), HCl (1 mL), DCM (6 mL) and H2O (6 mL) were added. The mixture was stirred at room temperature for 0.5 h. The mixture was basified to pH 8 with saturated NaHCO3 (aqueous). The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with water (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) and then repurified by preparative HPLC with the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 42% B, 42% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 8.97) to give Example 78 (5.1 mg, 12%). LCMS (ESI) m / z: 378.25 [M+H] + .

[0786] 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

[0787]

[0788] The title compound was prepared using the following procedure:

[0789]

[0790] To a solution of Example 30 (150 mg, 0.38 mmol) in MeOH (5 mL) was added Pd (dppf) Cl2 (27.7 mg, 0.038 mmol) and TEA (114.8 mg, 1.13 mmol) in a pressure tank. The mixture was purged with nitrogen for 10 min and then pressurized to 20 atm with carbon monoxide at 140 ° C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was extracted with EtOAc (2 × 80 mL). The combined organic layer was washed with brine (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (0%-10%) to give methyl 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoate (104 mg) as a red solid. LCMS (ESI) m / z: 421 [M+H] + .

[0791] 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 O (3 mL) and MeOH (3 mL) was stirred at room temperature for 2 h. The residue was purified by preparative TLC (10% MeOH / CH Cl) to give 2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzoic acid (40 mg) as a pink solid. LCMS (ESI) m / z: 407 [M+H] + .

[0792] 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) at room temperature, HATU (44.9 mg, 0.12 mmol) and DIEA (50.9 mg, 0.39 mmol) were added portionwise. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep Phenyl OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 15% B to 32% B, 32% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 6.75: to give Example 79 (10 mg, 23%). LCMS (ESI) m / z: 434.00 [M+H] + .

[0793] 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

[0794]

[0795] The title compound was prepared using the following procedure:

[0796]

[0797] To a solution of intermediate 6 (300 mg, 0.79 mmol) in 1-methylpiperazine (10 mL) was added K2CO3 (327 mg, 2.37 mmol) in portions at room temperature. The resulting mixture was stirred at 100 ° C for 2 days. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH (0%-10%) in CH2Cl2 to give 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]+ .

[0798] To a stirred solution of 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(4-methylpiperazin-1-yl)benzonitrile (100 mg, 0.22 mmol) and 6-fluoropyridin-3-ylboronic acid (63.4 mg, 0.45 mmol) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)Cl2CH2Cl2 (18.3 mg, 0.023 mmol) and K2CO3 (93.3 mg, 0.68 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 16 h. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Aeris PEPTIDE 10um XB-C18 Axia, 50mm×250mm, 10μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: ACN; flow rate: 100mL / min; gradient: 5% B to 35% B, 20% B in 30min; wavelength: 220 / 254nm; RT1 (min): 13.97; to give Example 80 (10.5mg, 10%). LCMS (ESI) m / z: 461.25[M+H] + .

[0799] Example 81: 6-(Cyclopropylamino)-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0800]

[0801] The title compound was prepared using the following procedure:

[0802]

[0803] To a stirred solution of Example 30 (200 mg, 0.5 mmol) and aminocyclopropane (43.2 mg, 0.76 mmol) in dioxane (20 mL) at room temperature under a nitrogen atmosphere were added Cs2CO3 (494 mg, 1.51 mmol) and Brettphos PdG3 (45.7 mg, 0.05 mmol) in portions. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 h. The reaction was quenched by adding water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: Aeris PEPTIDE 5um XB-C18 Axia, 21.2mm×250mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60mL / min; gradient: 22% B to 40% B, 40% B in 10min; wavelength: 220 / 254nm; RT1 (min): 13.97; to give Example 81 (1.2mg, 0.6%). LCMS (ESI) m / z: 418.30[M+H] + .

[0804] 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

[0805]

[0806] The title compound was prepared using the following procedure:

[0807]

[0808] A mixture of 2-[benzyl(methyl)amino]ethanol (138.9 mg, 0.84 mmol) and NaH (30.3 mg, 1.26 mmol) in DMF (8 mL) was stirred at 0° C. under a nitrogen atmosphere for 30 min. To the above mixture was added intermediate 6 (400 mg, 1.05 mmol) at 0° C. The resulting mixture was stirred for an additional 2 h at room temperature. 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 30% gradient over 15 min; detector, UV 254 nm to give 6-{2-[benzyl(methyl)amino]ethoxy}-3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (370 mg, 69%). LCMS (ESI) m / z: 509, 511 [M+H] + .

[0809] 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 O (1 mL) was added K CO (162.8 mg, 1.18 mmol), 6-fluoropyridin-3-ylboronic acid (83 mg, 0.59 mmol), and Pd(dppf)Cl (28.7 mg, 0.039 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 h. The crude mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient from 20% to 40% over 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] + .

