RU2797323C2 - Monoacylglycerol lipase modulators - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to bridge compounds of formula (I), while R², R³, R⁴, R⁵ and R⁶ are defined in paragraph 1 of the claims. The invention also relates to specific bridging compounds.

EFFECT: modulation of MGL (monoacylglycerol lipase), useful in the treatment of disorders and conditions associated with MGL modulation, such as those associated with pain, mental disorders, neurological disorders (including, without limitation, major depressive disorder, treatment-resistant depression, anxiety depression, bipolar disorder), cancers and eye diseases.

58 cl, 4 tbl, 444 ex

Description

FIELD OF THE INVENTION

The present invention relates to certain bridging chemicals having MGL (monoacylglycerol lipase) modulating properties, pharmaceutical compositions containing these chemicals, chemical processes for producing these chemicals, and their use in the treatment of diseases, disorders, or conditions associated with MGL receptor activity in subjects, in particular in humans.

BACKGROUND OF THE INVENTION

Hemp (Cannabis Sativa) and ^A9 -tetrahydrocannabinol analogs have been used therapeutically since the days of traditional medicine. The endocannabinoid system consists of two G protein-coupled receptors: the cannabinoid receptor type 1 (CB1) (Matsuda et al. , Nature , 1990, 346, 561-4) and the cannabinoid receptor type 2 (CB2) (Munro et al. , Nature , 1993, 365, 61-5). The CB1 receptor is one of the most abundant G-protein coupled receptors expressed in the brain (Herkenam et al. , Proc. Nat. Acad. Sci. , 1990, 87 (5), 1932-1936). The CB1 receptor is also peripherally expressed in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al. , Curr Opin Lipidol , 2007, 18, 129-140). CB2 is mainly expressed in immune cells such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), under certain conditions (in inflammation) in the brain ((Benito et al. , Brit J Pharmacol , 2008, 153, 277-285), as well as in skeletal (Cavuoto et al. , Biochem Biophys Res Commun , 2007, 364, 105-110) and cardiac muscles (Hajrasouliha et al. , Eur J Pharmacol , 2008, 579, 246-252).

In 1992, N-arachidonoylethanolamine (AEA or anandamide) was found to be an endogenous ligand for cannabinoid receptors (Devane et al. , Science , 1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) has also been identified as an additional endogenous cannabinoid receptor ligand (Mechoulam et al. , Biochem Pharmacol , 1995, 50, 83-90; Sugiura et al. , Biochem Biophys Res Commun , 1995, 215, 89 -97). 2-AG concentrations have been reported to be at least 100 times higher than anandamide concentrations in the rat brain (Buczynski and Parsons, Brit J Pharmacol , 2010, 160 (3), 423-42). Therefore, 2-AG may play a more important physiological role in the endocannabinoid system than anandamide (Sugiura et al. Prostaglandins Leukot Essent Fatty Acids., 2002, Feb-Mar, 66(2-3):173-92). The endocannabinoid 2-AG is a full CB1 and CB2 receptor agonist, while anandamide is a partial agonist of both receptors (Suguira et al., Prog Lipid Res , 2006, 45(5):405-46). Unlike many classic neurotransmitters, endocannabinoids signal through a retrograde mechanism. They are synthesized on demand in postsynaptic neurons and then rapidly degraded after binding to presynaptic cannabinoid receptors (Ahn et al., Chem Rev. 2008, 108(5):1687-707). Monoacylglycerol lipase (MGLL, also called MAG-lipase and MGL) is a serine hydrolase responsible for degrading 2-AG and converting the compound to arachidonic acid and glycerol in the central nervous system (Mechoulam et al. , Biochem Pharmacol , 1995, 50, 83- 90; Sugiura et al. , Biochem Biophys Res Commun , 1995, 215, 89-97; Long et al., Nat Chem Biol. 2009 Jan;5(1):37-44;), Schlosburg et al, Nat Neurosci. , 2010, Sep;13(9):1113-9) and peripheral tissues (Long et al., Chem Biol., 2009 Jul 31;16(7):744-53). Hydrolysis of ananandamide is performed by fatty acid amide hydrolase (FAAH) (Piomelli, Nat Rev Neurosci , 2003, 4, 873-884). MGL exists in both soluble and membrane bound form (Dinh et al., Proc Natl Acad Sci USA ., 2002, Aug 6;99(16):10819-24). In the brain, MGL is found in presynaptic neurons (Straiker et al., Mol Pharmacol., 2009, Dec;76(6):1220-7) and astrocytes (Walter et al., J Neurosci., 2004, Sep 15;24( 37):8068-74) in areas associated with a high density of CB1 receptors. Compared to wild-type controls, genetic ablation of MGL expression results in a 10-fold increase in brain 2-AG levels without affecting ananandamide concentration (Schlosburg et al., Nat Neurosci ., 2010, Sep;13(9): 1113-9).

Thus, MGL modulation is a promising strategy for increasing the potential of the cannabinoid system. The main advantage of this approach is that only those areas of the brain that are actively producing endocannabinoids will be modulated, potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL by covalent inhibitors in animals increases 2-AG levels in the brain and peripheral tissues and has been found to produce antinociceptive, anxiolytic, and anti-inflammatory effects that are dependent on CB1 and/or CB2 receptors (Long et al., Nat Chem Biol ., 2009, Jan, 5(1):37-44; Ghosh et al., Life Sci., 2013, Mar 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry., 2017 , Oct 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015, Jan, 63(1):163-76; Patel et al. Neurosci Biobehav Rev., 2017, May, 76 (Pt A):56-66; Betse et al., Transl Psychiatry ., 2018, Apr 26, 8(1):92). In addition to the role of MGL in facilitating the termination of 2-AG signaling, modulation of MGL, including inhibition of MGL, also contributes to the influence of CB1/2 receptors on neuroinflammatory processes (Nomura et al., Science., 2011, Nov 11;334(6057):809- 13. MGL modulation, including MGL inhibition, results in reduced pro-inflammatory prostanoid signaling in animal models used to simulate traumatic brain injury (Katz et al., J Neurotrauma., 2015, Mar 1;32(5): 297-306; Zhang et al., J Cereb Blood Flow Metab ., 2015, Mar 31;35(4):706), neurodegenerations including Alzheimer's disease (Piro et al., Cell Rep., 2012, Jun 28, 1 (6):617-23; Wenzel et al., Life Sci., 2018, Aug 15, 207:314-322; Chen et al., Cell Rep., 2012, Nov 29, 2(5):1329-39 ), Parkinson's disease (Nomura et al., Science, 2011, Nov 11, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., 2017, Nov, 110:14-24), amyotrophic lateral sclerosis ( Pasquarelli et al., Neuropharmacology, 2017, Sep 15, 124:157-169), multiple sclerosis (Hernadez-Torres et al., Angew Chem Int Ed Engl., 2014, Dec 8, 53(50):13765-70; Bernal-Chico et al., Glia., 2015, Jan, 63(1):163-76), Huntington's disease (Covey et al., Neuropsychopharmacology , 2018, 43, 2056-2063), Tourette's syndrome and epileptic condition (Terrone et al., Epilepsia ., 2018, Jan, 59(1), 79-91; von Ruden et al., Neurobiol Dis., 2015, May;77:238-45).

Thus, by enhancing the cannabinoid system and attenuating pro-inflammatory cascades, modulation of MGL, including inhibition of MGL, provides a promising therapeutic approach to the treatment of a wide range of complex diseases. It is important to note that MGL modulation, including MGL inhibition in animals, does not produce the full range of neurobehavioral effects seen with ^Δ9 -tetrahydrocannabinol and other CB1 agonists (Tuo et al., J Med Chem ., 2017, Jan 12, 60 (1), 4-46; Mulvihill et al., Life Sci., 2013, Mar 19, 92(8-9), 492-7).

Endocannabinoid underactivity is a risk factor in the treatment of depression, anxiety disorder, and post-traumatic stress disorder. Millennia of human use of Cannabis Sativa and the short period during which humans were treated with rimonabant, an endocannabinoid antagonist, support this hypothesis. 2-AG levels are reduced in subjects with major depressive disorder (Hill et al., Pharmacopsychiatry., 2008, Mar; 41(2): 48-53; Hill et al., Psychoneuroendocrinology ., 2009, Sep; 34(8): 1257-1262.). Low circulating 2-AG levels are predictive of depression scores (Hauer et al., Rev Neurosci. 2012, 23(5-6):681-90). Decreased circulating 2-AG levels have been found in patients with post-traumatic stress disorder (PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38(12), 2952-2961). Healthy volunteers exposed to chronic stressors showed a gradual decline in circulating 2-AG levels, consistent with the onset of decline in positive emotion scores (Yi et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97 ). Rimonabant, a CB1 receptor inverse agonist/antagonist, has been withdrawn from the market due to the high incidence of severe depression and suicidal ideation in patients (Christensen et al., The Lancet, 2007, 370, 1706-1713). Thus, MGL modulators are potentially useful in the treatment of mood disorders, anxiety disorder, and PTSD.

Cannabinoid receptor agonists are clinically used to treat pain, spasticity, vomiting and anorexia (Di Marzo, et al., Annu Rev Med., 2006, 57:553-74; Ligresti et al., Curr Opin Chem Biol ., 2009, Jun ;13(3):321-31). Thus, MGL modulators, including MGL inhibitors, may also be useful in this indication. MGL has a CB1-dependent antinociceptive effect in animal models used to model chemical, inflammatory, thermal, and neuropathic pain syndromes (Guindon et al., Br J Pharmacol ., 2011, Aug;163(7):1464-78; Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10; Long et al., Nat Chem Biol., 2009, Jan;5(1):37-44). Blockade of MGL reduces mechanical and acetone-induced cold allodynia in mice with chronic sciatic nerve constriction (Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10). Inhibition of MGL results in retention of opiates with reduced tolerability, constipation, and side effects of cannabimimetic use (Wilkerson et al., J Pharmacol Exp Ther ., 2016, Apr;357(1):145-56). Blockade of MGL is a protective measure in a model of inflammatory bowel disease (Alhouayek et al., FASEB J ., 2011, Aug;25(8):2711-21). MGL inhibition also reverses paclitaxel-induced nociceptive behavior as well as pro-inflammatory markers in a mouse model of chemotherapy - induced neuropathy (Curry et al., J Pharmacol Exp Ther. , 2018, Jul;366(1):169-18). MGL inhibitors may also be potentially useful in the treatment of chronic inflammatory diseases of the bladder, including interstitial cystitis (Chinnadurai et al., Med Hypotheses 2019, Oct; 131: 109321).

Inhibition of 2-AG hydrolysis has an antiproliferative effect and reduces the invasiveness of prostate cancer cells (Nithipatikom et al., Cancer Res., 2004, Dec 15, 64(24):8826-30; Nithipatikom et al., Biochem Biophys Res Commun. , 2005, Jul 15,332(4):1028-33; Nithipatikom et al., Prostaglandins Other Lipid Mediat., 2011, Feb, 94(1-2):34-43). MGL is upregulated in aggressive human cancer cells and primary tumors, where it plays a unique role in providing lipolytic sources of free fatty acids for the synthesis of oncogenic signaling lipids that promote aggressive cancer development. Thus, in addition to the physiological roles of MGL in endocannabinoid-mediated signaling, in cancer, MGL plays a role in modulating stocks of fatty acid precursors for the synthesis of protumorogenic signaling lipids in human malignant cancer cells.

Blockade of MGL demonstrates an antiemetic effect in a shrew simulation of emesis using lithium chloride (Sticht et al., Br J Pharmacol., 2012, Apr, 165(8):2425-35).

MGL modulators, including MGL inhibitors, may be useful in modulating opiate drug dependence. Blockade of MGL reduces the intensity of naloxone-induced morphine withdrawal symptoms in mice. Blockade of MGL also attenuated spontaneous withdrawal symptoms in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther., 2011, Oct, 339(1):173-85).

MGL modulators may also find use in the treatment of ocular diseases, including but not limited to glaucoma and painful conditions caused by increased intraocular pressure (Miller et al., Pharmaceuticals , 2018, 11, 50).

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to chemical structural compounds, pharmaceutical formulations containing them, methods for their preparation and purification, and methods for their use in the treatment of diseases, disorders and conditions associated with MGL modulation. A further embodiment of the present invention is a method of treating a patient diagnosed with a disease, disorder, or medical condition, or suffering from a disease, disorder, or medical condition associated with MGL modulation, with at least one chemical compound within the scope of the present invention.

Additional embodiments, features and advantages of the invention will become apparent from the following detailed description and practice of the invention.

Embodiments of this invention are compounds of formula (I),

Where

R ² is selected from the group consisting of:

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(c) a 5-membered heteroaryl selected from the group consisting of:

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(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

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(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

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Where

R ^a is selected from the group consisting of: H, halogen, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 haloalkyl;

R ^a1 is selected from the group consisting of: C _1-4 alkyl; OC _1-4 alkyl; OC _1-4 haloalkyl; N(C=O)CH ₃ ; oxazol-2-yl; pyrimidin-2-yl; and a 5-membered heteroaryl ring containing two, three or four nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one R ^a member;

R ^b is H or C _1-4 alkyl;

R ^c is H or C _1-4 haloalkyl;

R ^d is H or halogen.

