Novel heterocyclic compounds, compositions, methods of making and using same

Abstract

The present invention relates to a compound represented by formula (I) The present invention relates to compounds of the formula JPEG2024516455000239.jpg2644, their salts, solvates and solvates of salts and pharmaceutical compositions containing these compounds as active ingredients. The present invention further relates to their use as aldo-keto reductase family 1C3 (AKR1C3) (also known as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5, HSD17B5) and prostaglandin (PG)F2α synthase) inhibitors. The present invention further relates to methods for the preparation and uses of the compounds.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a novel class of aldo-keto reductase family 1C3 (AKR1C3) (also known as 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5, HSD17B5) and prostaglandin (PG)F2α synthase) inhibitors, their salts, solvates and solvates of the salts, as well as pharmaceutical compositions comprising these compounds as active ingredients. The invention further relates to methods for their preparation and their use. [Background technology]

[0002] 2. Background of the Invention Aldo-keto reductase family 1 member C3 (AKR1C3) inhibits 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5, HSD17B5) and prostaglandin (PG) F 2α Also known as synthase. AKR1C3 is a member of the aldo-ketoreductase 1C (AKR1C) subfamily of the aldo-ketoreductase (AKR) superfamily of enzymes, which contains >190 members. The human AKR1C subfamily consists of four isoforms (AKR1C1, -C2, -C3 and -C4) and is a phase I metabolic enzyme that depends on nicotinamide adenine dinucleotide phosphate (NADPH) for the reduction of 3-keto-, 17-keto- and 20-ketosteroids. AKR1C3 also reduces the carbonyl group of steroid hormones to the corresponding alcohols and therefore plays an important role in the metabolism, activation and deactivation of androgens, estrogens, progesterone and prostaglandins.

[0003] AKR1C3 shares high sequence homology (>86%) with AKR1C1, -C2 and -C4. Although the isoforms are similar in structure, the isomers are differentially distributed and exhibit distinct biological functions. AKR1C3 shows endocrine organ expression, including liver, GI tract, prostate, testis, adrenal gland, uterus, breast, lung, kidney, bladder, ovary, adipose tissue and brain.

[0004] More specifically, AKR1C3 can catalyze the conversion of estrone (a weak estrogen) to estradiol (a strong estrogen), progesterone (strong antiestrogenic activity) to 20-α-hydroxyprogesterone (weak antiestrogenic activity), dehydroepiandrosterone (DHEA, a weak androgen) to androstenediol (the precursor of testosterone), androstenedione (a weak androgen) to testosterone (a strong androgen), 5α-androstanedione (5α-dione, a weak androgen) to DHT (a strong androgen), and androsterone to 17β-dihydroandrosterone (Penning et al. Mol. Cell. Endocrinol. 2006, 248 (1-2), 182-191; Rizner TL, Pen-ning TM. Steroids 2014; 79: 49-63). In addition, AKR1C3 has enzymatic activity against the 11-keto forms of androgens, and is therefore capable of converting 11-ketoandrostenedione (a weak androgen) to 11-ketotestosterone (a strong androgen), 11-keto-5α-androstanedione to 11-keto-5α-dihydrotestosterone, and 11-ketoandrosterone to 11-keto-3α-androstanediol (Barnarda M. et al. J. Steroid Biochem. Mol. Biol. 2018; 183: 192-201; Schiffer L et al. Eur. J. Endocrinol. 2021; 184: 357-67; Storbeck KH et al. Mol. Cell Endocrinol. 2013; 377: 135-46). AKR1C3 is also PGH 2 From PGF 2α and PGD 2 From 11β-PGF 2and , both of which are known to stimulate inflammation and proliferation (Byrns M. et al., Biochem. Pharmacol. 2008, 75 (2), 484-493; Byrns M et al. J. Steroid Biochem. Mol. Biol. 118 (2010) 177-187; Penning TM. Mol. Cell Endocrin. 2019; 489; 82-91; Suzuki-Yamamoto T. et al. FEBS Lett. 462 (1999) 335-340; Komoto J et al. Biochemistry 45 (7) (2006) 1987-1996). Inhibition of AKR1C3 activity therefore reduces the levels of these end products and, as a result, AKR1C3 may mediate the regulation of ligands for androgen, estrogen, progesterone and prostaglandin receptors.

[0005] Furthermore, AKR1C3 has also been shown to metabolize a wide range of carbonyl compounds and xenobiotics. AKR1C3 as a carbonyl reductase can mediate anthracycline inactivation and resistance (Bukum N. et al. Chem.-Biol. Interact. 2019, 302, 101-107; Zhong et al. Biomed. Pharmacother. 2015, 69, 317-325; Hofman J. et al. Toxicol. Appl. Pharmacol. 2014, 278 (3), 238-248), and AKR1C3 as a nitroreductase can mediate the inactivation and resistance of nitrogen mustard anticancer drugs, such as PR-104A (Bortolozzi R. et al. Br. J. Cancer 2018, 118 (7), 985-994) and OBI-3424 / TH3424 (Evans K. et al. Clin. Cancer Res. 2019, 25 (14), 4493-4503) can be induced.

[0006] There is a need in the art for new compounds that inhibit AKR1C3. As mentioned above, AKR1C3 mediates the regulation of ligands of androgen, estrogen, progesterone and prostaglandin receptors, therefore, inhibition of AKR1C3 activity can reduce the levels of these end products, such that such AKR1C3 inhibitors are suitable for the treatment and / or prevention of diseases and disorders associated with altered levels of androgens, estrogens, progesterone and / or prostaglandins.

[0007] AKR1C3 inhibitors have been previously published. The most potent inhibitor published inhibited AKR1C3 with an IC of 0.035 ± 0.002 μM. 50 The pyridine derivative GTx-560 inhibits AKR1C3 at the IC level (Clin. Cancer Res. 2013, 19, 20; 5613-5625). 50 A flufenamic acid analogue with a potency of 35 nM was published in Heindriks et al., Bioorg. Med. Chem. Lett. 2015, 25 (20), 4437-4440. Furthermore, patent application EP3421483A1 discloses AKR1C3 inhibitors that are steroidal 17-beta heteroaryl compounds. One of the disclosed compounds is BAY-1128688, which was included in a Phase II clinical trial for the treatment of endometriosis, but increased bilirubin levels in patients and the trial was discontinued.

[0008] Additionally, morpholinyl ureas have been disclosed as AKRIC3 inhibitors; for example, the morpholinyl urea compound SN34037 has an IC 50 (Flanagan et al., Bioorg. Med. Chem. 2014, 22 (3), 967-977). Furthermore, among the published sulfonylurea compounds, glimepiride (GLM) has an AKR1C3 IC value of 0.85 μM. 50(Zhao Y. et al., Chem.-Biol. Interact. 2015, 240, 310-315). Many AKR1C3 inhibitors have been shown to inhibit other AKR and COX enzymes (Yang et al, J. Med. Chem. 2020, 63, 20, 11305-11329).

[0009] Due to the countervailing biological functions of certain closely related enzymes in the aldo-keto reductase (AKR) or hydroxysteroid (17β) dehydrogenase (HSD17B) enzyme family, it is beneficial to develop AKR1C3 inhibitors that selectively inhibit AKR1C3 over other AKRs or HSD17B. For example, in the prostate, AKR1C2 plays an important role in inactivating 5α-dihydrotestosterone. Meanwhile, AKR1C2 inhibition in prostate cancer can promote proliferative signaling in the prostate, and treatment of prostate carcinoma can be achieved by AKR1C3 inhibition. Therefore, isomer-selective AKR1C3 inhibitors are needed (Penning TM et al. Mol. Cell Endocrinol. 2008, 281, 1-8). On the other hand, type 2 17β-hydroxysteroid dehydrogenase (HSD17B2) induces steroid metabolism in the opposite direction to AKR1C3, converting potent steroid-like estradiol, testosterone and 5α-dihydrotestosterone to the less active forms estrone, androstenedione and 5α-androstanedione, respectively (Gao X. et al. Clin. Cancer Res. 2019, 25, 1291-301; Ko H. et al. Cell Rep. 2018, 22, 809-819). Its widespread and abundant expression in several different estrogen and androgen target tissues, such as uterus, placenta, liver and the digestive and urinary tracts, suggests that type 2 enzyme protects tissues from excessive steroid action. Therefore, it is important to have selective AKR1C3 inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0010] BRIEF DESCRIPTION OF THE DRAWINGS The object of the present invention is to provide compounds useful for the treatment or prevention of diseases and disorders associated with altered levels of androgens, estrogens, progesterone and / or prostaglandins and / or treatable by inhibition of the AKR1C3 enzyme. It is a further object of the present invention to provide compounds that selectively inhibit the AKR1C3 enzyme over the AKR1C2 enzyme. The object of the present invention is achieved by compounds that are characterized by what is stated in the independent claims. Preferred embodiments of the present invention are disclosed in the dependent claims. The embodiments, examples and features that do not fall within the scope of the independent claims, if any, should be interpreted as examples that are useful for the understanding of the various embodiments of the present invention. [Means for solving the problem]

[0011] In one aspect, the present invention provides a novel compound of formula (I): [ka] or a salt, solvate or solvate of a salt thereof, wherein R 1 , R 2 and R 3 is as defined in the claims.

[0012] In another aspect, embodiments of the present invention provide a process for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof.

[0013] In another aspect, an embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I) or a salt, solvate or solvate of the salt thereof, together with one or more pharma- ceutically acceptable excipients.

[0014] In another aspect, an embodiment of the present invention provides a compound of formula (I) for use as a medicament.

[0015] In another aspect, embodiments of the present invention provide a compound of formula (I) for use in the treatment or prevention of a disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-associated pain. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description of the Invention The present invention relates to a compound represented by formula (I) [ka] or a salt, solvate or solvate of the salt thereof, wherein R 1 , R 2 and R 3 are as defined in the claims. The present invention is based on the surprising realization and discovery that the novel compounds of formula (I) inhibit the AKR1C3 enzyme. A further surprising realization and advantage of the present invention is that the compounds of formula (I) selectively inhibit AKR1C3 over other aldo-keto reductases such as AKR1C2 and HSD17B2 (17β-HSD2) or hydroxysteroid (17β) dehydrogenase (HSD17B) enzymes. Therefore, an advantage of the present invention is that the novel compounds of formula (I) have no or only a reduced biological effect due to inhibition of AKR1C2. A further surprising realization and advantage of the present invention is that the compounds of formula (I) have no or only a reduced biological effect due to inhibition of HSD17B2.

[0017] The following embodiments are illustrative. Although the present invention may refer to "an", "one" or "several" embodiments in several places, this does not necessarily mean that each such reference is to the same embodiment or that the feature applies only to a single embodiment. Features of one of the different embodiments may also be combined to provide another embodiment. Furthermore, the terms "comprise", "include", "includes" and "comprises" should not be interpreted as limiting the described embodiment to only the described features, but such an embodiment may also include features / structures not specifically described.

[0018] In one aspect, the present invention provides a novel compound of formula (I): [ka] [During the ceremony R 1 is C 1-6 -Alkyl, C 1-6 -Haloalkyl, C 1-6 -perhaloalkyl, (CH 2 ) m OR', (CH 2 ) m N(R') 2 , 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which may optionally be independently selected from the group consisting of R 11 and is substituted with 1 to 6 substituents selected from; R 2 is C 1-6 -Alkyl, C 1-6 -Haloalkyl, C 1-6 -perhaloalkyl, (CH 2 ) m OR', (CH 2 ) m N(R') 2 , 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which may optionally be independently selected from the group consisting of R 12 and is substituted with 1 to 6 substituents selected from; or R 1 and R 2 form a 4- to 11-membered unsaturated or aromatic heterocycle or a 4- to 10-membered saturated or partially unsaturated heterocycle together with the ring nitrogen atom to which they are attached, and the heterocycles may each independently be R 13 and is substituted with 1 to 6 substituents selected from; R 3 are groups selected from the group consisting of 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which may optionally be independently R 31 and is substituted with 1 to 6 substituents selected from; R 11 is halogen, CN, C 1-6 -Alkyl, C 1-6 -Alkoxy, C 1-6 -(per)haloalkyl, C 1-6 -(per)haloalkoxy, OR', oxo, (OCH 2 ) n OR', SR', NO 2 , N(R') 2 , (CH 2 ) n N(R') 2 , (CH 2 ) n OR', CH(XR')R', CO 2 R', C(O)N(R') 2 , C(O)NR'C(O)R", NR'COR", C(=NH)R", C(=N-OR')R", C(O)R", NR'C(O)NR", NR'SO 2 R”, ​​SO 2 NHSO 2 R” and SO 2 N(R') 2 R', OR', N(R') 2 and is substituted with one or more substituents independently selected from the group consisting of: R 12 is halogen, CN, C 1-6 -Alkyl, C 1-6 -Alkoxy, C 1-6-(per)haloalkyl, C 1-6 -(per)haloalkoxy, OR', oxo, (OCH 2 ) n OR', SR', NO 2 , N(R') 2 , (CH 2 ) n N(R') 2 , (CH 2 ) n OR', CH(XR')R', CO 2 R', C(O)N(R') 2 , NHCOR”, C(=NH)R”, C(=N-OR')R”, C(O)R” and SO 2 N(R') 2 R', OR', N(R') 2 and is substituted with one or more substituents independently selected from the group consisting of: R 13 is halogen, CN, C 1-6 -Alkyl, C 1-6 -Alkoxy, C 1-6 -(per)haloalkyl, C 1-6 -(per)haloalkoxy, OR', oxo, (OCH 2 ) n OR', SR', NO 2 , N(R') 2 , (CH 2 ) n N(R') 2 , (CH 2 ) n OR', CH(XR')R', CO 2 R', C(O)N(R') 2 , C(O)NR'C(O)R", NR'C(O)R", C(=NH)R", C(=N-OR')R", C(O)R", NR'C(O)NR", NR'SO 2 R”, ​​SO 2 NHSO 2 R” and SO 2 N(R') 2 R', OR', N(R') 2 and is substituted with one or more substituents independently selected from the group consisting of: R 31is halogen, CN, C 1-6 -Alkyl, C 1-6 -Alkoxy, C 1-6 -(per)haloalkyl, C 1-6 -(per)haloalkoxy, OR', oxo, (OCH 2 ) n OR', SR', NO 2 , N(R') 2 , (CH 2 ) n N(R') 2 , (CH 2 ) n OR', CO 2 R', C(O)N(R') 2 , C(O)NR'C(O)R", NR'C(O)R", C(=NH)R", C(=N-OR'H)R", C(O)R", NR'C(O)NR", NR'SO 2 R”, ​​SO 2 NHSO 2 R” and SO 2 N(R') 2 R', OR', N(R') 2 and is substituted with one or more substituents independently selected from the group consisting of: Each R' is independently H, C 1-6 -Alkyl, C 1-6 -haloalkyl and C 1-6 -perhaloalkyl or any N(R') 2 when R is part of the formula (I), both R together with the nitrogen to which they are attached can each independently form a 3-6 membered aliphatic or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, S and O; Each R” is independently C 1-6 -Alkyl, C 1-6 -haloalkyl and C 1-6 -perhaloalkyl; X is O or S; m is 0 to 6; and n is 1 to 6. or a salt, solvate or solvate of the salt thereof.

[0019] The term "C" as used herein and hereinafter by itself or as part of a haloalkyl, perhaloalkyl or alkoxy group 1-6 "-alkyl" refers to an aliphatic linear, branched or cyclic, especially linear or branched, hydrocarbon group having the indicated number of carbon atoms; e.g., C 1-6 -Alkyl has 1 to 6 carbon atoms in the alkyl portion, e.g., C 1-3 -Alkyl includes methyl, ethyl, n-propyl, and isopropyl, and C 1-6 -Alkyl further includes branched and straight chain n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl. The hydrocarbon radicals suitably contain 1 to 6, preferably 1 to 3 carbon atoms in the alkyl portion. Examples of aliphatic cyclic hydrocarbon radicals include, but are not limited to, cyclopropyl and cyclohexyl.

[0020] The term "haloalkyl" as used herein and hereinafter refers to any of the above alkyl groups in which one or more hydrogen atoms have been replaced by a halogen: particularly I, Br, F or Cl. Examples of haloalkyl groups are chloromethyl, fluoromethyl, -CH 2 CF 3 Including, but not limited to:

[0021] The term "perhaloalkyl" is understood to refer to an alkyl group in which all hydrogen atoms are replaced by halogen atoms. A preferred example is trifluoromethyl (-CF 3 ) and trichloromethyl (-CCl 3 ).

[0022] The term "(per)haloalkyl" as used herein and hereinafter refers to a haloalkyl or a perhaloalkyl.

[0023] The term "halogen" as used herein and hereinafter by itself or as part of another group means Group VIIa elements, including F, Cl, Br and I.

[0024] The term "aryl" as used herein and hereinafter refers to monocyclic and polycyclic aromatic hydrocarbons having the indicated number of ring atoms, e.g., "6-13 membered aryl" refers to aryl having 6 to 13 ring atoms. Examples of aryl include, but are not limited to, phenyl, naphthalenyl and fluorenyl. Aryl may be substituted on any suitable ring atom with 1 to 6, preferably 1 or 2, and especially 1, substituents as indicated. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH 2 OH, CH 2 CH 2 CH 2 OH, OCH 2 CH 3 , 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0025] The term "heteroaryl" as used herein and hereinafter refers to mono-, bi-, tri-, and tetracyclic aromatic rings having one or more heteroatoms as ring atoms, the remaining ring atoms being carbon atoms. Thus, for example, "5- to 11-membered heteroaryl" refers to mono- and bicyclic heteroaryls having a total of 5 to 11 ring atoms, of which one or more ring atoms are heteroatoms, and the remaining ring atoms are carbon atoms. Preferably, the heteroaryl has 1 to 6 heteroatoms as ring atoms, more preferably 1 to 4 heteroatoms, and the remaining ring atoms are carbon atoms, where the heteroatoms include at least the heteroatoms indicated in the same context, and optionally one or more additional heteroatoms. Each heteroatom is independently selected from N, O, S, P, Si, and Se, preferably N, O, and S, unless otherwise specified. A heteroaryl group need only have some degree of aromaticity. Examples of monocyclic heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, furyl, thienyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, tetrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and tetrazinyl. Examples of bicyclic heteroaryls are indolyl, 1H- and 2H-indazolyl, indolinyl, isoindolinyl, quinolinyl, benzimidazolyl, benzazepinyl, benzothiazolyl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridinyl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazinyl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridinyl, 1,4,6,7-tetrahydropyrazolo[4, 3-c]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[1,5-a]pyrazinyl, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazinyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl, 6,7-dihydro-4H-thieno[3,2-c]pyridinyl and other bicyclic heteroaryls resulting from the fusion of a monocyclic heteroaryl with an aromatic ring, the same or another monocyclic aromatic heterocycle or a saturated or partially unsaturated cyclic or heterocyclic group.Examples of tricyclic heteroaryls include carbazolyl, acridinyl, and other tricyclic heteroaryls resulting from the fusion of mono- or bicyclic heteroaryls with aromatic rings, the same or other bicyclic aromatic heterocycles, or saturated or partially unsaturated cyclic or heterocyclic groups. Heteroaryls may be substituted at any suitable ring atom, including N, with 1 to 6, preferably 1 or 2, and especially 1, of the indicated substituents. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF. 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH 2 OH, CH 2 CH 2 CH 2 OH, OCH 2 CH 3 , 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0026] The term "cycloalkyl" as used herein and hereinafter refers to saturated or partially unsaturated mono-, bi-, tri-, and tetracyclic cycloalkyl groups having the indicated number of ring atoms. "3- to 12-membered cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexene, trans-cyclooctene, cyclooctyne, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, and bicyclo[4.4.0]decanyl. It is understood that cycloalkyl may be a spirocyclic, fused bicyclic, or bridged bicyclic cycloalkyl. Cycloalkyl may be substituted on any suitable ring atom with 1 to 6, preferably 1 or 2, substituents as indicated, especially 1. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH2 OH, CH 2 CH 2 CH 2 OH, OCH 2 CH 3 , 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0027] The term "heterocyclyl" is used to refer to saturated or partially unsaturated mono-, bi-, tri-, and tetracyclic rings having one or more heteroatoms as ring atoms, with the remaining ring atoms being carbon atoms. Thus, for example, "3- to 10-membered heterocyclyl" refers to saturated or partially unsaturated mono-, bi-, and tricyclic rings having a total of 3 to 10 ring atoms, of which one or more ring atoms are heteroatoms, and the remaining ring atoms are carbon atoms. Preferably, the heterocyclyl has 1 to 6 heteroatoms as ring atoms, more preferably 1 to 4 heteroatoms, with the remaining ring atoms being carbon atoms, where the heteroatoms include at least the heteroatoms indicated in the same context, and optionally one or more additional heteroatoms. Each heteroatom is independently selected from N, S, O, P, Si, and Se, preferably N, O, and S, unless otherwise specified. Examples of heterocyclyl include, but are not limited to, 1,4-diazabicyclo[2.2.2]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, azetidinyl, 2-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 2,5-diketopiperazine, piperazinedione, morpholinyl, thiomorpholinyl, dioxanyl, oxiranyl, dithianyl, dithiazolyl, oxazinyl, thiazinyl, diozinyl, dithiinyl, thiopyranyl, pyranyl, and tetrazolyl. It is understood that the heterocycle may be a spirocyclic, fused bicyclic, or bridged bicyclic heterocycle. Heterocyclyl may be substituted at any suitable ring atom, including N, with 1 to 6, preferably 1 or 2, and especially 1, substituents as indicated. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH 2 OH, CH 2 CH 2 CH 2 OH, OCH 2 CH 3, 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0028] "Optionally" or "optionally" means that the subsequently described event or circumstance may occur, but does not have to occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0029] The term "optionally substituted" as used herein and hereinafter means that the group with which it is described is unsubstituted or independently substituted with 1 to 6, preferably 1, 2, 3 or 4, substituents attached to any available atom to yield a stable compound. For example, phenyl is substituted once with the described substituent attached to the o-, m- or p-position of the phenyl ring. In general, unless otherwise specified, "substituted" refers to a substituent (group), as defined herein and hereinafter, in which one or more bonds to a hydrogen atom contained therein are replaced with a bond to a non-hydrogen atom.

[0030] The term "unsaturated or aromatic heterocycle" refers to unsaturated or aromatic mono-, bi-, tri-, and tetracyclic rings having one or more heteroatoms as ring atoms, with the remaining ring atoms being carbon atoms. Thus, for example, "4- to 11-membered unsaturated or aromatic heterocycle" refers to unsaturated or aromatic mono-, bi-, and tricyclic rings having a total of 4 to 11 ring atoms, of which one or more ring atoms are heteroatoms, with the remaining ring atoms being carbon atoms. Preferably, the unsaturated or aromatic heterocycle has 1 to 6 heteroatoms, more preferably 1 to 4 heteroatoms, each independently selected from the group consisting of N, S, and O, as ring atoms, with the remaining ring atoms being carbon atoms. It is understood that the unsaturated or aromatic heterocycle may be a spirocyclic, fused bicyclic, or bridged bicyclic heterocycle. Furthermore, R 1 and R 2When, together with the ring nitrogen atom to which they are attached, they form an unsaturated or aromatic heterocycle, such as a 9-membered unsaturated or aromatic heterocycle, it is sufficient that at least one of the cyclic rings of the 9-membered unsaturated or aromatic heterocycle is unsaturated or aromatic; 1 and R 2 However, a representative example of a ring that, together with the ring nitrogen atom to which it is attached, forms an unsaturated or aromatic heterocycle is indolinyl, which consists of a six-membered benzene ring fused to a five-membered pyrrolidinyl. 1 and R 2 The nitrogen to which is bonded is R 1 and R 2Together with the aryl group, it can form a saturated or partially unsaturated heterocycle fused to an unsaturated or aromatic ring and is therefore considered an unsaturated or aromatic heterocycle. Examples of unsaturated or aromatic heterocycles are pyrrolyl, pyrazolyl, furyl, thienyl, triazolyl, furazanyl, 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-oxadiazolyl, 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-thiadiazolyl, tetrazolyl, imidazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, 1H- and 2H-indazolyl, indolinyl, isoindolinyl, quinolinyl, benzimidazolyl, benzazepinyl, benzothiazolyl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridinyl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazinyl, 1,4,6,7-Tetrahydroimidazo[4,5-c]pyridinyl, 1,4,6,7-Tetrahydropyrazolo[4,3-c]pyridinyl, 5,6-Dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6-Dihydro-8H-imidazo[1,5-a]pyrazinyl, 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazinyl, 2,3-Dihydropyrrolo[2,3- b]pyridinyl, 6,7-dihydro-4H-thieno[3,2-c]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl and saturated or partially unsaturated heterocyclyl and an aromatic ring, the same or another unsaturated or aromatic heterocycle or other unsaturated or aromatic heterocycle resulting from the condensation of a saturated or partially unsaturated heterocycle.Preferably, the unsaturated or aromatic heterocycle is selected from the group consisting of indolin-1-yl, isoindolin-2-yl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridin-6-yl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridin-5-yl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazin-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, azetidin-1-yl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl, 1,4,6,7-tetrahydropyrazolo[4,3 -c]pyridin-5-yl, 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl, 5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl), 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl, 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl and 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. The heterocycle may be substituted at any suitable ring atom, including N, with 1 to 6, preferably 1 or 2, and especially 1, as indicated. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF. 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH 2 OH, CH 2 CH 2 CH 2 OH, OCH 2 CH 3 , 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0031] The term "saturated or partially unsaturated heterocycle" refers to saturated or partially unsaturated mono-, bi-, tri-, and tetracyclic rings having one or more heteroatoms as ring atoms, with the remaining ring atoms being carbon atoms. Thus, for example, "4-10 membered saturated or partially unsaturated heterocycle" refers to saturated or partially unsaturated mono-, bi-, and tricyclic rings having a total of 4-10 ring atoms, of which one or more ring atoms are heteroatoms, with the remaining ring atoms being carbon atoms. Preferably, the saturated or partially unsaturated heterocycle has 1-6 heteroatoms, more preferably 1-4 heteroatoms, each independently selected from the group consisting of N, S, and O, as ring atoms, with the remaining ring atoms being carbon atoms. It is understood that the saturated or partially unsaturated heterocycle can be a spirocyclic, fused bicyclic, or bridged bicyclic heterocycle. Examples of saturated or partially unsaturated heterocycles are 1,4-diazabicyclo[2.2.2]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, azetidinyl, 2-azabicyclo[2.2.1]heptanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, 2,5-diketopiperazine, piperazinedione, morpholinyl, thiomo Examples of the heterocyclic ring include, but are not limited to, fluoronyl, dioxanyl, oxiranyl, dithianyl, dithiazolyl, oxazinyl, thiazinyl, diozinyl, dithiinyl, thiopyranyl, pyranyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, tetrazolyl, and other saturated or partially unsaturated heterocyclic rings resulting from the fusion of a saturated or partially unsaturated heterocyclic ring with an aromatic ring, an unsaturated or aromatic heterocyclic ring, or the same or other saturated or partially unsaturated heterocyclic ring. The heterocyclic ring may be substituted at any suitable ring atom, including N, with 1 to 6, preferably 1 or 2, and especially 1, of the indicated substituents. Preferred substituents are halogen, especially F and Cl, cyano, methyl, ethyl, acetyl, trifluoromethyl, hydroxy, methoxy, OCF 3 , C.H. 2 OH, CH 2 OCH 3 , C.H. 2 CH 2 OH, CH 2 CH 2 CH2 OH, OCH 2 CH 3 , 1-hydroxyethyl, SO 2 NH 2 and acetyl.