[0810] 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) was added Pd / C (50.6 mg, 0.47 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 h. The mixture was filtered and the filter cake was washed with MeOH (2×20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 6% B to 23% B, 23% B in 10 min; wavelength: 200 / 220 nm; RT1 (min): 12.73; to give Example 82 (12.3 mg, 14%). LCMS (ESI) m / z: 436.10 [M+H] + .

[0811] 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

[0812]

[0813] The title compound was prepared using the following procedure:

[0814]

[0815] A mixture of Example 30 (100 mg, 0.25 mmol), methanesulfonamide (47.9 mg, 0.50 mmol), BINAP (15.7 mg, 0.025 mmol), t-BuONa (36.3 mg, 0.38 mmol), and BrettPhos Pd G3 (22.8 mg, 0.025 mmol) in 1,4-dioxane was stirred at 110° C. under a nitrogen atmosphere for 12 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 42% B, 42% B in 9 min; wavelength: 254 / 220 nm; Rt1 (min): 8.97.) to give Example 84 (12.5 mg, 11%). LCMS (ESI) m / z: 456.00 [M+H] + .

[0816] 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

[0817]

[0818] The title compound was prepared using the following procedure:

[0819]

[0820] To a stirred solution of intermediate 6 (300 mg, 0.79 mmol) in DMSO (10 mL) was 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 at 120° C. under a nitrogen atmosphere for 2 h. 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 40% gradient over 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 oil.

[0821] To a stirred solution of 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(piperazin-1-yl)benzonitrile (200 mg, 0.46 mmol) in dioxane (4 mL) and H2O (1 mL) were added K2CO3 (192.7 mg, 1.39 mmol), 6-fluoropyridin-3-ylboronic acid (98.2 mg, 0.7 mmol), and Pd(dppf)Cl2 (34 mg, 0.047 mmol) in portions at room temperature. The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 30% to 50% gradient over 25 min; detector, UV 254 nm to give a brown oil as the crude product. The crude product was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 6% B to 23% B, 23% B in 9 min; wavelength: 254 / 220 nm; RT1 (min): 15.72; to give Example 85 (56.3 mg, 27%). LCMS (ESI) m / z: 447.35 [M+H] + .

[0822] 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)

[0823]

[0824] The title compound was prepared using the following procedure:

[0825]

[0826] A solution of intermediate 6 (1 g, 2.63 mmol), TBAB (0.08 g, 0.26 mmol) and CsF (3.99 g, 26.3 mmol) in DMSO (5 mL) was stirred at 120 ° C overnight. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layer was washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV254 nm to give 3-bromo-6-fluoro-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (500 mg, 52%) as a yellow oil.

[0827] A solution of 5-bromo-2-fluorobenzonitrile (200 mg, 1 mmol), 1-methylpyrrolidin-3-ol (61.1 mg, 0.6 mmol) and NaH (26.4 mg, 1.1 mmol) in THF (6 mL) was stirred at 0 ° C for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was filtered and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layer was washed with brine (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to give 3-bromo-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-[(1-methylpyrrolidin-3-yl)oxy]benzonitrile (190 mg, 78%) as a yellow solid.

[0828] 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)Cl2C2Cl2 (18.9 mg, 0.023 mmol) in dioxane (10 mL) was stirred at 90 ° C under a nitrogen atmosphere for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), 10% to 50% gradient over 10 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12% B to 30% B in 10 min; wavelength: 220 nm; RT1 (min): 12.55) to give 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 separation under the following conditions (column: CHIRAL ART Cellulose-SZ, 4.6*50 mm, 3 μm; mobile phase A: Hex (0.1% DEA): EtOH = 50:50; flow rate: 1 mL / min; gradient: isocratic; injection volume: 5 μl) to give Example 90 (6.4 mg, 7%) and Example 91 (7.4 mg, 7%). LCMS (ESI) m / z: 462.40 [M+H] + .

[0829] 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

[0830]

[0831] The title compound was prepared using the following procedure:

[0832]

[0833] At room temperature, to a stirred mixture of 4-bromo-1H-pyrazole-3-amine (500mg, 3.09mmol) and di-tert-butyl dicarboxylate (1347.3mg, 6.17mmol) in THF (15mL), DMAP (37.7mg, 0.31mmol) was added in batches. The resulting mixture was stirred at room temperature for 2h. The reaction was quenched by adding water (50mL) and extracted with EtOAc (3×150mL). The combined organic layer was washed with brine (2×10mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (0%-10%) to give tert-butyl 3-amino-4-bromopyrazole-1-carboxylate (500mg) as a white solid.

[0834] 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)Cl2CH2Cl2 (62.2 mg, 0.076 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (10% MeOH / CH 2 Cl 2 ) to give tert-butyl 3-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (220 mg) as an off-white solid.