R ^e is selected from the group consisting of: H, halogen, C _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 alkyl and C _3-6 cycloalkyl;

R ^f is selected from the group consisting of: H, C _1-4 alkyl, CH ₂ CH ₂ OH, C _1-4 haloalkyl, cyclopropyl, phenyl and phenyl substituted with CF ₃ ;

R ^g is selected from the group consisting of: H, OC _1-4 alkyl and C _1-4 haloalkyl;

R ⁱ is selected from the group consisting of: H, halo, C _1-4 alkyl, C _1-4 haloalkyl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, and C _3-6 cycloalkyl;

R ^j is selected from the group consisting of: H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ;

R ³ is selected from the group consisting of:

(g) phenyl, where phenyl is independently substituted with one, two or three substituents each selected from the group consisting of halo, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl;

(h) 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; And

(i) cyclopropyl; And

R ⁴ is C _1-4 alkyl or C _3-4 cycloalkyl;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

Embodiments of the present invention are also compounds of formula (II),

Where

R ⁵ is selected from the group consisting of:

.(a) phenyl optionally independently substituted with one or two substituents selected from the group consisting of halo, OC _1-4 alkyl, and

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;(b) a 6-membered heteroaryl selected from the group consisting of:

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(c) a 5-membered heteroaryl selected from the group consisting of:

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Where

R ^k is selected from the group consisting of: H, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ^m is selected from the group consisting of: H, C _1-4 alkyl and C _1-4 haloalkyl;

R ⁿ is H or OC _1-4 alkyl;

R ^o is H or C _1-4 alkyl;

R ^p is selected from the group consisting of: H, halogen, C _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 alkyl; And

R6 is phenyl independently substituted with one, two or three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl and OC1-4 alkyl;;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

DETAILED DESCRIPTION OF THE INVENTION

The terms "including", "comprising", "consisting of" are used in an open, unrestricted sense.

Unless otherwise specified for specific uses, the term "alkyl" refers to a straight or branched chain alkyl group containing from 1 to 8 carbon atoms. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl (tBu), pentyl, isopentyl, t-pentyl, hexyl, isohexyl, as well as groups , which in light of the conventional wisdom expected of one of ordinary skill in the art and the concepts described herein, may be considered equivalent to any one of the above examples. The term "C ₁ -C ₄ alkyl" refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atoms.

The term "cycloalkyl" means a saturated or partially saturated monocyclic, fused polycyclic or spiro polycyclic carbocycle containing from 3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkyl groups include the following entities in the form of suitably linked functional groups:

The term "halogen" or "halo" means chlorine, fluorine, bromine or iodine.

The term "haloalkyl" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms in the chain, optionally replacing hydrogen atoms with halogen atoms. As used herein, the term "C ₁ -C ₄ haloalkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms in the chain optionally replacing hydrogen atoms with halogen atoms. Examples of "haloalkyl" groups include trifluoromethyl (CF ₃ ), difluoromethyl (CF ₂ H), monofluoromethyl (CH ₂ F), pentafluoroethyl (CF ₂ CF ₃ ), tetrafluoroethyl (CHFCF ₃ ), monofluoroethyl (CH ₂ CH ₂ F) , trifluoroethyl (CH ₂ CF ₃ ), tetrafluorotrifluoromethylethyl (CF(CF ₃ ) ₂ ), and groups which, in light of the conventional knowledge expected of one of ordinary skill in the art and the understanding given herein, can be considered equivalent to one of the above examples.

The term "aryl" refers to a monocyclic, aromatic carbocycle (a ring structure in which all ring atoms are carbon atoms) having 6 atoms per ring (The carbon atoms in the aryl groups undergo "sp2" hybridization).

The term "phenyl" represents the following functional group:

.

.

As used herein, the term "heteroaryl" refers to an aromatic monocyclic or multicyclic ring system containing 5 to 14 ring atoms, where 1 to 4 ring atoms are independently O, N, or S and the remaining ring atoms are carbon atoms. In one embodiment, the heteroaryl group has 5 to 10 ring atoms. In another embodiment, the heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, the heteroaryl group is monocyclic and has 5 or 6 ring atoms and at least one ring nitrogen atom. The heteroaryl group is attached via a ring carbon atom, and any heteroaryl nitrogen atom may optionally be oxidized to the corresponding N-oxide. The term "heteroaryl" also means a heteroaryl group, as defined above, which has been fused to a benzene ring.

As used herein, the term "5-membered heteroaryl" refers to a heteroaryl group, as defined above, which has 5 ring atoms. Illustrative non-limiting examples of 5-membered heteroaryls include:

As used herein, the term "6-membered heteroaryl" refers to a heteroaryl group as defined above that has 6 ring atoms. Illustrative non-limiting examples of 6-membered heteroaryls include:

As used herein, the term "5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl" refers to a heteroaryl group as defined above that has 9 ring atoms. Illustrative non-limiting examples of 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl include:

As used herein, the term "6,6-fused bicyclic heteroaryl" refers to a heteroaryl group as defined above that has 9 ring atoms. Illustrative non-limiting examples of 6,6-fused bicyclic heteroaryl include:

Those skilled in the art will recognize that the heteroaryl, cycloalkyl, and aryl groups listed or illustrated above are not exhaustive, and additional types may also be selected within these defined terms.

The term "substituted" means that the specified group or functional group has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group has no substituents or has one or more substituents. If the term "substituted" is used to describe a structural system, this means that the substitution occurs in any position of the system allowed by the valency.

The term "variable point of attachment" means that a group can be attached at more than one alternative position in the structure. The attached compound or group always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations within a connection are represented by a single diagram, as shown in the illustrations below.

Those skilled in the art will appreciate that if more than one such substituent is present on a given ring, then the binding of each substituent is independent of all the others. The groups listed or illustrated above are not exhaustive.

The term "substituted" means that the specified group or functional group has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group has no substituents or has one or more substituents. If the term "substituted" is used to describe a structural system, this means that the substitution occurs in any position of the system allowed by the valency.

Any of the formulas given herein is intended to represent both compounds with structures shown by a given structural formula, and some variations or forms of such structures. In particular, compounds of any of the formulas herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof, are considered within the scope of the formula. The compounds of this invention may have one or more asymmetric centers; thus, it is possible to obtain such compounds as individual ( R )- or ( S )-isomers or mixtures thereof. Thus, any formula given herein is intended to refer to the racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Furthermore, any formula given herein is also intended to refer to any of the hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof, even if such forms are not explicitly stated.

The term "R" in the stereocenter means that the stereocenter has a pure R- configuration, defined in accordance with the standards existing in this field; similarly, the term S denotes that the stereocenter has a pure S configuration. In this document, the term RS denotes a stereocenter that exists in the form of a mixture of R - and S -configurations.

Compounds containing one stereocenter without a stereolink designation are a mixture of 2 enantiomers. Compounds containing 2 stereocenters without a stereolink designation for both of them are a mixture of 4 diastereomers. Compounds with two stereocenters, each designated as "RS" and having stereobond designations, are a two-component mixture having a relative stereochemical structure as shown in the structural formula. Unmarked stereocenters, indicated in the structural formula without the designation of stereo bonds, are a mixture of R - and S -configurations. For unlabeled stereocenters whose structural formula is given with stereobond notation, the absolute stereochemical structure corresponds to the formula shown.

Reference to a compound herein means reference to any of the following: (a) the literally stated form of such compound, and (b) any form of such compound in the environment in which the compound is present at the time of mention. For example, reference herein to a compound such as R-COOH includes reference to any of the following forms, eg R-COOH(sol), R-COOH(sol) and R-COO-(sol). In this example, R-COOH(s) refers to a solid compound and may, for example, be contained in a tablet or some other solid pharmaceutical composition or preparation; R-COOH(sol.) refers to the undissociated form of the compound in a solvent; R-COO ^- (sol.) refers to the dissociated form of a compound in a solvent, such as the dissociated form of a compound in an aqueous medium, whether the dissociated form is derived from R-COOH, its salt, or any other substance that gives R-COO - after dissociation in the medium under consideration. In another example, an expression such as "action of a substance on a compound of the formula R-COOH" means the action of such a substance on the form or forms of the R-COOH compound that exists or that exist in the environment where such exposure occurs. In yet another example, a phrase such as "the reaction of a substance with a compound of the formula R-COOH" refers to the reaction: (a) of such a substance in the appropriate chemical form or forms that exists or that exist in the environment where the described reaction is carried out; c (b) the appropriate chemical form or forms of the compound R-COOH which exists or which exist in the medium in which such a reaction takes place. Thus, if such a substance is, for example, in an aqueous environment, it is understood that the compound R-COOH is in the same environment and, therefore, such a substance is affected by forms such as R-COOH (aq.) and/or R- COO-(aq.), where the subscript "(aq.)" means "water" in accordance with its generally accepted meaning in chemistry and biochemistry. In these examples, the nomenclature has chosen the carboxylic acid functional group; however, this choice is not a conscious limitation, but is merely an illustration. It is understood that similar examples may be given for other functional groups, including, without limitation, groups such as hydroxyl group, nitrogen basic groups, for example, as in amines, as well as any other groups that are known to interact or rearrange in the containing connection environment. Such interactions and rearrangements include, without limitation, dissociation, association, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation and deprotonation. This document does not provide further examples in this regard, since these interactions and rearrangements in each particular environment are well known to any person skilled in the art.

Any of the formulas given herein also represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures shown by the formulas presented herein, with the exception of substitution of one or more atoms by an atom having the selected atomic mass or mass number in enriched form. Examples of isotopes that can be included in the compounds of the present invention in excess of their natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine such as ² H (or chemical symbol D), ³ H (or chemical symbol T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I, respectively. Such isotopically labeled compounds are used in metabolism studies (preferably using ¹⁴ C), reaction kinetics (for example using ² H or ³ H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT)), including analysis of the distribution of the drug or substrate in tissues, or in radiotherapy of patients. In particular, compounds labeled with ¹⁸ F or ¹¹ C may be particularly preferred for PET or SPECT studies. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H or D) may provide some therapeutic benefits due to greater metabolic stability of the compounds, such as a longer in vivo half-life or a reduced dosage requirement. Isotopically labeled compounds of the present invention can be essentially prepared by following the procedures described in the Schemes or Examples below and preparation methods described below by substituting a readily available reagent containing no isotopically labeled atoms with an isotopically labeled reagent.

In describing any formula herein, the selection of a particular functional group from a list of possible options for a specified variable does not imply that such a choice of option is defined for that variable in other formulas. In other words, if any variable is present in the formula in more than one place, then the choice of an option from the specified list in one place does not depend on the choice of an option for the same variable elsewhere in the formula, unless otherwise specified.

The term "C _nm alkyl" means a linear or branched aliphatic chain with a total of N carbon atoms in the chain that satisfies the condition n ≤ N ≤ m, where m > n.

If the same plurality of substituents are assigned to different groups, it is understood that the specific individual substituent assignment of each of such groups is made independently of the specific individual assignment of substituents to the remaining groups. By way of illustration, and not limitation, if the Q and R groups can each be H or F, the choice of H or F for Q is independent of the choice of H or F for R, so the choice of destination for Q does not determine the choice of destination for R, or vice versa, unless explicitly stated otherwise. An exemplary listing of claims in this regard will be interpreted as "each compound of Q and R is independently H or F", or "each compound of Q and R is independently selected from the group consisting of H and F".

Unless otherwise indicated, the description or name of a particular compound in the description and claims includes both individual enantiomers and mixtures thereof (racemic or otherwise). Methods for determining stereochemistry and separating stereoisomers are well known in the art.

In another example, a zwitterionic compound would be included herein by referring to a compound that can form a zwitterion, even though it is not explicitly referred to in its zwitterionic form. Terms such as "zwitterion", "zwitterions" and their synonyms "zwitterionic compound(s)" are standard IUPAC-recommended terms that are well known and included in standard sets of certain scientific names. In this regard, the term "zwitterion" has been assigned the unique identifier CHEBI:27369 in the Dictionary of Chemical Objects of Biological Interest (ChEBI). As is essentially well known, a zwitterion or zwitterionic compound is a neutral compound having formal unit charges of opposite signs. Sometimes the term "internal salts" is also used for these compounds. Other sources refer to these compounds as "dipolar ions", although some sources consider the latter term to be a misnomer. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula H ₂ NCH ₂ COOH and in some environments (in this case neutral) exists in the form of zwitterion ⁺ H ₃ NCH ₂ COO ^- . Zwitterions, zwitterionic compounds, internal salts, and dipolar ions, in the known and well-established meanings of the listed terms, are within the scope of this invention, as will be readily determined by one skilled in the art. Because it is not necessary to name every single embodiment that a person skilled in the art can imagine, structures of zwitterionic compounds related to the compounds of the present invention are not explicitly given herein. However, all such structures are part of the embodiments of the present invention. This document lacks further examples in this regard, since the possible interactions and rearrangements in each particular environment, leading to different forms of each particular compound, are well known to the person skilled in the art.