[0032] As used here and hereafter, the term "C 1-6 -alkoxy" is "C 1-6 -alkyl" has the meaning defined above; 1-6 -alkyl) groups. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and iso-propyloxy.

[0033] As used here and hereafter, the term "C 1-6 -(per)haloalkoxy" is "C 1-6 -(per)haloalkyl" is -O-(C 1-6 -(per)haloalkyl) groups. Examples of preferred alkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trichloromethoxy, and 1,1,1,3,3,3-hexafluoro-isopropoxy.

[0034] The term "oxo" as used herein and hereinafter refers to a substituent oxygen atom attached to another atom by a double or single bond. Examples of functional groups that have an oxo include, but are not limited to, the carbonyl group (C=O).

[0035] The term "3-6 membered aliphatic or aromatic heterocyclic ring containing 1-4 heteroatoms each independently selected from N, S and O" as used herein and hereinafter refers to a monocyclic ring that is saturated, partially unsaturated, unsaturated or aromatic having 3-6 ring atoms, which may or may not contain one or more double bonds between the ring atoms, and which contains 1-4 heteroatoms each independently selected from the group consisting of N, S and O, with the remaining ring atoms being carbon atoms. Any suitable ring atom, including N, may be substituted with 1-4 substituents. Preferred substituents include, but are not limited to, halogen, especially fluoro, CN, methoxy, hydroxy, amino and methyl. Examples of heterocyclic rings include, but are not limited to, aziridinyl, azetidinyl, 1,3-diazetidinyl, pyrazolidinyl, imidazolidinyl, imidazolyl, piperidinyl, dihydrothiazolyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl dioxide, and methoxymethylpyrrolidinyl.

[0036] The term "salt" as used herein and hereafter refers to salts that are known to be non-toxic and physiologically and / or pharma- ceutically acceptable salts.Typically, these are acid addition salts or base addition salts of the compounds of the present invention described.Also included are salts that are not suitable for pharmaceutical applications themselves, but can be used, for example, for isolating or purifying the compounds of the present invention.

[0037] The expression "acid addition salts" includes all non-toxic organic and inorganic acid addition salts that the compounds of the present invention can form. Illustrative inorganic acids which form suitable acid addition salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Illustrative organic acids which form suitable acid addition salts include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, lactic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, salicylic acid, and the like. These salts also include salts useful for chiral resolution of racemates.

[0038] The expression "basic addition salt" includes any non-toxic basic addition salt that the compounds of the present invention can form. Suitable basic addition salts include, but are not limited to, those derived from inorganic bases such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium and zinc salts, especially sodium and ammonium salts. Examples of organic base addition salts include, but are not limited to, salts of trialkylamines such as triethylamine, trimethylamine, ethyldiisopropylamine, methylamine, dimethylamine, trimethylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, morpholine, arginine, lysine, ethylenediamine and N-methylpiperidine, and other salts of organic amines such as choline salts.

[0039] The term "solvate" as used herein and hereafter refers to a form of compound that forms a complex by coordination with solvent molecules in solid or liquid state. Examples of solvates include, but are not limited to, hydrates, alcoholates, etc. Hydrates are a specific form of solvate in which coordination is with water. The preferred solvates in the context of the present invention are hydrates.

[0040] When compounds of the invention exist in tautomeric forms, the present invention includes all tautomeric forms.

[0041] When the compounds of the present invention exist in stereochemical forms, the present invention encompasses all diastereomeric and enantiomeric forms.

[0042] Additionally or alternatively, embodiments of the present invention include R 3 is a group selected from the group consisting of 6-membered aryl and 5- to 9-membered heteroaryl, where each heteroaryl independently contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and each of the groups is optionally independently R 31 is substituted with 1 to 3 substituents selected from; R 31 is as defined above, Provided is a compound of formula (I) or a salt, solvate or solvate of the salt thereof. Preferably, the heteroaryl has 1, 2 or 3 heteroatoms as ring atoms, the remaining ring atoms being carbon atoms, and each heteroatom is independently selected from the group consisting of N, O and S.

[0043] Additionally or alternatively, embodiments of the present invention include R 1 is C 1-6 -alkyl, 5- to 9-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally independently R 11 and R 2 is C 1-6 -alkyl, 5- to 9-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally independently R 12 is substituted with 1 to 3 substituents selected from; R 11 and R 12 is as defined above, The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof:

[0044] Additionally or alternatively, embodiments of the present invention include R 1 and R 2 together with the ring nitrogen atom to which they are attached form a 5- to 9-membered aromatic heterocycle or a 4- to 9-membered saturated heterocycle, wherein the heterocycle optionally contains 1 to 4 additional heteroatoms each independently selected from the group consisting of N, O and S, and the heterocycle optionally contains 1 to 4 additional heteroatoms each independently selected from the group consisting of R 13 and is substituted with 1 to 4 substituents selected from; R 13 is as defined above, The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof. Preferably, the heterocycle has as ring atoms one nitrogen atom and 0-4 further heteroatoms, the remaining ring atoms being carbon atoms, each further heteroatom being independently selected from the group consisting of N, O and S, and the heterocycle is optionally each independently selected from R 13 wherein R 13 is as defined above.

[0045] Additionally or alternatively, embodiments of the present invention include R 3 are groups selected from the group consisting of phenyl, pyridinyl, thienyl, and 1H-indazolyl, each of which is optionally independently R 31 and is substituted with 1 or 2 substituents selected from: R 31 is as previously defined, The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof. 3 is a group selected from the group consisting of phenyl, pyridin-2-yl, thien-2-yl, 1H-indazol-4-yl, 1H-indazol-3-yl, 1H-indazol-6-yl, 1H-indazol-5-yl and 1H-indazol-7-yl, each of which may optionally be independently selected from R 31 More preferably, R 3 is a group selected from the group consisting of phenyl, pyridin-2-yl, thien-2-yl, 1-acetyl-1H-indazol-4-yl, 5-fluoro-1H-indazol-3-yl and 1-methyl-1H-indazol-7-yl, each of which may optionally be independently selected from R 31 wherein R 31 is as defined above.

[0046] Additionally or alternatively, embodiments of the present invention include R 31is halogen, C 1-3 -Alkyl, C 1-3 -(per)haloalkyl, C 1-3 -(per)haloalkoxy and C(O)C 1-6 -alkyl, The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof. 31 is F, Cl, methyl, CF 3 , OCF 3 and C(O)CH 3 is selected from.

[0047] Additionally or alternatively, embodiments of the present invention include R 1 is a group selected from methyl, ethyl and tetrahydropyranyl; R 2 is a radical selected from methyl, ethyl and tetrahydropyranyl; The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof:

[0048] Additionally or alternatively, embodiments of the present invention include R 1 and R 2together with the ring nitrogen atom to which they are attached, represent piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, indolinyl, isoindolinyl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridinyl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5- a]pyrazinyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, azetidinyl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridinyl, 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[ and optionally each independently forms an aromatic or saturated heterocycle selected from R1,5-a]pyrazinyl, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazinyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl, 2-azabicyclo[2.2.1]heptanyl, 6,7-dihydro-4H-thieno[3,2-c]pyridinyl, thiomorpholinyl, octahydrocyclopenta[c]pyrrolyl, N-methyl-N-(oxetan-3-yl), 4-hydroxyazepanyl, 5-fluoroindolinyl, 2-methylpiperidinyl, 4-isopropoxypiperidinyl, 4-propoxypiperidinyl, and 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl. 13 and is substituted with 1 or 2 substituents selected from: R 13 is as defined above, The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof:

[0049] Additionally or alternatively, embodiments of the present invention include R 13 CN, C 1-3 -(per)haloalkyl, OR', (CH 2 ) n OR', CH(OH)C 1-6 -Alkyl, C(O)R″ and SO 2 N(R') 2 Selected from; Each R' is independently H and C 1-6 - alkyl; Each R” is independently C 1-6 - alkyl; n is 1 to 3; The present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof. 13 CN, CF 3 , OH, methoxy, ethoxy, (CH 2 ) n OH, CH 2 OMe, CH(OH)C 1-6 -Alkyl, C(O)CH 3 and S.O. 2 NH 2 and n is 1 to 3.

[0050] One embodiment of the present invention provides a compound of formula (I), wherein the compound has the formula (Ia): [ka] [During the ceremony, Y is N or CR 4 where R 4 is H or F; R 5 is H, Cl or F; or Y is CR 4 and R 4 and R 5 together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; R 6 is F, Cl or H; or Y is N or CR 4 where R 4 is H or F; R 5 and R 6 together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; and R 1 and R 2is as defined above. or a salt, solvate or solvate of the salt thereof.

[0051] Additionally or alternatively, embodiments of the present invention include R 1 and R 2 together with the ring nitrogen atom to which they are attached, represent piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, indolin-1-yl, isoindolin-2-yl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridin-6-yl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridin-5-yl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazin-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, azetidin-1-yl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl, 1,4,6,7-tetrahydropyrazolo[ and optionally each independently represents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , R 79 , R 80 , R 81 , R 82 , R 83 , R 84 , R 85 , R 85 13 and is substituted with 1 or 2 substituents selected from: R 13 CN, C 1-3 -(per)haloalkyl, OR', (CH 2 ) n OR', CH(OH)C 1-6 -Alkyl, C(O)R″ and SO 2 N(R') 2 Selected from; Each R' is independently H and C1-6 - alkyl; Each R” is independently C 1-6 -alkyl, Provided is a compound of formula (I) or (Ia) or a salt, solvate or solvate of a salt thereof:

[0052] Additionally or alternatively, embodiments of the present invention include R 13 CN, CF 3 , OH, methoxy, ethoxy, (CH 2 ) n OH, CH 2 OMe, CH(OH)C 1-6 -Alkyl, C(O)CH 3 and S.O. 2 NH 2 is selected from; and n is 1 to 3; Provided is a compound of formula (I) or (Ia) or a salt, solvate or solvate of a salt thereof:

[0053] One embodiment of the present invention provides a compound of formula (I), wherein the compound has formula (Ib) or (Ic): [ka] [During the ceremony, D is C or N; E is N, NH or CH; F is O or N; Y is N or CR 4 where R 4 is H or F; R 5 is H, Cl or F; or Y is CR 4 and R 4 and R 5 together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; R 6 is F, Cl or H; or Y is N or CR 4 where R 4 is H or F; R 5 and R 6 together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; and R 7 is OH or CH 2 It is OH. or a salt, solvate or solvate of the salt thereof.

[0054] Ring A in formula (Ib) is a 5-membered aromatic heterocyclic ring having at least one nitrogen atom as a ring atom and one or two additional heteroatoms as ring atoms, where the one or two additional heteroatoms are each independently selected from the group consisting of N and O, and the remaining ring atoms are carbon atoms. Examples of Ring A include, but are not limited to, divalent radicals of imidazole, pyrazole, triazolyl, and isoxazole.

[0055] One embodiment of the present invention provides a compound of formula (I), wherein the compound is or a salt, solvate or solvate of a salt thereof, having the formula (Ia), (Ib) or (Ic), Y is CR 4 and R 4 and R 5 together with the carbon atom to which they are attached form a pyrazole group; R 6 is F, Cl or H; or Y is N or CR 4 where R 4 is H or F; R 5 and R 6 together with the carbon atoms to which they are attached form a pyrazole group; and R 1 , R 2 , D, E, F and R 7 is as defined above.

[0056] One embodiment of the present invention provides a compound of formula (I), wherein the compound is or a salt, solvate or solvate of a salt thereof, wherein ring A is [ka] It is.

[0057] In addition or alternatively: Y is CH; R 5 is H and R 6 is F or Cl, preferably Cl. Alternatively, R 5 and R 6 Both are F, or Y is CF; R 5 is H and R 6 is F or Cl.

[0058] One embodiment of the present invention provides a compound of formula (I), wherein the compound is or a salt, solvate or solvate of a salt thereof, wherein R 7 is OH or CH 2 is OH; Y is CH; R 5 is H and R 6は F or Cl, preferably Cl. Alternatively, R 5 and R 6 Both are F, or Y is CF; R 5 is H and R 6 is F or Cl.

[0059] An embodiment of the present invention provides a compound of formula (I), wherein the compound is selected from the compounds shown in Table 1.

[0060] An embodiment of the present invention provides a compound of formula (I), wherein the compound is: 2-(4-fluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (4); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (12); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)acetonitrile (13); 2-(4-chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (18); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (25); 2-(3,4-difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (41); 2-(2,4-difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (42); 2-(3,4-difluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (43); 2-(3,4-difluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile (44); 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile (48); 2-(5-chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (67); 2-(4-chlorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (74); 2-(3-chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (80); 2-(5-fluoropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (84); 1-(4-((3-chlorophenyl)(cyano)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide (99); 2-(4-chlorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (113); 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(1-methyl-1H-indazol-7-yl)acetonitrile (118); 2-(1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (138); 2-(3-chlorophenyl)-2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (140); 2-(4-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (141); 2-(1H-indazol-4-yl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (144); 2-(1H-indazol-4-yl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (145); 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(3-chlorophenyl)acetonitrile (156); 2-(5-chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (161); or a salt, solvate or solvate of the salt thereof.

[0061] In another aspect, an embodiment of the invention comprises: optionally in the presence of a base, [ka] wherein the dotted line represents an optional bond; R 7 is a leaving group A or is absent when the dotted line represents a bond, and R 3A R is defined for compounds of formula (I) or for the leaving group B 3 It is. and a compound of formula (III) [ka] [In the formula, R 1 and R 2 is as defined for compounds of formula (I). or reacting the compound or its hydrogen halide; or Formula (IV) [ka] [In the formula, R3A R is defined for compounds of formula (I) or for the leaving group B 3 It is. or a hydrogen halide of the compound of formula (V) [ka] wherein the dotted line represents an optional bond; R 7 is a leaving group A or is absent when the dotted line represents a bond, and R 1 and R 2 is as defined for compounds of formula (I). to react a compound of formula (I) [ka] [During the ceremony, R 1 , R 2 and R 3 is as defined for compounds of formula (I); or R 1 and R 2 is as defined for compounds of formula (I) and R 3 is the leaving group B. and optionally, R 3 is a leaving group B, the resulting compound of formula (I) is reacted with a compound of formula (VII) in the presence of a base and a coupling agent [ka] [During the ceremony, R 3B R is defined for compounds of formula (I) 3 and Z is a leaving group C or B(R 8 ) 2 where R 8 OH,OC 1-6 -alkyl or both R 8 together with the ring boron atom to which they are attached form a cyclic boronic ester. The compound R 1 , R 2 and R 3 is as defined for compounds of formula (I); and optionally converting the compound of formula (I) into a salt, solvate or solvate of the salt thereof. The present invention provides a method for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof, comprising the steps of: Preferably, leaving group A is selected from the group consisting of imidazol-1-yl, 3-methylimidazol-3-ium-1-yl iodide, Cl, I and Br; leaving group B is selected from the group consisting of Br and I; and leaving group C is selected from the group consisting of Br or I.

[0062] The term "leaving group" as used herein and hereinafter refers to a group of a compound that facilitates a reaction to occur and / or has a positive effect on the overall reaction rate and / or has a direct effect on the regioisomer of the product formed. The leaving group may or may not be part of the product formed, i.e., the leaving group may be present in the product or may be, for example, S N 2. S N 1. In cross-coupling and addition-elimination reactions, it is understood that the leaving group may be part of the product. The compounds disclosed herein may have one or more leaving groups, which may be the same or different. Examples of leaving groups include, but are not limited to, sulfonyl, such as phenylsulfonyl, tosyl (Ts), mesyl, and trifyl; halogens (fluoride, chloride, bromide, iodide), (substituted) amino groups, amides, esters, hydroxy, alkoxy, acyloxy, thiol, alkyl, (per)haloalkyl, (per)haloalkoxy, photolabile groups, leaving groups formed from boronic acids and (cyclic)boronic esters in cross-coupling reactions, imidazol-1-yl, 3-methylimidazol-3-ium-1-yl halides, such as iodides, and the like.

[0063] The term "hydrogen halide" as used herein and hereinafter refers to hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide.

[0064] The term "base" as used herein and hereinafter refers to organic and inorganic bases, such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, cesium, potassium, sodium and zinc and their acetates, hydroxides, alkoxides, phosphates and carbonates. Examples of inorganic bases are K, 2 CO 3 , KOtBu, KOAc, Cs 2 CO 3 , K 3 PO 4 and NaOH. Examples of organic bases include, but are not limited to, triethylamine, trimethylamine, ethyldiisopropylamine, methylamine, dimethylamine, trimethylamine, ethylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, morpholine, arginine, lysine, ethylenediamine, and N-methylpiperidine, and the like.

[0065] The term "cyclic boronic ester" as used herein and hereinafter refers to mono- and bicyclic heterocycles having one boron and two oxygen ring atoms, with the remaining ring atoms being carbon atoms. Preferably, the cyclic boronic ester is a 5- to 7-membered monocyclic heterocycle, such as dioxaborolane or dioxaborinane. An example of a cyclic boronic ester is an ester formed between a boronic acid and pinacol with an alcohol, such as, but not limited to, trimethylene glycol.

[0066] The term "coupling agent" as used herein and hereafter refers to a substance or compound that is added to a reaction to cause a chemical reaction to occur. The coupling agent may be an activator and may or may not be a catalyst. It is understood that the coupling agent may or may not be consumed during the reaction. An example of a coupling agent is tetrakis(triphenylphosphine)palladium(0) (Pd(PPh 3 ) 4) Palladium(0) complexes such as tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ); and palladium(II) such as palladium(II) acetate, [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (PdCl 2 (dtbpf)) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexes with dichloromethane (Pd(dppf)Cl 2 .DCM), etc., including but not limited to these.

[0067] Embodiments of the present invention are carried out in the presence of a base, preferably triethylamine, of formula (II)

Chemical formula

Chemical formula

[0068] An embodiment of the present invention is a method for the preparation of a compound of formula (II) in the presence of a base, preferably triethylamine [ka] [In the formula, R 7 is a leaving group A selected from the group consisting of imidazol-1-yl, 3-methylimidazol-3-ium-1-yl iodide, Cl, I and Br, and R 3A is a leaving group B selected from the group consisting of Br and I. and a compound of formula (III) [ka] [During the ceremony, R 1 and R 2 is as defined for compounds of formula (I). or its hydrogen halide, preferably its hydrogen chloride, to form a compound of formula (I) [ka] [In the formula, R 1 and R 2 is as defined for compounds of formula (I) and R 3 is the leaving group B. to obtain a compound of; A base, preferably Cs 2 CO 3 and a coupling agent, preferably Pd(dppf)Cl 2 in the presence of the compound of formula (I) and the compound of formula (VII) [ka] [During the ceremony, R 3B R is defined for compounds of formula (I) 3 and Z is a leaving group C, preferably Br or I or B(R 8 ) 2 where R8 OH,OC 1-6 -alkyl or both R 8 together with the ring boron atom to which they are attached form a cyclic boronic ester. The compound R 1 , R 2 and R 3 is as defined for compounds of formula (I); and optionally converting the compound of formula (I) into a salt, solvate or solvate of the salt thereof. The present invention provides a process for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof, comprising the steps of:

[0069] An embodiment of the present invention comprises reacting a compound of formula (IV) optionally in the presence of a base [ka] [In the formula, R 3A R is defined for compounds of formula (I) 3 It is. or a hydrogen halide of the compound of formula (V) [ka] wherein the dotted line represents an optional bond; R 7 is a leaving group A selected from the group consisting of imidazol-1-yl, 3-methylimidazol-3-ium-1-yl iodide, Cl, I and Br, and R 1 and R 2 is as defined for compounds of formula (I). to react a compound of formula (I) [ka] [In the formula, R 1 , R 2 and R 3 is as defined for compounds of formula (I). to obtain a compound of; and optionally converting the compound of formula (I) into a salt, solvate or solvate of the salt thereof. The present invention provides a process for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof, comprising the steps of:

[0070] An embodiment of the present invention comprises reacting a compound of formula (IV) optionally in the presence of a base [ka] [In the formula, R 3A is a leaving group B selected from the group consisting of Br and I. or its hydrogen halide with a compound of formula (V) [ka] wherein the dotted line represents an optional bond; R 7 is a leaving group A selected from the group consisting of imidazol-1-yl, 3-methylimidazol-3-ium-1-yl iodide, Cl, I and Br, and R 1 and R 2 is as defined for compounds of formula (I). to react a compound of formula (I) [ka] [In the formula, R 1 and R 2 is as defined for compounds of formula (I) and R 3 is the leaving group B. to obtain a compound of; In the presence of a base and a coupling agent, the resulting compound of formula (I) is reacted with a compound of formula (VII) [ka] [During the ceremony, R 3B R is defined for compounds of formula (I) 3 and Z is a leaving group C, preferably Br or I or B(R 8) 2 where R 8 OH,OC 1-6 -alkyl or both R 8 together with the ring boron atom to which they are attached form a cyclic boronic ester. The compound R 1 , R 2 and R 3 is as defined for compounds of formula (I); and optionally converting the compound of formula (I) into a salt, solvate or solvate of the salt thereof. The present invention provides a process for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof, comprising the steps of:

[0071] In another aspect, an embodiment of the present invention provides a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I), a salt, solvate or solvate of a salt thereof, together with one or more pharma- ceutically acceptable excipients.

[0072] The pharmaceutical compositions of the present invention can be administered in an effective amount within a wide dosage range, including any effective amount, preferably the dosage range is from about 0.1 μg / kg to about 300 mg / kg, more preferably 1.0 μg / kg to 10 mg / kg of body weight per day. The compounds of the present invention can be administered in a single daily dose or the total daily dosage may be administered in divided doses two, three or four times daily.

[0073] The term "effective amount" refers to an amount of a composition or pharmaceutical composition that produces a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs or sensations of the effect). Such treatment does not necessarily completely improve the disorder, condition, or disease. Moreover, such treatment or prevention may be used in conjunction with other traditional treatments for the reduction of the disorder, condition, or disease known to those skilled in the art. The effective amount is typically determined by a physician and depends on the disorder, condition, or disease being treated, the selected route of administration, the actual compound being administered, the age, sex, weight, and response of the patient, the severity of the patient's symptoms, and the like. For example, in some cases less than the minimum amount above may be sufficient, while in other cases the upper limit described must be exceeded.

[0074] Those skilled in the art possess the knowledge and skill to be able to select suitable pharma- ceutically acceptable additives in appropriate amounts for use in the present invention. Additionally, several sources are available to those skilled in the art that describe pharma- ceutically acceptable additives and may be useful in selecting suitable pharma- ceutically acceptable additives. Suitable pharma- ceutically acceptable excipients include the following types of excipients: diluents (e.g. starch, mannitol), fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate), binders (e.g. pregelatinized maize starch, polyvinylpyrrolidone or methylcellulose), additives (e.g. magnesium stearate, talc, silica), disintegrants (e.g. potato starch), lubricants (e.g. sodium lauryl sulfate), glidants (e.g. fumed silica, talc, magnesium carbonate), granulating agents (e.g. water, ethanol), coating agents (e.g. hydroxypropyl methylcellulose, gelatin, waxes, shellac, plasticizers, vegetable fibres), wetting agents (e.g. sorbitan monopalmitate, poloxamer 407), solvents (e.g. water), cosolvents (e.g. ethanol, propylene glycol), suspending agents (e.g. sorbitol, cellulose derivatives, edible hydrogenated fats), emulsifiers (e.g. lecithin or acacia), sweeteners (e.g. Examples of additives and / or auxiliary agents include, but are not limited to, flavoring agents (e.g., sucrose), flavoring agents (e.g., cherry, lime), flavor masking agents (e.g., vanilla, citrus), coloring agents (e.g., titanium dioxide), anti-caking agents (e.g., silicon dioxide), humectants (e.g., glycerin, sorbitol), chelating agents (e.g., EDTA salts, histidine, aspartic acid), plasticizers (e.g., tributyl citrate, diethyl phthalate), thickening agents (e.g., methylcellulose), antioxidants (e.g., ascorbic acid, cysteine), preservatives (e.g., methyl or propyl p-hydroxybenzoate, sorbic acid or ascorbic acid), stabilizers (e.g., polysorbate 20 and 80, poloxamer 407), surfactants (e.g., polyethylene glycol, polysorbate 80), and buffering agents (e.g., sodium and potassium salts of phosphate, citrate, acetate, carbonate or glycine buffer depending on the target pH range). Additives and / or auxiliary agents may facilitate processing of the active agent into a pharma- ceutically usable formulation.One of ordinary skill in the art will recognize that a given pharma- ceutically acceptable excipient may serve more than one function, and may serve other functions, depending on how much of the excipient is present in the pharmaceutical composition and what other components are present in the pharmaceutical composition.

[0075] The pharmaceutical composition of the present invention is most preferably used alone or in combination with one or more additional active ingredients, such as pharma- ceutical active compounds or biological agents, i.e., administered simultaneously, separately or sequentially.The amount and relative timing of administration of the pharmaceutical composition of the present invention, particularly the pharmaceutical composition comprising the compound of formula (I) or its salt, solvate or solvate of salt and additional active ingredients, are selected to achieve the desired combined therapeutic effect.The pharmaceutical composition of the present invention can be administered by various routes, such as oral, parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, topical, lingual, sublingual and intradermal injection, and dermal, transdermal, rectal, buccal, oral mucosa, nasal, ocular, and inhalation, and implant or stent.

[0076] The pharmaceutical composition may be formulated into a suitable pharmaceutical formulation; suitable dosage forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablets, pills, controlled release capsules, controlled release tablets, controlled release pills, suppositories, vaginal capsules, creams, vaginal rings, and stents. In addition to or alternatively to pharmaceutically acceptable additives and / or further active ingredients, the pharmaceutical formulation of the pharmaceutical composition may include one or more suitable pharmaceutically acceptable carriers.

[0077] The term "pharmaceutical acceptable carrier" as used herein and hereafter refers to a base contained in a pharmaceutical composition for drug delivery, which serves to improve drug administration selectivity, efficacy and / or safety. Examples of pharmaceutical acceptable carriers include, but are not limited to, pharmaceutical acceptable additives, liposomes, (polymeric) micelles, microspheres, nanoparticles and protein-drug conjugates.

[0078] The pharmaceutical composition of the present invention is prepared using techniques and methods known to those skilled in the art. The pharmaceutical composition of the present invention includes, but is not limited to, parenteral and topical administration, including, but not limited to, sterile aqueous or non-aqueous solvents, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, fish oils and injectable organic esters. Aqueous carriers include, but are not limited to, water, water-alcohol solutions, including saline and buffered intermediate parenteral media, including sodium chloride solution, Ringer's dextrose solution, dextrose + sodium chloride solution, Ringer's with lactose or fixed oils. Intravenous media include, but are not limited to, fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. The aqueous pharmaceutical composition of the present invention may include suitable buffers, such as sodium and potassium salts of phosphate, citrate, acetate, carbonate or glycine buffer, depending on the target pH range. The use of sodium chloride as a tonicity adjusting agent is also useful. The pharmaceutical composition may include other additives, such as stabilizers or preservatives. Useful stabilizing additives include surfactants (polysorbate 20 and 80, poloxamer 407), polymers (polyethylene glycol, povidone), carbohydrates (sucrose, mannitol, glucose, lactose), alcohols (sorbitol, glycerol propylene glycol, ethylene glycol), suitable proteins (albumin), suitable amino acids (glycine, glutamic acid), fatty acids (ethanolamine), antioxidants (ascorbic acid, cysteine, etc.), chelating agents (EDTA salts, histidine, aspartic acid) or metal ions (Ca, Ni, Mg, Mn). Particularly useful preservatives include benzyl alcohol, chlorobutanol, benzalkonium chloride and possibly parabens. The pharmaceutical composition of the present invention may be provided in a concentrated form or powder form for reconstitution when required. In such cases, a powder formulation for a solution for the above-mentioned injection / infusion additives may be used. For lyophilization, certain cryoprotectants are preferred, including polymers (povidone, polyethylene glycol, dextran), sugars (sucrose, glucose, lactose), amino acids (glycine, arginine, glutamic acid) and albumin.If a solution for reconstitution is included in the package, it may consist, for example, of pure or sodium chloride solution for injection or of dextrose or glucose solution.