[0835] 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 O (1 mL) was added K CO (295 mg, 2.14 mmol) and Pd(dppf)Cl CHCl (52.2 mg, 0.064 mmol) in portions at room temperature. The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 1.5 h. The residue was purified by silica gel column chromatography eluting with MeOH / CH2Cl2 (0%-10%) to give tert-butyl 3-amino-4-[2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl]pyrazole-1-carboxylate (317 mg) as a brown solid.

[0836] A mixture of tert-butyl 3-amino-4-[2-cyano-4-(6-fluoropyridin-3-yl)-3-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]phenyl]pyrazole-1-carboxylate (300 mg, 0.55 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 0.5 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 50% over 10 min; detector, UV 254 nm. The crude product was purified by preparative HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 4% B to 24% B, 24% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 11.58; to give Example 92 (25 mg, 6%). LCMS (ESI) m / z: 444.30 [M+H] + .

[0837] Example 93: 3-(Imidazolo[1,2-a]pyrimidin-6-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0838]

[0839] The title compound was prepared using the following procedure:

[0840]

[0841] 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)Cl2CH2Cl2 (20.6 mg, 0.025 mmol) and AcOK (74.3 mg, 0.76 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The resulting mixture was evaporated in vacuo and used directly in the next step without further purification.

[0842] To a stirred mixture of intermediate 1 (50 mg, 0.14 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyrimidine (35.5 mg, 0.14 mmol) in H2O (0.5 mL) was added K2CO3 (60 mg, 0.42 mmol) and Pd(dppf)Cl2CH2Cl2 (11.8 mg, 0.014 mmol) in portions at room temperature. The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 2 h. The crude product was purified by preparative HPLC under the following conditions (column: XBridgeShield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 4% B to 24% B in 8 min; wavelength: 254 / 220 nm; RT1 (min): 11.58) to give Example 93 (43 mg, 77%). LCMS (ESI) m / z: 385.10 [M+H] + .

[0843] 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

[0844]

[0845] The title compound was prepared using the following procedure:

[0846]

[0847] A mixture of Example 30 (200 mg, 0.5 mmol) and CsCO (328.4 mg, 1 mmol) in dioxane (5 mL) was stirred at room temperature for 5 min. To the above mixture was added Pd-PEPPSI-IPentCl 3-chloropyridine (49 mg, 0.05 mmol) and 3-[(tert-butyldimethylsilyl)oxy]azetidine (188.8 mg, 1 mmol). The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (400 mL). The combined organic layer was washed with brine (400 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 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] + .

[0848] At room temperature, 6-{3-[(tert-butyldimethylsilyl)oxy]azetidine-1-yl}-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazole-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) were added to a vial. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc (300 mL). The combined organic layer was washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: isocratic 10% B to 28% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.62) to give Example 95 (14.7 mg, 11%). LCMS (ESI) m / z: 434.05 [M+H] + .

[0849] Example 97: 6-Acetyl-3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0850]

[0851] The title compound was prepared using the following procedure:

[0852]

[0853] To a vial was added Example 30 (320 mg, 0.81 mmol) and DMF (5 mL), PdAMPHOS (57.1 mg, 0.081 mmol), and tributyl(1-ethoxyvinyl)stannane (436.8 mg, 1.21 mmol). The resulting mixture was stirred at 130°C for 2 h. The reaction was quenched with water and extracted with EtOAc (500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (9:1) to afford 6-(1-ethoxyvinyl)-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] + .

[0854] To a vial was added 6-(1-ethoxyvinyl)-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg, 0.69 mmol), TFA (1.2 mL), and DCM (12 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The crude product was purified by preparative HPLC with the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 30% B in 7 min; wavelength: 254 / 220 nm; RT1 (min): 6.92) to afford Example 97 (85.5 mg, 30%). LCMS (ESI) m / z: 405.20 [M+H] + .

[0855] Example 100: 5-(6-fluoropyridin-3-yl)-4-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)isophthalonitrile

[0856]

[0857] The title compound was prepared using the following procedure:

[0858]

[0859] To a stirred solution of intermediate 17 (200 mg, 0.61 mmol) in dioxane (5 mL) and H O (1 mL) was added K CO (253.7 mg, 1.84 mmol), 6-fluoropyridin-3-ylboronic acid (172.5 mg, 1.22 mmol) and Pd (dppf) Cl (44.8 mg, 0.061 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C. under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (8:1) to give a brown solid, which was further purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 9% B to 25% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.78) to give Example 100 (19.3 mg, 8%). LCMS (ESI) m / z: 388.25 [M+H] + .

[0860] Example 101: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-5-(methylsulfonyl)benzonitrile

[0861]

[0862] The title compound was prepared using the following procedure:

[0863]

[0864] To a stirred solution of intermediate 18 (160 mg, 0.42 mmol) in dioxane (6 mL) and H O (1.5 mL) was added K CO (174.6 mg, 1.26 mmol), 6-fluoropyridin-3-ylboronic acid (71.2 mg, 0.5 mmol) and Pd (dppf) Cl (30.8 mg, 0.042 mmol) in portions at room temperature. The resulting mixture was stirred at 100 ° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give a brown solid, which was further purified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 9% B to 25% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.78) to give Example 101 (69.6 mg, 37%). LCMS (ESI) m / z: 441.00 [M+H] + .