When describing any formula herein, the selection of a particular functional group from a list of possible options for a specified variable does not imply that such a choice of option for a variable in other formulas is determined. In other words, if any variable is present in the formula in more than one place, then the choice of an option from the specified list in one place does not depend on the choice of an option for the same variable elsewhere in the formula, unless otherwise specified.

As a first example of substituent terminology, if substituent S ¹ _example is one of S ₁ and S ₂ and substituent S ² _example is one of S ₃ and S ₄ , these designations refer to embodiments of the present invention given in accordance with variants, where S ¹ _example is S ₁ and S ² _example is S ₃ ; S ¹ _example is S ₁ and S ² _example is S ₄ ; S ¹ _example is S ₂ and S ² _example is S ₃ ; S ¹ _example is S ₂ and S ² _example is S ₄ ; as well as the equivalents of each of these options. The more concise terminology "S ¹ _example is one of S ₁ and S ₂ and S ² _example is one of S ₃ and S ₄ ", respectively, is used herein for brevity and not limitation. The above first example of the terminology used to designate substituents, given in general terms, is intended to illustrate the various substituent designations described herein.

Moreover, if more than one designation is given for any element of the chemical structure or substituent, embodiments of the present invention contain various, taken independently, combinations of options from the listed designations, as well as their equivalents. As a second example of substituent terminology, if this document describes that if the substituent S _example is one of S ₁ , S ₂ and S ₃ , then this list refers to embodiments of the present invention for which S _example is S ₁ ; S _example is S ₂ ; S _example is S ₃ ; S _example is one of S ₁ and S ₂ ; S _example is one of S ₁ and S ₃ ; S _example is one of S ₂ and S ₃ ; S _example is one of S ₁ , S ₂ and S ₃ ; and S _example is any equivalent of each of these options. For brevity, and not limitation, the abbreviated terminology used herein is accordingly: "An S _example is one of S ₁ , S _{2 ,} and S ₃ ". The above second example of the terminology used to designate substituents, given in general terms, is intended to illustrate the various designations of substituents described herein.

It is intended that the nomenclature "C _i -C", where j > i, used herein to denote a class of substituents, is intended to indicate embodiments of the present invention for which each and all possible numbers of carbon atoms from i to j are individually implemented, including i and j. By way of example, the term "C ₁ -C ₃ " refers independently to embodiments in which there is one carbon atom (C ₁ ), embodiments in which there are two carbon atoms (C ₂ ), and embodiments in which there are three carbon atom (C ₃ ).

The term "pharmaceutically acceptable salt" means an acid or base salt of a compound represented by formula (I) (as well as compounds of formula (II)), which is non-toxic, biologically tolerable, or otherwise biologically acceptable for administration to a subject. See essentially SM Berge, et al. , "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are salts which have pharmacological effect and are acceptable for contact with patient tissues without undue irritant, toxic or allergic reaction.

The compound of formula (I) (as well as compounds of formula (II)) may have a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and, accordingly, react with a number of inorganic or organic bases, as well as inorganic and organic acids to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates. , propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates .

Compounds of formula (I) (as well as compounds of formula (II)) may contain at least one basic nitrogen atom, so the desired pharmaceutically acceptable salts may be prepared by any appropriate procedure known to those skilled in the art, for example by treating the free base with an inorganic acid such as as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc., or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as mandelic acid, citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid, sulfonic acid such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, any compatible mixture of acids such as those given in the examples herein, and any other acid or mixture of acids considered equivalent.

Compounds of formula (I) (as well as compounds of formula (II) may contain a carboxylic acid functional group, the desired pharmaceutically acceptable salt may be obtained by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases, such as those exemplified herein, and any other base, and mixtures thereof, that are considered equivalent or acceptable substitutes in light of the conventional state of the art in the art. examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary and tertiary amines, as well as cyclic amines such as benzylamines, pyrrolidines, piperidine, morpholine, piperazine, N -methylglucamine and tromethamine and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The compounds of the invention, including their pharmaceutically acceptable salts, alone or in combination (collectively referred to as the "active agent" or "active agents") of the present invention can be used as MGL modulators in the methods of the invention. Such methods for modulating MGL include the use of a therapeutically effective amount of at least one chemical compound of the present invention.

In some embodiments, an MGL modulator is used as an inhibitor for the treatment of patients diagnosed with, or suffering from, a disease, disorder, or medical condition mediated by MGL receptor activity, including those described herein. . The symptoms or conditions of a disease are intended to be included within the scope of the term "diseases, disorders or conditions".

Accordingly, the present invention relates to methods of using the active agents described herein for the treatment of patients who are diagnosed with a disease, disorder or medical condition, or who suffer from a disease, disorder or medical condition associated with the activity of MGL receptors. As used herein, the term "treat" or "treatment" refers to the administration of an active agent or composition of the invention to a subject for therapeutic or prophylactic benefit by modulating MGL receptor activity. Treatment includes reversing, alleviating, attenuating, slowing progression, lessening the severity, or preventing the disease, disorder, or condition, or one or more of the symptoms of such disease, disorder, or condition, associated with MGL modulation. The term "patient" refers to a mammalian patient in need of such treatment, such as a human.

The term "composition" means a product comprising specified ingredients in therapeutically effective amounts, as well as any product obtained directly or indirectly from combinations of specified ingredients in specified amounts.

The term "MGL inhibitor" encompasses a compound that interacts with MGL substantially to reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s). The term "MGL-modulated" is used to refer to a state of dependence on modulation of the MGL enzyme, including a state of dependence on inhibition of the MGL enzyme. This invention relates to methods of treating, alleviating symptoms and/or preventing diseases, conditions or disorders associated with pain (including inflammatory pain syndrome), as well as psychiatric disorders, neurological disorders, cancers and eye diseases by administering therapeutically effective doses MGL modulators to patients in need of such an intervention.

The term "modulators" includes both inhibitors and activators, where the term "inhibitors" refers to compounds that reduce, prevent, deactivate, desensitize, or decrease MGL expression or activity, and "activators" are compounds that increase, activate , facilitate, sensitize or increase the expression or activity of MGL.

Unless otherwise indicated, as used herein, the term "affect" or "affected" (when referring to a disease, condition, or disorder dependent on MGL inhibition) includes a reduction in the frequency and/or severity of one or more of the symptoms or manifestations of said disease, conditions or disorders; and/or includes preventing the development of one or more symptoms or manifestations of said disease, condition or disorder, or the development of the disease, condition or disorder.

In the methods of treatment according to the invention, a therapeutically effective amount of at least one active agent according to the invention is administered to a patient who has been diagnosed with a disease, disorder or condition, or who is suffering from a disease, disorder or condition. The term "therapeutically effective amount" means an amount or dose sufficient to achieve essentially the desired therapeutic or prophylactic effect in patients requiring such treatment for the specified disease, disorder or condition. Effective amounts or dosages of the active substances of the present invention can be determined by standard methods, such as modeling, dose escalation studies or clinical trials, taking into account standard factors such as the method or route of administration or delivery of the drug, the pharmacokinetics of the substance, the severity and nature of the disease, disorders or conditions, the subject's previous or current treatment, the subject's medical condition and response to medications, and the opinion of the attending physician. For a 70 kg human, an exemplary acceptable dosage is from about 1 to 1000 mg/day taken at one or more times (eg, BID, TID, QID, or otherwise, depending on the method).

After improvement in the patient's condition, alleviation of the symptoms of the disease or disorder, you can adjust the dose for prophylactic or maintenance treatment. For example, the dosage, or the frequency of administration, or both, may be reduced depending on the symptoms to a level that maintains the desired therapeutic or prophylactic effect. Of course, if the manifestations of symptoms are reduced to an acceptable level, treatment can be stopped. However, if symptoms recur, the patient may require long-term intermittent treatment.

In addition, the compounds of the present invention are intended for use alone, in combination with one or more of the other compounds of the present invention, or in combination with additional active ingredients for the treatment of the conditions described below. Additional active ingredients can be administered as a separate dosage form along with at least one compound of the present invention, with active agents of the invention, or included in a pharmaceutical composition in accordance with the present invention. In an exemplary embodiment, the additional active ingredients are components with known or proven efficacy in the treatment of conditions, disorders, or diseases associated with MGL modulation, such as another MGL inhibitor, or a compound active on another target associated with a particular condition, disorder, or disease. . Said combination of components may serve to increase effectiveness (for example, by including in the combination a compound that increases the effectiveness or activity of an agent in accordance with the present invention), reduce one or more side effects, or reduce the required dosage of an active agent in accordance with the present invention.

In the context of target inhibition, an "effective amount" means an amount sufficient to interfere with the MGL modulation process.

The active agents of the present invention are provided for use alone or in combination with one or more additional active ingredients for the preparation of pharmaceutical compositions of the invention. The composition corresponding to the purposes of the invention pharmaceutical composition includes a therapeutically effective amount of at least one active agent in accordance with the invention.

Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are substances that are non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a patient, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent. to facilitate the introduction of the agent, as well as compatible with this agent. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of pharmaceutical compositions containing one or more dosage units of active agents can be prepared using pharmaceutically acceptable excipients and preparation techniques currently known or available to those skilled in the art in the future. The compositions can be administered using methods having the features of the invention, suitable delivery route, for example, orally, parenterally, rectally, topically, through the eyes or by inhalation.

The preparation may be presented in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, reconstitution powders, liquid preparations or suppositories. Compositions may be prepared for any one of a variety of routes of administration such as intravenous infusion, topical application, or oral administration. Preferably, the compositions may be prepared for oral administration.

For oral administration, the active agents of the invention may be provided in the form of tablets, capsules or granules, or as a solution, emulsion or suspension. For oral compositions, the active agents may be mixed to provide a dose, for example, for a 70 kg human, from about 1 to about 1000 mg/day, intended to be taken at one time or multiple times, as an illustrative range.

Tablets for oral administration may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrators, binders, lubricants, sweeteners, flavors , dyes and preservatives. Suitable excipients include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of oral liquid excipients include ethanol, glycerin, water, and the like. Examples of tablet disintegrating agents are starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binding agents may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or they may be enteric coated.

Capsules for oral administration include hard and soft gelatin capsules or (hydroxypropyl)methylcellulose capsules. For the preparation of hard gelatin capsules, the active ingredients may be mixed with a solid, semi-solid or liquid diluent. Liquids for oral administration may be presented in the form of suspensions, solutions, emulsions or syrups, or they may be lyophilized or presented dry for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients such as suspending agents (eg, sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous carrier vehicles such as oil (eg almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (eg methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if necessary, flavoring or coloring agents.

The active agents of this invention can also be administered in a non-oral manner. For example, the compositions may be formulated for rectal administration as a suppository, enema, or foam. In the case of formulations for parenteral administration, including intravenous, intramuscular, intraperitoneal or subcutaneous administration, the agents of the invention may be formulated as sterile aqueous solutions or suspensions with the addition of appropriate buffer solutions to obtain the desired pH and isotonicity, or as a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride solution. Such dosage forms may be prepared in a single dose form such as ampoules or disposable injection devices, in a multi-dose form such as vials from which the required amount of the drug can be withdrawn, or in solid form or in the form of a primary concentrate, which can be used to prepare compositions for injection. Typical doses for infusion are in the range of about 1 to 1000 μg/kg/min of the substance as admixture with a pharmaceutical carrier over a period of time from several minutes to several days.

For topical application, the agents may be mixed with a pharmaceutical carrier at a concentration of from about 0.01% to about 20% of the drug in the vehicle, preferably 0.1-10%. In another route of administration, the agents of the invention may be administered as a patch formulation for transdermal delivery.

Alternatively, in the methods of the invention, the active substances may be administered by inhalation, through the nose or mouth, for example in the form of a spray also containing an appropriate carrier.

In a further embodiment, the invention relates to a method of treating a patient diagnosed with a disease, disorder or condition, or suffering from a disease, disorder or condition associated with MGL modulation, comprising administering to a patient in need of such treatment a therapeutically effective amount of an active agent.

The compounds of formula (I) (as well as the compounds of formula (II)) are suitable for methods of treating, alleviating and/or preventing a disease, condition or disorder dependent on MGL inhibition. Such methods include administering to a patient, including an animal, mammal, and human in need of such treatment, relief and/or prophylaxis, a therapeutically effective amount of a compound of formula (I) (as well as compounds of formula (II)) or an enantiomer, diastereomer, solvate or pharmaceutically effective amount thereof. acceptable salt.

In particular, compounds of formula (I) (as well as compounds of formula (II)) or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers are used for the treatment, alleviation and/or prevention of diseases, conditions or disorders that cause pain. , mental disorders, neurological disorders, cancers and pathological conditions of the eye. More specifically, compounds of formula (I) (as well as compounds of formula (II)) or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers are used for the treatment, alleviation and/or prevention of inflammatory pain, major depressive disorder, treatment resistant depression, anxious depression, or bipolar disorder by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) (as well as compounds of formula (II)) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, as defined herein. document.