[0079] In addition to or alternatively to pharma- ceutically acceptable additives and / or pharma- ceutically acceptable carriers, the pharmaceutical compositions of the present invention comprise an effective amount of one or more compounds of formula (I), or salts, solvates, or solvates of salts thereof, in combination with one or more additional active ingredients.Thus, in certain embodiments, the pharmaceutical compositions comprise an effective amount of one or more compounds of formula (I), or salts, solvates, or solvates of salts thereof, together with one or more pharma- ceutically acceptable additives and / or one or more pharma- ceutically acceptable carriers and / or one or more other active ingredients, or any combination thereof.

[0080] An embodiment of the present invention provides pharmaceutical compositions comprising one or more compounds of formula (I), salts, solvates or solvates of salts thereof, together with one or more pharma- ceutically acceptable excipients, in combination with one or more further active ingredients, wherein the one or more further active ingredients are each independently selected from antihyperproliferative, cytostatic and cytotoxic agents.

[0081] An embodiment of the present invention provides the compound of formula (I) or its salt, solvate or solvate of salt for use in treating or preventing the disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorder, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-related pain.Preferably, treating or preventing the disease or disorder requires the inhibition of AKR1C3 enzyme.

[0082] The term "treatment" or "treating" as used herein and hereinafter includes alleviating, ameliorating, attenuating, eliminating, inhibiting, delaying, suppressing, attenuating, restricting, reducing, inhibiting, warding off, relieving or curing a disease, condition, disorder, injury or health problem or the development, course or progression of such condition and / or symptoms of such condition. The term "treatment" is understood to be synonymous with the term "treating."

[0083] In the context of the present invention, the terms "prevention", "prophylaxis" or "prevention" are used interchangeably and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, condition, disorder, injury or health problem or the development or progression of such a condition and / or symptoms of such a condition.

[0084] Treatment or prevention of a disease, condition, disorder, injury or health problem may be partial or complete.

[0085] The term "administering" or "administration" to a subject or patient refers to the dispensing, delivery or application of a composition or pharmaceutical composition to a subject by any suitable route for delivery of the composition or pharmaceutical composition to a desired internal site.

[0086] An embodiment of the present invention provides a compound of formula (I) or a salt, solvate or solvate of the salt thereof for use in the treatment or prophylaxis of a disease or disorder which requires inhibition of the AKR1C3 enzyme.

[0087] An embodiment of the present invention provides a compound of formula (I) or a salt, solvate or solvate of a salt thereof for use in the treatment or prevention of a steroid hormone or prostaglandin dependent malignant or benign disease or disorder. Preferably, the steroid hormone is selected from the group consisting of androgens, estrogens and progesterone.

[0088] Certain aspects of the invention provide methods of treating or preventing a disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-associated pain.

[0089] One embodiment provides a method of treating or preventing a steroid hormone or prostaglandin dependent malignant or benign disease or disorder comprising administering to a patient in need of treatment a compound of formula (I) or a salt, solvate or solvate of the salt thereof.

[0090] Certain embodiments provide a method of treating or preventing a steroid hormone or prostaglandin dependent malignant or benign disease or disorder comprising administering to a patient in need of treatment a compound of formula (I) or a salt, solvate or solvate of the salt thereof, wherein the disease or disorder is selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-associated pain.

[0091] Another aspect of the present invention provides the use of one or more compounds of formula (I) for the manufacture of a medicament for use in the treatment or prevention of a disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-associated pain.

[0092] Certain embodiments provide the use of one or more compounds of formula (I) for the manufacture of a medicament for use in the treatment or prevention of a steroid hormone or prostaglandin dependent malignant or benign disease or disorder.

[0093] Certain embodiments provide the use of one or more compounds of formula (I) for the manufacture of a medicament for use in the treatment or prevention of a steroid hormone or prostaglandin dependent malignant or benign disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, premature sexual maturation, obesity and inflammation-related pain.

[0094] Furthermore, the compounds of formula (I) can be used as synthetic intermediates for the preparation of other compounds, in particular other pharma- ceutical active compositions, which are obtained from the compounds of formula (I), for example, by the introduction of substituents or modification of functional moieties.

[0095] The compounds and pharmaceutical compositions of the present invention may also be useful in medical devices and medical kits. EXAMPLES

[0096] Example of the invention Representative examples of compounds of formula (I), (Ia), (Ib) and (Ic) are compounds 1 to 173 shown in Table 1. [Table 1] [Table 2] [Table 3]

[0097] experiment General manufacturing method The compounds of the invention may be prepared by methods known in the art.

[0098] General information Commercial grade reagents and solvents were used without further purification. Thin layer chromatography (TLC) was performed on Merck plates; pre-coated aluminum sheets. Visualization of the plates was performed by the following techniques: 1) UV irradiation (254 nm), 2) immersion of the plates in ninhydrin solution followed by heating. 1 1 H-NMR spectra were recorded on a Bruker Avance III 400 (400 MHz) spectrometer using the solvents indicated.

[0099] The example compounds of the present invention can be prepared by Knoevenagel reaction starting from 1-Boc-4-piperidone and substituted acetonitrile (Scheme 1). After Boc deprotection under acidic conditions, the hydrochloride derivative is treated with carbonyldiimidazole (CDI) to give the imidazole derivative, which is methylated with methyl iodide (MeI) to give the iodide salt of the methylated imidazole derivative. The formed iodide salt can be used as an intermediate for the preparation of compound (I).

[0100] [ka] Scheme 1. General synthetic route that may be used to prepare compounds of the invention of formula (I).

[0101] [Table 4]

[0102] General Method A: Knoevenagel Reaction To a solution of 1-Boc-4-piperidone (100 mol%) and substituted acetonitrile (100 mol%) in MeOH (1.67 mL / mmol substituted acetonitrile) was added a 25% solution of NaOMe in MeOH (110 mol%) and the reaction mixture was heated at 70° C. for 2 h (or until completion). The reaction mixture was cooled and then concentrated under reduced pressure. The residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography using EtOAc in hexanes as eluent.

[0103] General method B: Boc deprotection To the Boc-protected piperidine (100 mol%) [neat or in dichloromethane (DCM) or tert-butyl methyl ether (MTBE)] was added 4M HCl in dioxane (1000 mol%) and the reaction was stirred for 1 h or until judged complete by TLC or LCMS. The reaction mixture was concentrated under reduced pressure and the residue was suspended in EtOAc or MTBE, filtered, washed repeatedly with EtOAc and / or MTBE, and then dried.

[0104] General method C: Boc deprotection To the Boc-protected piperidine (100 mol%) was added 4M HCl in dioxane (1000 mol%) and the reaction was stirred for 1 h or until judged complete by TLC or LCMS. The reaction mixture was diluted with MTBE or EtOAc, filtered, washed repeatedly with MTBE or EtOAc, and then dried.

[0105] General Method D: Suzuki Coupling of tert-Butyl 4-[bromo(cyano)methylidene]piperidine-1-carboxylate To a mixture of tert-butyl 4-[bromo(cyano)methylidene]piperidine-1-carboxylate (100 mol%), boronic acid or ester (120 mol%) and cesium carbonate (200 mol%) in 1,4-dioxane (3.25 mL / mmol substrate) and water (0.37 mL / mmol substrate), [1,1'-bis(di-tert-butylphosphino)ferrocene]-dichloropalladium(II) (2.5 mol%) was added and nitrogen was bubbled through the mixture for 2 min. The reaction mixture was heated at 60° C. under nitrogen for 20 h and then cooled. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, concentrated under reduced pressure and the precipitate was purified by column chromatography using EtOAc in hexane as eluent.

[0106] General Method E: Miyaura Coupling for the Synthesis of Boronic Esters To a solution of aryl bromide (100 mol%) in 1,4-dioxane (4 mL / mmol substrate) was added bis(pinacolato)diboron (115 mol%) and potassium acetate (460 mol%) at 20 °C. Nitrogen was bubbled through the reaction mixture for 5 min, and then Pd(dppf)Cl 2 DCM (8 mol%) was added and aeration was repeated. The reaction was heated at reflux for 1.5 h, cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc and water, the organic layer was separated, washed successively with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography.

[0107] Production of INT-2 and INT-4 [ka] INT-1: Synthesis of tert-butyl 4-[cyano(4-fluorophenyl)methylidene]piperidine-1-carboxylate To a solution of 2-(4-fluorophenyl)acetonitrile (4.07 g, 120 mol%) in THF (100 mL) at 0° C., sodium hexamethyldisilazide (NaHMDS; 1 M solution in THF, 30.1 mL, 120 mol%) was added and the reaction mixture was stirred at 0° C. for 30 min. A solution of 1-Boc-4-piperidone (5.0 g, 100 mol%) in THF (20 mL) was added and the mixture was stirred for 20 h and allowed to warm to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (100 mL), then dried over sodium sulfate, concentrated and the residue was purified by column chromatography (0–20% EtOAc in isohexane) to give INT-1 (2.54 g, 32%) as a colorless oil that solidified upon standing. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.28 - 7.23 (m, 2H), 7.13 - 7.06 (m, 2H), 3.61 (t, 2H), 3.42 (t, 2H), 2.76 (t, 2H), 2.40 (t, 2H), 1.47 (s, 9H). m / z (ES+) 217.1 (M-Boc+H) +

[0108] INT-2: 2-(4-fluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride Prepared from INT-1 according to general procedure C to give INT-2 (1.54 g, 76%) as an off-white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 2H), 7.48 - 7.41 (m, 2H), 7.36 - 7.29 (m, 2H), 3.28 (t, 2H), 3.11 (t, 2H), 2.92 (t, 2H), 2.59 (t, 2H). m / z (ES+) 217.1 (M+H) +

[0109] INT-3: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile INT-2 (3.00 g, 100 mol%) was dissolved in dry THF (30 mL). Carbonyldiimidazole (CDI) (3.46 g, 180 mol%) was added. Stirred at +60° C. for 2 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 ml). The reaction mixture was washed with water (5×10 mL) and brine (3×10 mL). Dried over sodium sulfate. Yield of INT-3 was 3.54 g; 96%. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.55 (m, 2H), 2.86 (m, 2H), 3.53 (m, 2H), 3.71 (m, 2H), 7.05 (s, 1H), 7.33 (dd, 2H), 7.43 (dd, 2H), 7.50 (s, 1H), 8.06 (s, 1H)

[0110] INT-4: 1-(4-(cyano(4-fluorophenyl)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide INT-3 (3.5 g, 100 mol%) was dissolved in dry acetonitrile (30 mL). Methyl iodide (7.1 mL, 1000 mol%) was added under nitrogen atmosphere. The reaction mixture was stirred at +40° C. for 3 h. Water (1 ml) was added followed by coevaporation with toluene (3×10 mL). The crude product was purified by trituration with heptane / DCM. The yield of INT-4 was 4.82 g; 94%. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.58 (m, 2H), 2.89 (m, 2H), 3.56 (m, 2H), 3.73 (m, 2H), 3.92 (s, 3H), 7.34 (dd, 2H), 7.44 (dd, 2H), 7.86 (s, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0111] Manufacturing of INT-6 and INT-8 [ka] INT-5: Prepared following general procedure A to afford tert-butyl 4-[cyano(4-chlorophenyl)methylidene]piperidine-1-carboxylate in 72% yield as an off-white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.39 (d, 2H), 7.22 (d, 2H), 3.61 (t, 2H), 3.42 (t, 2H), 2.76 (t, 2H), 2.40 (t, 2H), 1.43 (s, 9H)

[0112] INT-6: Prepared according to general procedure B to give 2-(4-chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 79% yield as an off-white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.31 (s, 2H), 7.60 - 7.52 (m, 2H), 7.46 - 7.38 (m, 2H), 3.31 - 3.27 (m, 2H), 3.14 - 3.10 (m, 2H), 2.91 (t, 2H), 2.59 (t, 2H). m / z (ES+) 233.1 / 235.1 (M+H) +

[0113] INT-7: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(4-chlorophenyl)acetonitrile INT-6 (2.74 g, 100 mol%) was dissolved in dry THF (30 mL). Carbonyldiimidazole CDI (2.48 g, 150 mol%) was added. Stirred at +60° C. for 3 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (30 ml). The reaction mixture was washed with water (3×20 mL) and brine (3×10 mL). Dried over sodium sulfate. Yield of INT-7 was 3.14 g; 94%. 1 H-NMR (400 MHz, DMSO-d 6): 2.56 (t, 2H), 2.86 (t, 2H), 3.53 (t, 2H), 3.71 (t, 2H), 7.05 (s, 1H), 7.41 (d, 2H), 7.50 (s, 1H), 7.56 (d, 2H), 8.06 (s, 1H)

[0114] INT-8: 1-(4-((4-chlorophenyl)(cyano)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide INT-7 (2.4 g, 100 mol%) was dissolved in dry acetonitrile (20 mL). Methyl iodide (2.3 mL, 500 mol%) was added under nitrogen atmosphere. An additional amount of methyl iodide (2×500 mol%) was added over 7 h at +40° C. The reaction mixture was stirred overnight at room temperature. Water (1 ml) was added followed by coevaporation with toluene (3×10 mL). The crude product was purified by trituration with heptane / DCM (v / v 5:0.5). The yield of INT-8 was 3.37 g; 87%. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.59 (t, 2H), 2.89 (t, 2H), 3.56 (m, 2H), 3.73 (m, 2H), 3.92 (s, 3H), 7.42 (d, 2H), 7.57 (d, 2H), 7.86 (s, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0115] Manufacturing of INT-10 [ka] INT-9: To a solution of piperidine-4,4-diol hydrochloride (10.0 g, 100 mol%) and triethylamine (18.1 mL, 200 mol%) in toluene (288 mL) was added piperidine-1-carbonyl chloride (8.1 mL, 100 mol%) and the suspension was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (20-100% EtOAc in isohexane) to give 1-(piperidine-1-carbonyl)piperidin-4-one in 59% yield as an off-white crystalline solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 3.51 (t, 4H), 3.26 (t, 4H), 2.48 (t, 4H), 1.65 - 1.55 (m, 6H). m / z (ES+) 211.2 (M+H) +

[0116] INT-10: To a suspension of sodium hydride (60% suspension in mineral oil, 203 mg, 512 mol%) in THF (4 mL) at -78°C, a solution of diethylbromo(cyano)methyl]phosphonate (1.08 g, 100 mol%) in THF (5 mL) was added. The dark grey-brown suspension was stirred for 15 min, then a solution of 1-(piperidine-1-carbonyl)piperidin-4-one (1.07 g, 120 mol%) in THF (6 mL) was added. The mixture was allowed to warm to 20°C over 1 h, then saturated aqueous ammonium chloride solution (20 mL) was added slowly and the mixture was extracted with EtOAc (3 x 20 mL). The combined extracts were dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (20–70% EtOAc in hexanes) to give 2-bromo-2-[1-(piperidine-1-carbonyl)piperidin-4-ylidene]acetonitrile in 87% yield as a colorless solid. 1 H-NMR (400 MHz, CDCl 3) δ ppm 3.32 (q, 4H), 3.22 (dd, 4H), 2.71 - 2.64 (m, 2H), 2.62 - 2.54 (m, 2H), 1.63-1.54 (m, 6H). m / z (ES+) 312.0 / 314.0 (M+H) +

[0117] Production of INT-12 and INT-14 [ka] INT-11: Prepared according to general procedure A to afford tert-butyl 4-[cyano(3,4-difluorophenyl)methylidene]piperidine-1-carboxylate in 64% yield as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm δ 7.25 - 7.17 (m, 1H), 7.16 - 7.08 (m, 1H), 7.02 - 6.98 (m, 1H), 3.61 (t, 2H), 3.43 (t, 2H), 2.76 (t, 2H), 2.40 (t, 2H), 1.47 (s, 9H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -135.73 (dd, J=21.2, 6.2 Hz), -136.30 (d, J=21.2 Hz). m / z (ES+) 235.2 (M-Boc+H) +

[0118] INT-12: Prepared according to general procedure B to give 2-(3,4-difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 89% yield as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 2H), 7.61 - 7.51 (m, 2H), 7.30 - 7.24 (m, 1H), 3.27 (t, 2H), 3.12 (t, 2H), 2.94 - 2.88 (m, 2H), 2.59 (t, 2H). 19F NMR (376 MHz, DMSO-d 6 ) δ ppm -137.11 (d, J=22.6 Hz), -137.55 (d, J=22.5 Hz). m / z (ES+) 235.2 (M+H) +

[0119] INT-13: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(3,4-difluorophenyl)acetonitrile It was produced in 92% yield by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.55 (m, 2H), 2.86 (m, 2H), 3.54 (m, 2H), 3.71 (m, 2H), 7.05 (s, 1H), 7.26 (m, 1H), 7.50-7.55 (m, 3H), 8.07 (s, 1H)

[0120] INT-14: 1-(4-(cyano(3,4-difluorophenyl)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide It was produced in 79% yield by the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.58 (m, 2H), 2.89 (m, 2H), 3.57 (m, 2H), 3.73 (m, 2H) 3.92 (s, 3H), 7.27 (m, 1H), 7.57 (m, 2H), 7.87 (s, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0121] Production of INT-16 and INT-18 [ka] INT-15: Prepared following general procedure A to give tert-butyl 4-[cyano(2,4-difluorophenyl)methylidene]piperidine-1-carboxylate in 65% yield as an off-white powder. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.31 - 7.21 (m, 1H), 7.00 - 6.85 (m, 2H), 3.62 (t, 2H), 3.44 (t, 2H), 2.77 (t, 2H), 2.30 - 2.15 (m, 2H), 1.47 (s, 9H)

[0122] INT-16: Prepared according to general procedure B to give 2-(2,4-difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 81% yield as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.13 (s, 2H), 7.53 (td, 1H), 7.50 - 7.41 (m, 1H), 7.25 (td, 1H), 3.31 (s, 2H), 3.17 - 3.07 (m, 2H), 2.97 - 2.86 (m, 2H), 2.48 - 2.44 (m, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm -107.43 (dd, J=9.7, 4.1 Hz), -108.98 (dd, J=9.0, 4.3 Hz). m / z (ES+) 235.2 (M+H) +

[0123] INT-17: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(2,4-difluorophenyl)acetonitrile The compound was produced in 93% yield with a reaction time of 3 hours using the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6): 2.41 (t, 2H), 2.88 (t, 2H), 3.53 (t, 2H), 3.71 (t, 2H), 7.05 (s, 1H), 7.24 (m, 1H), 7.45 (m, 1H), 7.50 (m, 2H), 8.06 (s, 1H)

[0124] INT-18: 2-(2,4-difluorophenyl)-2-(1-(3-methyl-1H-3λ) 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide Prepared in 81% yield by the method used to prepare INT-4, with a reaction time of 5.5 hours at +40° C. The crude product was purified by trituration with ethyl acetate. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.45 (t, 2H), 2.92 (t, 2H), 3.56 (t, 2H), 3.74 (t, 2H), 3.92 (s, 3H), 7.26 (m, 1H), 7.44-7.54 (m, 2H), 7.87 (m, 1H), 8.04 (s, 1H), 9.57 (s, 1H)

[0125] Manufacturing of INT-20 and INT-22 [ka] INT-19: Prepared following general procedure A to afford tert-butyl 4-[cyano(3,5-difluorophenyl)methylidene]piperidine-1-carboxylate in 35% yield as a pale yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 6.91 - 6.79 (m, 3H), 3.62 (t, 2H), 3.45 (t, 2H), 2.76 (t, 2H), 2.43 (t, 2H), 1.48 (s, 9H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -107.95. m / z (ES+) 235.2 (M-Boc+H) +

[0126] INT-20: Prepared according to general procedure B to give 2-(3,5-difluorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 93% yield as an off-white solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.47 (s, 2H), 7.41 - 7.33 (m, 1H), 7.24 - 7.16 (m, 2H), 3.27 (t, 2H), 3.14 (t, 2H), 2.95 - 2.88 (m, 2H), 2.60 (t, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm -108.37. m / z (ES+) 235.2 (M+H) +

[0127] INT-21: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(3,5-difluorophenyl)acetonitrile It was produced in 95% yield with a reaction time of 3 hours by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.57 (t, 2H), 2.85 (t, 2H), 3.55 (t, 2H), 3.70 (t, 2H), 7.05 (s, 1H), 7.16-7.19 (m, 2H), 7.37 (m, 1H), 7.50 (s, 1H), 8.06 (s, 1H)

[0128] INT-22: 2-(3,5-difluorophenyl)-2-(1-(3-methyl-1H-3λ 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide It was prepared in 99% yield by the method used to prepare INT-4, with reaction times of 5 hours at +40° C. and overnight at room temperature. 1 H-NMR (400 MHz, DMSO-d 6): 2.59 (m, 2H), 2.89 (m, 2H), 3.57 (m, 2H), 3.73 (m, 2H), 3.92 (s, 3H), 7.19 (m, 2H), 7.38 (m, 1H), 7.86 (s, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0129] Production of INT-24 and INT-26 [ka] INT-23: The reaction was carried out according to general procedure D to afford tert-butyl 4-{cyano[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methylene}piperidine-1-carboxylate in 93% yield as a pale yellow gum. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.99 (d, 1H), 7.64 (dt, 1H), 7.41 (dd, 1H), 7.05 (dd, 1H), 5.75 (dd, 1H), 4.04 (d, 1H), 3.81 - 3.71 (m, 1H), 3.66 (t, 2H), 3.38 (t, 2H), 2.85 (t, 2H), 2.66 - 2.51 (m, 1H), 2.31 (t, 2H), 2.23 - 2.06 (m, 2H), 1.86 - 1.60 (m, 3H), 1.47 (s, 9H). m / z (ES+) 423.3 (M+H) +

[0130] INT-24: To a solution of INT-23 (2.86 g, 100 mol%) in MTBE (0.5 mL) at 0° C. was added 4 M HCl in dioxane (5.9 mL, 380 mol%). After 10 min, MeOH (3 mL) was added and the mixture was stirred for 16 h. MTBE was added and the solid was filtered and triturated with EtOAc to give 2-(1H-indazol-4-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride in 85% as a light pink solid. 1 H-NMR (400 MHz, DMSO-d6 ) δ ppm 9.53 (s, 2H), 8.13 (d, 1H), 7.64 (d, 1H), 7.42 (dd, 1H), 7.10 (d, 1H), 5.88 - 4.46 (m, 2H), 3.43 - 3.28 (m, 2H), 3.14 - 3.05 (m, 2H), 3.01 (t, 2H), 2.56 - 2.50 (m, 2H). m / z (ES+) 239.2 (M+H) +

[0131] INT-25: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile The method used to prepare INT-3 produced a quantitative yield in a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.47 (t, 2H), 2.95 (t, 2H), 3.51 (t, 2H), 3.78 (t, 2H), 7.04 (s, 1H), 7.10 (d, 1H), 7.44 (t, 1H), 7.50 (s, 1H), 7.63 (d, 1H), 8.06 (s, 1H), 8.10 (s, 1H), 13.37 (s, 1H)

[0132] INT-26: 1-(4-(cyano(1H-indazol-4-yl)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide It was prepared by the method used to prepare INT-4, with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.99 (m, 2H), 3.35 (m, 2H), 3.53 (m, 2H), 3.81 (m, 2H), 3.91 (s, 3H), 7.11 (d, 1H), 7.45 (d, 1H), 7.65 (d, 1H), 7.86 (s, 1H), 8.03 (s, 1H), 8.10 (s, 1H), 9.57 (s, 1H), 13.39 (s, 1H)

[0133] Manufacturing of INT-28 and INT-30 [ka] INT-27: Prepared following general procedure A to afford tert-butyl 4-[(3-chlorophenyl)(cyano)methylene]piperidine-1-carboxylate in 45% yield as an off-white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.38 - 7.27 (m, 3H), 7.20 - 7.13 (m, 1H), 3.61 (t, 2H), 3.43 (t, 2H), 2.76 (t, 2H), 2.41 (t, 2H), 1.48 (s, 9H). m / z (ES+) 277.2 / 279.2, (Mt-Bu+H) +

[0134] INT-28: Prepared according to general procedure B to provide 2-(3-chlorophenyl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 83% yield as an off-white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.46 (s, 2H), 7.52 (d, 2H), 7.49 (s, 1H), 7.38 - 7.35 (m, 1H), 3.28 (t, 2H), 3.12 (t, 2H), 2.92 (t, 2H), 2.60 (t, 2H). m / z (ES+) 233.2 / 255.2 (Cl isotope pattern) (M+H) +

[0135] INT-29: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(3-chlorophenyl)acetonitrile The method used to prepare INT-3 produced the compound in 98% yield with a reaction time of 7 hours. 1 H-NMR (400 MHz, DMSO-d 6): 2.56 (t, 2H), 2.86 (t, 2H), 3.54 (t, 2H), 3.71 (t, 2H), 7.05 (s, 1H), 7.36 (m, 1H), 7.46 (m, 1H), 7.49-7.52 (m, 3H), 8.07 (s, 1H)

[0136] INT-30: 2-(3-chlorophenyl)-2-(1-(3-methyl-1H-3λ 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide Prepared in 95% yield by the method used to prepare INT-4, with reaction times of 3 hours at +40° C. and overnight at room temperature. The crude product was purified by trituration with heptane:ethyl acetate. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.59 (t, 2H), 2.89 (t, 2H), 3.57 (t, 2H), 3.73 (t, 2H), 3.92 (s, 3H), 7.37 (m, 1H), 7.47 (s, 1H), 7.50-7.54 (m, 2H), 7.86 (m, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0137] Manufacturing of INT-32 and INT-34 [ka] INT-31: Prepared following general procedure A to afford tert-butyl 4-{cyano[4-(trifluoromethoxy)phenyl]methylene}piperidine-1-carboxylate in 77% yield as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.35 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 3.62 (t, 2H), 3.44 (t, 2H), 2.77 (t, 2H), 2.41 (t, 2H), 1.48 (s, 9H)

[0138] INT-32: Prepared according to general procedure B to provide 2-(piperidin-4-ylidene)-2-[4-(trifluoromethoxy)phenyl]acetonitrile hydrochloride in 82% yield as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 9.21 (s, 2H), 7.72 - 7.31 (m, 4H), 3.33 - 3.24 (m, 2H), 3.18 - 3.08 (m, 2H), 2.91 (t, 2H), 2.59 (t, 2H). 19 F NMR (400 MHz, DMSO-d6) δ ppm - 56.74. m / z (ES+) 283.1 (M+H) +

[0139] INT-33: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile It was produced in quantitative yield by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.57 (t, 2H), 2.87 (t, 2H), 3.54 (t, 2H), 3.72 (t, 2H), 7.05 (s, 1H), 7.46-7.55 (m, 5H), 8.06 (s, 1H)

[0140] INT-34: 2-(1-(3-methyl-1H-3λ 4 -imidazole-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile iodide It was produced in 94% yield by the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.59 (t, 2H), 2.91 (t, 2H), 3.57 (t, 2H), 3.74 (t, 2H), 3.92 (s, 3H), 7.49-7.55 (m, 4H), 7.87 (s, 1H), 8.03 (s, 1H), 9.57 (s, 1H)