[0865] 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

[0866]

[0867] The title compound was prepared using the following procedure:

[0868]

[0869] A solution of intermediate 19 (50 mg, 0.13 mmol), 6-fluoropyridin-3-ylboronic acid (21.9 mg, 0.15 mmol), K2CO3 (53.7 mg, 0.39 mmol) and Pd(dppf)Cl2 (9.5 mg, 0.013 mmol) in 1,4-dioxane (8 mL) and H2O (2 mL) was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 11% B to 28% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.65) to give Example 105 (0.9 mg, 2%). LCMS (ESI) m / z: 403.50 [M+H] + .

[0870] Example 106: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)benzonitrile

[0871]

[0872] The title compound was prepared using the following procedure:

[0873]

[0874] To a stirred mixture of intermediate 20 (60 mg, 0.17 mmol) and 6-fluoropyridin-3-ylboronic acid (29.2 mg, 0.21 mmol) in H2O (1 mL) and 1,4-dioxane (4 mL) was added K2CO3 (47.8 mg, 0.35 mmol) and Pd(dppf)Cl2CH2Cl2 (14.1 mg, 0.017 mmol) in portions at room temperature. The resulting mixture was stirred at 90°C under nitrogen atmosphere for 2 h. The residue was purified by preparative TLC (10% MeOH / CH2Cl2) and further purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: isocratic 10% B-30% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 11.68) to give Example 106 (10 mg, 16%). LCMS (ESI) m / z: 364.05 [M+H] + .

[0875] 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

[0876]

[0877] The title compound was prepared using the following procedure:

[0878]

[0879] To a stirred mixture of intermediate 21 (200 mg, 0.49 mmol) and 6-fluoropyridin-3-ylboronic acid (102.9 mg, 0.73 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (135 mg, 0.97 mmol) and Pd(dppf)Cl2 (35.6 mg, 0.049 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere overnight. The reaction was quenched by adding water (30 mL) at room temperature and extracted with EtOAc (3×80 mL). The combined organic layer was washed with brine (2×15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min; detector, UV 254 nm. It was then purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 15% B to 45% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.77) to afford 4-chloro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile as a white solid.

[0880] To a stirred mixture of 4-chloro-3-(6-fluoropyridin-3-yl)-6-methoxy-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (25 mg, 0.059 mmol) and CsF (89 mg, 0.59 mmol) in DMSO (10 mL) was added TBAB (2 mg, 0.006 mmol) in portions at room temperature. The resulting mixture was stirred at 120° C. for 4 h. The crude product was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: isocratic 15% B to 35% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.1) to give Example 107 (5 mg, 20%). LCMS (ESI) m / z: 411.25 [M+H] + .

[0881] Example 108: 3-(6-fluoropyridin-3-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-6-(oxetan-3-yl)benzonitrile

[0882]

[0883] The title compound was prepared using the following procedure:

[0884]

[0885] To a stirred mixture of Example 30 (70 mg, 0.18 mmol) and 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2-dioxaborolane (64.9 mg, 0.35 mmol) in DMF (3 mL) at room temperature were added portionwise 4,4'-di-tert-butyl-2,2'-bipyridine; bis[3,5-difluoro-2-(5-methylpyridin-2-yl)phenyl]iridiumylium; hexafluoro-λ5-phosphoramide (3.6 mg, 0.004 mmol) 1-methoxy-2-(2-methoxyethoxy)ethane; nickel dibromide (3.1 mg, 0.009 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (2.4 mg, 0.009 mmol) and morpholine (30.7 mg, 0.35 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere during blue light conditions. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC with the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150mm, 5μm; mobile phase A: water (10mmol / L NH4HCO3+0.05% NH3H2O), mobile phase B: ACN; flow rate: 60mL / min mL / min; gradient: 17% B to 34% B in 10min; wavelength: 254nm / 220n m; RT1 (min): 11.63) to obtain Example 108 (2.4mg, 3%). LCMS (ESI) m / z: 419.20[M+H] + .

[0886] Example 113: 3-(3-Hydroxy-1H-indazol-5-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0887]

[0888] The title compound was prepared using the following procedure:

[0889]

[0890] At room temperature under a nitrogen atmosphere, to a stirred mixture of 5-bromo-1,2-dihydro-3H-indazol-3-one (2.0 g, 9.4 mmol) and K2CO3 (3.9 g, 28.2 mmol) and 4-methoxybenzyl chloride (2.9 g, 18.8 mmol) in DME (20 mL) and DMF (20 mL), lithium bromide (2.5 g, 28.2 mmol) was added in batches. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched by adding saturated NH4Cl (aqueous) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layer was washed with water (2×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:3) to give 5-bromo-1,2-bis(4-methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (1.5 g, 48%) as a white solid.