(1) Pain syndrome

Examples of inflammatory pain include, but are not limited to, pain caused by a disease, condition, disorder, or disease state, including inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pains, diseases of the musculoskeletal system, skin diseases, toothache, heartburn, burn, sunburn, snake bite, venomous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, post-mastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache or arachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesia include a disease, condition, disorder, or disease state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, muscle disease, skin disease, postoperative pain, headaches, toothache, burn, sunburn, insect bite, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity and/or skin allergy, pruritus, eczema, pharyngitis, enteritis, syndrome irritable bowel, inflammatory bowel disease, including Crohn's disease, ulcerative colitis, benign prostatic hypertrophy, and hypersensitivity of the nasal mucosa.

In one embodiment, the present invention relates to a method of treating, alleviating symptoms and/or preventing inflammatory visceral hyperalgesia associated with increased visceral irritability, comprising, essentially comprising, or consisting of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of the formula ( I) (as well as compounds of formula (II)) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof. In another embodiment, the present invention relates to a method of treating inflammatory somatic hyperalgesia, which is characterized by increased sensitivity to thermal, mechanical and (or) chemical influences, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) (as well as compounds of formula (II)) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

An additional embodiment of the present invention relates to a method for treating, alleviating symptoms and/or preventing the onset of neuropathic pain. Examples of the manifestation of neuropathic pain include pain caused by a disease, condition, disorder or disease state, including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord injury, chronic pain syndrome , fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, types of neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis nerve, neuralgia of the mandibular joint, peripheral neuritis, polyneuritis, stump pain, phantom pain in amputated limbs, bone fractures, oral neuropathic pain, Charcot pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barré syndrome , paresthetic meralgia, paresthesia of the oral cavity, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombo's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate syndrome, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia glands, Morton's neuralgia, nasociliary nerve syndrome, occipital neuralgia, postherpetic neuralgia, causalgia, Mitchell's disease, Sluder's neuralgia, palatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, vidian neuralgia, or chemotherapy-induced neuropathy .

One type of neuropathic pain is neuropathic cold allodynia, which is characterized by the presence of an allodynic condition associated with neuropathy with increased sensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia caused by a disease, condition, disorder or disease state, including neuropathic pain (neuralgia), pain caused by spinal and peripheral nerve surgery or trauma, traumatic brain injury (TBI). trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II), and radiculopathy.

In another embodiment, the present invention relates to a method of treating, alleviating symptoms and/or preventing neuropathic cold allodynia with increased sensitivity to cold stimuli, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) (as well as compounds of formula (II )) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

2) Mental disorders

Examples of mental disorders include, without limitation, anxiety disorders such as social anxiety, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, including its manifestations such as major depressive disorder, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression and bipolar depression, mood disorders and affective mood disorders that can be treated in accordance with the present invention include, without limitation, bipolar disorder type I depressive, hypomanic, manic and mixed forms; bipolar disorder type II; depressive disorders such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, treatment resistant depression, anxiety depression, bipolar disorder, postpartum depressive disorder, depressive disorders with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, euthymia; and premenstrual dysphoric disorder; psychoses.

3) Neurological disorders

Examples of neurological disorders include, without limitation, tremors, dyskinesias, dystonias, spasticity, Tourette's syndrome; neuromyelitis of the optic nerve, Parkinson's disease; Alzheimer's disease; senile dementia; Huntington's disease; Epilepsy/seizure disorders and sleep disorders.

4) Cancer diseases:

Examples of cancers include, without limitation, benign skin tumors, prostate tumors, ovarian tumors, and cerebral tumors (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastomas, ependymomas, oligodendroheliomas, neuroepitheliomas, epiphyseal tumors, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, neurinomas).

5) Eye diseases

Examples of eye diseases include, without limitation, ocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

In other embodiments, the present invention provides a method for modulating the activity of an MGL receptor, including when such a receptor is present in a subject, comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the invention.

Embodiments of this invention are compounds of formula (I),

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R ^a is selected from the group consisting of: H, halogen, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 haloalkyl;

R ^a1 is selected from the group consisting of: C _1-4 alkyl; OC _1-4 alkyl; OC _1-4 haloalkyl; N(C=O)CH ₃ ; oxazol-2-yl; pyrimidin-2-yl; and a 5-membered heteroaryl ring containing two, three or four nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one R ^a member;

R ^b is H or C _1-4 alkyl;

R ^c is H or C _1-4 haloalkyl;

R ^d is H or halogen.

R ^e is selected from the group consisting of: H, halogen, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl and C _3-6 cycloalkyl;

R ^f is selected from the group consisting of: H, C _1-4 alkyl, CH ₂ CH ₂ OH, C _1-4 haloalkyl, cyclopropyl, phenyl and phenyl substituted with CF ₃ ;

R ^g is selected from the group consisting of: H, OC _1-4 alkyl and C _1-4 haloalkyl;

R ⁱ is selected from the group consisting of: H, halo, C _1-4 alkyl, C _1-4 haloalkyl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, and C _3-6 cycloalkyl;

R ^j is selected from the group consisting of: H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ;

R ³ is selected from the group consisting of:

(g) phenyl, wherein the phenyl is independently substituted with one, two or three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl, and OC1-4 alkyl;

(h) 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; And

(i) cyclopropyl; And

R ⁴ is C _1-4 alkyl or C _3-4 cycloalkyl;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

, где R^a представляет собой H, галоген, C_1-4алкил или OC_1-4алкил; и R^a1 представляет собой C_1-4алкил, OC_1-4алкил, OC_1-4галогеналкил или (C=O)NHCH₃.An additional embodiment of the invention is a compound of Formula (I) wherein R ² is

, where R ^a represents H, halogen, C _1-4 alkyl or OC _1-4 alkyl; and R ^a1 is C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl or (C=O)NHCH ₃ .

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

, где R^a представляет собой H, галоген, C_1-4алкил, OC_1-4алкил или C_1-4галогеналкил; и R^a1 представляет собой

,

,

,

,

,

,

,

,

,

или

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

, where R ^a represents H, halogen, C _1-4 alkyl, OC _1-4 alkyl or C _1-4 haloalkyl; and R ^a1 is

,

,

,

,

,

,

,

,

,

or

.

An additional embodiment of the invention is a compound of formula (I) wherein R ^a1 is

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

или

.

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

.

An additional embodiment of the invention is a compound of formula (I) wherein R ^a is H, Cl, F, CH ₃ , CF ₃ or OCH ₃ .

An additional embodiment of the invention is a compound of formula (I) wherein R ^b is H or CH ₃ ;

An additional embodiment of the invention is a compound of formula (I) wherein R ^c is H or CH ₃ ;

An additional embodiment of the invention is a compound of formula (I) wherein R ^d is H, Cl, or F.

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

,

или

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

,

or

.

, где R^a представляет собой H, Cl, Br, F или OCH₃, и R^a1 представляет собой OCH₃ или

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

where R ^a is H, Cl, Br, F or OCH ₃ and R ^a1 is OCH ₃ or

.

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

.

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) where R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

или

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

or

.

, и R^e независимо выбран из группы, состоящей из: H, галогена, C_1-4алкила_, C_1-4галогеналкила, OC_1-4алкила, и циклопропила.An additional embodiment of the invention is a compound of formula (I) wherein R ² is:

, and R ^e is independently selected from the group consisting of: H, halo, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl, and cyclopropyl.

, и R^f выбирают из группы, состоящей из: H, C_1-4алкила, CH₂CH₂OH, CH₂CF₃, циклопропила, фенила и фенила, замещенного CF₃.An additional embodiment of the invention is a compound of formula (I) where R ² is:

, and R ^f is selected from the group consisting of: H, C _1-4 alkyl, CH ₂ CH ₂ OH, CH ₂ CF ₃ , cyclopropyl, phenyl and phenyl substituted with CF ₃ .

, и R^g представляет собой H, OCH₃ или CF₃.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

, and R ^g is H, OCH ₃ or CF ₃ .

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

или

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

or

.

или

, и R^a независимо выбран из группы, состоящей из: H, Cl, F, C_1-4алкила, ОC_1-4алкила и C_1-4галогеналкила; и R^b представляет собой CH₃ или CH(CH₃)₂.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

or

, and R ^a is independently selected from the group consisting of: H, Cl, F, C _1-4 alkyl, OC _1-4 alkyl, and C _1-4 haloalkyl; and R ^b is CH ₃ or CH(CH ₃ ) ₂ .

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

.An additional embodiment of the invention is a compound of formula (I) wherein R ² is

.

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

Дополнительный вариант осуществления изобретения представляет собой соединение формулы (I), где R² представляет собой

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) wherein R ² is

An additional embodiment of the invention is a compound of formula (I) where R ² is

An additional embodiment of the invention is a compound of formula (I) where R ² is

An additional embodiment of the invention is a compound of formula (I) where R ² is

An additional embodiment of the invention is a compound of formula (I) where R ² is

An additional embodiment of the invention is a compound of formula (I) where R ³ is

An additional embodiment of the invention is a compound of formula (I) wherein R ³ is cyclopropyl and R ⁴ is CH ₃ .

In a further embodiment, this invention provides a compound of formula (I) wherein R ³ is 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; and R ⁴ is CH _3.

A further embodiment of the invention is a compound of formula (I) wherein R ³ is 3-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, and 4- chloro-3-fluorophenyl.

An additional embodiment of the invention is a compound of formula (I) wherein R ⁴ is CH ₃ .

An additional embodiment of the invention is a compound of formula (I) wherein R ⁴ is cyclopropyl.

, где R^a представляет собой F, Cl или OCH₃, R^a1 представляет собой OCH_3, CH₃ или 2H-1,2,3-триазол-2-ил, и R⁴ представляет собой CH_3. An additional embodiment of the invention is a compound of formula (I) wherein R² represents

, where R^a is F, Cl or OCH₃, R^a1 is OCH_3, CH₃or 2H-1,2,3-triazol-2-yl, and R⁴ is CH_3.

An additional embodiment of the invention is a compound of formula (I) having formula (IA):

Where

R ² is selected from the group consisting of:

(a)

(b)

(c)

(d)

R ⁴ is CH ₃ or cyclopropyl;

R ^q is halogen or CHF ₂ ; And

n is 0, 1 or 2;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a compound of formula (I) having formula (IB):

Where

R ² is phenyl optionally independently substituted with one or two substituents selected from the group consisting of: halo, C _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, NH(C =O)(CH ₃ ),

Where

R ^a is selected from the group consisting of: H, halogen, C _1-4 alkyl, OC _1-4 alkyl and C _1-4 haloalkyl;

R ^b is C _1-4 alkyl;

R ^c represents H or CF _3;

R ^d is H or halogen.

each R ^q is independently selected from the group consisting of: Cl, F, CF ₃ and OCH ₃ ; And

n is 0, 1, 2, or 3;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a compound of formula (I) having formula (IC):

Where

R ² is selected from the group consisting of:

(a) a 5-membered heteroaryl selected from the group consisting of:

и

And

,

,

,

,

,

,

,

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyridinyl substituted with C _1-4 alkyl or OC _1-4 alkyl; and pyridinyl, the pyridinyl being substituted with one or two substituents each independently selected from the group consisting of halo, C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, cyclopropyl, NH ₂ , CN, N( CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

And

;

Where

R ^a is selected from the group consisting of: H, halogen, OC _1-4 alkyl and C _1-4 haloalkyl;

R ^b is C _1-4 alkyl;

R ^e is selected from the group consisting of: F, C _1-4 alkyl, CF ₂ H, CF ₃ , OCH ₃ and cyclopropyl;

R ^f is selected from the group consisting of: H, C _1-4 alkyl, cyclopropyl and phenyl;

R ^g is H or CF ₃ ; And

R ³ is phenyl substituted with one, two or three substituents each independently selected from the group consisting of: Cl and F;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

.An additional embodiment of the invention is a compound of formula (I) comprising formula (IC) where R ² is:

.

An additional embodiment of the invention is a compound of formula (I) comprising formula (IC) where R ² is:

An additional embodiment of the invention is a compound of formula (I) having the formula (ID):

Where

Ring A is selected from the group consisting of:

(a) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

; и

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; And

(b) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

;

,

,

,

,

,

,

,

,

,

And

;

Where

R ^a is selected from the group consisting of: H, Cl, F, CH ₃ , OCH ₃ , CF ₃ and CF ₂ H;

R ^b is H or CH ₃ ;

R ^c is H or CF ₃ ;

R ^d is selected from the group consisting of: H, Cl and F;

R ^e is selected from the group consisting of: H, C _1-4 alkyl and cyclopropyl;

R ⁱ is selected from the group consisting of: H, Cl, Br, CH ₃ , CF ₃ , OH and OCH ₂ CH ₂ F;

R ^j is selected from the group consisting of: H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ; And

R ³ is cyclopropyl, 1-methyl-1H-indol-2-yl or phenyl substituted with one, two or three substituents each independently selected from the group consisting of: Cl, F, CH ₃ , OCH ₃ and CF ₃ ;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a compound of formula (I) comprising formula (ID) where R ³ is:

An additional embodiment of the invention is a compound of formula (I) comprising formula (ID) wherein ring A is:

An additional embodiment of the invention is a compound of formula (I) comprising formula (ID) wherein ring A is:

An additional embodiment of the invention is a compound selected from the group consisting of compounds of formula (I), formula (IA), formula (IB), formula (IC), formula (ID), or combinations thereof.

An additional embodiment of the present invention is a compound as shown in Table 1 below.

Table 1.