[0141] Production of INT-36 and INT-38 [ka] INT-35: Prepared following general procedure A to give tert-butyl 4-{cyano[4-(trifluoromethyl)phenyl]methylene}piperidine-1-carboxylate in 52% yield as a cream solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.73 - 7.62 (m, 2H), 7.52 - 7.37 (m, 2H), 3.71 - 3.54 (m, 2H), 3.50 - 3.37 (m, 2H), 2.84 - 2.73 (m, 2H), 2.47 - 2.36 (m, 2H), 1.48 (s, 9H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -62.86 - -62.76 (m)(rotamer). m / z (ES+) 365.3 (MH) -

[0142] INT-36: Prepared according to general procedure B to provide 2-(piperidin-4-ylidene)-2-[4-(trifluoromethyl)phenyl]acetonitrile hydrochloride in 83% yield as an off-white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 2H), 7.86 (d, 2H), 7.64 (d, 2H), 3.32 - 3.26 (m, 2H), 3.12 (t, 2H), 2.95 (t, 2H), 2.62 (t, 2H). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm -61.28. m / z (ES+) 267.3 (M+H) +

[0143] INT-37: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile The compound was produced in 97% yield with a reaction time of 3 hours using the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.59 (m, 2H), 2.90 (m, 2H), 3.54 (m, 2H), 3.73 (m, 2H), 7.05 (s, 1H), 7.50 (s, 1H), 7.63 (d, 2H), 7.86 (d, 2H), 8.07 (s, 1H)

[0144] INT-38: 1-(4-(cyano(4-(trifluoromethyl)phenyl)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide It was produced in 94% yield by the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.62 (m, 2H), 2.93 (m, 2H), 3.57 (m, 2H), 3.75 (m, 2H), 3.92 (s, 3H), 7.64 (d, 2H), 7.87 (m, 3H), 8.03 (s, 1H), 9.57 (s, 1H)

[0145] Manufacturing of INT-40 and INT-42 [ka] INT-39: Prepared following general procedure D to give tert-butyl 4-[(5-chlorothiophen-2-yl)(cyano)methylene]piperidine-1-carboxylate in 81% yield as an orange gum. 1 H-NMR (400 MHz, CDCl 3) δ ppm 6.92 (d, 1H), 6.88 (d, 1H), 3.59 (t, 2H), 3.49 (t, 2H), 2.85 - 2.71 (m, 2H), 2.61 (t, 2H), 1.48 (s, 9H). m / z (ES+) 239.1 / 241.1 (M-Boc+H) +

[0146] INT-40: Prepared following general procedure B to provide 2-(5-chlorothiophen-2-yl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 89% yield as a light tan solid. 1 H (400 MHz, DMSO-d 6 ) δ ppm 9.37 (s, 2H), 7.21 (d, 1H), 7.15 (d, 1H), 3.33 - 3.24 (m, 3H), 3.20 - 3.10 (m, 2H), 2.91 (t, 2H), 2.78 (t, 2H). m / z (ES+) 239.1 / 241.1 (M+H) +

[0147] INT-41: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(5-chlorothiophen-2-yl)acetonitrile The method used to prepare INT-3 produced a quantitative yield in a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.76 (t, 2H), 2.88 (t, 2H), 3.59 (t, 2H), 3.69 (t, 2H), 7.05 (s, 1H), 7.13 (d, 1H), 7.21 (d, 1H), 7.50 (s, 1H), 8.06 (s, 1H)

[0148] INT-42: 2-(5-chlorothiophene-2-yl)-2-(1-(3-methyl-1H-3λ) 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide It was prepared in 90% yield by the method used to prepare INT-4, with reaction times of 5 hours at +40° C. and overnight at room temperature. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.80 (t, 2H), 2.92 (t, 2H), 3.62 (t, 2H), 3.72 (t, 2H), 3.92 (s, 3H), 7.14 (d, 1H), 7.22 (d, 1H), 7.87 (s, 1H), 8.04 (s, 1H), 9.57 (s, 1H)

[0149] Manufacturing of INT-44 and INT-46 [ka] INT-43: Prepared following general procedure A to afford tert-butyl 4-[(5-chloropyridin-2-yl)(cyano)methylene]piperidine-1-carboxylate in 36% yield as an orange oil. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.58 (d, 1H), 7.77 - 7.70 (m, 1H), 7.45 (d, 1H), 3.63 (t, 2H), 3.49 (t, 2H), 2.85 - 2.76 (m, 4H), 1.48 (s, 9H). m / z (ES+) 334.2 (M+H) +

[0150] INT-44: Following general procedure B, 2-(5-chloropyridin-2-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride was obtained in 84% yield as a beige solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.52 (s, 2H), 8.73 (d, 1H), 8.08 (dd, 1H), 7.62 (d, 1H), 6.44 (s, 1H), 3.36 - 3.27 (m, 2H), 3.18 - 3.09 (m, 2H), 2.98 (t2H), 2.89 (t, 2H). m / z (ES+) 234.1 (M+H)+

[0151] INT-45: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(5-chloropyridin-2-yl)acetonitrile It was produced in 87% yield by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.83 (t, 2H), 2.92 (t, 2H), 3.56 (t, 2H), 3.73 (t, 2H), 7.05 (s, 1H), 7.51 (s, 1H), 7.59 (d, 1H), 8.07 (m, 2H), 8.74 (d, 1H)

[0152] INT-46: 1-(4-((5-chloropyridin-2-yl)(cyano)methylene)piperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide It was produced in 93% yield by the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.90 (t, 2H), 2.96 (t, 2H), 3.59 (m, 2H), 3.76 (m, 2H), 3.92 (s, 3H), 7.61 (d, 1H), 7.87 (s, 1H), 8.04 (s, 1H), 8.10 (dd, 1H), 8.74 (d, 1H), 9.58 (s, 1H)

[0153] Manufacturing of INT-48 and INT-50 [ka] INT-47: A mixture of 2-(5-fluoropyridin-2-yl)acetonitrile (2.48 g, 100 mol%), tert-butyl 4-oxopiperidine-1-carboxylate (3.71 g, 102 mol%) and ammonium acetate (2.89 g, 205 mol%) in toluene (17 mL) was heated at 100° C. for 8 h. The reaction mixture was cooled, concentrated under reduced pressure and purified by column chromatography (10-50% EtOAc in hexanes) to give tert-butyl 4-[cyano(5-fluoropyridin-2-yl)methylene]piperidine-1-carboxylate (3.34 g, 58%) as a yellow solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.49 (d, 1H), 7.54 - 7.42 (m, 2H), 3.63 (t, 2H), 3.49 (t, 2H), 2.81 (t, 2H), 2.79 - 2.72 (m, 2H), 1.48 (s, 9H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -126.18. m / z (ES+) 318.2 (M+H) +

[0154] INT-48: To a solution of INT-47 (3.63 g, 100 mol%) in DCM (8 mL) was added 4M HCl in dioxane (11 mL) and then stirred at room temperature for 1 h. Further 4M HCl in dioxane (6 mL) was added followed by DCM (5 mL) and MeOH (3 mL) and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in a small amount of MeOH and diluted with MTBE. The formed precipitate was collected and dried to give 2-(5-fluoropyridin-2-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride (2.96 g, 89%) as a pale orange solid. 1 H-NMR (400 MHz, DMSO-d 6) δ ppm 9.55 (s, 1H), 8.69 (d, 1H), 7.88 (td, 1H), 7.66 (dd, 1H), 7.35 (s, 1H), 3.35 - 3.26 (m, 2H), 3.15 - 3.11 (m, 2H), 2.97 (t, 2H), 2.86 (t, 2H). 19 F NMR (376 MHz, DMSO) δ ppm -126.38. m / z (ES+) 218.2 (M+H) +

[0155] INT-49: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(5-fluoropyridin-2-yl)acetonitrile It was produced in 71% yield by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm 2.80 (m, 2H), 2.92 (m, 2H), 3.56 (m, 2H), 3.73 (m, 2H), 7.05 (s, 1H), 7.51 (s, 1H), 7.63 (d, 1H), 7.87 (d, 1H), 8.07 (s, 1H), 8.69 (s, 1H)

[0156] INT-50: 2-(5-fluoropyridin-2-yl)-2-(1-(3-methyl-1H-3λ) 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide The compound was produced in 86% yield with a reaction time of 3 hours using the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): δ ppm 2.86 (m, 2H), 2.95 (m, 2H), 3.59 (m, 2H), 3.76 (m, 2H), 3.92 (s, 3H), 7.76 (m, 1H), 7.90 (m, 2H), 8.04 (s, 1H), 8.70 (d, 1H), 9.58 (s, 1H)

[0157] Manufacturing of INT-53 and INT-55 [ka] INT-51: Prepared according to general procedure E to give 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl]ethan-1-one in 57% yield as an off-white powder. 1 H-NMR (400 MHz, CDCl 3 ): δ ppm 8.59 - 8.51 (m, 2H), 7.82 (d, 1H), 7.53 (t, 1H), 2.78 (s, 3H), 1.43 (s, 12H)

[0158] INT-52: Prepared following general procedure D to afford tert-butyl 4-[(1-acetyl-1H-indazol-4-yl)(cyano)methylene]piperidine-1-carboxylate in 84% yield as an off-white foam. 1 H-NMR (400 MHz, CDCl 3 ): δ ppm 8.50 (d, 1H), 8.14 (s, 1H), 7.59 (dd, 1H), 7.22 (d, 1H), 3.68 (t, 2H), 3.41 (t, 2H), 2.87 (t, 2H), 2.81 (s, 3H), 2.33 (t, 2H), 1.48 (s, 9H). m / z (ES+) 281.2 (M-Boc+H) +

[0159] INT-53: Prepared according to general method B to afford 2-(1-acetyl-1H-indazol-4-yl)-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 93% yield as a colorless solid. 1 H-NMR (400 MHz, DMSO-d 6) δ ppm 9.25 (s, 2H), 8.57 (d, 1H), 8.40 (d, 1H), 7.73 (dd, 1H), 7.43 (dd, 1H), 3.39 (t, 2H), 3.09 (t, 2H), 3.01 (t, 2H), 2.75 (s, 3H), 2.46 (t, 2H). m / z (ES+) 281.1 (M+H) +

[0160] INT-54: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(1-acetyl-1H-indazol-4-yl)acetonitrile The method used to prepare INT-3 produced the compound in 83% yield with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.75 (s, 3H), 2.96 (t, 2H), 3.50 (t, 2H), 3.80 (t, 2H), 7.05 (s, 1H), 7.42 (d, 1H), 7.50 (s, 1H), 7.70-7.76 (m, 1H), 8.06 (s, 1H), 8.39 (d, 1H), 8.53 (s, 1H)

[0161] INT-55: 2-(1-acetyl-1H-indazol-4-yl)-2-(1-(3-methyl-1H-3λ) 4 -Imidazole-1-carbonyl)piperidin-4-ylidene)acetonitrile iodide The method used to prepare INT-4 produced a 91% yield with reaction times of 7 hours at +40° C. and overnight at room temperature. 1 H-NMR (400 MHz, DMSO-d 6): 2.46 (t, 2H), 2.75 (s, 3H), 3.00 (t, 2H), 3.53 (t, 2H), 3.83 (t, 2H), 3.92 (s, 3H), 7.43 (d, 1H), 7.70-7.80 (m, 1H), 7.86 (s, 1H), 8.03 (s, 1H), 8.40 (d, 1H), 8.54 (s, 1H), 9.58 (s, 1H)

[0162] Manufacturing of INT-59 and INT-61 [ka] INT-56: A solution of 7-bromo-1H-indazole (1.31 g, 100 mol%), 3,4-dihydro-2H-pyran (1.2 mL, 200 mol%) and pyridinium p-toluenesulfonate (0.17 g, 100 mol%) in DCM (5 mL) was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (3–40% EtOAc in hexanes) to give 7-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (27%) as an off-white solid and 7-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (71%) as a colorless oil, both of which were used in the subsequent step without purification.

[0163] 7-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: 1 H-NMR (400 MHz, CDCl 3) δ ppm 8.05 (s, 1H), 7.68 (dd, 1H), 7.59 (dd, 1H), 7.02 (t, 1H), 6.53 (dd, 1H), 4.11 - 3.98 (m, 1H), 3.90 - 3.74 (m, 1H), 2.80 - 2.58 (m, 1H), 2.25 - 2.07 (m, 2H), 1.90 - 1.57 (m, 3H). m / z (ES+) 281.1 / 283.1 (M+H) +

[0164] 7-Bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole: 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.27 (s, 1H), 7.63 (dd, 1H), 7.50 (dd, 1H), 6.93 (dd, 1H), 5.77 (dd, 1H), 4.23 - 4.07 (m, 1H), 3.84 - 3.70 (m, 1H), 2.36 - 2.24 (m, 1H), 2.14 - 1.94 (m, 2H), 1.95 - 1.38 (m, 3H). m / z (ES+) 281.1 / 283.1 (M+H) +

[0165] INT-57: Prepared according to general procedure E to afford 2-(tetrahydro-2H-pyran-2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole) in 76% yield as a yellow solid which was used in the subsequent step without purification. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.18 (s, 1H), 7.82 (dd, 1H), 7.77 (dd, 1H), 7.07 (dd, 1H), 5.82 (dd, 1H), 4.21 - 4.07 (m, 1H), 3.83 - 3.72 (m, 1H), 2.32 - 2.19 (m, 1H), 2.12 - 2.01 (m, 2H), 1.86 - 1.57 (m, 3H), 1.41 (s, 12H)

[0166] INT-58: Prepared following general procedure D to afford tert-butyl 4-{cyano[2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-7-yl]methylene}piperidine-1-carboxylate) in 74% yield as an orange gum. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.22 (s, 1H), 7.70 (dd, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 5.70 (dd, 1H), 4.16 - 4.08 (m, 1H), 3.82 - 3.72 (m, 1H), 3.71 - 3.63 (m, 2H), 3.46 (t, 2H), 2.85 (t, 2H), 2.32 (t, 2H), 2.26 - 2.20 (m, 1H), 2.15 - 2.05 (m, 2H), 1.82 - 1.63 (m, 3H), 1.23 (s, 9H). m / z (ES+) 423.4 (M+H) +

[0167] INT-59: To a stirring solution of INT-58 (623 mg, 100 mol%) in DCM (2 mL) at 0° C. was added 4 M HCl in dioxane (1.3 mL, 384 mol%). After 10 min, MeOH (1.5 mL) was added and the mixture was stirred at 20° C. for 18 h. MTBE was added and the solid was filtered and dried to give 2-(1H-indazol-7-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride (284 mg, 69%) as an off-white powder. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.49 (s, 2H), 8.20 (s, 1H), 7.87 (dd, 1H), 7.33 (dd, 1H), 7.21 (dd, 1H), 7.13 - 6.04 (bs, 2H), 3.43 - 3.30 (m, 2H), 3.11 - 3.03 (m, 2H), 3.03 - 2.96 (m, 2H), 2.34 (t, 2H). m / z (ES+) 239.2 (M+H)+

[0168] INT-60: 2-(1-(1H-imidazole-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-7-yl)acetonitrile It was produced in 96% yield by the method used to produce INT-3. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.30 (t, 2H), 2.93 (t, 2H), 3.49 (t, 2H), 3.79 (t, 2H), 7.04 (s, 1H), 7.21 (t, 1H), 7.31 (d, 1H), 7.49 (s, 1H), 7.86 (d, 1H), 8.06 (s, 1H), 8.20 (s, 1H), 13.29 (s, 1H)

[0169] INT-61: 1-(4-(cyano(1-methyl-1H-indazol-7-yl)methylene)piperidine-1-carbonyl)-3-methyl-1H-3λ 4 -Imidazol-1-ium iodide It was produced in 98% yield by the method used to produce INT-4. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.46 (t, 2H), 2.97 (t, 2H), 3.57 (m, 2H), 3.77 (m, 2H), 3.92 (s, 3H), 4.20 (s, 3H), 7.12 (t, 1H), 7.22 (m, 1H), 7.81 (d, 1H), 7.86 (m, 1H), 8.04 (m, 1H), 8.47 (s, 1H), 9.57 (s, 1H)

[0170] Manufacturing of INT-63 [ka] INT-62: Prepared according to general procedure C to give 2-bromo-2-(piperidin-4-ylidene)acetonitrile hydrochloride in 87% yield as a colorless powder. 1H-NMR (400 MHz, DMSO-d 6 ) δ ppm 9.40 (s, 2H), 3.20 (dt, 4H), 2.82 (t, 2H), 2.74 (t, 2H). m / z (ES+) 203.0 / 205.0 (M+H) +

[0171] INT-63: Prepared from INT-62 and INT-64 by the method used to prepare compound 3 to give 2-bromo-2-[1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene]acetonitrile in 50% yield as a brown solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 3.93 - 3.83 (m, 1H), 3.59 (dt, 2H), 3.38 - 3.30 (m, 4H), 3.02 (ddd, 2H), 2.72 - 2.65 (m, 2H), 2.63 - 2.55 (m, 2H), 1.95 - 1.85 (m, 2H), 1.57 - 1.47 (m, 2H). m / z (ES+) 328.0 / 330.0 (M+H) +

[0172] INT-64: 1-(4-hydroxypiperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide [ka] A stirred solution of piperidin-4-ol (2.00 g, 100 mol%) and carbonyldiimidazole (3.21 g, 100 mol%) in THF (25 mL) was heated under reflux for 18 h and then cooled. The solvent was concentrated under reduced pressure to give 1-(1H-imidazole-1-carbonyl)piperidin-4-ol as a colorless, viscous oil (5.23 g). This intermediate was dissolved in MeCN (20 mL), iodomethane (2.5 mL, 400 mol%) was added and the reaction mixture was stirred in a sealed vessel for 24 h. The volatiles were concentrated under reduced pressure to give 1-(4-hydroxypiperidine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (5.40 g) as an orange oil which was used in the subsequent step without purification. m / z (ES+) 210 M +

[0173] compound 1 2-(4-Fluorophenyl)-2-(1-(morpholine-4-carbonyl)piperidin-4-ylidene)acetonitrile [ka] INT-2 (50.0 mg, 100 mol%) was dissolved in dry dichloromethane (DCM) (2 ml). 4-Morpholinecarbonyl chloride (26 μl, 110 mol%) and triethylamine (83 μl, 300 mol%) were added. Stirred at room temperature under nitrogen for 3 h. The reaction mixture was diluted with DCM (5 mL) and washed with 0.25 N HCl (3×5 mL), 0.1 N NaOH (3×5 mL), water (3×5 mL) and brine (3×5 mL). Dried over sodium sulfate. The crude product was purified by trituration with heptane. The yield was 80%. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.38 (t, 2H), 2.70 (t, 2H), 3.16 (m, 4H), 3.21 (t, 2H), 3.38 (t, 2H), 3.57 (m, 4H), 7.29-7.33 (m, 2H), 7.39-7.43 (m, 2H)

[0174] compound 2 2-(4-Chlorophenyl)-2-(1-(morpholine-4-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 2 was synthesized in 81% yield by the method used to prepare compound 1 using INT-6 and 4-morpholinecarbonyl chloride as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.40 (t, 2H), 2.70 (t, 2H), 3.16 (m, 4H), 3.22 (t, 2H), 3.39 (t, 2H), 3.57 (m, 4H), 7.38-7.40 (m, 2H), 7.53-7.55 (m, 2H)

[0175] compound 3 2-(4-Fluorophenyl)-2-(1-(piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] INT-4 (70 mg, 100 mol%) was dissolved in dry DCM (2 mL). Piperidine (19 μl, 120 mol%) and triethylamine (43 μl, 200 mol%) were added. Stirred at room temperature under nitrogen for 3 h. The reaction mixture was diluted with DCM (8 mL) and washed with water (1×5 mL), 0.5 N HCl (2×5 mL), water (1×5 mL) and brine (1×10 mL). Drying over sodium sulfate followed by purification by chromatography gave 19 mg of product. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.47 (m, 6H), 2.38 (m, 2H), 2.68 (m, 2H), 3.13 (m, 6H), 3.35 (m, 2H), 7.30 (m, 2H), 7.40 (m, 2H)

[0176] compound 4 2-(4-Fluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 4 was synthesized in 59% yield by the method used to prepare compound 3 using INT-4 and piperidin-4-ol as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33 (m, 2H), 1.72 (m, 2H), 2.38 (s, 2H), 2.69 (s, 2H), 2.88 (m, 2H), 3.18 (s, 2H), 3.45 (m, 4H), 3.62 (s, 1H), 4.70 (s, 1H), 7.30 (m, 2H), 7.41 (m, 2H)

[0177] compound 5 4-(Cyano(4-fluorophenyl)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 5 was synthesized in 59% yield by the method used to prepare compound 3 using INT-4 and diethylamine as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.05 (m, 6H), 2.37 (m, 2H), 2.70 (m, 2H), 3.14 (m, 6H), 3.30 (m, 2H), 7.31 (m, 2H), 7.41 (m, 2H)

[0178] compound 6 2-(4-Fluorophenyl)-2-(1-(pyrrolidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 6 was synthesized in quantitative yield by the method used to prepare compound 3 using INT-4 and pyrrolidine as starting materials with a reaction time of 1 h. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.75 (m, 4H), 2.38 (m, 2H), 2.69 (m, 2H), 3.22 (m, 2H), 3.28 (m, 4H), 3.39 (m, 2H), 7.31 (m, 2H), 7.41 (m, 2H)

[0179] compound 7 (R)-2-(4-fluorophenyl)-2-(1-(3-methoxypyrrolidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 7 was synthesized in 64% yield by the method used to prepare compound 3, using INT-4 and (3R)-3-methoxypyrrolidine hydrochloride as starting materials. 1H-NMR (400 MHz, DMSO-d 6 ): 1.78-1.93 (m, 2H), 2.37 (s, 2H), 2.67 (s, 2H), 3.18-3.49 (m, 11H), 3.90 (m, 1H), 7.31 (m, 2H), 7.41 (m, 2H)

[0180] compound 8 (S)-2-(4-fluorophenyl)-2-(1-(2-(methoxymethyl)pyrrolidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 8 was synthesized in 73% yield by the method used to prepare compound 3 using INT-4 and (S)-(+)-2-(methoxymethyl)pyrrolidine as starting materials. 1 H-NMR (400 MHz, DMSO-d 6): 1.61-1.68 (m, 2H), 1.85 (m, 1H), 1.99 (m, 1H), 2.30 (m, 1H), 2.46 (m, 1H), 2.59 (m, 1H), 2.76 (m, 1H), 3.16 (m, 2H), 3.23 (s, 3H), 3.28 -3.46 (m, 6H), 4.06 (m, 1H), 7.30 (dd, 2H), 7.41 (dd, 2H)

[0181] compound 9 (S)-2-(4-fluorophenyl)-2-(1-(3-hydroxypyrrolidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 9 was synthesized in 79% yield by the method used to prepare compound 3 using INT-4 and (S)-3-hydroxypyrrolidine as starting materials. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.72 (m, 1H), 1.82 (m, 1H), 2.37 (m, 2H), 2.69 (m, 2H), 3.08 (d, 1H), 3.19-3.28 (m, 3H), 3.38-3.51 (m, 5H), 4.21 (d, 1H), 7.30 (dd, 2H), 7.41 (dd, 2H)

[0182] compound 10 2-(3,5-difluorophenyl)-2-(1-(piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] INT-10 (50 mg, 100 mol%) was dissolved in tetrahydrofuran (THF) (3 ml) and water (1 ml). 3,5-Difluorophenylboronic acid (40 mg, 150 mol%), Cs 2 CO 3 (157 mg, 300 mol%) and Pd(dppf)Cl 2(12 mg, 10 mol%) was added. Stirred at 90° C. under nitrogen for 1.5 h. The solvent was evaporated and ethyl acetate (10 ml) was added. The reaction mixture was washed with water (2×5 ml) and brine (1×5 ml) and dried over sodium sulfate. After chromatographic purification and trituration with heptane the yield was 35%. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.47 (m, 4H), 1.53 (m, 2H), 2.40 (t, 2H), 2.69 (t, 2H), 3.13 (m, 4H), 3.19 (t, 2H), 3.33 (m, 2H), 7.13-7.19 (m, 2H), 7.30-7.38 (m, 1H)

[0183] compound 11 2-(4-Fluorophenyl)-2-(1-(isoindoline-2-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 11 was synthesized in 80% yield using INT-4 and isoindoline as starting materials by the method used to prepare compound 3, and the crude product was purified by trituration with methanol. 1 H-NMR (400 MHz, CDCl 3 ): 2.54 (m, 2H), 2.88 (m, 2H), 3.36 (m, 2H), 3.56 (m, 2H), 4.81 (s, 4H), 7.12 (dd, 2H), 7.26 (m, 6H). 1 H-NMR (400 MHz, DMSO-d 6 ): 2.40 (s, 2H), 2.77 (s, 2H), 3.30 (s, 2H), 3.49 (s, 2H), 4.74 (s, 4H), 7.32 (br s, 6H), 7.43 (s, 2H)

[0184] compound 12 2-(4-Fluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 12 was synthesized in 71% yield by the method used to prepare compound 3 using INT-4 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine×HCl (150 mol%) as starting materials, and the crude product was purified by trituration with a mixture of DCM and heptane. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (s, 2H), 2.72 (s, 2H), 2.86 (s, 2H), 3.25 (s, 2H), 3.44 (s, 4H), 4.30 (s, 2H), 7.31 (m, 2H), 7.41 (s, 2H), 8.67 (s, 1H)

[0185] compound 13 2-(4-Fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 13 was synthesized in 59% yield using INT-4 and 4,5,6,7-tetrahydro-1,2,3-triazolo[1,5-a]pyrazine (150 mol%) as starting materials by the method used to prepare compound 3, with a reaction time of 3 h, and the crude product was purified by trituration with a mixture of DCM and heptane. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (s, 3H), 2.73 (s, 2H), 3.47 (s, 3H), 3.67 (s, 2H), 4.43 (s, 2H), 4.53 (s, 2H), 7.32 (s, 2H), 7.41 (s, 2H), 7.59 (s, 1H)

[0186] compound 14 4-(Cyano(4-fluorophenyl)methylene)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide [ka] Compound 14 was synthesized in 44% yield using the method used to prepare compound 3, starting with INT-4 and methyl-(tetrahydro-pyran-4-yl)-amine HCl (150 mol%), with a reaction time of 3 h, and the crude product was purified by chromatography. 1 H-NMR (400 MHz, DMSO-d 6 ): 0.86 (t, 1H), 1.24 (m, 2H), 1.53 (d, 2H), 1.73 (m, 2H), 2.39 (t, 2H), 2.69 (s, 3H), 2.72 (s, 1H), 3.15 (t, 2H), 3.31 (m, 1H), 3.36 (s, 1H), 3.73 (m, 1H), 3.90 (m, 2H), 7.30 (dd, 2H), 7.40 (m, 2H)

[0187] compound 15 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 15 was synthesized in 83% yield using the method used to prepare compound 3, starting with INT-4 and 3-oxa-8-azabicyclo[3.2.1]octane, HCl (150 mol%), for a reaction time of 1.5 h, and the crude product was purified by trituration with heptane. 1 H-NMR (400 MHz, DMSO-d 6): 1.72-1.80 (m, 4H), 2.39 (t, 2H), 2.70 (t, 2H), 3.33 (m, 2H), 3.48-3.51 (m, 4H), 3.60 (s, 1H), 3.63 (s, 1H), 3.84 (br s, 2H), 7.31 (m, 2H), 7.41 (m, 2H)