[0891] To a stirred mixture of 5-bromo-1,2-bis(4-methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (1.5 g, 3.3 mmol) and bis(pinacolato)diboron (1.3 g, 5.0 mmol) in dioxane (15 mL) at room temperature under a nitrogen atmosphere, Pd(dppf)Cl2 (0.2 g, 0.3 mmol) and KOAc (1.0 g, 10.0 mmol) were added in portions. The resulting mixture was stirred at 80 ° C. under a nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with water (2×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3) 10% to give (1,2-bis(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl)boronic acid (492 mg, 29%) as a brown viscous oil.

[0892] To a stirred mixture of Intermediate 1 (291 mg, 0.8 mmol) and (1,2-bis(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl)boronic acid (490.1 mg, 1.0 mmol) in dioxane (15 mL) and H O (1.7 mL) at room temperature under a nitrogen atmosphere were added Pd(dppf)Cl (61.5 mg, 0.1 mmol) and KCO (348.5 mg, 2.5 mmol) in portions. The resulting mixture was stirred at 70° C. under a nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water (0.1% FA), gradient 10% to 50% in 10 min; detector, UV 254 nm to give 3-{1,2-bis[(p-methoxyphenyl)methyl]-3-oxo-1,2-dihydro-3H-indazol-5-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1-piperidinyl]benzonitrile (225 mg, 42%) as a light yellow solid.

[0893] A solution of 3-{1,2-bis[(p-methoxyphenyl)methyl]-3-oxo-1,2-dihydro-3H-indazol-5-yl}-2-[4-(4-methyl-4H-1,2,4-triazol-3-yl)-1-piperidinyl]benzonitrile (225 mg, 0.4 mmol) in TFA (10 mL) was stirred under a nitrogen atmosphere overnight at 70° C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column 19*250 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 13% B to 31% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 6.81) to give Example 113 (14.3 mg, 6%). LCMS (ESI) m / z: 400.20 [M+H] + .

[0894] Example 117: (5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-yl)boronic acid

[0895]

[0896] The title compound was prepared using the following procedure:

[0897]

[0898] To a stirred mixture of Example 115 (90 mg, 0.24 mmol) and bis(pinacolato)diboron (72.4 mg, 0.28 mmol) in dioxane (2 mL) was added XPhos Pd G3 (20.1 mg, 0.02 mmol) and KOAc (69.9 mg, 0.71 mmol) portionwise at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 4 h. The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 2% B to 17% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 13.8) to give Example 117 (11.2 mg, 12%). LCMS (ESI) m / z: 389.15 [M+H] + .

[0899] Example 118: 5-(3-cyano-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)phenyl)pyridin-3-ylsulfonyl fluoride

[0900]

[0901] The title compound was prepared using the following procedure:

[0902]

[0903] To a stirred solution of Example 120 (50 mg, 0.14 mmol) in anhydrous ACN (5 mL) was added DIEA (35.9 mg, 0.28 mmol) at room temperature under a sulfonyl fluoride atmosphere. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash evaporation with the following conditions (column: Xselect CSHF-Phenyl OBD column 30*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 19% B to 37% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12.63) to obtain Example 118 (3.1 mg, 5%). LCMS (ESI) m / z: 443.20 [M+H]+ .

[0904] Example 121: 3-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-6-yl)-2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)benzonitrile

[0905]

[0906] The title compound was prepared using the following procedure:

[0907]

[0908] To a stirred mixture of intermediate 1 (200 mg, 0.58 mmol) and 3-chloro-4-formylphenylboronic acid (127.8 mg, 0.69 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was added K2CO3 (159.7 mg, 1.16 mmol) and Pd(dppf)Cl2CH2Cl2 (47.1 mg, 0.058 mmol) in batches at room temperature. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 h. The reaction was quenched by adding water (2 mL) at room temperature and extracted with EtOAc (50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 3'-chloro-4'-formyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-carbonitrile as a brown solid (120 mg, 51%).

[0909] To a stirred solution of 3'-chloro-4'-formyl-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-carbonitrile (100 mg, 0.25 mmol) in anhydrous 1,4-dioxane (5 mL) was added bis(pinacolato)diboron (75.1 mg, 0.3 mmol) and potassium trifluoroacetate (15 mg, 0.098 mmol) at room temperature, followed by a catalytic amount of SPhos Pd Gen.3 (19.2 mg, 0.025 mmol) and SPhos (10.1 mg, 0.025 mmol). The reaction mixture was stirred at 65 ° C. overnight. The reaction was quenched by adding water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (9:1) to give 3'-cyano-4-formyl-2'-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-ylboronic acid (80 mg, 77%) as a brown solid.