No. approx. Connection name 1 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin- 6-yl) methanone; 2 ((5R,9S)-3-Cyclopropyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6- yl) methanone; 3 racemic-(2-Chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) methanone; 4 (2-Chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; 5 (2-Chloro-3-methoxyphenyl) ((5S,9R)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; 6 racemic-(2-(1H-1,2,4-Triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7 racemic-(3-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 8 racemic-(4-(1H-1,2,4-Triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 9 racemic-(3-(1H-Imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazol-10-yl) methanone; 10 racemic-(1-Methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; eleven racemic-(5-Chloro-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 12 racemic-(5-Methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 13 racemic-(4-Bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 14 racemic-(5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 15 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1- phenyl-1H-1,2,4-triazol-3-yl)methanone; 16 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1- phenyl-1H-pyrazol-3-yl) methanone; 17 racemic-(5-Methoxy-1-phenyl-1H-pyrazol-3-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 18 racemic-(1-Methyl-1H-indol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 19 racemic-(5-Chloro-1H-indol-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; 20 racemic-(7-Methyl-1H-indazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; 21 racemic-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 22 racemic-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 23 racemic-(4-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 24 racemic-(1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 25 racemic- [1,2,4] Triazolo[1,5-a] pyridin-5-yl((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 27 racemic-(4-Chloroquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) methanone; 28 racemic-(4-Hydroxyquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) methanone; 29 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin- 5-yl) methanone; thirty racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin- 6-yl) methanone; 31 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinazolin- 6-yl) methanone; 32 racemic-((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)(2- (trifluoromethyl)-1,8-naphthyridin-3-yl) methanone; 33 racemic-(2-Chloro-3-methoxyphenyl) ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; 34 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 35 racemic-(1,4-Dimethyl-1H-pyrazol-3-yl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 36 ((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; 37 racemic-((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 38 ((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 39 racemic-(2-Chloro-3-methoxyphenyl) ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; 40 racemic-((5R,9S)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-phenyl-1H-1,2,4-triazol-3-yl) methanone; 41 ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( furo[3,2-b]pyridin-6-yl) methanone; 42 racemic-((5R,9S)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 43 ((5S,9R)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 44 ((5R,9S)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 45 racemic-((5R,9S)-2-Cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 46 (3-(1H-1,2,4-Triazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 47 (3-(1H-Pyrazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 48 (3-(1H-Pyrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 49 (3-(1H-Tetrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 50 (2-Chloro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 51 (4-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 52 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-isopropyl-1H-1,2,4-triazol-3-yl)methanone; 53 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; 54 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl) methanone; 55 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; 56 (1-(3-Chlorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 57 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl) methanone; 58 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; 59 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; 60 (1-Benzyl-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 61 Benzo[d]isoxazol-3-yl((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 62 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-indazol-3-yl) methanone; 63 racemic-((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 64 ((5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinoxalin-6-yl) methanone; 65 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-(2-fluoroethoxy)quinolin-6-yl)methanone; 66 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(2-fluoroethoxy)phenyl)methanone; 67 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(2-(fluoro-18F)ethoxy)phenyl)methanone; 68 racemic-(2-(2H-1,2,3-Triazol-2-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 69 (2-(1H-1,2,4-Triazol-5-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 70 (2-(5-Chloro-1H-1,2,4-triazol-3-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 71 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone; 72 (3-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 73 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; 74 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) methanone; 75 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-fluoro-2-(oxazol-2-yl)phenyl)methanone; 76 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(pyrimidin-2-yl)phenyl)methanone; 77 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methoxy-1-methyl-1H-pyrazol-4-yl)methanone; 78 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; 79 racemic-(5-Cyclopropyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 80 racemic-(5-Cyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 81 racemic-(3-Cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4, 5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 82 racemic-(5-Cyclopropyl-1-phenyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 83 racemic-(5-Cyclopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 84 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 85 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)methanone; 86 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 87 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-fluoropyridin-4-yl)methanone; 88 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; 89 (5-Aminopyridin-2-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 90 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxybenzofuran-2-yl) methanone; 91 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (2-methylbenzo[d]oxazol-6-yl) methanone; 92 (2-Aminobenzo[d]oxazol-6-yl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 93 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (furo[3,2-b]pyridin-2-yl) methanone; 94 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-c]pyridin-4-yl)methanone; 95 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone; 96 racemic-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 97 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; 98 ((5S,9R)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 99 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (isoquinolin-3-yl) methanone; 100 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-7-yl)methanone; 101 (4-Bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 102 (3-Bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 103 (8-Bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 104 (2-Chloroquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 105 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-5-yl)methanone; 106 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-6-yl) methanone; 107 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-(trifluoromethyl)quinolin-6-yl)methanone; 108 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-hydroxyquinolin-6-yl)methanone; 109 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxyquinolin-3-yl)methanone; 110 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-nitroquinolin-6-yl) methanone; 111 (8-Aminoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 112 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinazolin-7-yl) methanone; 113 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinoxalin-6-yl) methanone; 114 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinazolin-6-yl) methanone; 115 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylquinoxalin-6-yl)methanone; 116 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (7-fluoroquinoxalin-6-yl) methanone; 117 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,6-naphthyridin-5-yl) methanone; 118 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-3-yl)methanone; 119 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-4-yl)methanone; 120 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,7-naphthyridin-4-yl)methanone; 121 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,6-naphthyridin-4-yl)methanone; 122 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,5-naphthyridin-2-yl) methanone; 123 6-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-1-(2-fluoroethyl)quinoline-4(1H)-one; 124 6-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one; 125 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; 126 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 127 racemic-((5R,9S)-3-(3,4-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 128 ((5R,9S)-3-(3,4-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; 129 racemic-((5R,9S)-3-(3,4-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 130 ((5R,9S)-3-(3-Fluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 131 ((5R,9S)-3-(4-Chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 132 ((5R,9S)-3-(3-Chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 133 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 134 ((5R,9S)-3-(3-Chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; 135 ((5R,9S)-3-(3-Chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl)methanone; 136 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylbenzo[d]oxazol-6-yl)methanone; 137 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl)methanone; 138 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl)methanone; 139 ((5R,9S)-3-(3,5-Dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 140 ((5R,9S)-3-(3,5-Dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; 141 (3-(4H-1,2,4Ttriazol-4-yl)phenyl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 142 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; 143 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxy-1-methyl-1H-pyrazol-4-yl) methanone; 144 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 145 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 146 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; 147 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; 148 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 149 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-b]pyridin-2-yl)methanone; 150 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,5-a]pyridin-8-yl)methanone; 151 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,2-a]pyridin-3-yl)methanone; 152 (4-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 153 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; 154 racemic-((5R,9S)-3-(3-(Difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinolin-6-yl) methanone; 155 racemic-((5R,9S)-3-(3-(Difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinoxalin-6-yl) methanone; 156 ((5R,9S)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone; 157 (3-Chloro-5-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 158 N-(3-Methoxy-5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole-10-carbonyl)phenyl)acetamide; 159 (3-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 160 (2-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 161 (3-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 162 (4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 163 (5-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 164 (4-Methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 165 (5-Methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 166 (2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 167 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone; 168 (2-(1H-Imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 169 (5-Fluoro-2-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 170 (3-(1-Methyl-1H-pyrazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 171 (3-(4-Fluoro-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 172 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; 173 (3-(4-Methoxy-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 174 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; 175 (3-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 176 (5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 177 (3-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 178 (3-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 179 (4-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 180 (5-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 181 (2-(2H-1,2,3-Triazol-2-yl)-4-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 182 (2-(2H-1,2,3-Triazol-2-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 183 (2-(1H-1,2,3-Triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 184 (3-Methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 185 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)methanone; 186 (3,4-Dihydro-2H-pyrano[3,2-b]pyridin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 187 (6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 188 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methanone; 189 (6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 190 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone; 191 (1-(tert-Butyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 192 (5-Ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 193 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; 194 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)methanone; 195 (5-Methoxy-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 196 (1-(3-Fluorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 197 (1-(4-Fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)- 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 198 (1-(2-Methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 199 (1-(3-Methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 200 (4-Methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 201 (6-Methoxypyridin-2-yl) ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 202 (4-Methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 203 (5-Methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 204 (6-Methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 205 (5-Isopropoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 206 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-(trifluoromethoxy)pyridin-2-yl)methanone; 207 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(trifluoromethoxy)pyridin-2-yl)methanone; 208 6-((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-carbonyl) picolinonitrile; 209 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazin-2-yl)methanone; 210 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-4-yl)methanone; 211 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyridazin-4-yl)methanone; 212 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-5-yl)methanone; 213 (5-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 214 (6-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 215 (6-(1H-Pyrrol-1-yl) pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 216 (6-(1H-Imidazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 217 (6-Methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 218 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone; 219 1-(5-((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-3-yl)pyrrolidin-2-one; 220 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-morpholinopyridin-3-yl)methanone; 221 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylindolizin-6-yl)methanone; 222 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (2-methylbenzo[d]oxazol-6-yl) methanone; 223 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-3-yl)methanone; 224 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 225 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-5-yl)methanone; 226 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-6-yl)methanone; 227 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-2-yl)methanone; 228 Imidazo[1,2-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 229 Imidazo[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 230 Imidazo[1,5-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 231 Imidazo[1,2-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 232 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-3-yl)methanone; 233 (1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 234 (1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 235 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-b]pyridazin-5-yl)methanone; 236 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-a]pyrazin-8-yl)methanone; 237 (4-Methoxy-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 238 (1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 239 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-b]pyridazin-3-yl)methanone; 240 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-2-yl)methanone; 241 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; 242 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 243 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone; 244 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrazin-3-yl)methanone; 245 Imidazo[1,2-b]pyridazin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 246 Imidazo[1,2-b]pyridazin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 247 [1,2,4]Triazolo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 248 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)methanone; 249 Imidazo[1,2-a]pyrimidin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 250 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-4-yl)methanone; 251 Isoquinolin-1-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 252 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 253 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-7-yl)methanone; 254 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinazolin-4-yl)methanone; 255 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 256 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylquinoxalin-6-yl)methanone; 257 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-2-yl)methanone; 258 Cinnolin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 259 Cinnolin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl) methanone; 260 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-2-yl)methanone; 261 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-3-yl)methanone; 262 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,6-naphthyridin-8-yl)methanone; 263 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 264 ((5R,9S)-3-(3,5-Difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; 265 ((5R,9S)-3-(3,5-Difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; 266 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 267 ((5R,9S)-3-(3,4-Difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone; 268 ((5R,9S)-3-(3,4-Difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; 269 ((5R,9S)-2-Methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinolin-6-yl) methanone; And 270 racemic-((5R,9S)-2-Methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(quinolin-6-yl)methanone;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

Table 2.

No. approx. Connection name 271 (4-Methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 272 (2-Fluoro-4-methylphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 273 (2-Fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 274 (3-Fluoro-5-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 275 (3-Fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 276 (4-Fluoro-3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 277 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 278 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-5-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 279 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 280 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 281 (4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 282 (3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 283 (5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 284 (5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 285 (2-(2H-1,2,3-Triazol-2-yl)-3-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 286 (2-(4-Methyl-2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 287 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)phenyl)methanone; 288 (5-Methoxy-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 289 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanone; 290 (6-Isopropylpyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 291 (6-Methoxypyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 292 (6-(Dimethylamino)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 293 (5-Methoxy-4-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 294 (6-Methoxy-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 295 (5-Fluoro-6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 296 (5-Fluoro-2-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 297 (5,6-Dimethoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 298 (5,6-Dimethoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 299 (3-Chloro-2-methoxypyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 300 (5-Chloro-6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 301 (4-Chloro-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 302 (4-Chloro-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 303 (3-Chloro-5-fluoropyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 304 (6-Cyclopropyl-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 305 1-(5-((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-2-yl)cyclopropan-1-carbonitrile; 306 (2-(1H-Pyrazol-1-yl)pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 307 (4-(1H-Pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 308 (4-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 309 (6-(1H-Pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 310 (6-Methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 311 (4-Methoxy-5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 312 (6-Methyl-3-(1H-1,2,4-triazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 313 (5-(4H-1,2,4-Triazol-4-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 314 (4-(4H-1,2,4-Triazol-4-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 315 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)methanone; 316 (5-(2H-1,2,3-Triazol-2-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 317 (3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 318 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; 319 (1,5-Dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 320 (5-Ethyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 321 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone; 322 (5-Methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 323 (3-Methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 324 (3-Fluoro-1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 325 (5-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 326 (1-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 327 (1-Cyclopropyl-3-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 328 (3-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 329 Indolizin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 330 (4-Fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 331 (6-Fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 332 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 333 (4-Methoxypyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 334 (6-Methoxypyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 335 Imidazo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 336 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,5-a]pyridin-6-yl)methanone; 337 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyridin-6-yl)methanone; 338 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-6-yl)methanone; 339 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-5-yl)methanone; 340 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-5-yl)methanone; 341 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-6-yl)methanone; 342 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-6-yl)methanone; 343 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-5-yl)methanone; 344 Imidazo[1,2-a]pyridin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 345 (7-Fluorimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 346 (7-Chlorimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 347 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl) methanone; 348 (2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 349 ((5R,9S)-3-(3-Fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 350 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone; 351 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone; 352 (2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 353 (2-Methyl-2H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 354 (2,7-Dimethylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 355 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone; 356 (5-Isopropyl-3-methylpyrazolo[1,5-a]pyrimidin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 357 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,3,5-trimethylpyrazolo[1,5-a]pyrimidin-7-yl)methanone; 358 (7-Cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 359 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 360 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-b]pyridazin-3-yl)methanone; 361 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyrazin-8-yl)methanone; 362 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,5,8-trimethylimidazo[1,2-a]pyrazin-3-yl)methanone; 363 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone; 364 (2,7-Dimethylimidazo[1,2-b]pyridazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 365 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methanone; 366 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone; 367 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone; 368 (1-Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 369 (1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 370 [1,2,4]Triazolo[4,3-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 371 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyrazin-1-yl)methanone; 372 ((5R,9S)-3-(3-Fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl)methanone; 373 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methylquinolin-6-yl)methanone; 374 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-hydroxyquinolin-6-yl)methanone; 375 6-((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl) quinoline 1-oxide; 376 ((5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl-4-t) methanone; 377 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylquinazolin-4-yl)methanone; 378 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2-d) methanone; 379 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2,3-d2) methanone; 380 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 381 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; And 382 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,6,6-trimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)methanone;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the present invention is a compound selected from the group consisting of the following compounds:

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a pharmaceutical composition containing:

(A) a therapeutically effective amount of at least one compound selected from the compounds of formula (I):

Where

R ² is selected from the group consisting of:

;(a)

;

,

,

,

,

,

,

,

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyridinyl substituted with C _1-4 alkyl or OC _1-4 alkyl; and pyridinyl, wherein the pyridinyl is substituted with one or two substituents each independently selected from the group consisting of halo, C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, C _3-6 cycloalkyl, NH ₂ , CN, N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

And

;

(c) a 5-membered heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

и

;

,

,

,

,

,

,

,

And

;

(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

;

,

,

,

,

,

,

,

,

,

,

,

And

;

(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

; и

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; And

(f)

,

,

,

,

,

,

и

;

,

,

,

,

,

,

And

;

R ^a is selected from the group consisting of: H, halogen, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 haloalkyl;

R ^a1 is selected from the group consisting of: C _1-4 alkyl; OC _1-4 alkyl; OC _1-4 haloalkyl; N(C=O)CH ₃ ; oxazol-2-yl; pyrimidin-2-yl; and a 5-membered heteroaryl ring containing two, three or four nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one R ^a member;

R ^b is H or C _1-4 alkyl;

R ^c is H or C _1-4 haloalkyl;

R ^d is H or halogen.

R ^e is selected from the group consisting of: H, halogen, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl and C _3-6 cycloalkyl;

R ^f is selected from the group consisting of: H, C _1-4 alkyl, CH ₂ CH ₂ OH, C _1-4 haloalkyl, cyclopropyl, phenyl and phenyl substituted with CF ₃ ;

R ^g is selected from the group consisting of: H, OC _1-4 alkyl and C _1-4 haloalkyl;

R ⁱ is selected from the group consisting of: H, halo, C _1-4 alkyl, C _1-4 haloalkyl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, and C _3-6 cycloalkyl;

R ^j is selected from the group consisting of: H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ;

R ³ is selected from the group consisting of:

(g) phenyl, where phenyl is independently substituted with one, two or three substituents each selected from the group consisting of halo, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl;

(h) 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; And

(i) cyclopropyl; And

R ⁴ is C _1-4 alkyl or C _3-4 cycloalkyl;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers

compounds of formula (I),

and (B) at least one pharmaceutically acceptable excipient.

A further embodiment of the invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IA), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of formula (IA), pharmaceutically acceptable prodrugs of compounds of formula (IA), and pharmaceutically acceptable active metabolites of formula (IA); and at least one pharmaceutically acceptable excipient.

A further embodiment of the invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IB), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of formula (IB), pharmaceutically acceptable prodrugs of compounds of formula (IB), and pharmaceutically acceptable active metabolites of formula (IB); and at least one pharmaceutically acceptable excipient.

A further embodiment of the invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (IC), as well as pharmaceutically acceptable salts, N-oxides or solvates of compounds of formula (IC), pharmaceutically acceptable prodrugs of compounds of formula (IC), and pharmaceutically acceptable active metabolites of the formula (IC); and at least one pharmaceutically acceptable excipient.

A further embodiment of the invention is a pharmaceutical composition comprising an effective amount of at least one compound of formula (ID), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (ID), pharmaceutically acceptable prodrugs of compounds of formula (ID), and pharmaceutically acceptable active metabolites of the formula (ID); and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceutical composition containing an effective amount of at least one compound listed in Table 1 (as well as Table 2), as well as pharmaceutically acceptable salts, N-oxides or solvates of the compounds listed in Table 1 (as well as in table 2), pharmaceutically acceptable prodrugs of the compounds listed in table 1, and pharmaceutically active metabolites listed in table 1 (as well as in table 2); and at least one pharmaceutically acceptable excipient.

Also within the scope of the invention are the enantiomers and diastereomers of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)). Also within the scope of the invention are pharmaceutically acceptable salts, N-oxides or solvates of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)). Also within the scope of the invention are pharmaceutically acceptable prodrugs of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)) and pharmaceutically active metabolites of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)).

Also within the scope of the invention are isotopic variants of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), such as, for example, the deuterated compounds of formula (I). In addition, pharmaceutically acceptable salts, N-oxides or solvates of isotopic variants of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)) are within the scope of the invention. In addition, pharmaceutically acceptable prodrugs from isotopic variants of the compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)) and pharmaceutically active metabolites of isotopic variants of the compounds of formula (I) are within the scope of the invention. (as well as formulas (IA), (IB), (IC) and (ID)).

In a further embodiment, the invention provides a method of treating a subject who has been diagnosed with a disease, disorder, or condition, or is suffering from a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound, selected from compounds of formula (I):

Where

R ² is selected from the group consisting of:

;(a)

;

,

,

,

,

,

,

,

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyridinyl substituted with C _1-4 alkyl or OC _1-4 alkyl; and pyridinyl, wherein the pyridinyl is substituted with one or two substituents each independently selected from the group consisting of halo, C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, C _3-6 cycloalkyl, NH ₂ , CN, N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

And

;

(c) a 5-membered heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

и

;

,

,

,

,

,

,

,

And

;

(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, и

;

,

,

,

,

,

,

,

,

,

,

, And

;

(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

и

; и

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; And

(f)

,

,

,

,

,

,

и

;

,

,

,

,

,

,

And

;

R ^a is selected from the group consisting of: H, halogen, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 haloalkyl;

R ^a1 is selected from the group consisting of: C _1-4 alkyl; OC _1-4 alkyl; OC _1-4 haloalkyl; N(C=O)CH ₃ ; oxazol-2-yl; pyrimidin-2-yl; and a 5-membered heteroaryl ring containing two, three or four nitrogen members, wherein the 5-membered heteroaryl ring is optionally substituted with one R ^a member;

R ^b is H or C _1-4 alkyl;

R ^c is H or C _1-4 haloalkyl;

R ^d is H or halogen.

R ^e is selected from the group consisting of: H, halogen, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl and C _3-6 cycloalkyl;

R ^f is selected from the group consisting of: H, C _1-4 alkyl, CH ₂ CH ₂ OH, C _1-4 haloalkyl, cyclopropyl, phenyl and phenyl substituted with CF ₃ ;

R ^g is selected from the group consisting of: H, OC _1-4 alkyl and C _1-4 haloalkyl;

R ⁱ is selected from the group consisting of: H, halo, C _1-4 alkyl, C _1-4 haloalkyl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, and C _3-6 cycloalkyl;

R ^j is selected from the group consisting of: H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ;

R ³ is selected from the group consisting of:

(g) phenyl, where phenyl is independently substituted with one, two or three substituents each selected from the group consisting of halo, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl;

(h) 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; And

(i) cyclopropyl; And

R ⁴ is C _1-4 alkyl or C _3-4 cycloalkyl;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers, requiring this subject.

An additional embodiment of the invention is a method of treating a subject who has been diagnosed with a disease, disorder or condition, or who suffers from a disease, disorder or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound, selected from compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), enantiomers and diastereomers of compounds of formula (I), isotopic variants of compounds of formula (I) and pharmaceutically acceptable salts of all of the above connections.

Embodiments of this invention are compounds of formula (II),

Where

R ⁵ is selected from the group consisting of:

.(a) phenyl optionally independently substituted with one or two substituents selected from the group consisting of halo, OC _1-4 alkyl, and

.

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of:

,

And

;

(c) a 5-membered heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(f)

,

и

;

,

And

;

Where

R ^k is selected from the group consisting of: H, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ^m is selected from the group consisting of: H, C _1-4 alkyl and C _1-4 haloalkyl;

R ⁿ is H or OC _1-4 alkyl;

R ^o is H or C _1-4 alkyl;

R ^p is selected from the group consisting of: H, halogen, C _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 alkyl; And

R6 is phenyl independently substituted with one, two or three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl and OC1-4 alkyl;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

.An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

.

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁵ is

An additional embodiment of the invention is a compound of formula (II) wherein R ⁶ is

An additional embodiment of the present invention is a compound as shown in Table 3 below.

Table 3

No. approx. Connection name 26 racemic-((5R,8S)-2-Methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl) (quinolin-6- silt) methanone; 383 (3-Chlorophenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 384 (3-Methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 385 ((5R,8S)-3-(2,5-Difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)( 3-methoxyphenyl) methanone; 386 (3-Methoxyphenyl)((5R,8S)-2-methyl-3-(2,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 387 ((5R,8S)-3-(2,3-Difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)( 3-methoxyphenyl) methanone; 388 (2,3-Dimethoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazol-9-yl)methanone; 389 (2-Fluoro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 390 (2-Chloro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 391 (6-Methoxypyridin-2-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 392 (1,5-Dimethyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 393 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3-fluoro-5-methylphenyl)-2-methyl-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 394 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 395 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,4-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 396 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(2,4-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 397 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,5-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 398 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(2,3,4-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 399 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 400 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)methanone; 401 (1H-Indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 402 (6-Fluoro-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 403 (2,3-Dimethyl-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 404 (1H-Indazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 405 (1H-Benzo[d]imidazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 406 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 407 Furo[3,2-c]pyridin-4-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 408 (1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 409 (1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 410 Imidazo[1,2-a]pyridin-5-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 411 Imidazo[1,2-a]pyridin-3-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 412 (2-Chlorimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 413 (7-Methoxyimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 414 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 415 (2,5-Dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6, 7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 416 (2,6-Dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6, 7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 417 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 418 (5-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 419 (2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 420 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone; 421 (5-Methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4 ,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 422 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyridin-3-yl)methanone; 423 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 424 (6-Methoxypyrazolo[1,5-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 425 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)methanone; 426 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyrazin-3-yl)methanone; 427 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; 428 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone; 429 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 430 (1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 431 ((5R,8S)-2-Methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)(quinolin-6-yl) methanone; 432 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-8-yl)methanone; 433 ((5S,8R)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-6-yl)methanone; 434 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-6-yl)methanone; 435 (2,4-Dimethylquinolin-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5, 8-epimincyclohepta[c]pyrazol-9-yl)methanone; 436 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(6-methylquinolin-8-yl)methanone; 437 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinoxalin-6-yl)methanone; 438 (2,3-Dimethylquinoxalin-6-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5, 8-epimincyclohepta[c]pyrazol-9-yl)methanone; 439 ((5R,8S)-2-Methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)(quinoxalin-5-yl) methanone; 440 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(1,5-naphthyridin-3-yl)methanone; 441 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 442 ((5R,8S)-2-Methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 443 Isochroman-7-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; And 444 (2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.

An additional embodiment of the invention is a pharmaceutical composition containing:

(A) a therapeutically effective amount of at least one compound selected from the compounds of formula (II),

Where

R ⁵ is selected from the group consisting of:

.(a) phenyl optionally independently substituted with one or two substituents selected from the group consisting of halo, OC _1-4 alkyl, and

.

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of:

,

And

;

(c) a 5-membered heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(f)

,

и

;

,

And

;

Where

R ^k is selected from the group consisting of: H, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ^m is selected from the group consisting of: H, C _1-4 alkyl and C _1-4 haloalkyl;

R ⁿ is H or OC _1-4 alkyl;

R ^o is H or C _1-4 alkyl;

R ^p is selected from the group consisting of: H, halogen, C _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 alkyl; And

R6 is phenyl independently substituted with one, two or three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl and OC1-4 alkyl;

and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers

compounds of formula (II);

and (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceutical composition containing an effective amount of at least one compound listed in table 3, as well as pharmaceutically acceptable salts, N-oxides or solvates of the compounds listed in table 3, pharmaceutically acceptable prodrugs of the compounds listed in table 3 and pharmaceutically active metabolites listed in table 3; and at least one pharmaceutically acceptable excipient.