[0188] compound 16 4-(Cyano(4-fluorophenyl)methylene)-N,N-dimethylpiperidine-1-carboxamide [ka] Compound 16 was synthesized in 97% yield using the method used to prepare compound 3, starting with INT-4 and dimethylamine hydrochloride (200 mol%), with a reaction time of 1.5 h, and the crude product was purified by trituration with heptane. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.38 (t, 2H), 2.69 (t, 2H), 3.16 (t, 2H), 3.33 (s, 2H), 2.75 (s, 6H), 7.30 (m, 2H), 7.40 (m, 2H)

[0189] compound 17 2-(3-chlorophenyl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 17 was synthesized as a clear oil in 99% yield by the method used to prepare compound 3 using INT-30 and 4-methoxypiperidine (150 mol%) as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.38 (t, 2H), 1.82 (m, 2H), 2.39 (t, 2H), 2.69 (t, 2H), 2.93 (t, 2H), 3.19 (t, 2H), 3.24 (s, 3H), 3.31-3.42 (m, 5H), 7.33 (m, 1H), 7.44 (s, 1H), 7.50 (m, 2H)

[0190] compound 18 2-(4-Chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 18 was synthesized by the method used to prepare compound 3 using INT-8 and piperidin-4-ol (150 mol%) as starting materials with 400 mol% triethylamine for a reaction time of 90 min at room temperature in 96% yield as a white solid, and the crude product was purified by trituration with heptane:DCM (v / v 5:0.5). 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33 (m, 2H), 1.71 (m, 2H), 2.39 (dd, 2H), 2.69 (dd, 2H), 2.88 (dd, 2H), 3.18 (dd, 2H), 3.35 (s, 2H), 3.44 (m, 2H), 3.61 (m, 1H), 4.69 (d, 1H), 7.39 (d, 2H), 7.54 (d, 2H)

[0191] compound 19 2-(4-Fluorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 19 was synthesized in 75% yield by the method used to prepare compound 3 using INT-4 and piperidin-4-ylmethanol as starting materials with a reaction time of 3 hours.1 H-NMR (400 MHz, DMSO-d 6 ): 1.03-1.11 (m, 2H), 1.52 (m, 1H), 1.60-1.66 (m, 2H), 2.38 (t, 2H), 2.69-2.74 (m, 4H), 3.17 (t, 2H), 3.25 (t, 2H), 3.33 (m, 2H), 3.59-3.63 (m, 2H), 4.47 (s, 1H), 7.30 (m, 2H), 7.41 (m, 2H)

[0192] compound 20 2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 20 was synthesized in 56% yield by the method used to prepare compound 3 using INT-4 and 4-ethoxypiperidine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.33-1.40 (m, 2H), 1.80-1.82 (m, 2H), 2.37 (t, 2H), 2.68 (t, 2H), 2.88-2.93 (m, 2H), 3.18 (t, 2H), 3.33 (t, 2H), 3.40-3.49 (m, 5H), 7.28-7.33 (m, 2H), 7.39-7.43 (m, 2H)

[0193] compound 21 2-(4-Fluorophenyl)-2-(1-(4-(1-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 21 was synthesized as a clear oil in 87% yield by the method used to prepare compound 3 using INT-4 and 1-(piperidin-4-yl)ethan-1-ol (150 mol%) as starting materials with a reaction time of 1 h. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.03 (s, 3H), 1.12-1.31 (m, 4H), 1.52 (d, 1H), 1.74 (d, 1H), 2.38 (s, 2H), 2.69 (s, 4H), 3.18 (s, 2H), 3.35 (s, 2H), 3.63 (d, 2H), 4.39 (s, 1H), 7.30 (br s, 2H), 7.41 (br s, 2H)

[0194] compound 22 2-(4-Fluorophenyl)-2-(1-(3-methoxyazetidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 22 was synthesized as a clear oil in 84% yield by the method used to prepare compound 3 using INT-4 and 3-hydroxy-3-methylazetidine, HCl (150 mol%) as starting materials with a reaction time of 90 minutes. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.35 (m, 2H), 2.66 (m, 2H), 3.19 (s, 3H), 3.26 (m, 2H), 3.43 (m, 2H), 3.74 (m, 2H), 4.08 (m, 3H), 7.31 (m, 2H), 7.40 (m, 2H)

[0195] compound 23 1-(4-(cyano(4-fluorophenyl)methylene)piperidine-1-carbonyl)azetidine-3-carbonitrile [ka] Compound 23 was synthesized as a clear oil in 82% yield by the method used to prepare compound 3 using INT-4 and azetidine-3-carbonitrile, HCl (150 mol%) as starting materials with a reaction time of 60 minutes. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.35 (m, 2H), 2.67 (m, 2H), 3.27 (m, 2H), 3.44 (m, 2H), 3.74 (m, 1H), 4.07 (dd, 2H), 4.18 (dd, 2H), 7.31 (dd, 2H), 7.40 (m, 2H)

[0196] compound 24 2-(4-Fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 24 was synthesized in 34% yield by the method used to prepare compound 3 using INT-4 and 4,5,6,7-tetrahydro-1H-imidazole[4,5-c]-pyridine diHCl (150 mol%) as starting materials, stirred for 7 hours at +50° C. and then overnight at room temperature. The crude oily product was purified by chromatography, followed by coevaporation with DCM and heptane to give a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (m, 2H), 2.66 (m, 2H), 2.72 (m, 2H), 3.23 (m, 2H), 3.44-3.46 (m, 4H), 4.18 (br s, 2H), 7.31 (dd, 2H), 7.42 (m, 2H), 7.48 (s, 1H), 11.84 (br s, 1H)

[0197] compound 25 2-(4-Fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 25 was synthesized in 70% yield as a clear oil by the method used to prepare compound 3 using INT-4 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (150 mol%) as starting materials by stirring at room temperature overnight. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (s, 2H), 2.72 (s, 4H), 3.23 (s, 2H), 3.42 (m, 4H), 4.24 (s, 2H), 7.31 (s, 2H), 7.41 (br s, 3H), 12.48 (s, 1H)

[0198] compound 26 2-(4-Fluorophenyl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 26 was synthesized in 37% yield by the method used to prepare compound 3 using INT-4 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (150 mol%) as starting materials with THF as solvent and stirring at room temperature for 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (dd, 2H), 2.74 (dd, 2H), 3.30 (m, 2H), 3.48 (dd, 2H), 3.70 (dd, 2H), 4.21 (dd, 2H), 4.50 (s, 2H), 7.32 (dd, 2H), 7.42 (m, 2H), 7.96 (s, 1H)

[0199] compound 27 2-(4-Fluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 27 was synthesized in 62% yield by the method used to prepare compound 3 using INT-4 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials with THF as solvent and stirring at room temperature for 3.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (m, 2H), 2.74 (m, 2H), 3.35 (m, 2H), 3.47 (m, 2H), 3.65 (m, 2H), 4.30 (m, 2H), 4.51 (m, 2H), 7.32 (m, 2H), 7.45 (m, 3H), 9.05 (s, 1H)

[0200] compound 28 2-(4-Fluorophenyl)-2-(1-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-2-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 28 was synthesized in 28% yield by the method used to prepare compound 3 using INT-4 and 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (150 mol%) as starting materials with THF as solvent and stirring at room temperature for 4 hours. 1 H-NMR (400 MHz, DMSO-d 6): 2.41 (m, 2H), 2.72 (m, 2H), 3.26 (m, 2H), 3.43 (m, 2H), 3.56 (m, 2H), 3.98 (m, 2H), 4.37 (m, 2H), 5.80 (d, 1H), 5.99 (d, 1H), 6.65 (d, 1H), 7.31 (m, 2H), 7.41 (m, 2H)

[0201] compound 29 2-(1-((1R,4R)-2-azabicyclo[2.2.1]heptane-2-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 29 was synthesized in 99% yield as an oil by the method used to prepare compound 3 using INT-4 and 2-azabicyclo[2.2.1]heptane (150 mol%) as starting materials with DCM as the solvent and stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.24-1.34 (m, 3H), 1.46 (d, 1H), 1.58 (s, 2H), 1.72 (d, 1H), 2.37 (m, 2H), 2.68 (m, 2H), 2.83 (d, 1H), 3.18-3.40 (m, 5H), 4.00 (s, 1H), 7.20 (m, 2H), 7.40 (m, 2H)

[0202] compound 30 2-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 30 was synthesized in 14% yield after chromatographic purification by the method used to prepare compound 3 using INT-4 and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.58 (t, 2H), 2.95 (t, 2H), 3.02 (t, 2H), 3.52 (t, 2H), 3.68 (t, 2H), 3.98 (t, 2H), 6.76 (m, 1H), 7.11 (m, 2H), 7.26 (m, 2H), 7.40 (m, 1H), 8.02 (m, 1H)

[0203] compound 31 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(3,4-difluorophenyl)acetonitrile [ka] Compound 31 was synthesized in 75% yield by the method used to prepare compound 3 using INT-14 and 3-oxa-8-azabicyclo[3.2.1]octane, HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.76 (m, 4H), 2.39 (m, 2H), 2.69 (m, 2H), 3.33 (m, 2H), 3.50 (m, 4H), 3.61 (m, 2H), 3.83 (s, 2H), 7.24 (br s, 1H), 7.53 (m, 2H)

[0204] compound 32 2-(3,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 32 was synthesized in 71% yield by the method used to prepare compound 3 using INT-14 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine, HCl (150 mol%) as starting materials with stirring at room temperature for 2.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (m, 2H), 2.72 (m, 2H), 2.86 (m, 2H), 3.26 (m, 2H), 3.45 (m, 4H), 4.30 (s, 2H), 7.24 (br s, 1H), 7.53 (m, 2H), 8.67 (s, 1H)

[0205] compound 33 2-(3,4-Difluorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 33 was synthesized in 67% yield by the method used to prepare compound 3 using INT-14 and piperidin-4-ylmethanol (150 mol%) as starting materials and stirring at room temperature. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.08 (m, 2H), 1.51-1.64 (m, 3H), 2.37 (m, 2H), 2.71 (m, 4H), 3.20 (m, 5H), 3.33 (m, 1H), 3.61 (d, 2H), 4.48 (s, 1H), 7.23 (s, 1H), 7.52 (m, 2H)

[0206] compound 34 2-(1-((1R,4R)-2-azabicyclo[2.2.1]heptane-2-carbonyl)piperidin-4-ylidene)-2-(3,4-difluorophenyl)acetonitrile [ka] Compound 34 was synthesized as an oil in 99% yield by the method used to prepare compound 3 using INT-14 and 2-azabicyclo[2.2.1]heptane (150 mol%) as starting materials by stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33 (d, 2H), 1.47 (d, 1H), 1.59 (m, 2H), 1.73 (d, 1H), 2.30-2.43 (m, 3H), 2.60-2.74 (m, 2H), 2.83 (d, 1H), 3.14-3.29 (m, 2H), 3.36-3.45 (m, 4H), 7.23 (m, 1H), 7.48-7.58 (m, 2H)

[0207] compound 35 2-(3,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 35 was synthesized in 81% yield by the method used to prepare compound 3 using INT-14 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.42 (m, 2H), 2.72 (m, 2H), 2.86 (m, 2H), 3.25 (m, 2H), 3.41-3.48 (m, 4H), 4.31 (s, 2H), 6.87 (d, 1H), 7.25 (m, 1H), 7.33 (d, 1H), 7.54 (m, 2H)

[0208] compound 36 1-(4-(cyano(3,4-difluorophenyl)methylene)piperidine-1-carbonyl)azetidine-3-carbonitrile [ka] Compound 36 was synthesized in 84% yield by the method used to prepare compound 3 using INT-14 and azetidine-3-carbonitrile, HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.36 (m, 2H), 2.67 (m, 2H), 3.27 (m, 2H), 3.43 (m, 2H), 3.74 (m, 1H), 4.07 (t, 2H), 4.19 (t, 2H), 7.24 (m, 1H), 7.49-7.59 (m, 2H)

[0209] compound 37 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(2,4-difluorophenyl)acetonitrile [ka] Compound 37 was synthesized in 47% yield by the method used to prepare compound 3 using INT-18 and 3-oxa-8-azabicyclo[3.2.1]octane as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.70-1.80 (m, 4H), 2.55 (t, 2H), 2.72 (t, 2H), 3.30-3.40 (m, 2H), 3.50 (m, 4H), 3.59-3.63 (m, 2H), 3.84 (m, 2H), 7.22 (m, 1H), 7.40-7.50 (m, 2H)

[0210] compound 38 2-(2,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 38 was synthesized in 92% yield by the method used to prepare compound 3 using INT-18 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.27 (t, 2H), 2.75 (t, 2H), 2.86 (t, 2H), 3.24 (t, 2H), 3.40-3.50 (m, 4H), 4.31 (s, 2H), 7.22 (m, 1H), 7.40-7.55 (m, 2H), 8.67 (s, 1H)

[0211] compound 39 2-(2,4-Difluorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 39 was synthesized in 77% yield by the method used to prepare compound 3 using INT-18 and piperidin-4-ylmethanol as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02-1.10 (m, 2H), 1.51 (m, 1H), 1.60-1.65 (m, 2H), 2.23 (t, 2H), 2.65-2.75 (m, 4H), 3.16 (t, 2H), 3.24 (t, 2H), 3.35 (m, 2H), 3.58-3.63 (m, 2H), 4.47 (s, 1H), 7.22 (m, 1H), 7.38-7.52 (m, 2H)

[0212] compound 40 1-(4-(cyano(2,4-difluorophenyl)methylene)piperidine-1-carbonyl)azetidine-3-carbonitrile [ka] Compound 40 was synthesized in 58% yield by the method used to prepare compound 3 using INT-18 and azetidine-3-carbonitrile as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.21 (t, 2H), 2.69 (t, 2H), 3.26 (t, 2H), 3.44 (t, 2H), 3.69-3.77 (m, 1H), 4.05-4.08 (m, 2H), 4.16-4.20 (m, 2H), 7.22 (m, 1H), 7.40-7.52 (m, 2H)

[0213] compound 41 2-(3,4-Difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 41 was prepared from INT-12 and INT-64 (140 mol%) by stirring overnight at room temperature in the presence of triethylamine (300 mol%) in DCM, then diluted with DCM and washed successively with 1M HCl solution, saturated aqueous sodium bicarbonate and brine, then dried (sodium sulfate) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (EtOAc in hexanes). The yield of the product was 49% as an off-white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.25-7.17 (m, 1H), 7.15-7.09 (m, 1H), 7.05-6.98 (m, 1H), 3.91-3.84 (m, 1H), 3.63-3.56 (m, 2H), 3.45-3.40 (m, 2H), 3.25 (t, 2H), 3.05-2.97 (m, 2H), 2.82-2.76 (m, 2H), 2.48-2.43 (m, 2H), 1.94-1.87 (m, 2H), 1.56-1.46 (m, 3H). 19 F NMR (376 MHz, CDCl 3) δ ppm -135.77 (d, J=21.2 Hz), -136.34 (d, J=21.1 Hz). m / z (ES+) 362.2 (M+H) +

[0214] compound 42 2-(2,4-Difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 42 was synthesized in 52% yield by the method used to prepare compound 41 using INT-18 and INT-64 as starting materials. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.35 - 7.18 (m, 1H), 7.01 - 6.85 (m, 2H), 3.93 - 3.83 (m, 1H), 3.65 - 3.54 (m, 2H), 3.44 (t, 2H), 3.27 (t, 2H), 3.01 (ddd, 2H), 2.85 - 2.78 (m, 2H), 2.33 - 2.25 (m, 2H), 1.95 - 1.86 (m, 2H), 1.56 - 1.46 (m, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -107.36 (d, J=8.8 Hz), -108.21 (d, J=8.8 Hz). m / z (ES+) 362.2 (M+H) +

[0215] compound 43 2-(3,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 43 was synthesized in 63% yield by the method used to prepare compound 3 using INT-14 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (150 mol%) as starting materials with stirring at room temperature overnight. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (t, 2H), 2.72 (m, 4H), 3.24 (t, 2H), 3.39-3.45 (m, 5H), 4.24 (s, 2H), 7.23 (m, 1H), 7.39 (br s, 1H), 7.50-7.59 (m, 2H)

[0216] compound 44 2-(3,4-Difluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 44 was synthesized in 77% yield by the method used to prepare compound 3 using INT-14 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials with stirring at room temperature for 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.40 (m, 2H), 2.72 (m, 2H), 3.27 (m, 2H), 3.44 (m, 2H), 3.56 (m, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.72 (s, 1H), 7.25 (m, 1H), 7.49-7.59 (m, 3H)

[0217] compound 45 2-(1H-indazol-4-yl)-2-(1-(morpholine-4-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 45 was synthesized in 52% yield using INT-24 as the starting material by the method used to prepare compound 1, followed by dropwise addition of morpholine-4-carbonyl chloride (110 mol%) and stirring at room temperature for 3 hours. The product was triturated with heptane-EtOAc (v / v 10:1) and methanol. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.30 (t, 2H), 2.79 (t, 2H), 3.17 (m, 6H), 3.45 (t, 2H), 3.56 (m, 4H), 7.08 (d, 1H), 7.42 (t, 1H), 7.62 (d, 1H), 8.08 (s, 1H), 13.35 (s, 1H)

[0218] compound 46 2-(4-Chlorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 46 was synthesized in 62% yield by the method used to prepare compound 3 using INT-8 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials with stirring at room temperature for 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.42 (t, 2H), 2.73 (t, 2H), 3.27 (m, 2H), 3.44 (m, 2H), 3.55 (t, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.72 (s, 1H), 7.38 (d, 2H), 7.54 (d, 2H), 7.59 (s, 1H)

[0219] compound 47 2-(4-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 47 was synthesized in 67% yield by the method used to prepare compound 3 using INT-8 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (m, 2H), 2.73 (m, 2H), 2.86 (m, 2H), 3.25 (m, 2H), 3.42 (m, 2H), 3.48 (m, 2H), 4.31 (s, 2H), 6.87 (d, 1H), 7.33(d, 1H), 7.40 (d, 2H), 7.54 (d, 2H)

[0220] compound 48 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile [ka] Compound 48 was synthesized in 16% yield by the method used to prepare compound 41 using INT-24 and INT-64 as starting materials. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 13.33 (s, 1H), 8.07 (t, 1H), 7.61 (d, 1H), 7.42 (dd, 1H), 7.07 (d, 1H), 4.67 (d, 1H), 3.61 (dq, 1H), 3.51 - 3.36 (m, 4H), 3.14 (t, 2H), 2.93 - 2.82 (m, 2H), 2.78 (t, 2H), 2.29 (t, 2H), 1.70 (d, 2H), 1.39 - 1.23 (m, 1H). m / z (ES+) 366.2 (M+H) +

[0221] compound 49 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile [ka] Compound 49 was synthesized in 11% yield by the method used to prepare compound 3 using INT-26 and piperidin-4-ylmethanol (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.08 (m 2H), 1.62 (d, 2H), 2.29 (m, 2H), 2.71 (m, 3H), 2.77 (t, 2H), 3.14 (t, 2H), 3.24 (t, 2H), 3.42 (t, 2H), 3.61 (d, 2H), 4.44 (t, 1H), 7.07 (d, 1H), 7.42 (t, 1H), 7.61 (d, 1H), 8.07 (s, 1H), 13.33 (s, 1H)

[0222] compound 50 2-(3,5-difluorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 50 was synthesized in 57% yield by the method used to prepare compound 3 using INT-22 and piperidin-4-ylmethanol as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.01-1.12 (m, 2H), 1.52 (m, 1H), 1.60-1.65 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.18 (t, 2H), 3.24 (t, 2H), 3.33 (m, 2H), 3.58-3.63 (m, 2H), 4.46 (t, 1H), 7.12-7.17 (m, 2H), 7.34 (m, 1H)

[0223] compound 51 2-(3,5-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 51 was synthesized in 75% yield using INT-22 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as starting materials in THF by the method used to prepare compound 3, with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.44 (t, 2H), 2.73 (t, 2H), 2.86 (t, 2H), 3.26 (t, 2H), 3.42 (t, 2H), 3.48 (t, 2H), 4.31 (s, 2H), 6.87 (d, 1H), 7.14-7.19 (m, 2H), 7.32 (d, 1H), 7.35-7.38 (m, 1H)

[0224] compound 52 2-(3,5-Difluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 52 was synthesized in 39% yield after chromatographic purification by the method used to prepare compound 3 using INT-22 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.73 (t, 2H), 3.28 (t, 2H), 3.44 (t, 2H), 3.55 (t, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.71 (s, 1H), 7.14-7.19 (m, 2H), 7.35 (m, 1H), 7.57 (s, 1H)

[0225] compound 53 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 53 was synthesized in 75% yield by the method used to prepare compound 3 using INT-34 and piperidin-4-ylmethanol as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02-1.13 (m, 2H), 1.52 (m, 1H), 1.60-1.65 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.18 (t, 2H), 3.25 (t, 2H), 3.35 (m, 2H), 3.58-3.64 (m, 2H), 4.47 (t, 1H), 7.44-7.53 (m, 4H)

[0226] compound 54 2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 54 was synthesized by the method used to prepare compound 3 using INT-34 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials with a reaction time of 5 hours in 67% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.42 (t, 2H), 2.70-2.74 (m, 4H), 3.24 (t, 2H), 3.40-3.45 (m, 4H), 4.25 (br s, 2H), 7.20-7.50 (m, 1H, isomer), 7.45-7.53 (m, 4H), 12.48 (s, 1H)

[0227] compound 55 2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 55 was synthesized in 41% yield by the method used to prepare compound 3 using INT-34 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.74 (t, 2H), 3.27 (t, 2H), 3.45 (t, 2H), 3.55 (t, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.71 (s, 1H), 7.44-7.53 (m, 4H), 7.57 (s, 1H)

[0228] compound 56 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-7-yl)acetonitrile [ka] Compound 56 was synthesized in 35% yield by the method used to prepare compound 41 using INT-59 and INT-64 as starting materials. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.08 (s, 1H), 7.77 (dd, 1H), 7.24 (dd, 1H), 7.17 (dd, 1H), 3.86 - 3.75 (m, 1H), 3.61 - 3.51 (m, 2H), 3.47 (t, 2H), 3.18 (dd, 2H), 2.98 (ddd, 2H), 2.88 (t, 2H), 2.30 (t, 2H), 1.91 - 1.79 (m, 2H), 1.56 - 1.41 (m, 2H). 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 13.20 (s, 1H), 8.18 (s, 1H), 7.84 (dd, 1H), 7.29 (dd, 1H), 7.19 (dd, 1H), 4.67 (d, 1H), 3.66 - 3.56 (m, 1H), 3.50 - 3.38 (m, m / z (ES+) 366.2 (M+H) +

[0229] compound 57 2-(5-chlorothiophene-2-yl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 57 was synthesized in 12% yield as a yellow gum by the method used to prepare compound 41 using INT-40 and INT-64 as starting materials. 1H-NMR (400 MHz, CDCl 3 ) δ ppm 6.91 (d, 1H), 6.88 (d, 1H), 3.88 (dt, 1H), 3.60 (dt, 2H), 3.42 (t, 2H), 3.31 (t, 2H), 3.02 (ddd, 2H), 2.83 - 2.77 (m, 2H), 2.67 (dd, 2H), 1.96 - 1.85 (m, 2H), 1.56 - 1.47 (m, 2H). m / z (ES+) 366.2 / 368.2 (M+H) +

[0230] compound 58 2-(3,5-difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 58 was synthesized in 44% yield as an off-white solid by the method used to prepare compound 41 using INT-20 and INT-64 as starting materials. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 6.86 - 6.79 (m, 3H), 3.93 - 3.83 (m, 1H), 3.64 - 3.55 (m, 2H), 3.43 (t, 2H), 3.26 (t, 2H), 3.06 - 2.97 (m, 2H), 2.82 - 2.77 (m, 2H), 2.51 - 2.46 (m, 2H), 1.96 - 1.86 (m, 2H), 1.58 - 1.47 (m, 3H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -107.99. m / z (ES+) 362.2 (M+H) +

[0231] compound 59 2-(1-Methyl-1H-indazol-7-yl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 59 was synthesized in 12% yield by the method used to prepare compound 3 using INT-61 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials by stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.41 (t, 2H), 2.94 (t, 2H), 3.34 (t, 2H), 3.57 (t, 2H), 3.67 (t, 2H), 4.12 (t, 2H), 4.24 (s, 3H), 4.54 (s, 2H), 6.85 (s, 1H), 7.10 (t, 1H), 7.20 (d, 1H), 7.45 (s, 1H), 7.69 (d, 1H), 7.96 (s, 1H)

[0232] compound 60 2-(1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 60 was synthesized in 13% yield by the method used to prepare compound 3 using INT-24 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (150 mol%) as starting materials by stirring at +50° C. for 4 hours. 1 H-NMR (400 MHz, DMSO-d 6): 2.32 (m, 2H), 2.71 (m, 2H), 2.81 (m, 2H), 3.20 (m, 2H), 3.45 (m, 4H), 4.24 (s, 2H), 7.08 (d, 1H), 7.42 (t, 2H), 7.62 (d, 1H), 8.09 (s, 1H), 12.47 (s, 1H), 13.27 (s, 1H)

[0233] compound 61 2-(1H-indazol-4-yl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 61 was synthesized in 31% yield by the method used to prepare compound 3 using INT-24 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials by stirring at +50° C. for 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.33 (m, 2H), 2.82 (m, 2H), 3.24 (m, 2H), 3.53 (m, 4H), 4.08 (m, 2H), 4.42 (s, 2H), 6.71 (s, 1H), 7.09 (d, 1H), 7.43 (m, 1H), 7.57-7.63 (m, 2H), 8.09 (s, 1H), 13.36 (s, 1H)

[0234] compound 62 2-(5-chloropyridin-2-yl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 62 was synthesized in 52% yield as a pale yellow solid by the method used to prepare compound 41 using INT-44 and INT-64 as starting materials. 1H-NMR (400 MHz, CDCl 3 ) δ ppm 8.58 (d, 1H), 7.74 (dd, 1H), 7.45 (d, 1H), 3.92 - 3.83 (m, 1H), 3.64 - 3.56 (m, 2H), 3.47 (t, 2H), 3.33 (t, 2H), 3.05 - 2.97 (m, 2H), 2.87 - 2.80 (m, 4H), 1.95 - 1.87 (m, 2H), 1.58 - 1.48 (m, 3H). m / z (ES+) 361.2 (M+H) +

[0235] compound 63 2-(5-chlorothiophene-2-yl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 63 was synthesized in 88% yield by the method used to prepare compound 3 using INT-42 and piperidin-4-ylmethanol as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02-1.14 (m, 2H), 1.52 (m, 1H), 1.60-1.65 (m, 2H), 2.57 (t, 2H), 2.65-2.75 (m, 4H), 3.20-3.27 (m, 4H), 3.33 (m, 2H), 3.58-3.63 (m, 2H), 4.47 (s, 1H), 7.09 (d, 1H), 7.18 (d, 1H)

[0236] compound 64 2-(5-chlorothiophene-2-yl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 64 was synthesized in 48% yield after chromatographic purification by the method used to prepare compound 3 using INT-42 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.61 (t, 2H), 2.74 (t, 2H), 2.86 (t, 2H), 3.33 (m, 2H), 3.41 (t, 2H), 3.48 (t, 2H), 4.31 (s, 2H), 6.87 (d, 1H), 7.10 (d, 1H), 7.18 (d, 1H), 7.32 (d, 1H)

[0237] compound 65 2-(5-chloropyridin-2-yl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 65 was synthesized in 44% yield by the method used to prepare compound 3 using INT-46 and piperidin-4-ylmethanol (150 mol%) as starting materials with THF as solvent and stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.06 (m, 2H), 1.53 (m, 1H), 1.64 (d, 2H), 2.63 (t, 2H), 2.74 (m, 4H), 3.19-3.27 (m, 4H),3.38 (t, 2H), 3.62 (d, 2H), 4.47 (t, 1H), 7.56 (d, 1H), 8.06 (dd,1H), 8.72 (d, 1H)