[0910] To a stirred mixture of 3'-cyano-4-formyl-2'-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-[1,1'-biphenyl]-3-ylboronic acid (50 mg, 0.12 mmol) in THF (5 mL) was added NaBH4 (9.1 mg, 0.24 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction mixture was purified by preparative HPLC with the following conditions (column: Sunfire prep C18 column, 30*150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: isocratic 10% B to 30% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 15.75) to give Example 121 (3.6 mg, 8%). LCMS (ESI) m / z: 400.30 [M+H] + .

[0911] Example 122: 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)benzonitrile

[0912]

[0913] The title compound was prepared using the following procedure:

[0914]

[0915] To a stirred mixture of intermediate 22 (140 mg, 0.37 mmol) and 6-fluoropyridin-3-ylboronic acid (25.8 mg, 0.18 mmol) in H2O (0.8 mL) and 1,4-dioxane (8 mL) was added K2CO3 (101.4 mg, 0.73 mmol) and Pd(dppf)Cl2CHCl2 (30 mg, 0.037 mmol) in portions at room temperature. The resulting mixture was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (0%-10%) to give 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (120 mg, 81%) as a light brown solid. LCMS (ESI) m / z: 398 [M+H] + .

[0916] To a stirred mixture of 6-chloro-3-(6-fluoropyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperazin-1-yl]benzonitrile (50 mg, 0.13 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (31.4 mg, 0.15 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (34.7 mg, 0.25 mmol) and Pd(dppf)Cl2CHCl (9.2 mg, 0.013 mmol) in portions at room temperature. The resulting mixture was stirred at 90°C under a nitrogen atmosphere overnight. The residue was purified by preparative TLC (CH2Cl2 / MeOH 9:1) and then repurified by preparative HPLC with the following conditions (column: XBridge Prep OBD C18 column 30*150 mm, 5 m; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min mL / min; gradient: 14% B to 32% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 12) to give Example 122 (7 mg, 13%). LCMS (ESI) m / z: 444.30 [M+H] + .

[0917] Example 125: 2-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)benzonitrile

[0918]

[0919] The title compound was prepared using the following procedure:

[0920]

[0921] A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol), bis(pinacolato)diboron (961.8 mg, 3.79 mmol), KOAc (743.4 mg, 7.57 mmol) and Pd(dppf)Cl2 (184.7 mg, 0.25 mmol) in 1,4-dioxane (10 mL) was stirred at 110 ° C under a nitrogen atmosphere for 7 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 1H-pyrazolo[4,3-b]pyridin-6-ylboronic acid as a brown oil. LCMS (ESI) m / z: 164 [M+H] + .

[0922] A mixture of intermediate 1 (70 mg, 0.20 mmol), K2CO3 (84.4 mg, 0.61 mmol), 1H-pyrazolo[4,3-b]pyridin-6-ylboronic acid (49.4 mg, 0.3 mmol) and Pd(dppf)Cl2 (14.8 mg, 0.02 mmol) in water (0.2 mL) and dioxane (2 mL) was stirred at 100 ° C. under a nitrogen atmosphere for 4 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give Example 125 (11 mg, 14%). LCMS (ESI) m / z: 385.15 [M+H] + .

[0923] Example 126: (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 acid

[0924]

[0925] The title compound was prepared using the following procedure:

[0926]

[0927] A mixture of intermediate 6 (500 mg, 1.31 mmol), 5-hydroxypyridin-3-ylboronic acid (182.5 mg, 1.31 mmol), K2CO3 (453.8 mg, 3.28 mmol) and Pd(dppf)Cl2 (96.1 mg, 0.13 mmol) in dioxane (10 mL), DMF (5 mL) and H2O (1 mL) was stirred overnight at 100 ° C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (12:1) to give 6-chloro-3-(5-hydroxypyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (342 mg, 66%) as a brown solid. LCMS (ESI) m / z: 395 [M+H] + .

[0928] A mixture of 6-chloro-3-(5-hydroxypyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]benzonitrile (300 mg, 0.76 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolidine (193.4 mg, 0.91 mmol), Pd(dppf)Cl2 (55.6 mg, 0.076 mmol) and K2CO3 (315 mg, 2.28 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 100 ° C. under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The reaction was quenched by adding water (30 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (10:1) to give 3-(5-hydroxypyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(1-methylpyrazol-3-yl)benzonitrile (180 mg, 54%) as a brown solid. LCMS (ESI) m / z: 441 [M+H] + .

[0929] A mixture of 3-(5-hydroxypyridin-3-yl)-2-[4-(4-methyl-1,2,4-triazol-3-yl)piperidin-1-yl]-6-(1-methylpyrazol-3-yl)benzonitrile (160 mg, 0.36 mmol), TEA (55.1 mg, 0.54 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (155.7 mg, 0.44 mmol) in DCM (3 mL) was stirred at room temperature for 2 h. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtr...