In a further embodiment, the invention provides a method of treating a subject who has been diagnosed with a disease, disorder, or condition, or is suffering from a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to the subject in need of such treatment an effective amount of at least one compound selected from compounds of formula (II):

Where

R ⁵ is selected from the group consisting of:

.(a) phenyl optionally independently substituted with one or two substituents selected from the group consisting of halo, OC _1-4 alkyl, and

.

,

и

;(b) a 6-membered heteroaryl selected from the group consisting of:

,

And

;

(c) a 5-membered heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

(e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

и

;

,

And

;

(f)

,

и

;

,

And

;

Where

R ^k is selected from the group consisting of: H, halo, C _1-4 alkyl and C _1-4 haloalkyl;

R ^m is selected from the group consisting of: H, C _1-4 alkyl and C _1-4 haloalkyl;

R ⁿ is H or OC _1-4 alkyl;

R ^o is H or C _1-4 alkyl;

R ^p is selected from the group consisting of: H, halogen, C _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 alkyl; And

R6 is phenyl independently substituted with one, two or three substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 haloalkyl and OC1-4 alkyl;

and their pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers, requiring this subject.

Examples of compounds used in the methods of the invention are described below by reference to the following illustrative synthetic schemes for their general preparation and the following specific examples. As will be appreciated by those skilled in the art, to prepare the various compounds described herein, the starting materials can be suitably chosen so that the desired substituents can be carried through the reaction scheme, with or without protection, as appropriate, to obtain the desired product. . Alternatively, it may be necessary or desirable to introduce a suitable group in place of the desired substituent, which can be carried through the reaction scheme and then, if necessary, replaced by the desired substituent. Unless otherwise indicated, all chemical variables are defined as above with reference to formula (I). The reactions can be carried out between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. The reaction mixtures can be heated conventionally or in a microwave oven. The reactions can also be carried out in sealed pressure vessels at a temperature that is above the normal reflux temperature of the solvent.

The following abbreviations and abbreviations are used in this document.

Table:

Term Reduction Acetonitrile ACN, MeCN Water aq. Atmosphere atm Broadened br. diatomaceous earth ^Celite® Dimethyl sulfoxide DMSO diethyl ether Ether, Et ₂ O ethyl acetate EtOAc or EA ethanol EtOH Electrospray ionization IES Normal phase chromatography on silica gel KFH grams G Watch h, hour. High Performance Liquid Chromatography HPLC Hertz Hz Isopropyl alcohol i PrOH, IPA Liquid chromatography with mass spectrometry HCMS: Molar M Mass-to-charge ratio m/z methanol MeOH milligrams mg Minute min Milliliter ml microliter µl millimoly mmol Mass spectrometry MS: Normal N Nuclear magnetic resonance NMR CF₃SO₃- or triflat OTf parts per million ppm Sediment ppt Polytetrafluoroethylene PTFE retention time R _t Room temperature k.t. Saturated sat. Supercritical Fluid Chromatography SFH Temperature T Thin layer chromatography TLC Volume in millimeters of solvent per gram of substrate V or volumes

RECEIVING EXAMPLES

Examples of compounds used in the methods of the invention are described below by reference to illustrative synthetic schemes for their general preparation, as well as the following specific examples.

SCHEME 1

According to CHART 1, Ullmann's copper-mediated substitution of an optionally substituted aryl halide compound of formula (III) wherein R ^a is independently selected from the group consisting of halo, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl; with a nitrogen-containing nucleophilic reagent such as a 5-membered heteroaryl containing 2 or 3 nitrogen members of formula (IV), where R ^a is independently selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 alkyl; in the presence of a copper catalyst such as copper powder, copper (I) iodide, etc.; an inorganic base such as cesium carbonate, potassium carbonate, K ₃ PO ₄ and the like; an auxiliary bidentate amine ligand such as trans-N,N′ -dimethylcyclohexane-1,2-diamine; in an inert high boiling solvent such as nitrobenzene, toluene, xylene, N-methylpyrrolidone (NMP), N,N -dimethylformamide (DMF), etc., at temperatures ranging from 100-200 °C; using traditional or microwave heating; allows you to get the compound of formula (XVIII), where X represents CH. For example, 3-iodobenzoic acid is reacted with 3-(trifluoromethyl)pyrazole, a base such as cesium carbonate, a copper catalyst such as CuI, a ligand such as trans - N,N′ -dimethylcyclohexane-1,2-diamine, in an appropriate solvent such as DMF at temperatures ranging from 100 to 140 °C, under microwave irradiation to form 3-[3-(trifluoromethyl)pyrazol-1-yl]benzoic acid.

SCHEME 2

According to CHART 2, the condensation of an arylhydrazine of formula (V) wherein Ar is and optionally substituted phenyl; with ethyl 2-amino-2-thioxoacetate; in a mixture of acetic acid and toluene; allows you to get an intermediate amine compound of formula (VI). The amino intermediate of formula (VI) is further cyclized with triphosgene to give ethyl 5-oxo-1-aryl-1H-1,2,4-triazole3-carboxylate of formula (VII). The aryl ester of formula (VIII) is synthesized by treating 1,2,4-triazolone of formula (VII) with alkyloxonium salts such as trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate; in a suitable solvent such as dichloromethane (DCM) and the like at temperatures ranging from 0°C to room temperature. Saponification of an ester compound of formula (VIII) with a base such as an aqueous solution of lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran (THF), dioxane, methanol (MeOH), ethanol (EtOH), or a mixture thereof, makes it possible to obtain an acid compound of the formula (IX).

SCHEME 3

According to CHART 3, the triazoles of formula (Xa) and (Xb) are prepared by a [3+2] cycloaddition reaction between azidomethylbenzene and 4,4,4-trifluoro-2-butynic acid ester; in a suitable solvent such as toluene, etc.; at a temperature of approximately 115 °C; during a period of 16 to 24 hours; to obtain a mixture of isomeric compounds of triazole. The hydrolysis of the ester functional group in the compounds of formula (Xa) and (Xb) is carried out under the conditions described above. Decarboxylation is performed with silver carbonate; in a suitable solvent such as dimethyl sulfoxide (DMSO) and the like; in the presence of acetic acid: at a temperature of 120 °C; during the period of 18 hours; to give compounds of formula (XIa) and (XIb) wherein PG is benzyl. Cleavage of the benzyl protecting group of compounds of formula (XIa) and (XIb) is performed according to procedures known to those skilled in the art using standard techniques, including those described in TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, p. 579-580; 620-621. For example, if PG is benzyl, deprotection is performed using 10% palladium on carbon Selcat-Q-6, Pd/C, etc.; in an H ₂ atmosphere at a pressure of 1 atm.; in a suitable solvent such as 1,4-dioxane, ethanol, MeOH, ethyl acetate (EtOAc) or a mixture thereof, preferably 1,4-dioxane; in the presence or absence of HCl over a period of 24 to 78 hours to give 4-(trifluoromethyl)-1H-1,2,3-triazole and 5-(trifluoromethyl)-1H-1,2,3-triazole.

SCHEME 4

According to CHART 4, a compound of formula (XII) wherein R ^b is H is introduced into a metal-mediated cross-coupling reaction; with cycloalkyl boronic acid suitably substituted with a boronic acid ester and the like; a copper catalyst such as Cu(OAc) ₂ , a ligand such as 2,2'-bipyridine, and the like; a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , lithium bis(trimethylsilyl)amide (LHMDS), sodium tert-butoxide (NaOtBu), K ₃ PO ₄ and the like; in a suitable solvent such as toluene, THF, DMF, dioxane, 1,2-dichloroethane, or a mixture thereof; obtaining a mixture of isomeric compounds of ethyl 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylate and ethyl 1-cyclopropyl-3-methyl-1H-pyrazole-4-carboxylate. Hydrolysis of ethyl 1-cyclopropyl-5-methyl-1H-pyrazole-4-carboxylate and ethyl 1-cyclopropyl-3-methyl-1H-pyrazole-4-carboxylate using the previously described methods affords 1-cyclopropyl-5-methyl-1H -pyrazole-4-carboxylic acid; and 1-cyclopropyl-3-methyl-1H-pyrazole-4-carboxylic acid.

A compound of formula (XII) wherein R ^b is CH ₃ is fluorinated using an electrophilic fluorine source such as N -fluorobenzenesulfonimide (NFSI) and a base such as lithium diisopropylamide (LDA); in a suitable solvent such as THF, etc.; at temperatures ranging from -78°C to room. pace.; during the period of 18-24 hours; with the formation of ethyl 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylate. Subsequent acid hydrolysis of ethyl 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylate with HCl at approximately 110°C for 3 hours affords 3-fluoro-1,5-dimethyl-1H-pyrazole-4 -carboxylic acid.

SCHEME 5

According to CHART 5, the compound of formula (XIV) is subjected to palladium-catalyzed cyanation using conditions known to those skilled in the art. For example, a compound of formula (XIV) is reacted with a palladium catalyst such as tetrakis (triphenylphosphine)palladium(0) and the like; zinc cyanide as a nucleophilic reagent; in a suitable solvent such as N,N -dimethylformamide (DMF) and the like; at a temperature of approximately 80 °C; during the period of 18-24 hours; to form a cyano compound. Reduction of the nitro group is carried out with iron in acetic acid to give a compound of formula (XV). The arylamine compound of formula (XV) undergoes a two-step diazotization-iodination reaction under conditions known to those skilled in the art. For example, diazotization of arylamine is carried out using hydrochloric or sulfuric acid in the presence of sodium nitrite; a subsequent iodination reaction with KI produces an iodine compound. Reaction of an iodine intermediate in an Ullmann copper-mediated displacement reaction with a commercially available or synthetically produced 5-membered heteroaryl ring containing 2 or 3 nitrogen members of formula (XIX) to give a compound of formula (XVI). The nitrile compound of formula (XVI) is hydrolyzed with a base such as sodium hydroxide, potassium hydroxide, and the like; in a suitable solvent such as 1,4-dioxane and water; to form a compound of formula (XVIII) wherein X is CH or N (wherein only one value of X may be N); HET ¹ is a 5-membered heteroaryl containing 2 or 3 nitrogen members, and R ^a is H, halogen, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl.

In an alternative method, a compound of formula (XVIII) wherein X is CH or N (wherein only one value of X can be N); is prepared in two steps from a compound of formula (XV). The compound of formula (XV) interacts with diformylhydrazine; in the presence of trimethylsilyl chloride as a Lewis acid; a base such as triethylamine; in a suitable solvent such as pyridine; at a temperature of approximately 100 °C; over a period of approximately 16 hours; allows you to get 1,2,4-triazol-4-yl intermediate connection. Alkaline hydrolysis of a nitrile compound of formula (XVII) is performed with a hydroxide base such as NaOH or KOH in a suitable solvent such as 1,4-dioxane and water to give a compound of formula (XVIII) where X is CH or N ( where only one X value can be N) and HET ¹ is 1,2,4-triazol-4-yl.

SCHEME 6

According to CHART 6, a compound of formula (XVIII) where X is CH, HET ¹ is 1,2,4-triazol-4-yl is obtained in two steps from a compound of formula (XX) where R ^a is halogen or C _1-4 alkyl. In the first step, a compound of formula (XX) where R ^a is halogen or C _1-4 alkyl is reacted with diformylhydrazine, in the presence of trimethylsilyl chloride as a Lewis acid, triethylamine, in a suitable solvent such as pyridine, at a temperature of about 100 °C, over a period of approximately 16 hours to give the 1,2,4-triazol-4-yl intermediate; in the second stage, the saponification is carried out in accordance with the conditions known to those skilled in the art, or the conditions described above.

Similarly, instead of a compound of formula (XX), methyl 4-aminopyridine-2-carboxylate and methyl 5-aminonicotinate can be used to give compounds of formula (XVIII) where only one value of X is NG.

SCHEME 7

According to CHART 7, commercially available or synthetically produced 4-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine reacts with copper-catalyzed cyanation using CuCN, which can function as both a copper catalyst and and as a cyanating agent; with or without addition of CuI; in a suitable solvent such as DMSO, etc.; at a temperature of about 120 °C; over a period of 20 to 48 hours; to give 1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carbonitrile. Hydrolysis of the nitrile to the formation of the corresponding acid is carried out in accordance with the previously described procedures. Similarly, 5-bromo-7-methylimidazo[1,2-a]pyridine is converted to (7-methylimidazo[1,2-a]pyridin-5-yl)(λ ¹ -oxidanyl)methanone.

SCHEME 8

According to CHART 8, 1-aminopyridin-1-th reacts in a 1,3-dipolar addition reaction with a compound of formula (XXII) where R ^a is H, C _1-4 alkyl or C _1-4 haloalkyl; in the presence of a base such as TEA, etc.; 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ); in a suitable solvent such as DMF, etc.; at temperatures ranging from 0 ºC to room. pace. during the period of 16-24 hours; to obtain a compound of formula (XXIII). The hydrolysis of the ester to the formation of the corresponding acid is carried out in accordance with the previously described procedures.