[0238] compound 66 2-(5-Chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 66 was synthesized in 55% yield by the method used to prepare compound 3 using INT-46 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, HCl (150 mol%) as starting materials with THF as solvent and stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.68 (t, 2H), 2.78 (t, 2H), 2.86 (t, 2H), 3.28 (t, 2H), 3.44 (t, 2H), 3.49 (t, 2H), 4.32 (s, 2H), 6.88 (d, 1H), 7.33 (d, 1H), 7.57 (d, 1H), 8.06 (dd, 1H), 8.73 (d, 1H)

[0239] compound 67 2-(5-Chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 67 was synthesized in 38% yield by the method used to prepare compound 3 using INT-46 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (150 mol%) as starting materials with THF as solvent and stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.66 (t, 2H), 2.72 (t, 2H), 2.77 (t, 2H), 3.26 (t, 2H), 3.44 (m, 4H), 4.25 (s, 2H), 7.28-7.49 (m, 1H), 7.57 (d, 1H), 8.06 (dd, 1H), 8.73 (d, 1H), 12.48 (s, 1H)

[0240] compound 68 2-(5-Chloropyridin-2-yl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 68 was synthesized in 57% yield by the method used to prepare compound 3 using INT-46 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials with THF as solvent and stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.68 (t, 2H), 2.78 (t, 2H), 3.30 (t, 2H), 3.47 (t, 2H),3.56 (t, 2H), 4.09 (t, 2H), 4.43 (s, 2H), 6.72 (s, 1H), 7.57 (m, 2H), 8.06 (dd, 1H), 8.73 (d, 1H)

[0241] compound 69 4-((4-chlorophenyl)(cyano)methylene)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide [ka] Compound 69 was synthesized in 17% yield after chromatographic purification using INT-8 and methyl-(tetrahydro-pyran-4-yl)-amine as starting materials by the method used to prepare compound 3, with a reaction time of 6 hours. 1 H-NMR (400 MHz, CDCl 3): 1.60-1.70 (m, 2H), 1.78-1.90 (m, 2H), 2.48 (t, 2H), 2.79 (s, 3H), 2.81 (t, 2H), 3.22 (t, 2H), 3.40 (t, 2H), 3.46 (t, 2H), 3.93 (m, 1H), 4.01-4.06 (m, 2H), 7.21-7.25 (m, 2H), 7.37-7.41 (m, 2H)

[0242] compound 70 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-3-yl)acetonitrile [ka] INT-70i: To a solution of 2-(1H-indazol-3-yl)acetonitrile (250 mg, 100 mol%) in MeCN (6.3 mL) was added di-tert-butyl dicarbonate (417 mg, 120 mol%) and DMAP (3.9 mg, 2 mol%) and the reaction was stirred for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue which was dissolved in water (20 mL) and extracted with EtOAc (3×30 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (30 mL), brine (30 mL), dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (0-25% EtOAc in hexanes) to give tert-butyl 3-(cyanomethyl)-1H-indazole-1-carboxylate (400 mg, 98%) as a yellow oil. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 8.17 (d, 1H), 7.86 (dt, 1H), 7.59 (ddd, 1H), 7.40 (ddd, 1H), 4.12 (s, 2H), 1.73 (s, 9H). m / z (ES+) 202.1 (Mt-Bu+H)

[0243] INT-70ii: Prepared following general procedure A to afford tert-butyl-4-[cyano(1H-indazol-3-yl)methylidene]piperidine-1-carboxylate in 58% yield as an off-white solid. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm 7.99 (dq, 1H), 7.65 - 7.50 (m, 2H), 3.77 (t, 2H), 3.60 (s, 1H), 2.98 (t, 2H), 2.89 - 2.77 (m, 2H), 1.58 (s, 9H). m / z (ES+) 239.2 (M-Boc+H) +

[0244] INT-70iii: Prepared according to general method B to afford 2-(1H-indazol-3-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride in 62% yield as a pale yellow solid. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 13.65 (s, 1H), 9.38 (s, 2H), 7.82 (dt, 1H), 7.63 (dd, 1H), 7.44 (ddd, 1H), 7.25 (ddd, 1H), 3.42 - 3.28 (m, 2H), 3.21 - 3.10 (m, 2H), 3.03 (t, 2H), 2.91 (t, 2H). m / z (ES+) 239.2 (M+H) +

[0245] Compound 70 was synthesized in 20% yield as an off-white powder by the method used to prepare compound 41 using INT-70iii and INT-64 as starting materials. 1 H-NMR (400 MHz, CDCl 3) δ ppm 10.26 (s, 1H), 7.89 (d, 1H), 7.56 - 7.50 (m, 1H), 7.50 - 7.41 (m, 1H), 7.30 - 7.22 (m, 1H), 3.99 - 3.83 (m, 1H), 3.66 - 3.56 (m, 2H), 3.51 (t, 2H), 3.33 (t, 2H), 3.02 (ddd, 2H), 2.96 - 2.89 (m, 2H), 2.78 (t, 2H), 1.96 - 1.88 (m, 2H), 1.66 - 1.39 (m, 3H). m / z (ES+) 366.2 (M+H) +

[0246] compound 71 2-(1H-indazol-7-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 71 was synthesized in 9% yield by the method used to prepare compound 3 using a mixture of non-methylated and methylated INT-61 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (150 mol%) as starting materials, using THF as solvent and stirring at +50° C. for 3 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.43 (t, 2H), 2.85 and 2.86 (2 xt, 4H), 3.28 (t, 2H), 3.51 (t, 2H), 3.57 (t, 2H), 4.36 (s, 2H), 7.22 (t, 1H), 7.29 (d, 1H), 7.37 (s, 1H), 7.81 (d, 1H), 8.14 (s, 1H), 10.51 (br s, 1H), 11.55 (br s, 1H)

[0247] compound 72 2-(1H-indazol-7-yl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 72 was synthesized in 9% yield by the method used to prepare compound 3 using a mixture of methylated and non-methylated INT-61 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (150 mol%) as starting materials by stirring for 3 hours at +50°C. 1 H-NMR (400 MHz, CDCl 3 ): 2.45 (t, 2H), 2.88 (t, 2H), 3.29 (t, 2H), 3.51 (t, 2H), 3.68 (t, 2H), 4.12 (t, 2H), 4.54 (s, 2H), 6.85 (s, 1H), 7.22 (t, 1H), 7.28 (m, 1H), 7.51 (s, 1H), 7.82 (d, 1H), 8.15 (s, 1H), 11.68 (br s, 1H)

[0248] compound 73 2-(2,4-Difluorophenyl)-2-(1-(4-(methoxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 73 was synthesized in 88% yield by the method used to prepare compound 3 using INT-18 and 4-(methoxymethyl)piperidine (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.06-1.16 (m, 2H), 1.25 (m, 1H), 1.62 (d, 2H), 1.69 (br s, 1H), 2.23 (t, 2H), 2.69-2.75 (m, 4H), 3.17 (d, 4H), 3.18 (s, 3H), 3.36 (m, 1H), 3.61 (d, 2H), 7.22 (t, 1H), 7.40-7.51 (m, 2H)

[0249] compound 74 2-(4-Chlorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 74 was synthesized in 84% yield by the method used to prepare compound 3 using INT-8 and piperidin-4-ylmethanol as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.03-1.11 (m, 2H), 1.52 (m, 1H), 1.60-1.66 (m, 2H), 2.39 (t, 2H), 2.68-2.75 (m, 4H), 3.17 (t, 2H), 3.25 (t, 2H), 3.33 (m, 2H), 3.59-3.63 (m, 2H), 4.47 (s, 1H), 7.37-7.40 (m, 2H), 7.52-7.55 (m, 2H)

[0250] compound 75 2-(5-chlorothiophene-2-yl)-2-(1-(4-(methoxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 75 was synthesized by the method used to prepare compound 3 using INT-42 and 4-(methoxymethyl)piperidine as starting materials with a reaction time of 3 hours in 71% yield after chromatographic purification.1 H-NMR (400 MHz, DMSO-d 6 ): 1.05-1.17 (m, 2H), 1.59-1.65 (m, 2H), 1.70 (m, 1H), 2.57 (t, 2H), 2.65-2.76 (m, 4H), 3.16-3.19 (m, 2H), 3.20-3.25 (m, 2H), 3.23 (s, 3H), 3.33 (m, 2H), 3.57-3.63 (m, 2H), 7.09 (d, 1H), 7.18 (d, 1H)

[0251] compound 76 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 76 was synthesized in 94% yield by the method used to prepare compound 3 using INT-38 and piperidin-4-ylmethanol (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.08 (m, 2H), 1.24 (s, 1H), 1.52 (br s 1H), 1.63 (d, 2H), 2.41 (s, 2H), 2.72 (m, 4H), 3.19 (m, 2H), 3.25 (m, 2H)), 3.36 (m, 1H), 3.62 (d, 2H), 4.47 (s, 1H), 7.61 (d, 2H), 7.84 (d, 2H)

[0252] compound 77 1-(4-((5-chlorothiophen-2-yl)(cyano)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide [ka] Compound 77 was synthesized by the method used to prepare compound 3 using INT-42 and piperidine-4-sulfonamide as starting materials with a reaction time of 4 hours in 51% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.55 (m, 2H), 1.98 (m, 2H), 2.59 (m, 2H), 2.71 (m, 2H), 2.81 (m, 2H), 3.02 (m, 1H), 3.26 (m, 2H), 3.33 (m, 2H), 3.70 (m, 2H), 6.76 (br s, 2H), 7.09 (d, 1H), 7.18 (d, 1H)

[0253] compound 78 2-(5-chlorothiophene-2-yl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 78 was synthesized in 85% yield by the method used to prepare compound 3 using INT-42 and 4-methoxypiperidine (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.38 (m, 2H), 1.82 (m, 2H), 2.57 (m, 2H), 2.69 (m, 2H), 2.93 (t, 2H), 3.25 (m, 5H), 3.30-3.42 (m, 5H), 7.09 (d, 1H), 7.18 (d, 1H)

[0254] compound 79 2-(4-Chlorophenyl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 79 was synthesized in 85% yield by the method used to prepare compound 3 using INT-8 and 4-methoxypiperidine (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.38 (m, 2H), 1.82 (m, 2H), 2.39 (m, 2H), 2.69 (m, 2H), 2.92 (t, 2H), 3.18 (m, 2H), 3.24 (s, 3H), 3.35-3.42 (m, 5H), 7.39 (d, 2H), 7.54 (d, 2H)

[0255] compound 80 2-(3-chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 80 was synthesized as a colorless foam in 63% yield by the method used to prepare compound 41 using INT-28 and INT-64 as starting materials. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm 7.53 - 7.47 (m, 2H), 7.43 (s, 1H), 7.36 - 7.30 (m, 1H), 3.65 - 3.58 (m, 1H), 3.48 - 3.38 (m, 2H), 3.34 (t, 2H), 3.18 (t, m / z (ES+) 360.2 / 362.2 (M+H) +

[0256] compound 81 2-(5-chloropyridin-2-yl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 82 was synthesized in 86% yield by the method used to prepare compound 3 using INT-46 and 4-methoxypiperidine (150 mol%) as starting materials with stirring at room temperature for 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.38 (m, 2H), 1.82 (m, 2H), 2.64 (m, 2H), 2.74 (m, 2H), 2.93 (t, 2H), 3.22 (m, 2H), 3.25 (s, 3H), 3.30-3.42 (m, 5H), 7.56 (d, 1H), 8.05 (d, 1H), 8.72 (s, 1H)

[0257] compound 82 (S)-2-(4-chlorophenyl)-2-(1-(2-(methoxymethyl)pyrrolidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 82 was synthesized in 77% yield as an oil by the method used to prepare compound 3 using INT-8 and (S)-(+)-2-(methoxymethyl)pyrrolidine (150 mol%) as starting materials by stirring at room temperature for 1.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.61 (m, 2H), 1.82 (m, 1H), 1.98 (m, 1H), 2.32 (m, 1H), 2.44 (m, 1H), 2.62 (m, 1H), 2.76 (m, 1H), 3.17 (t, 2H), 3.24 (s, 3H), 3.41 (m, 6H), 4.06 (br s, 1H), 7.39 (d, 2H), 7.54 (d, 2H)

[0258] compound 83 2-(5-fluoropyridin-2-yl)-2-(1-(morpholine-4-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 83 was synthesized in 86% yield by the method used to prepare compound 1 using INT-48 and 4-morpholinecarbonyl chloride (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.83 (m, 4H), 3.30 (t, 4H), 3.35 (t, 2H), 3.49 (t, 2H), 3.70 (t, 4H), 7.46-7.53 (m, 2H), 8.49 (d, 1H)

[0259] compound 84 2-(5-fluoropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 84 was synthesized in 68% yield by the method used to prepare compound 3 using INT-50 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine×HCl (150 mol%) as starting materials with stirring at room temperature for 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.64 (m, 2H), 2.77 (m, 2H), 2.87 (m, 2H), 3.29 (m, 2H), 3.46 (m, 4H), 4.31 (s, 2H), 7.61 (s, 1H), 7.86 (s, 1H), 8.68 (s, 2H)

[0260] compound 85 2-(4-Fluorophenyl)-2-(1-(3-(hydroxymethyl)azetidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 85 was synthesized in 62% yield by the method used to prepare compound 3 using INT-4 and azetidin-3-ylmethanol, HCl (150 mol%) as starting materials with stirring at room temperature for 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.34 (t, 2H), 2.59 (m, 1H), 2.65 (t, 2H), 3.25 (t, 2H), 3.42 (t, 2H), 3.49 (t, 2H), 3.64 (t, 2H), 3.90 (t, 2H), 4.75 (t, 1H), 7.31 (dd, 2H), 7.40 (dd, 2H)

[0261] compound 86 2-(5-chloropyridin-3-yl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 86 was prepared from tert-butyl 4-oxopiperidine-1-carboxylate and 2-(5-chloropyridin-3-yl)acetonitrile in 38% yield by general method A, followed by the dihydrochloride intermediate as an off-white powder in 77% yield by general method B. Finally, compound 86 was synthesized in 62% yield as a cream solid by the method used to prepare compound 41 using 2-(5-chloropyridin-3-yl)-2-(piperidin-4-ylidene)acetonitrile dihydrochloride and INT-64 as starting materials. 1 H-NMR (400 MHz, CDCl 3) δ ppm 8.58 (d, 1H), 8.40 (d, 1H), 7.65 (t, 1H), 3.98 - 3.82 (m, 1H), 3.60 (dt, 2H), 3.45 (t, 2H), 3.28 (t, 2H), 3.03 (ddd, 2H), 2.84 (t, 2H), 2.48 (t, 2H), 1.90 (dt, 2H), 1.58 - 1.44 (m, 3H). m / z (ES+) 361.2 / 363.2 (M+H) +

[0262] compound 87 2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 87 was synthesized in 93% yield by the method used to prepare compound 3 using INT-38 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine, HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.44 (t, 2H), 2.76 (t, 2H), 2.87 (t, 2H), 3.27 (t, 2H), 3.46 (m, 4H), 4.31 (s, 2H), 7.61 (d, 2H), 7.85 (d, 2H), 8.68 (s, 1H)

[0263] compound 88 2-(3-chlorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 88 was synthesized in 64% yield by the method used to prepare compound 3 using INT-30 and piperidin-4-ylmethanol as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02-1.10 (m, 2H), 1.51 (m, 1H), 1.60-1.65 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.18 (t, 2H), 3.24 (t, 2H), 3.30-3.40 (m, 2H), 3.58-3.63 (m, 2H), 4.46 (s, 1H), 7.33 (m, 1H), 7.44 (m, 1H), 7.46-7.54 (m, 2H)

[0264] compound 89 2-(3-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 89 was synthesized in 74% yield by the method used to prepare compound 3 using INT-30 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine×HCl as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.42 (t, 2H), 2.73 (t, 2H), 2.87 (t, 2H), 3.26 (t, 2H), 3.40-3.50 (m, 4H), 4.31 (s, 2H), 7.34 (m, 1H), 7.45 (m, 1H), 7.48-7.52 (m, 2H), 8.68 (s, 1H)

[0265] compound 90 2-(4-Chlorophenyl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 90 was synthesized in 82% yield by the method used to prepare compound 3 using INT-8 and 4-(trifluoromethyl)piperidine as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33-1.46 (m, 2H), 1.75-1.80 (m, 2H), 2.39 (t, 2H), 2.50-2.55 (m, 1H), 2.70 (t, 2H), 2.73-2.83 (m, 2H), 3.20 (t, 2H), 3.37 (t, 2H), 3.60-3.70 (m, 2H), 7.37-7.41 (m, 2H), 7.52-7.56 (m, 2H)

[0266] compound 91 2-(2,4-difluorophenyl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 91 was synthesized in 63% yield by the method used to prepare compound 3 using INT-18 and 4-methoxypiperidine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33-1.42 (m, 2H), 1.75-1.85 (m, 2H), 2.23 (t, 2H), 2.71 (t, 2H), 2.88-3.00 (m, 2H), 3.17 (t, 2H), 3.24 (t, 3H), 3.25-3.45 (m, 5H), 7.18-7.25 (m, 1H), 7.38-7.52 (m, 2H)

[0267] compound 92 2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile [ka] Compound 92 was synthesized using INT-55 and 4-ethoxypiperidine as starting materials with a reaction time of 4 hours by the method used to prepare compound 3. The product was purified by chromatography, followed by removal of acetate in 2N HCl in methanol at room temperature with a reaction time of 6 hours. The overall yield was 50%. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.30-1.42 (m, 2H), 1.75-1.85 (m, 2H), 2.29 (t, 2H), 2.78 (t, 2H), 2.85-2.95 (m, 2H), 3.15 (t, 2H), 3.35-3.50 (m, 7H), 7.08 (d, 1H), 7.39-7.45 (m, 1H), 7.61 (d, 1H), 8.08 (s, 1H), 13.35 (br s, 1H)

[0268] compound 93 2-(1-Acetyl-1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 93 was synthesized by the method used to prepare compound 3 using INT-55 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine×HCl as starting materials with a reaction time of 7 hours in 46% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6): 2.29 (t, 2H), 2.75 (s, 3H), 2.80-2.90 (m, 4H), 3.22 (t, 2H), 3.46 (t, 2H), 3.51 (t, 2H), 4.31 (s, 2H), 7.41 (d, 1H), 7.69-7.75 (m, 1H), 8.38 (d, 1H), 8.53 (s, 1H), 8.68 (s, 1H)

[0269] compound 94 2-(5-Fluoro-1H-indazol-3-yl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] INT-94i: To a mixture of INT-63 (120 mg, 100 mol%), 1-[5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl]ethan-1-one (133 mg, 120 mol%) and cesium carbonate (238 mg, 200 mol%) in 1,4-dioxane (1.4 mL) and water (0.2 mL) was added [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6 mg, 0.025 mol%) and nitrogen was bubbled through the mixture for 2 min. The reaction mixture was heated at 60° C. under nitrogen for 18 h and then cooled. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried (sodium sulfate) and concentrated under reduced pressure to give 2-(1-acetyl-5-fluoro-1H-indazol-3-yl)-2-[1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene]acetonitrile as a brown gum which was used without purification. m / z (ES+) 426.3 (M+H). +

[0270] Compound 94 was prepared from INT-94i by adding 1M NaOH solution (0.40 mL, 0.40 mmol) and stirring the mixture at 20° C. for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (sodium sulfate), concentrated under reduced pressure and purified by column chromatography (1-10% MeOH in DCM) to give a light brown solid in 14% yield. 1 H-NMR (400 MHz, CD 3 OD + 10% CDCl 3 ) δ ppm 7.57 (dd, 1H), 7.44 (dd, 1H), 7.25 (td, 1H), 3.83 - 3.72 (m, 1H), 3.68 - 3.57 (m, 1H), 3.52 (t, 2H), 3.38 - 3.32 (m, 2H), 3.02 (ddd, 2H), 2.91 (t, 2H), 2.70 (t, 2H), 1.91 - 1.80 (m, 2H), 1.56 - 1.41 (m, 2H). 19 F NMR (376 MHz, CD 3 OD + 10% CDCl 3 ) δ ppm -122.86. m / z (ES+) 382.2, (M+H) +

[0271] compound 95 2-(3-chlorophenyl)-2-(1-(4-(3-hydroxypropyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 95 was synthesized in 73% yield by the method used to prepare compound 3 using INT-28 and 4-piperidinepropanol (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.05 (m, 2H), 1.22 (m, 2H), 1.42 (m, 3H), 1.63 (m, 2H), 2.35 (s, 3H), 2.70 (m, 4H), 3.18 (m, 2H), 3.30 (m, 3H), 3.59 (m, 2H), 4.37 (s, 1H), 7.33 (br s, 1H), 7.44 (s, 1H), 7.50 (m, 2H)

[0272] compound 96 2-(1-(4-acetylpiperazine-1-carbonyl)piperidin-4-ylidene)-2-(3-chlorophenyl)acetonitrile [ka] Compound 96 was synthesized in 67% yield by the method used to prepare compound 3 using INT-28 and 1-acetylpiperazine (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.01 (s, 3H), 2.40 (m, 2H), 2.71 (m, 2H), 3.13 (m, 2H), 3.19 (m, 2H), 3.24 (m, 2H), 3.44 (m, 6H), 7.34 (m, 1H), 7.45 (s, 1H), 7.50 (m, 2H)

[0273] compound 97 2-(4-Fluorophenyl)-2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 97 was synthesized by the method used to prepare compound 3 using INT-4 and 4-piperidineethanol as starting materials with a reaction time of 4 hours in 61% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6): 1.00-1.12 (m, 2H), 1.32-1.40 (m, 2H), 1.50-1.59 (m, 1H), 1.59-1.65 (m, 2H), 2.37 (t, 2H), 2.65-2.75 (m, 4H), 3.17 (t, 2H), 3.30-3.37 (m, 2H), 3.40-3.49 (m, 2H), 3.55-3.62 (m, 2H), 4.36 (t, 1H), 7.28-7.34 (m, 2H), 7.37-7.43 (m, 2H)

[0274] compound 98 2-(4-Fluorophenyl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 98 was synthesized in 74% yield by the method used to prepare compound 3 using INT-4 and 4-(trifluoromethyl)piperidine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.33-1.47 (m, 2H), 1.75-1.82 (m, 2H), 2.39 (t, 2H), 2.45-2.55 (m, 1H), 2.70 (t, 2H), 2.79 (t, 2H), 3.21 (t, 2H), 3.30-3.40 (m, 2H), 3.62-3.70 (m, 2H), 7.28-7.34 (m, 2H), 7.39-7.45 (m, 2H)

[0275] compound 99 1-(4-((3-chlorophenyl)(cyano)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide [ka] Compound 99 was synthesized in 64% yield by the method used to prepare compound 3 using INT-28 and 4-piperidinesulfonamide HCl (150 mol%) as starting materials with stirring at room temperature for 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.53 (m, 2H), 1.97 (m, 2H), 2.40 (m, 2H), 2.70 (t, 2H), 2.81 (t, 2H), 3.02 (t, 1H), 3.21 (t, 2H), 3.37 (m, 2H), 3.70 (m, 2H), 6.76 (s, 2H), 7.33 (m, 1H), 7.44 (s, 1H), 7.50 (m, 2H)

[0276] compound 100 2-(4-Fluorophenyl)-2-(1-(thiomorpholine-4-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 100 was synthesized by the method used to prepare compound 3 using INT-4 and thiomorpholine as starting materials in 48% yield with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.38 (m, 2H), 2.40-2.60 (m, 6H), 2.69 (m, 2H), 3.19 (m, 2H), 3.41 (s, 4H), 7.31 (m, 2H), 7.41 (m, 2H)

[0277] Compound 101 2-(4-Fluorophenyl)-2-(1-(octahydrocyclopenta[c]pyrrole-2-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 101 was synthesized in 70% yield by the method used to prepare compound 3 using INT-4 and octahydrocyclopenta[c]pyrrole as starting materials with a reaction time of 1 hour. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.37 (t, 2H), 1.52 (m, 1H), 1.62-1.73 (m, 3H), 2.37 (m, 2H), 2.54 (m, 2H), 2.68 (m, 2H), 3.05 (d, 2H), 3.21 (m, 2H), 3.38 (m, 2H), 3.47 (t, 2H), 7.30 (t, 2H), 7.41 (t, 2H)

[0278] Compound 102 2-(4-Fluorophenyl)-2-(1-(indoline-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 102 was synthesized in 17% yield using INT-4 and indoline as starting materials with an overnight reaction time by the method used to prepare compound 3. Purified as an oil by heptane trituration. 1 H-NMR (400 MHz, CDCl 3 ): 2.53 (t, 2H), 2.86 (t, 2H), 3.05 (t, 2H), 3.40 (t, 2H), 3.57 (t, 2H), 3.95 (t, 2H), 6.92 (t, 1H), 7.01 (d, 1H), 7.11 (m, 3H), 7.19 (d, 1H), 7.29 (m, 2H)

[0279] Compound 103 4-((5-chlorothiophen-2-yl)(cyano)methylene)-N-methyl-N-(oxetan-3-yl)piperidine-1-carboxamide [ka] Compound 103 was synthesized in 94% yield by the method used to prepare compound 3 using INT-42 and N-methyl-3-oxetanamine as starting materials with a reaction time of 4.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.59 (t, 2H), 2.71 (t, 2H), 2.80 (s, 3H), 3.26 (t, 2H), 3.38 (t, 2H), 4.50-4.65 (m, 5H), 7.11 (d, 1H), 7.19 (d, 1H)

[0280] Compound 104 2-(4-Chlorophenyl)-2-(1-(piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 104 was synthesized in 59% yield by the method used to prepare compound 3 using INT-8 and piperidine as starting materials with a reaction time of 1.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.40-1.60 (m, 6H), 2.39 (m, 2H), 2.69 (m, 2H), 3.10-3.20 (m, 6H), 3.30-3.40 (m, 2H), 7.38 (d, 2H), 7.53 (d, 2H)

[0281] Compound 105 4-((4-chlorophenyl)(cyano)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 105 was synthesized in 81% yield by the method used to prepare compound 3 using INT-8 and diethylamine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.05 (t, 6H), 2.40 (t, 2H), 2.70 (t, 2H), 3.10-3.17 (m, 6H), 3.28-3.30 (m, 2H), 7.39 (d, 2H), 7.54 (d, 2H)

[0282] compound 106 2-(4-Fluorophenyl)-2-(1-(4-(methoxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 106 was synthesized in 58% yield by the method used to prepare compound 3 using INT-4 and 4-(methoxymethyl)piperidine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.05-1.18 (m, 2H), 1.58-1.68 (m, 2H), 1.69-1.75 (m, 1H), 2.37 (t, 2H), 2.65-2.76 (m, 4H), 3.17 (m, 4H), 3.22 (s, 3H), 3.30-3.40 (m, 2H), 3.56-3.63 (m, 2H), 7.30 (m, 2H), 7.41 (m, 2H)

[0283] compound 107 2-(4-Fluorophenyl)-2-(1-(4-hydroxyazepane-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 107 was synthesized in 71% yield by the method used to prepare compound 3 using INT-4 and azepan-4-ol as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.40-1.58 (m, 2H), 1.60-1.72 (m, 2H), 1.75-1.90 (m, 2H), 2.39 (t, 2H), 2.70 (t, 2H), 3.08-3.17 (m, 3H), 3.20-3.30 (m, 3H), 3.30-3.35 (m, 2H), 3.63 (m, 1H), 4.50 (d, 1H), 7.30 (m, 2H), 7.40 (m, 2H)