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt and / or solvate thereof: in W 1 N or CR 1 , W 2 N or CR 2 , and W 3 N or CR 3 , where W 1 , W 2 and W 3 No more than one of them is N; X 1 and X 2 Independently selected from CR 4 and N; Ring Y With formula (a): where Y 1 , Y 2 , Y 3 and Y 4 Independently selected from CR 5 and N, where Y 1 , Y 2 , Y 3 and Y 4 Not N at the same time, Or Ring Y With formula (b): where Y 1 CR 5 , and Y 2 NR 5’ ; Or Ring Y With formula (c): where Y 1 , Y 2 , Y 3 and Y 4 Independently selected from CR 5 and N; Optionally, Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 Any of represents a fused ring selected from the following: C5-C8 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5-8 membered heterocycloalkyl (wherein 1 to 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, 3-6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -OR a (N(R a )2)-R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR 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), A, B and E are independently selected from C, N, O and S, and D is C or N, in denotes the presence of a double bond, such that the ring ABDEN 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; No more than two of A, B, D and E are simultaneously N, O, or S; 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 -OR c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, -(C1-C6 alkyl) (C6-C 10 aryl), 5 to 10 membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) optionally fused to 3 to 6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), and 3 to 6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), or R 1 and R 2 , or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a fused C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); Where R 1 , R 2 and R 3 Any heteroaryl or heterocycloalkyl in is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxy, C3-C8 cycloalkyl, heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S) and -R b -N(R a )2; R 4 is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy at each occurrence; R 5 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -R b -OR a , -R b -OR c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2、-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 (wherein t is 1 or 2), C1-C6 alkyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R 5 '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 -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); Where R 5 and R 5 Any heteroaryl or heterocycloalkyl in ' is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halo, hydroxy, C3-C8 cycloalkyl and -R b -N(R a )2; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h independently selected from the group consisting of: H, halogen, NO2, OH, CN, -R b -N(R a )2. -R b -OH, C1-C6 alkyl and C1-C6 alkoxy; and / or optionally, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently represent oxo, thio, imino, or oxime; and / or optionally, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently combine together with the carbon atoms to which they are attached to form a fused ring selected from C3-C6 cycloalkyl and C3-C6-heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); and / or optionally, R 6c and R 6d One of them and R 6e and R 6f One of them together represents a bond between the ring carbon members to which it is bound; R a is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, -(C1-C6 alkyl)(C3-C8 cycloalkyl), C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R b is independently selected at each occurrence from a direct bond, a straight or branched C2-C6-alkylene and a C2-C6-alkenylene chain; wherein R a and R b Any heteroaryl or heterocycloalkyl in is optionally and independently substituted by 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, halo, hydroxyl, R c is independently selected at each occurrence from straight-chain or branched C2-C6-alkylene and C2-C6-alkenylene chains.

2. The compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound has formula (I): in X 1 and X 2 Independently selected from CR 4 and N; Ring Y With formula (a): where Y 1 , Y 2 , Y 3 and Y 4 Independently selected from CR 5 and N, where Y 1 , Y 2 , Y 3 and Y 4 Not N at the same time, Or Ring Y With formula (b): where Y 1 CR 5 , and Y 2 NR 5’ ; Optionally, Y 1 and Y 2 , or Y 2 and Y 3 , or Y 3 and Y 4 Any of represents a fused ring selected from the following: C5-C8 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5-8 membered heterocycloalkyl (wherein 1 to 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, 3-6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, oxo, thioxo, cyano, nitro, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -OR a (N(R a )2)-R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR 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), A, B and E are independently selected from C, N, O and S, and D is C or N, in denotes the presence of a double bond, such that the ring ABDEN 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; No more than two of A, B, D and E are simultaneously N, O, or S; 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 -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, -(C1-C6 alkyl) (C6-C 10 aryl), 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), or R 1 and R 2 , or R 2 and R 3 Together with the carbon atom to which it is attached, it forms a fused C5-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 5- to 8-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R 4 is independently H, OH, halo, C1-C6 alkyl, or C1-C6 alkoxy at each occurrence; R 5 is independently selected from the group consisting of hydrogen, halo, cyano, nitro, -R b -OR a , -R b -OR c -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2. -R b -N(R a )2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2. -R b -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R 5 '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 -OR c -C(O)N(R a )2. -R b -OR c -N(R a )2. -R b -N(R a )-R c -N(R a )2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t N(R a )2 (wherein t is 1 or 2), C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h independently selected from the group consisting of: H, halogen, NO2, OH, CN, -R b -N(R a )2. -R b -OH, C1-C6 alkyl and C1-C6 alkoxy; or optionally, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently represent oxo, thio, imino, or oxime; or optionally, R 6a and R 6b , or R 6c and R 6d , or R 6e and R 6f , or R 6g and R 6h independently combine together with the carbon atoms to which they are attached to form a fused ring selected from C3-C6 cycloalkyl and C3-C6-heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R a is independently selected at each occurrence from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R b is independently selected at each occurrence from a direct bond, a straight or branched C2-C6-alkylene and C2-C6-alkenylene chain; R c is independently selected at each occurrence from straight-chain or branched C2-C6-alkylene and C2-C6-alkenylene chains.

3. The compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof, wherein W 1 N, W 2 CR 2 , and W 3 CR 3 .

4. The compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof, wherein W 1 CR 1 , W 2 CR 2 , and W 3 is N.

5. The compound according to claim 1 or a pharmaceutically acceptable salt and / or solvate thereof, wherein W 1 CR 1 , W 2 CR 2 , and W 3 CR 3 . 6 . The compound according to claim 1 , or a pharmaceutically acceptable salt and / or solvate thereof, wherein D is C. 7 .

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt and / or solvate thereof, wherein A, B and E are independently selected from C and N. 8 . The compound according to claim 1 , or a pharmaceutically acceptable salt and / or solvate thereof, wherein at least one of A, B and E is N. 9 . The compound or pharmaceutically acceptable salt and / or solvate thereof according to claim 1 , wherein two of A, B and E are N.

10. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5, wherein the ABDEN ring is an optionally substituted ring selected from the group consisting of:

11. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 5 or 10, wherein the optionally substituted ABDEN ring is selected from one of the group consisting of:

12. A compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the optionally substituted ABDEN ring is 13. The compound or pharmaceutically acceptable salt and / or solvate thereof according to any one of claims 1 to 12, wherein ring Y has formula (a).

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 One of them is N, and each of the other three is CR 5 .

15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 , Y 2 , Y 3 Each of them is CR 5 , and Y 4 is N.

16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 and Y 2 Each of them is CH, and Y 3 For CF.

17. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 Two of them are N, and each of the other two is CR 5 .

18. A compound as described in any one of claims 1 to 13 and 17, or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 and Y 2 Each of them is CR 5 , and Y 3 and Y 4 Each of them is N.

19. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 and Y 2 or Y 3 and Y 4 Any of represents an optionally substituted fused ring.

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

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

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

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

24. A compound as claimed in any one of claims 1 to 23 or a pharmaceutically acceptable salt and / or solvate thereof, wherein R 4 For H.

25. A compound as described in any one of claims 1 to 24 or a pharmaceutically acceptable salt and / or solvate thereof, wherein R 1 Selected from the group consisting of: H, halogen, C1-C6 alkoxy, C6-C 10 Aryl, C3-C8 cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S) and 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S).

26. A compound as described in any one of claims 1 to 25, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R 2 and R 3 Each of the above is independently H, halo, cyano, CH3, or CF3.

27. A compound as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h Independently selected from the group consisting of H, halo, C1-C6 alkyl and C1-C6 alkoxy.

28. A compound as described in any one of claims 1 to 27, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h Each of them is H.

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

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

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

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

33. A compound according to any one of claims 29 to 32, or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R 1 Selected from the group consisting of: H, halogen, C1-C6 alkoxy, C6-C 10 Aryl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl (wherein 1 to 4 heteroaryl members are independently selected from N, O and S) and 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S); R 2 and R 3 Each of which, when present, is independently H, F, cyano, CH3, or CF3.

34. A compound as described in any one of claims 29 to 33, or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 One of them is N, and each of the other three is CR 5 .

35. A compound as described in any one of claims 29 to 34 or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 and Y 2 Each of them is CH, and Y 3 For CF.

36. A compound as described in any one of claims 29 to 33, or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 Two of them are N, and each of the other two is CR 5 .

37. A compound as described in any one of claims 29 to 33 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound contains Y 1 , Y 2 , Y 3 and Y 4 The ring is:

38. A compound as described in any one of claims 29 to 33 and 37 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound contains Y 1 , Y 2 , Y 3 and Y 4 The ring is:

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

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

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

42. A method for treating a disease in a patient suffering from the disease, wherein the disease is associated with the expression of glutaminyl-peptide cyclotransferase protein (QPCT) or glutaminyl-peptide cyclotransferase-like protein (QPCTL), the method comprising administering to the patient a compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt and / or solvate thereof.

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

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

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

46. ​​The method of claim 45, wherein the cancer is leukemia or lymphoma.

47. The method of claim 46, wherein the leukemia or lymphoma is 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's 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 (BCL), and lymphocytic leukemia (B-CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL) and pre-B acute lymphoblastic leukemia (pre-B ALL).

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

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

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

51. The method of claim 50, wherein 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.

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

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

54. The method of claim 42, wherein the disease is cardiovascular disease.

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

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

57. The method of claim 56, wherein the contacting is performed in vitro.

58. The method of claim 56, wherein the contacting is performed in vivo.

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

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

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