[0284] compound 108 2-(4-Fluorophenyl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 108 was synthesized in 87% yield using INT-4 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (150 mol%) as starting materials with a reaction time of 90 min by the method used to prepare compound 3. The crude product was purified by trituration with heptane:methanol (v / v 1:1) to give a white solid. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (t, 2H), 2.72 (t, 2H), 2.85 (m, 2H), 3.24 (t, 2H), 3.41 (t, 2H), 3.48 (t, 2H), 4.31 (s, 2H), 6.86 (d, 1H), 7.28-7.34 (m, 3H), 7.41 (m, 2H)

[0285] Compound 109 2-(1-(5-fluoroindoline-1-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 109 was synthesized in 9% yield after chromatographic purification using INT-4 and 5-fluoroindoline (300 mol%) as starting materials by the method used to prepare compound 3 in THF at 50-66 °C for 6 h and then at room temperature overnight. 1 H-NMR (400 MHz, CDCl 3 ): 2.53 (t, 2H), 2.86 (t, 2H), 3.04 (t, 2H), 3.38 (t, 2H), 3.56 (t, 2H), 3.97 (t, 2H), 6.83 (m, 1H), 6.90 (m, 1H), 6.95-7.01 (m, 1H), 7.11 (m, 2H), 7.25-7.30 (m, 2H)

[0286] compound 110 (R)-2-(4-fluorophenyl)-2-(1-(2-methylpiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 110 was synthesized in 6% yield by the method used to prepare compound 3 using INT-4 and (R)-2-methylpiperidine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, CDCl 3 ): 1.19 / 1.20 (2 xs, isom, 3H), 1.40-1.53 ​​(m, 2H), 1.61-1.73 (m, 5H), 2.46 (m, 2H), 2.80 (m, 2H), 2.98-3.05 (m, 1H), 3.21 (m, 2H), 3.39 (m, 2H), 4.03 (m, 1H), 7.07-7.14 (m, 2H), 7.24-7.30 (m, 2H)

[0287] Compound 111 2-(1-((1R,4R)-2-azabicyclo[2.2.1]heptane-2-carbonyl)piperidin-4-ylidene)-2-(2,4-difluorophenyl)acetonitrile [ka] Compound 111 was synthesized in 46% yield by the method used to prepare compound 3 using INT-18 and 2-azabicyclo[2.2.1]heptane as starting materials with a reaction time of 2.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.30-1.35 (m, 2H), 1.44-1.48 (m, 1H), 1.58 (m, 2H), 1.69-1.74 (m, 1H), 2.14-2.30 (m, 2H), 2.60-2.78 (m, 2H), 2.83 (m, 1H), 3.10-3.30 (m, 2H), 3.31-3.46 (m, 4H), 4.00 (s, 1H), 7.22 (m, 1H), 7.40-7.52 (m, 2H)

[0288] compound 112 2-(2,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 112 was synthesized in 78% yield by the method used to prepare compound 3 using INT-18 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine×HCl as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.27 (t, 2H), 2.75 (t, 2H), 2.85 (m, 2H), 3.10-3.50 (m, 6H), 4.31 (s, 2H), 6.87 (m, 1H), 7.23 (m, 1H), 7.32 (m, 1H), 7.47 (m, 2H)

[0289] compound 113 2-(4-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 113 was synthesized in 68% yield after chromatographic purification by the method used to prepare compound 3 using INT-8 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials with a reaction time of 3.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (t, 2H), 2.70-2.74 (m, 4H), 3.23 (t, 2H), 3.34-3.50 (m, 4H), 4.24 (s, 2H), 7.37-7.41 (m, 3H), 7.54 (d, 2H), 12.48 (br s, 1H)

[0290] compound 114 2-(1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 114 was synthesized in 19% yield after chromatographic purification using INT-26 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as starting materials by the method used to prepare compound 3 in THF at 50° C. for a reaction time of 6.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.33 (m, 2H), 2.80-2.87 (m, 4H), 3.21 (t, 2H), 3.48 (m, 4H), 4.31 (s, 2H), 6.87 (d, 1H), 7.08 (d, 1H), 7.32 (d, 1H), 7.43 (m, 1H), 7.62 (d, 1H), 8.09 (s, 1H), 13.35 (s, 1H)

[0291] compound 115 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 115 was synthesized in 24% yield by the method used to prepare compound 41 using INT-32 and INT-64 as starting materials. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.36 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 3.93 - 3.82 (m, 1H), 3.65 - 3.55 (m, 2H), 3.44 (t, J=5.8 Hz, 2H), 3.26 (t, J=5.8 Hz, 2H), 3.02 (ddd, J=13.1, 9.5, 3.2 Hz, 2H), 2.85 - 2.77 (m, 2H), 2.51 - 2.44 (m, 2H), 1.96 - 1.85 (m, 2H), 1.56 - 1.47 (m, 2H). 19 F NMR (376 MHz, CDCl 3 ) δ ppm -57.82

[0292] compound 116 2-(3,5-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 116 was synthesized by the method used to prepare compound 3 using INT-22 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials with a reaction time of 5 hours in 75% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6): 2.43 (t, 2H), 2.72 (m, 4H), 3.25 (t, 2H), 3.35- 3.50 (m, 4H), 4.25 (s, 2H), 7.14-7.19 (m, 2H), 7.35 (m, 1H), 7.26 / 7.47 (br m, 1H, isomer), 12.48 (s, 1H)

[0293] compound 117 2-(1-(4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 117 was synthesized in 80% yield by the method used to prepare compound 3 using INT-34 and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine×HCl as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.75 (t, 2H), 2.86 (t, 2H), 3.25 (t, 2H), 3.43 (m, 2H), 3.48 (m, 2H), 4.31 (s, 2H), 6.87 (m, 1H), 7.32 (m, 1H), 7.44-7.55 (m, 4H)

[0294] compound 118 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(1-methyl-1H-indazol-7-yl)acetonitrile [ka] Compound 118 was synthesized in 17% yield after chromatographic purification using INT-61 and piperidin-4-ylmethanol as starting materials by the method used to prepare compound 3 in THF at +50° C. for 1 hour reaction time. 1H-NMR (400 MHz, CDCl 3 ): 1.20-1.30 (m, 2H), 1.63-1.80 (m, 3H), 2.38 (t, 2H), 2.81 (m, 2H), 2.90 (m, 2H), 3.28 (t, 2H), 3.48-3.55 (m, 4H), 3.72-3.79 (m, 2H), 4.24 (s, 3H), 7.09 (m, 1H), 7.18 (d, 1H), 7.68 (d, 1H), 7.95 (s, 1H)

[0295] Compound 119 2-(1-Methyl-1H-indazol-7-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 119 was synthesized in 15% yield after chromatographic purification using INT-61 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials by the method used for the preparation of compound 3 in THF at +50° C. for a reaction time of 3 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.41 (t, 2H), 2.87 (t, 2H), 2.93 (t, 2H), 3.33 (t, 2H), 3.52-3.60 (m, 4H), 4.24 (s, 3H), 4.37 (s, 2H), 7.07-7.13 (m, 1H), 7.19 (d, 1H), 7.37 (s, 1H), 7.68 (d, 1H), 7.96 (s, 1H)

[0296] compound 120 2-(5-chlorothiophene-2-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 120 was synthesized in 39% yield by the method used to prepare compound 3 using INT-42 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.60 (t, 2H), 2.72 (m, 4H), 3.28 (t, 2H), 3.35-3.49 (m, 4H), 4.26 (s, 2H), 7.09 (d, 1H), 7.18 (d, 1H), 7.26 / 7.48 (br m, 1H, isomer), 12.48 (s, 1H)

[0297] compound 121 2-(5-Chlorothiophen-2-yl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 121 was synthesized in 47% yield by the method used to prepare compound 3 using INT-42 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine as starting materials with a reaction time of 5.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.61 (t, 2H), 2.74 (t, 2H), 3.25-3.40 (m, 2H), 3.43 (t, 2H), 3.55 (t, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.71 (s, 1H), 7.09 (d, 1H), 7.19 (d, 1H), 7.57 (s, 1H)

[0298] compound 122 2-(2,4-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 122 was synthesized by the method used to prepare compound 3 using INT-18 and 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as starting materials with a reaction time of 4 hours in 66% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.27 (t, 2H), 2.73 (m, 4H), 3.23 (t, 2H), 3.35-3.50 (m, 4H), 4.25 (s, 2H), 7.18-7.25 (m, 1H), 7.39-7.53 (m, 2H), 7.20-7.53 (m, 1H, isomer), 12.47 (s, 1H)

[0299] compound 123 2-(2,4-Difluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 123 was synthesized in 58% yield by the method used to prepare compound 3 using INT-18 and 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.28 (t, 2H), 2.75 (t, 2H), 3.26 (t, 2H), 3.44 (t, 2H), 3.55 (t, 2H), 4.08 (t, 2H), 4.42 (s, 2H), 6.71 (s, 1H), 7.23 (m, 1H), 7.40-7.55 (m, 2H), 7.57 (s, 1H)

[0300] compound 124 2-(1-(4-(1-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 124 was synthesized in 49% yield by the method used to prepare compound 3 using INT-34 and 1-(piperidin-4-yl)ethan-1-ol as starting materials with a reaction time of 2.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02 (d, 3H), 1.05-1.22 (m, 2H), 1.31 (m, 1H), 1.50-1.53 ​​(m, 1H), 1.72-1.75 (m, 1H), 2.39 (t, 2H), 2.60-2.75 (m, 4H), 3.18 (t, 2H), 3.28-3.40 (m, 3H), 3.60-3.66 (m, 2H), 4.39 (d, 1H), 7.44-7.53 (m, 4H)

[0301] compound 125 2-(5-chlorothiophene-2-yl)-2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 125 was synthesized in 64% yield by the method used to prepare compound 3 using INT-42 and 4-ethoxypiperidine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.30-1.40 (m, 2H), 1.75-1.85 (m, 2H), 2.57 (t, 2H), 2.69 (t, 2H), 2.91 (t, 2H), 3.23 (m, 2H), 3.30-3.40 (m, 2H), 3.41-3.50 (m, 5H), 7.09 (m, 1H), 7.18 (m, 1H)

[0302] compound 126 1-(4-((4-chlorophenyl)(cyano)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide [ka] Compound 126 was synthesized by the method used to prepare compound 3 using INT-8 and 4-piperidinesulfonamide as starting materials with a reaction time of 5.5 hours in 52% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.50-1.60 (m, 2H), 1.96 (m, 2H), 2.40 (t, 2H), 2.70 (t, 2H), 2.81 (m, 2H), 3.02 (m, 1H), 3.20 (m, 2H), 3.37 (m, 2H), 3.65-3.72 (m, 2H), 6.76 (s, 2H), 7.39 (d, 2H), 7.54 (d, 2H)

[0303] compound 127 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 127 was synthesized in 62% yield by the method used to prepare compound 41 using INT-36 and INT-64 as starting materials. 1 H NMR (400 MHz, CDCl 3) δ ppm 7.68 (d, J=7.7 Hz, 2H), 7.44 - 7.39 (m, 2H), 3.91 - 3.85 (m, 1H), 3.63 - 3.56 (m, 2H), 3.45 (t, J=5.8 Hz, 2H), 3.26 (t, J=5.8 19F NMR (376 MHz, CDCl3) δ -62.83. m / z (ES+) 394.2 (M+H) +

[0304] compound 128 2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 128 was synthesized in 89% yield by the method used to prepare compound 3 using INT-38 and 4-ethoxypiperidine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.34-1.40 (m, 2H), 1.75-1.85 (m, 2H), 2.41 (t, 2H), 2.72 (t, 2H), 2.91 (m, 2H), 3.19 (m, 2H), 3.30-3.50 (m, 7H), 7.61 (d, 2H), 7.84 (d, 2H)

[0305] compound 129 2-(3-chlorophenyl)-2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 129 was synthesized in 53% yield by the method used to prepare compound 3 using INT-30 and 4-ethoxypiperidine (150 mol%) as starting materials with a reaction time of 3.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.33-1.45 (m, 2H), 1.76-1.85 (m, 2H), 2.39 (t, 2H), 2.69 (t, 2H), 2.91 (t, 2H), 3.19 (t, 2H), 3.35 (m, 2H), 3.40-3.50 (m, 5H), 7.33 (m, 1H), 7.44 (s, 1H), 7.50 (m, 2H)

[0306] compound 130 2-(1-(4-acetylpiperazine-1-carbonyl)piperidin-4-ylidene)-2-(4-chlorophenyl)acetonitrile [ka] Compound 130 was synthesized in 93% yield by the method used to prepare compound 3 using INT-8 and 1-acetylpiperazine (150 mol%) as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.01 (s, 3H), 2.40 (t, 2H), 2.70 (t, 2H), 3.13 (m, 2H), 3.15-3.25 (m, 4H), 3.35-3.45 (m, 6H), 7.39 (d, 2H), 7.54 (d, 2H)

[0307] compound 131 2-(4-Chlorophenyl)-2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 131 was synthesized in 83% yield by the method used to prepare compound 3 using INT-8 and 4-piperidineethanol as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.00-1.10 (m, 2H), 1.35 (m, 2H), 1.54 (m, 1H), 1.60-1.65 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.17 (t, 2H), 3.30-3.40 (m, 2H), 3.43 (t, 2H), 3.53-3.62 (m, 2H), 4.36 (s, 1H), 7.39 (d, 2H), 7.53 (d, 2H)

[0308] compound 132 2-(4-Chlorophenyl)-2-(1-(4-(3-hydroxypropyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 132 was synthesized in 75% yield by the method used to prepare compound 3 using INT-8 and 4-piperidinepropanol as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.00-1.10 (m, 2H), 1.20 (m, 2H), 1.30-1.45 (m, 3H), 1.60-1.65 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.17 (t, 2H), 3.30-3.40 (m, 4H), 3.55-3.63 (m, 2H), 4.35 (m, 1H), 7.39 (d, 2H), 7.53 (d, 2H)

[0309] compound 133 2-(4-Chlorophenyl)-2-(1-(4-isopropoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 133 was synthesized in 98% yield by the method used to prepare compound 3 using INT-8 and 4-isopropoxypiperidine as starting materials with a reaction time of 6 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.05-1.08 (m, 6H), 1.30-1.38 (m, 2H), 1.70-1.80 (m, 2H), 2.38 (t, 2H), 2.68 (t, 2H), 2.85-2.95 (m, 2H), 3.18 (m, 2H), 3.30-3.37 (m, 2H), 3.38-3.45 (m, 2H), 3.52 (m, 1H), 3.69 (m, 1H), 7.39 (d, 2H), 7.53 (d, 2H)

[0310] compound 134 2-(4-Chlorophenyl)-2-(1-(4-propoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 134 was synthesized in 70% yield by the method used to prepare compound 3 using INT-8 and 4-propoxypiperidine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 0.87 (t, 3H), 1.36-1.44 (m, 2H), 1.45-1.54 (m, 2H), 1.75-1.85 (m, 2H), 2.39 (t, 2H), 2.70 (t, 2H), 2.93 (t, 2H), 3.19 (m, 2H), 3.30-3.39 (m, 4H), 3.39-3.45 (m, 3H), 7.39 (d, 2H), 7.54 (d, 2H)

[0311] compound 135 2-(5-chloropyridin-2-yl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 135 was synthesized in quantitative yield by the method used to prepare compound 3 using INT-46 and 4-(trifluoromethyl)piperidine (150 mol%) as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.35-1.46 (m, 2H), 1.75-1.82 (m, 2H), 2.64 (t, 2H), 2.70-2.85 (m, 4H), 3.24 (t, 2H), 3.30-3.35 (m, 1H), 3.40 (t, 2H), 3.63-3.71 (m, 2H), 7.56 (d, 1H), 8.05 (dd, 1H), 8.72 (d, 1H)

[0312] compound 136 2-(1-Methyl-1H-indazol-7-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 136 was synthesized in 12% yield by the method used to prepare compound 3 using INT-61 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (150 mol%) as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, CDCl 3): 2.41 (t, 2H), 2.90-3.00 (m, 4H), 3.34 (t, 2H), 3.50-3.60 (m, 4H), 4.24 (s, 3H), 4.38 (s, 2H), 7.10 (m, 1H), 7.19 (d, 1H), 7.69 (d, 1H), 7.96 (s, 1H), 8.21 (s, 1H)

[0313] compound 137 2-(2,4-difluorophenyl)-2-(1-(4-ethoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 137 was synthesized in 85% yield by the method used to prepare compound 3 using INT-18 and 4-ethoxypiperidine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.10 (t, 3H), 1.30-1.40 (m, 2H), 1.75-1.85 (m, 2H), 2.23 (t, 2H), 2.70 (t, 2H), 2.91 (m, 2H), 3.17 (t, 2H), 3.35-3-50 (m, 7H), 7.21 (m, 1H), 7.39-7.53 (m, 2H)

[0314] compound 138 2-(1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 138 was synthesized in 87% yield from compound 93 by acetate removal at room temperature with 2N HCl in methanol and overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6): 2.33 (t, 2H), 2.80-2.90 (m, 4H), 3.22 (t, 2H), 3.40-3.52 (m, 4H), 4.30 (s, 2H), 7.08 (d, 1H), 7.43 (m, 1H), 7.62 (d, 1H), 8.09 (s, 1H), 8.67 (s, 1H), 13.35 (br s, 1H)

[0315] compound 139 2-(3-chlorophenyl)-2-(1-(4-isopropoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 139 was synthesized in 96% yield by the method used to prepare compound 3 using INT-30 and 4-isopropoxypiperidine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.07 (d, 6H), 1.30-1.40 (m, 2H), 1.71-1.80 (m, 2H), 2.39 (t, 2H), 2.69 (t, 2H), 2.85-2.97 (m, 2H), 3.19 (t, 2H), 3.30-3.45 (m, 4H), 3.52 (m, 1H), 3.69 (m, 1H), 7.33 (m, 1H), 7.44 (s, 1H), 7.49 (m, 2H)

[0316] compound 140 2-(3-chlorophenyl)-2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 140 was synthesized in 93% yield by the method used to prepare compound 3 using INT-30 and 4-piperidineethanol as starting materials with a reaction time of 2 hours. 1H-NMR (400 MHz, DMSO-d 6 ): 1.00-1.12 (m, 2H), 1.30-1.40 (m, 2H), 1.50-1.58 (m, 1H), 1.60-1.66 (m, 2H), 2.39 (t, 2H), 2.65-2.75 (m, 4H), 3.18 (t, 2H), 3.30-3.40 (m, 2H), 3.40-3.47 (m, 2H), 3.55-3.65 (m, 2H), 4.36 (s, 1H), 7.33 (m, 1H), 7.44 (s, 1H), 7.47-7.54 (m, 2H)

[0317] compound 141 2-(4-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 141 was synthesized in 82% yield by the method used to prepare compound 3 using INT-8 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.42 (t, 2H), 2.73 (t, 2H), 2.86 (t, 2H), 3.25 (t, 2H), 3.40-3.50 (m, 4H), 4.30 (s, 2H), 7.39 (d, 2H), 7.54 (d, 2H), 8.68 (s, 1H)

[0318] compound 142 2-(4-Fluorophenyl)-2-(1-(4-(3-hydroxypropyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 142 was synthesized in 78% yield by the method used to prepare compound 3 using INT-4 and 4-piperidinepropanol as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 0.98-1.10 (m, 2H), 1.22 (m, 2H), 1.30-1.50 (m, 3H), 1.60-1.66 (m, 2H), 2.38 (t, 2H), 2.65-2.75 (m, 4H), 3.17 (t, 2H), 3.30-3.40 (m, 4H), 3.55-3.65 (m, 2H), 4.37 (s, 1H), 7.30 (m, 2H), 7.41 (m, 2H)

[0319] compound 143 2-(1-(4-acetylpiperazine-1-carbonyl)piperidin-4-ylidene)-2-(4-fluorophenyl)acetonitrile [ka] Compound 143 was synthesized in 91% yield by the method used to prepare compound 3 using INT-4 and 1-acetylpiperazine as starting materials with a reaction time of 4.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.01 (s, 3H), 2.39 (t, 2H), 2.70 (t, 2H), 3.13 (t, 2H), 3.15-3.25 (m, 4H), 3.35-3.50 (m, 6H), 7.31 (m, 2H), 7.42 (m, 2H)

[0320] compound 144 2-(1H-indazol-4-yl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 144 was synthesized as a by-product by the method used to prepare compound 3, using INT-55 and 4-methoxypiperidine as starting materials with a reaction time of 6 hours. After chromatographic purification, the yield was 43%. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.37 (m, 2H), 1.81 (m, 2H), 2.29 (t, 2H), 2.78 (t, 2H), 2.85-2.98 (m, 2H), 3.14 (m, 2H), 3.24 (s, 3H), 3.30-3.45 (m, 5H), 7.08 (m, 1H), 7.43 (m, 1H), 7.61 (m, 1H), 8.08 (s, 1H), 13.34 (br s, 1H)

[0321] compound 145 2-(1H-indazol-4-yl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 145 was synthesized using INT-55 and 4-(trifluoromethyl)piperidine as starting materials with a reaction time of 6 hours by the method used to prepare compound 3. The product was obtained in 36% yield by acetate removal at room temperature with a reaction time of 6 hours using 2N HCl in methanol. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.32-1.46 (m, 2H), 1.75-1.80 (m, 2H), 2.30 (t, 2H), 2.75-2.85 (m, 4H), 3.17 (t, 2H), 3.30-3.35 (m, 1H), 3.44 (t, 2H), 3.63-3.69 (m, 2H), 7.08 (d, 1H), 7.39-7.45 (m, 1H), 7.62 (d, 1H), 8.08 (s, 1H), 13.35 (br s, 1H)

[0322] compound 146 2-(1-(4-Methoxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 146 was synthesized in 84% yield by the method used to prepare compound 3 using INT-38 and 4-methoxypiperidine as starting materials with a reaction time of 1.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.35-1.45 (m, 2H), 1.75-1.90 (m, 2H), 2.41 (t, 2H), 2.73 (t, 2H), 2.93 (m, 2H), 3.19 (m, 2H), 3.24 (s, 3H), 3.30-3.45 (m, 5H), 7.61 (d, 2H), 7.84 (d, 2H)

[0323] compound 147 2-(1-(morpholine-4-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 147 was synthesized in 95% yield by the method used to prepare compound 1 using INT-36 and 4-morpholinecarbonyl chloride as starting materials with a reaction time of 1.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.41 (t, 2H), 2.73 (t, 2H), 3.10-3.20 (m, 4H), 3.22 (t, 2H), 3.41 (t, 2H), 3.57 (m, 4H), 7.61 (d, 2H), 7.84 (d, 2H)

[0324] compound 148 1-(4-(cyano(4-(trifluoromethyl)phenyl)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide [ka] Compound 148 was synthesized in 65% yield by the method used to prepare compound 3 using INT-38 and 4-piperidinesulfonamide as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.48-1.62 (m, 2H), 1.94-2.00 (m, 2H), 2.42 (t, 2H), 2.74 (t, 2H), 2.82 (m, 2H), 3.02 (m, 1H), 3.21 (t, 2H), 3.39 (t, 2H), 3.67-3.72 (m, 2H), 6.77 (s, 2H), 7.61 (d, 2H), 7.84 (d, 2H)

[0325] compound 149 2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 149 was synthesized in 87% yield by the method used to prepare compound 3 using INT-38 and 4-piperidineethanol as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.00-1.14 (m, 2H), 1.30-1.40 (m, 2H), 1.50-1.59 (m, 1H), 1.60-1.65 (m, 2H), 2.41 (t, 2H), 2.65-2.80 (m, 4H), 3.18 (m, 2H), 3.30-3.38 (m, 2H), 3.40-3.48 (m, 2H), 3.55-3.65 (m, 2H), 4.36 (t, 1H), 7.61 (d, 2H), 7.84 (d, 2H)

[0326] compound 150 2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 150 was synthesized by the method used to prepare compound 3 using INT-38 and 4,5,6,7-tetrahydro-1,2,3-triazolo[1,5-a]pyrazine as starting materials in 53% yield after chromatographic purification with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.45 (t, 2H), 2.77 (t, 2H), 3.25-3.40 (m, 2H), 3.49 (t, 2H), 3.69 (t, 2H), 4.43 (M, 2H), 4.54 (s, 2H), 7.58-7.65 (m, 3H), 7.85 (d, 2H)

[0327] Compound 151 2-(1-(4-(1-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 151 was synthesized in 69% yield by the method used to prepare compound 3 using INT-38 and 1-(piperidin-4-yl)ethan-1-ol as starting materials with a reaction time of 1.5 hours. 1 H-NMR (400 MHz, DMSO-d 6): 1.02 (d, 3H), 1.05-1.35 (m, 2H), 1.50-1.55 (m, 1H), 1.70-1.78 (m, 1H), 2.41 (t, 2H), 2.60-2.80 (m, 4H), 3.19 (m, 2H), 3.30-3.40 (m, 4H), 3.60-3.68 (m, 2H), 4.39 (d, 1H), 7.61 (d, 2H), 7.84 (d, 2H)

[0328] compound 152 2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethyl)phenyl)acetonitrile [ka] Compound 152 was synthesized in 66% yield by the method used to prepare compound 3 using INT-38 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.46 (m, 2H), 2.77 (m, 2H), 3.30-3.36 (m, 2H), 3.50 (m, 2H), 3.71 (m, 2H), 4.21 (m, 2H), 4.50 (s, 2H), 7.62 (d, 2H), 7.85 (d, 2H), 7.96 (s, 1H)

[0329] compound 153 2-(3-chlorophenyl)-2-(1-(4-(methoxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 153 was synthesized in 91% yield by the method used to prepare compound 3 using INT-30 and 4-(methoxymethyl)piperidine as starting materials with a reaction time of 6 hours.1 H-NMR (400 MHz, DMSO-d 6 ): 1.05-1.16 (m, 2H), 1.58-1.65 (m, 2H), 1.65-1.75 (m, 1H), 2.38 (t, 2H), 2.69 (t, 2H), 2.69-2.76 (m, 2H), 3.15-3.20 (m, 4H), 3.22 (s, 3H), 3.30-3.40 (m, 2H), 3.56-3.64 (m, 2H), 7.33 (m, 1H), 7.44 (s, 1H), 7.48-7.52 (m, 2H)

[0330] compound 154 2-(3-chlorophenyl)-2-(1-(4-(1-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 154 was synthesized in quantitative yield by the method used to prepare compound 3 using INT-30 and 1-(piperidin-4-yl)ethan-1-ol as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.02 (d, 3H), 1.06-1.24 (m, 2H), 1.25-1.37 (m, 1H), 1.50-1.55 (m, 1H), 1.70-1.78 (m, 1H), 2.39 (t, 2H), 2.60-2.75 (m, 4H), 3.18 (t, 2H), 3.30-3.40 (m, 3H), 3.60-3.68 (m, 2H), 4.39 (d, 1H), 7.33 (m, 1H), 7.44 (s, 1H), 7.48-7.52 (m, 2H)

[0331] compound 155 2-(3-Chlorophenyl)-2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 155 was synthesized in 57% yield after chromatographic purification by the method used to prepare compound 3 using INT-30 and 4,5,6,7-tetrahydro-1,2,3-triazolo[1,5-a]pyrazine as starting materials with a reaction time of 4 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.74 (t, 2H), 3.25-3.35 (m, 2H), 3.47 (t, 2H), 3.67 (t, 2H), 4.43 (t, 2H), 4.53 (s, 2H), 7.34 (m, 1H), 7.45 (s, 1H), 7.48-7.53 (m, 2H), 7.60 (s, 1H)

[0332] compound 156 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(3-chlorophenyl)acetonitrile [ka] Compound 156 was synthesized in 55% yield after chromatographic purification by the method used to prepare compound 3 using INT-30 and 3-oxa-8-azabicyclo[3.2.1]octane as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.70-1.85 (m, 4H), 2.40 (t, 2H), 2.70 (t, 2H), 3.30-3.40 (m, 2H), 3.45-3.55 (m, 4H), 3.58-3.65 (m, 2H), 3.84 (m, 2H), 7.34 (m, 1H), 7.45 (s, 1H), 7.51 (m, 2H)

[0333] compound 157 2-(3-Chlorophenyl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 157 was synthesized by the method used to prepare compound 3 using INT-30 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with a reaction time of 6 hours in 53% yield after chromatographic purification. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.44 (t, 2H), 2.74 (t, 2H), 3.28-3.35 (m, 2H), 3.48 (t, 2H), 3.70 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 7.34 (m, 1H), 7.45 (s, 1H), 7.49-7.53 (m, 2H), 7.95 (s, 1H)

[0334] compound 158 2-(3,5-Difluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 158 was synthesized in 67% yield after chromatographic purification by the method used to prepare compound 3 using INT-22 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.73 (t, 2H), 2.87 (t, 2H), 3.27 (t, 2H), 3.35-3.50 (m, 4H), 4.31 (s, 2H), 7.14-7.19 (m, 2H), 7.35 (m, 1H), 8.68 (s, 1H)

[0335] Compound 159 2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 159 was synthesized in 63% yield by the method used to prepare compound 3 using INT-34 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.43 (t, 2H), 2.75 (t, 2H), 2.87 (t, 2H), 3.27 (t, 2H), 3.35-3.50 (m, 4H), 4.31 (s, 2H), 7.44-7.54 (m, 4H), 8.68 (s, 1H)

[0336] compound 160 2-(5-Chlorothiophene-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 160 was synthesized in 67% yield by the method used to prepare compound 3 using INT-42 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 2 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.61 (t, 2H), 2.73 (t, 2H), 2.87 (t, 2H), 3.31 (m, 2H), 3.35-3.50 (m, 4H), 4.31 (s, 2H), 7.10 (d, 1H), 7.19 (d, 1H), 8.68 (s, 1H)

[0337] compound 161 2-(5-Chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 161 was synthesized in 20% yield by the method used to prepare compound 3 using INT-46 and 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.85-2.93 (m, 4H), 2.99 (t, 2H), 3.39 (t, 2H), 3.50-3.60 (m, 4H), 4.39 (s, 2H), 7.47 (d, 1H), 7.75 (dd, 1H), 8.22 (s, 1H), 8.58 (d, 1H)

[0338] compound 162 2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 162 was synthesized in 63% yield by the method used to prepare compound 3 using INT-34 and 4,5,6,7-tetrahydro-1,2,3-triazolo[1,5-a]pyrazine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.44 (t, 2H), 2.75 (t, 2H), 3.30 (t, 2H), 3.48 (t, 2H), 3.68 (t, 2H), 4.43 (t, 2H), 4.53 (s, 2H), 7.44-7.55 (m, 4H), 7.60 (s, 1H)

[0339] compound 163 2-(5-Chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 163 was synthesized in 20% yield by the method used to prepare compound 3 using INT-46 and 4,5,6,7-tetrahydro-1,2,3-triazolo[1,5-a]pyrazine as starting materials with a reaction time of 3 hours. 1 H-NMR (400 MHz, CDCl 3 ): 2.85-2.96 (m, 4H), 3.42 (t, 2H), 3.57 (t, 2H), 3.76 (t, 2H), 4.53 (t, 2H), 4.62 (s, 2H), 7.48 (d, 1H), 7.55 (s, 1H), 7.76 (dd, 1H), 8.59 (d, 1H)

[0340] compound 164 2-(4-Chlorophenyl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 164 was synthesized in 60% yield by the method used to prepare compound 3 using INT-8 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6): 2.44 (t, 2H), 2.74 (t, 2H), 3.28-3.35 (m, 2H), 3.48 (t, 2H), 3.70 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 7.40 (d, 2H), 7.55 (d, 2H), 7.95 (m, 1H)

[0341] compound 165 2-(5-Chloropyridin-2-yl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 165 was synthesized in 25% yield after chromatographic purification by the method used to prepare compound 3 using INT-46 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with a reaction time of 5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.69 (t, 2H), 2.79 (t, 2H), 3.28-3.35 (m, 2H), 3.51 (t, 2H), 3.71 (t, 2H), 4.21 (t, 2H), 4.51 (s, 2H), 7.57 (d, 1H), 7.96 (s, 1H), 8.06 (dd,1H), 8.73 (d, 1H)

[0342] compound 166 2-(3,5-Difluorophenyl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 166 was synthesized in 26% yield after chromatographic purification by the method used to prepare compound 3 using INT-22 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with a reaction time of 6.5 hours. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.45 (t, 2H), 2.74 (t, 2H), 3.28-3.40 (m, 2H), 3.48 (t, 2H), 3.70 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 7.10-7.20 (m, 2H), 7.30-7.40 (m, 1H), 7.96 (s, 1H)

[0343] compound 167 2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)-2-(4-(trifluoromethoxy)phenyl)acetonitrile [ka] Compound 167 was synthesized in 60% yield by the method used to prepare compound 3 using INT-34 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.44 (t, 2H), 2.75 (t, 2H), 3.28-3.35 (m, 2H), 3.49 (t, 2H), 3.70 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 7.44-7.54 (m, 4H), 7.96 (s, 1H)

[0344] compound 168 2-(5-Chlorothiophene-2-yl)-2-(1-(5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile [ka] Compound 168 was synthesized in 54% yield by the method used to prepare compound 3 using INT-42 and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.63 (t, 2H), 2.75 (t, 2H), 3.28-3.35 (m, 2H), 3.47 (t, 2H), 3.70 (t, 2H), 4.21 (t, 2H), 4.50 (s, 2H), 7.10 (d, 1H), 7.19 (d, 1H), 7.96 (s, 1H)

[0345] compound 169 4-((4-chlorophenyl)(cyano)methylene)-N-methyl-N-(oxetan-3-yl)piperidine-1-carboxamide [ka] Compound 169 was synthesized in 90% yield by the method used to prepare compound 3 using INT-8 and N-methyl-3-oxetanamine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 2.40 (t, 2H), 2.71 (t, 2H), 2.80 (s, 3H), 3.21 (t, 2H), 3.39 (t, 2H), 4.48-4.65 (m, 5H), 7.39 (d, 2H), 7.54 (d, 2H)

[0346] compound 170 4-(cyano(4-(trifluoromethoxy)phenyl)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 170 was synthesized in 56% yield by the method used to prepare compound 3 using INT-34 and diethylamine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.06 (t, 6H), 2.40 (t, 2H), 2.71 (t, 2H), 3.10-3.17 (m, 6H), 3.30-3.35 (m, 2H), 7.44-7.53 (m, 4H)

[0347] Compound 171 4-(cyano(4-(trifluoromethyl)phenyl)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 171 was synthesized in 47% yield by the method used to prepare compound 3 using INT-38 and diethylamine as starting materials with an overnight reaction time. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.06 (t, 6H), 2.42 (t, 2H), 2.73 (t, 2H), 3.10-3.18 (m, 6H), 3.30-3.36 (m, 2H), 7.61 (d, 2H), 7.84 (d, 2H)

[0348] compound 172 4-(Cyano(5-fluoropyridin-2-yl)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 172 was synthesized in 25% yield by the method used to prepare compound 3 using INT-50 and diethylamine as starting materials by stirring at room temperature overnight. 1 H-NMR (400 MHz, DMSO-d 6): 1.06 (t, 6H), 2.60 (m, 2H), 2.74 (m, 2H), 3.08-3.20 (m, 6H), 3.29-3.36 (m, 2H), 7.61 (m, 1H), 7.86 (m, 1H), 8.67 (m, 1H)

[0349] compound 173 4-((5-chlorothiophen-2-yl)(cyano)methylene)-N,N-diethylpiperidine-1-carboxamide [ka] Compound 173 was synthesized in 54% yield by the method used to prepare compound 3 using INT-42 and diethylamine as starting materials by stirring overnight at room temperature. 1 H-NMR (400 MHz, DMSO-d 6 ): 1.06 (t, 6H), 2.58 (t, 2H), 2.70 (t, 2H), 3.09-3.17 (m, 4H), 3.19 (t, 2H), 3.29-3.33 (m, 2H), 7.09 (d, 1H), 7.18 (d, 1H)

[0350] Pharmacological testing The following test is provided to illustrate the present invention and should not be construed as limiting the scope of the present invention. Furthermore, the concentrations of compounds in the assay are examples and should not be construed as limiting. Those skilled in the art can define pharmacologic relevant concentrations by methods known in the art.

[0351] Inhibition of the AKR1C3 (17β-hydroxysteroid dehydrogenase type 5) enzyme Recombinant human AKR1C3 (17β-HSD5) protein (GenBank Accession No. NM_003739.6) produced in Escherichia coli was used for screening. The recombinant protein (27 nM / 1 μg / ml) was incubated with 20 mM KH 2 PO 4, 1 mM EDTA, Complete Protease Inhibitor Cocktail, pH 7.4, in the presence of 500 nM concentrations of potential inhibitors, 1 μM 9-acetyl-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one and 1 mM NADPH for 60-120 min at RT. Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO was adjusted to 1% in all samples. Samples were analyzed by fluorescence measurements using a Tecan Spark microplate reader at an excitation wavelength of 420 nm and an emission wavelength of 510 nm. Samples were evaluated against standards of 9-(1-hydroxyethyl)-2,3,6,7-tetrahydro-1H,5H,11H-pyrano[2,3-f]pyrido[3,2,1-ij]quinolin-11-one at concentrations ranging from 1 μM to 10 nM. Background fluorescence was subtracted from all samples and standards. The concentration of product formed was calculated from the standard curve using Tecan Spark Magellan software. The concentration of product formed was used to calculate the percentage of conversion. The percentage of inhibition of the samples was calculated from the percentage of conversion.

[0352] The percentage of inhibition for the samples was calculated using the following formula:

number

[0353] Inhibition of 17β-hydroxysteroid dehydrogenase type 2 enzyme Recombinant human 17β-HSD2 protein (GenBank Accession No. NM_002153.3) produced in Sf-9 insect cells using baculovirus was used for screening. The recombinant protein (105 nM / 4.5 μg / ml) was incubated in 20 mM KH 2 PO 4 In the presence of 10 μM concentrations of potential inhibitors, 56.25 nM testosterone ( 3H-labeled testosterone) for 30 min at RT. Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO was adjusted to 1% in all samples. The enzyme reaction was stopped by the addition of 10% trichloroacetic acid (final concentration 1%). Samples were filtered through a 0.22 μm filtration plate. Analysis of the samples was performed on a Waters Acquity UPLC H-class equipped with an XBridge C18 column and an XBridge VanGuard C18 guard column. Acetonitrile:0.1% aqueous formic acid (42 / 58 v / v) with a flow rate of 1.2 ml / min was used as the mobile phase. The eluent was mixed with scintillant and radioactivity was monitored in the eluent by a Scintillation Analyser. The conversion percentage of retylated substrate (testosterone) to product tritylated (androstenedione) for each sample was determined by the relative percentages of substrate and product in the chromatograms. The percentage of inhibition for the samples was calculated using the following formula:

number

[0354] Inhibition of aldo-keto reductase family 1 member C2 Recombinant human aldo-keto reductase family 1 member C2 (AKR1C2) protein (GenBank Accession No. NM_001354.6) produced in Sf-9 insect cells using baculovirus was used for screening. The recombinant protein (13.6 nM / 0.5 μg / ml) was incubated in 20 mM KH 2 PO 4 pH 7.4, 1 mM EDTA, Complete Protease Inhibitor Tablets, 1 mM NADPH, 6.25 nM 3H-labeled dihydrotestosterone was incubated for 45 min at +37°C in the presence of potential inhibitors at a concentration of 10 μM. Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO was adjusted to 1% in all samples. The enzymatic reaction was stopped by the addition of 10% trichloroacetic acid (final concentration 1%). Samples were filtered through 0.22 μm filtration plates (Merck). Analysis of the samples was performed on a Waters Acquity UPLC H-class equipped with an XBridge C18 column and an XBridge VanGuard C18 guard column. Acetonitrile:0.1% aqueous formic acid (42 / 58 v / v) with a flow rate of 1.2 ml / min was used as the mobile phase. The eluent was mixed with scintillant and radioactivity was monitored in the eluent by a Scintillation Analyser. The percentage of conversion of the tritylated substrate (dihydrotestosterone) to the tritylated product (5α-androstane-3α,17β-diol) for each sample was determined by the relative percentages of substrate and product in the chromatogram. The percentage of inhibition for the sample was calculated using the following formula:

number

[0355] Pharmacological test results [Table 5] [Table 6] [Table 7] [Table 8] [Table 9]

[0356] It is obvious to a person skilled in the art that as technology advances, the concept of the present invention can be implemented in various ways. The present invention and its embodiments are not limited to the above examples but may vary within the scope of the claims.

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, R １ is C １－６ -Alkyl, C １－６ -Haloalkyl, C １－６ -perhaloalkyl, (CH ２ ) ｍ OR', (CH ２ ) ｍ N(R') ２ , 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which is optionally independently selected from the group consisting of R １１ Substituted with 1 to 6 substituents selected from: R ２ is C １－６ -Alkyl, C １－６ -Haloalkyl, C １－６ -perhaloalkyl, (CH ２ ) ｍ OR', (CH ２ ) ｍ N(R') ２ , 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which is optionally independently selected from the group consisting of R １２ Substituted with 1 to 6 substituents selected from: or R １ and R ２ form, together with the ring nitrogen atom to which they are attached, a 4- to 11-membered unsaturated or aromatic heterocycle or a 4- to 10-membered saturated or partially unsaturated heterocycle, and the heterocycles may each optionally be independently selected from R １３ Substituted with 1 to 6 substituents selected from: R ３ are groups selected from the group consisting of 6- to 13-membered aryl, 5- to 11-membered heteroaryl, 3- to 12-membered cycloalkyl, and 3- to 10-membered heterocyclyl, each of which is optionally independently R ３１ Substituted with 1 to 6 substituents selected from: R １１ is halogen, CN, C １－６ -Alkyl, C １－６ -Alkoxy, C １－６ -(per)haloalkyl, C １－６ -(per)haloalkoxy, OR', oxo, (OCH ２ ) ｎ OR', SR', NO ２ , N(R') ２ , (CH ２ ) ｎ N(R') ２ , (CH ２ ) ｎ OR', CH(XR')R', CO ２ R', C(O)N(R') ２ , C(O)NR'C(O)R", NR'COR", C(=NH)R", C(=N-OR')R", C(O)R", NR'C(O)NR", NR'SO ２ R”, ​​SO ２ N.H.S.O. ２ R" and SO ２ N(R') ２ R', OR', N(R') ２ and is substituted with one or more substituents independently selected from the group consisting of: R １２ is halogen, CN, C １－６ -Alkyl, C １－６ -Alkoxy, C １－６ -(per)haloalkyl, C １－６ -(per)haloalkoxy, OR', oxo, (OCH ２ ) ｎ OR', SR', NO ２ , N(R') ２ , (CH ２ ) ｎ N(R') ２ , (CH ２ ) ｎ OR', CH(XR')R', CO ２ R', C(O)N(R') ２ , NHCOR", C(=NH)R", C(=N-OR')R", C(O)R" and SO ２ N(R') ２ R', OR', N(R') ２ and is substituted with one or more substituents independently selected from the group consisting of: R １３ is halogen, CN, C １－６ -Alkyl, C １－６ -Alkoxy, C １－６ -(per)haloalkyl, C １－６ -(per)haloalkoxy, OR', oxo, (OCH ２ ) ｎ OR', SR', NO ２ , N(R') ２ , (CH ２ ) ｎ N(R') ２ , (CH ２ ) ｎ OR', CH(XR')R', CO ２ R', C(O)N(R') ２ , C(O)NR'C(O)R", NR'C(O)R", C(=NH)R", C(=N-OR')R", C(O)R", NR'C(O)NR", NR'SO ２ R”, ​​SO ２ N.H.S.O. ２ R" and SO ２ N(R') ２ R', OR', N(R') ２ and is substituted with one or more substituents independently selected from the group consisting of: R ３１ is halogen, CN, C １－６ -Alkyl, C １－６ -Alkoxy, C １－６ -(per)haloalkyl, C １－６ -(per)haloalkoxy, OR', oxo, (OCH ２ ) ｎ OR', SR', NO ２ , N(R') ２ , (CH ２ ) ｎ N(R') ２ , (CH ２ ) ｎ OR', CO ２ R', C(O)N(R') ２ , C(O)NR'C(O)R", NR'C(O)R", C(=NH)R", C(=N-OR'H)R", C(O)R", NR'C(O)NR", NR'SO ２ R”, ​​SO ２ N.H.S.O. ２ R" and SO ２ N(R') ２ R', OR', N(R') ２ and is substituted with one or more substituents independently selected from the group consisting of: Each R' is independently H, C １－６ -Alkyl, C １－６ -Haloalkyl and C １－６ -perhaloalkyl or any N(R') ２ when R is part of, both R together with the nitrogen to which they are attached can each independently form a 3-6 membered aliphatic or aromatic heterocyclic ring containing 1-4 heteroatoms selected from N, S and O; Each R" is independently C １－６ -Alkyl, C １－６ -Haloalkyl and C １－６ - perhaloalkyl; X is O or S; m is 0 to 6; and n is 1 to 6. or a salt, solvate or solvate of the salt thereof.

2. R ３ is a 6-membered aryl and a 5- to 9-membered heteroaryl, each of which contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and each of which is optionally independently R ３１ Substituted with 1 to 3 substituents selected from: R ３１ is as defined in claim 1; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

3. R １ C １－６ - a group selected from the group consisting of alkyl, 5- to 9-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally independently R １１ and R ２ C １－６ - a group selected from the group consisting of alkyl, 5- to 9-membered heteroaryl, and 5- to 7-membered heterocyclyl, each of which is optionally independently R １２ Substituted with 1 to 3 substituents selected from: R １１ and R １２ is as defined in claim 1; 2. The compound according to claim 1, or a salt, solvate or solvate of the salt thereof.

4. R １ and R ２ together with the ring nitrogen atom to which they are attached form a 5- to 9-membered aromatic heterocycle or a 4- to 9-membered saturated heterocycle, wherein the heterocycle optionally contains 1 to 4 additional heteroatoms, each independently selected from the group consisting of N, O and S, and the heterocycle optionally contains 1 to 4 additional heteroatoms, each independently selected from the group consisting of R １３ Substituted with 1 to 4 substituents selected from: R １３ is as defined in claim 1; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

5. R ３ are groups selected from the group consisting of phenyl, pyridinyl, thienyl, and 1H-indazolyl, each of which is optionally independently R ３１ and is substituted with 1 or 2 substituents selected from R ３１ is as defined in claim 1; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

6. R ３１ is halogen, C １－３ -Alkyl, C １－３ -(per)haloalkyl, C １－３ -(per)haloalkoxy and C(O)C １－６ - selected from alkyl; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

7. R １ is a group selected from methyl, ethyl and tetrahydropyranyl; R ２ is a group selected from methyl, ethyl and tetrahydropyranyl; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

8. R １ and R ２ together with the ring nitrogen atom to which they are attached, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, indolinyl, isoindolinyl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridinyl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridinyl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5- a]pyrazinyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, azetidinyl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridinyl, 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridinyl, 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[ forming an aromatic or saturated heterocycle selected from 1,5-a]pyrazinyl, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazinyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl, 2-azabicyclo[2.2.1]heptanyl, 6,7-dihydro-4H-thieno[3,2-c]pyridinyl, thiomorpholinyl, octahydrocyclopenta[c]pyrrolyl, N-methyl-N-(oxetan-3-yl), 4-hydroxyazepanyl, 5-fluoroindolinyl, 2-methylpiperidinyl, 4-isopropoxypiperidinyl, 4-propoxypiperidinyl and 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, wherein the heterocycle optionally each independently represents R １３ and is substituted with 1 or 2 substituents selected from R １３ is as defined in claim 1; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

9. R １３ CN, C １－３ -(per)haloalkyl, OR', (CH ２ ) ｎ OR', CH(OH)C １－６ -Alkyl, C(O)R″ and SO ２ N(R') ２ Selected from: Each R' is independently H and C １－６ - alkyl; Each R" is independently C １－６ - alkyl; n is 1 to 3; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

10. The compound has formula (Ia) 【Chemistry 2】 [During the ceremony, Y is N or C-R ４ where R ４ is H or F; R ５ is H, Cl or F; or Y is C-R ４ and R ４ and R ５ together with the carbon atoms to which they are attached form a 5-membered aromatic heterocycle; R ６ is F, Cl or H; or Y is N or C-R ４ where R ４ is H or F; R ５ and R ６ together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; and R １ and R ２ is as defined in claim 1.

2. The compound of claim 1 , which has the formula:

11. R １ and R ２ together with the ring nitrogen atom to which they are attached, represent piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, indolin-1-yl, isoindolin-2-yl, 4,5-dihydro-7H-isoxazolo[3,4-c]pyridin-6-yl, 6,7-dihydro-4H-isoxazolo[4,3-c]pyridin-5-yl, 6,7-dihydro-4H-[1,2,3]triazolo[1,5-a]pyrazin-5-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, azetidin-1-yl, 1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl, 1,4,6,7-tetrahydropyrazolo forming an aromatic or saturated heterocycle selected from the group consisting of 5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazin-7-yl, 5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl, 2,3-dihydropyrrolo[2,3-b]pyridin-1-yl, 2-azabicyclo[2.2.1]heptan-2-yl, 6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl and 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, wherein the heterocycles are each optionally independently selected from R １３ and is substituted with 1 or 2 substituents selected from R １３ CN, C １－３ -(per)haloalkyl, OR', (CH ２ ) ｎ OR', CH(OH)C １－６ -Alkyl, C(O)R″ and SO ２ N(R') ２ Selected from: Each R' is independently H and C １－６ - alkyl; Each R" is independently C １－６ - selected from alkyl; 2. A compound according to claim 1, or a salt, solvate or solvate of a salt thereof.

12. The compound has formula (Ib) or (Ic) 【Chemistry 3】 [During the ceremony, D is C or N; E is N, NH or CH; F is O or N; Y is N or C-R ４ where R ４ is H or F; R ５ is H, Cl or F; or Y is C-R ４ and R ４ and R ５ together with the carbon atoms to which they are attached form a 5-membered aromatic heterocycle; R ６ is F, Cl or H; or Y is N or C-R ４ where R ４ is H or F; R ５ and R ６ together with the carbon atoms to which they are attached form a five-membered aromatic heterocycle; and R ７ is OH or CH ２ OH.

2. The compound of claim 1 , which has the formula:

13. 10. A compound of claim 1 or a salt, solvate or solvate of a salt thereof, selected from the group consisting of: 2-(4-fluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (4); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (12); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine-5-carbonyl)piperidin-4-ylidene)acetonitrile (13); 2-(4-chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (18); 2-(4-fluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (25); 2-(3,4-difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (41); 2-(2,4-difluorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (42); 2-(3,4-difluorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (43); 2-(3,4-difluorophenyl)-2-(1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)piperidin-4-ylidene)acetonitrile (44); 2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)-2-(1H-indazol-4-yl)acetonitrile (48); 2-(5-chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (67); 2-(4-chlorophenyl)-2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (74); 2-(3-chlorophenyl)-2-(1-(4-hydroxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (80); 2-(5-fluoropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (84); 1-(4-((3-chlorophenyl)(cyano)methylene)piperidine-1-carbonyl)piperidine-4-sulfonamide (99); 2-(4-chlorophenyl)-2-(1-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (113); 2-(1-(4-(hydroxymethyl)piperidine-1-carbonyl)piperidin-4-ylidene)-2-(1-methyl-1H-indazol-7-yl)acetonitrile (118); 2-(1H-indazol-4-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (138); 2-(3-chlorophenyl)-2-(1-(4-(2-hydroxyethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (140); 2-(4-chlorophenyl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (141); 2-(1H-indazol-4-yl)-2-(1-(4-methoxypiperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (144); 2-(1H-indazol-4-yl)-2-(1-(4-(trifluoromethyl)piperidine-1-carbonyl)piperidin-4-ylidene)acetonitrile (145); 2-(1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)piperidin-4-ylidene)-2-(3-chlorophenyl)acetonitrile (156); 2-(5-Chloropyridin-2-yl)-2-(1-(4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine-5-carbonyl)piperidin-4-ylidene)acetonitrile (161).

14. A method for preparing a compound of formula (I) or a salt, solvate or solvate of a salt thereof according to any one of claims 1 to 13, comprising the steps of: Optionally, in the presence of a base, 【Chemistry 4】 wherein the dotted line represents an optional bond; R ７ is a leaving group A or is absent when the dotted line represents a bond, and R ３Ａ R is defined for the compound of formula (I) or for the leaving group B ３ It is. and a compound of formula (III) 【Chemistry 5】 [In the formula, R １ and R ２ is as defined for compounds of formula (I). or a hydrogen halide thereof; or Formula (IV) 【Chemistry 6】 [In the formula, R ３Ａ R is defined for the compound of formula (I) or for the leaving group B ３ It is. or a hydrogen halide of the compound of formula (V) 【Chemistry 7】 wherein the dotted line represents an optional bond; R ７ is a leaving group A or is absent when the dotted line represents a bond, and R １ and R ２ is as defined for compounds of formula (I). to react a compound of formula (I) 【Chemistry 8】 [In the formula, R １ , R ２ and R ３ is as defined for compounds of formula (I); or R １ and R ２ is as defined for compounds of formula (I), R ３ is the leaving group B. to obtain a compound of formula (I): Optionally, R ３ is a leaving group B, the resulting compound of formula (I) is reacted with a compound of formula (VII) in the presence of a base and a coupling agent 【Chemistry 9】 [During the ceremony, R ３Ｂ R is defined for compounds of formula (I) ３ and Z is a leaving group C or B(R ８ ) ２ where R ８ OH, OC １－６ - alkyl or both R ８ together with the ring boron atom to which they are attached to form a cyclic boronic ester. By reacting a compound of R １ , R ２ and R ３ to obtain a compound of formula (I) wherein and optionally converting the compound of formula (I) into a salt, solvate or solvate of the salt thereof. A method comprising the steps of:

15. A pharmaceutical composition comprising an effective amount of one or more compounds of formula (I) according to any one of claims 1 to 13, or a salt, solvate or solvate of a salt thereof, together with one or more pharma- ceutically acceptable excipients.

16. 15. The pharmaceutical composition of claim 14, comprising one or more compounds of any of claims 1 to 13 in combination with one or more further active ingredients.

17. A medicine comprising a compound according to any one of claims 1 to 13, or a salt, solvate or solvate of a salt thereof.

18. 18. The pharmaceutical composition of claim 17 for use in the treatment or prevention of a disease or disorder selected from the group consisting of polycystic ovary syndrome, endometriosis, uterine fibroids, uterine bleeding disorders, dysmenorrhea, hyperandrogenism, chronic obstructive pulmonary disease (COPD), lung cancer, non-small cell lung cancer, prostate cancer including castration-resistant prostate cancer, prostatic hyperplasia, breast cancer, invasive ductal carcinoma of the breast, triple-negative breast cancer, endometrial carcinoma, renal cell carcinoma, bladder cancer, pancreatic adenocarcinoma, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, melanoma, non-Hodgkin's lymphoma, acne, seborrhea, hair loss, precocious sexual maturation, obesity and inflammation-associated pain.

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