SCHEME 9

According to CHART 9, compounds of formulas (XXVIa, XXVIb and XXVIc) are prepared under conditions known to those skilled in the art by condensation of commercially available or synthetically substituted substituted pyridine. pyridazine and pyrazine amines of the formulas (XXVa, XXVb and XXVc), where R ^a is as defined in paragraph 1, using ethyl 2-chloro-3-oxobutanoate in a suitable solvent such as 1,2-dimethoxyethane (DME) and so on.; at a temperature of 90 ºC for a period of approximately 2-16 hours. The saponification of the esters (XXVIa, XXVIb and XXVIc) to the formation of the corresponding acid is carried out under conditions known to those skilled in the art. For example, using a suitable base such as potassium trimethylsilanylate (TMSOK), NaOH, LiOH, etc. in a suitable solvent such as water/THF/MeOH at a temperature of approximately 60°C for a period of approximately 24 hours, to give compounds of formulas (XXVIIa, XXVIIb and XXVIIc), where M is potassium, Na or Li, preferably potassium.

SCHEME 10

b

b

According to CHART 10, 2-methylquinoxaline-6-carboxylic acid (where R ^b is H) is prepared by the condensation of commercially available or synthetically produced 2-amino-4-aminobenzoic acid with 1,2-dioxoalkanes such as 2- oxopropanal, etc.; in a suitable solvent such as EtOH, etc. at a temperature of 80 ºC for a period of about 16-24 hours to obtain 2-methylquinoxaline-6-carboxylic acid.

Similarly, methyl 3,4-diaminobenzoate (where R ^b is CH ₃ ) is condensed with diethyl oxalate in a suitable solvent such as ethanol, etc.; at a temperature of approximately 140 ºC; over a period of approximately 16-24 hours; allows you to get methyl-2,3-dihydroxyquinoxaline-6-carboxylate. Subsequent chlorination with a chlorinating agent such as thionyl chloride, etc.; neat or in a suitable solvent such as toluene, etc.; followed by the addition of a catalytic amount of DMF; at reflux temperature; allows you to get methyl-2,3-dichloroquinoxaline-6-carboxylate. Palladium catalyzed reductive deuteration of 2,3-dichloroquinoxaline-6-carboxylate methyl ester using a commercially available deuterated reagent such as sodium borodeuteride; in the presence of a palladium catalyst such as 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl ₂ (dppf)) and the like; a base such as N ¹ , N ¹ , N ² , N ² -tetramethylethane-1,2-diamine (TMEDA) and the like; in a suitable solvent such as THF, etc.; at room temperature; over a period of 1-3 hours; allows you to get methylquinoxaline-6-carboxylate-2,3-d ₂ . Saponification of the ester to form the corresponding acid is carried out using conditions known to those skilled in the art, for example using a suitable base such as NaOH, LiOH, KOH, etc., preferably Li; in a suitable solvent such as water/THF/MeOH at room temperature over a period of approximately 1 hour, quinoxaline-6-carboxylic acid-2,3-d ₂ (where M is Li) is obtained. Potassium, sodium and lithium salts are isolated depending on the base used in the saponification process.

SCHEME 11

According to CHART 11, treatment of 4-amino-3-bromobenzoic acid with excess glycerol under Skraup conditions known to those skilled in the art (R.H.F. Manske and M. Kulka, "The Skraup Synthesis of Quinolines"; Org. Reaction, vol. 7, pp. 59-98, 1953), allows you to get 6-carboxy-8-bromoquinoline. For example, the reaction mixture of 4-amino-3-bromobenzoic acid is heated at 140 ºC with the addition of sulfuric acid, glycerol, an oxidizing agent such as nitrobenzene, in the presence of ferrous sulfate, to obtain 6-carboxy-8-bromoquinoline.

SCHEME 12

According to CHART 12, 6,6-dimethylmorpholine-3-carboxylic acid is prepared in two steps from 4-(tert-butyl) 3-methyl 6,6-dimethylmorpholine-3,4-dicarboxylate. In the first step, deprotection of the BOC group is performed according to procedures known to those skilled in the art using standard techniques, including those described in TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, p. 518-525. For example, removal of protective groups in an acidic environment, including in the presence of trifluoroacetic acid (TFA)/CH ₂ Cl ₂ , HCl/dioxane, etc., at room temperature for 2 hours. Subsequent hydrolysis directly in the reaction mixture using a suitable base such as NaOH and the like in a solvent such as MeOH/water affords 6,6-dimethylmorpholine-3-carboxylic acid. Diazotization of 6,6-dimethylmorpholine-3-carboxylic acid is performed using sodium nitrite; in water; in an acidic environment, including in the presence of conc. HCl; at temperatures ranging from 0°C to room temperature; within 16 hours, the resulting nitroso acid is treated with trifluoroacetic anhydride (TFAA) in a suitable solvent such as acetonitrile (ACN) and the like; at room temperature; during a period of 2 hours; to obtain 6,6-dimethyl-6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8-ium-3-olate ( Link : Nikitenko, AA, et al., Org. Process Res. Dev., 2006, 10 (4), pp 712-716)

6,6-Dimethyl-6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8-ium-3-olate undergoes the reaction [3+2] cycloadditions with an alkinoate of formula (XLV) wherein R ⁱ is C _1-4 alkyl; in a suitable solvent such as xylene, etc. at a temperature of approximately 140 ºC; within 2 hours. The subsequent saponification of the two regioisomeric esters obtained to form the corresponding acids is carried out under the conditions described above. For example, using an acceptable base such as NaOH, LiOH, KOH, etc.; in a suitable solvent such as water, THF, MeOH or a mixture thereof; at a temperature of about 60 °C; over a period of approximately 24 hours; to give compounds of formulas (XLIIIa) and (XLIIIb) wherein M is K, Na or Li.

SCHEME 13

According to CHART 13 (1S,8S)-(+)-trans-8-[(R)-phenylethylamino)cyclooct-4-enol and (1R,8R)-(-)-trans-8-[(R) -phenylethylamino]cyclooct-4-enol is prepared according to the methods described in Carroll, F.I., et al., “Synthesis and Pharmacological Characterization of Nicotinic Acetylcholine Receptor Properties of (+)- and (-)-Pyrido-[3, 4-b]homotropanes, Journal of Medicinal Chemistry, 49(11), 3244-3250; 2006.

(1S,8S,Z)-8-(((R)-1-phenylethyl)amino)cyclooct-4-en-1-ol is converted to (1S,2S,5R)-9-((R)-1- phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol in two steps. In the first step, the reaction of (1S,8S,Z)-8-(((R)-1-phenylethyl)amino)cyclooct-4-en-1-ol with mercury(II) chloride in a suitable solvent such as diethyl ether, tetrahydrofuran, dioxane, water, or a mixture thereof, at room temperature for a period of 12-24 hours allows you to get a complex of mercury chloride in the alkenyl functional group. In the second step, the reduction of the aforementioned mercuric chloride complex is carried out by reacting with 3 M sodium hydroxide and a reducing agent such as sodium borohydride at a temperature of approximately 0°C to obtain a cyclized product, which is (1S,2S,5R)-9-(( R)-1-phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol.

Deprotection of chiral (R)-methylbenzyl is performed using hydrogenation conditions known to those skilled in the art and using standard techniques, including those described in TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3 ed. , John Wiley & Sons, 1999; With. 579-580; 620-621. For example, using H ₂ in the presence of a catalyst such as Pd/C etc. in a suitable solvent such as MeOH etc. to give (1S,2S,5R)-9-azabicyclo[3.3 .1] nonan-2-ol.

The amino functional group of (1S,2S,5R)-9-azabicyclo[3.3.1]nonan-2-ol is protected by a carbamate protecting group such as t-butyloxycarbonyl (BOC). For example, reaction of (1S,2S,5R)-9-azabicyclo[3.3.1]nonan-2-ol with BOC anhydride at room temperature for a period of approximately 4-7 hours provides a compound of formula (XXVIII), where PG is BOC.

A compound of formula (XXVIII) is converted to a compound of formula (XXIX) under oxidizing conditions such as a Swern (Moffott-Swern) oxidation. For example, a compound of formula (XXVIII) is treated with DMSO, oxalyl chloride, triethylamine in a suitable solvent such as DCM, etc. to form a compound of formula (XXIX). According to the preferred method, the reaction is initially carried out at -78 °C, and then the reactants are warmed to room temperature and stirred overnight.

The compound of formula (XXIX) is converted to compound (XXX) by treatment with a strong base such as lithium bis(trimethylsilyl)amide (LiHMDS/LHMDS) and the like in a suitable solvent such as THF and the like at a temperature approximately -78°C for a period of approximately 30 minutes. The resulting lithium enolate is taken up in methyl or ethyl cyanoformate at a temperature of approximately -78° C. for 1-3 hours to give a β-keto ester compound of formula (XXX) where PG is BOC and R ^b is C _1-4 alkyl.

SCHEME 14

According to CHART 14, a ketoester compound of formula (XXX) is reacted with a commercially available or synthetically produced hydrazine of formula R ^4a NHNH ₂ in an inert solvent such as toluene, etc., at a temperature of approximately 100°C to obtain a pyrazolone compound of formula (XXXI) wherein R ^4a is C _1-4 alkyl or C _3-6 cycloalkyl.

Preparation of a pyrazolone compound of formula (XXXI) with a sulfonate-based substitutable group such as trifluoromethanesulfonyl (triflate) is carried out by reaction with a triflating agent such as trifluoromethanesulfonic anhydride (Tf ₂ O), a base such as triethylamine (TEA), pyridine, etc. etc., in a suitable solvent such as DCM, etc. Milder triflating agents, such as N-phenylbis(trifluoromethanesulfonimide) (Tf ₂ NPh), a base such as TEA, DIEA, etc., in a suitable a solvent such as DCM and the like; are used to improve selectivity to give a compound of formula (XXXII).

Racemic (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole is prepared according to methods analogous to those described above.

SCHEME 15

According to CHART 15, a compound of formula (XXXII) reacts in a metal-mediated cross-coupling reaction to give a compound of formula (XXXIII) where R^4ais H or C_1-4alkyl, PG is BOC, and R³ is phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of halo or C_1-4haloalkyl; or pyridinyl substituted with CF₃. For example, a compound of formula (XXXII) where R^4a represents H or C_1-4alkyl and PG; reacts with an appropriately substituted commercially or synthetically produced alkyl, cycloalkyl, aryl or heteroaryl boronic acid, boronate ester, etc., in the presence of a palladium catalyst such as [1,1′-bis(di- tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl₂(dtbpf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), [1,1′ -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl₂(dppf)), palladium(II)bis(triphenylphosphine) dichloride (Pd(PPh₃)₂Cl₂) etc., a base such as K₃PO₄, aq. Na solution₂CO₃, Na₂CO₃, Cs₂CO₃ etc., in a suitable solvent such as 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, or a mixture thereof, at temperatures ranging from 60 to 180 °C, using conventional or microwave heating, for a period of about 30 minutes to 16 hours to give a compound of formula (XXXIII).

In an alternative process, tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carboxylate is subjected to a metal-mediated coupling reaction with a commercially available or synthetically produced aryl or heteroaryl boronic acid, a boronate ester of formula R ³ -B(OH) ₂ , where R ³ is phenyl optionally substituted with one , two or three substituents independently selected from the group consisting of halogen, C _1-4 haloalkyl, OC _1-4 alkyl; or 1-methyl-1H-indol-2-yl; using a catalyst such as chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II ) (XPhos Pd G2), etc.; base, such as K ₃ PO ₄ , aq. a solution of Na ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO _{3 ,} etc., in a suitable solvent such as 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, or a mixture thereof, at temperatures in the range 60 to 180°C using conventional or microwave heating over a period of about 30 minutes to 16 hours to give a compound of formula (XIII).

Cleavage of the BOC protecting group of the compound of formula (XXXIII) is performed according to procedures known to those skilled in the art using standard techniques, including those described in TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, p. 518-525. For example, in an acidic environment, including in the presence of TFA/CH ₂ Cl ₂ , HCl/dioxane, etc., allows you to get the compound of formula (XXXIV).

The compound of formula (IB) is prepared by conventional amide bond formation methods such as coupling reactions well known to those skilled in the art (examples: HATU (1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4 ,5- b ]pyridinium 3-oxide hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate) or by converting the acid to the acid chloride). For example, the reaction of a compound of formula (XXXIV) wherein R ^4a is H or C _1-4 alkyl and R ³ is as described in paragraph 1; with a commercially available or synthetically produced acid, wherein the acid is activated with an appropriate activating agent, e.g. a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), optionally in the presence of hydroxybenzotriazole (HOBt) and/or a catalyst such as 4-dimethylaminopyridine (DMAP); a halotrisaminophosphonium salt such as (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or bromtripyrrolidinophosphonium hexafluorophosphate ( ^PyBroP® ); an acceptable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or other suitable coupling agent such as N,N,N',N' -tetramethyl- O- ( 1H -benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene] -1H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinan-2,4, 6-trioxide ( ^T3P® ), etc. The coupling reactions are carried out in a suitable solvent such as DCM, THF, DMF, etc., optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA) or triethylamine (TEA), at a temperature in the range from 0 °C to room. pace. to obtain a compound of formula (IA) or formula (IB).

A compound of formula (IB) (and also a compound of formula (I)) wherein ^R2 is heteroaryl substituted with a reactive functional group such as a hydroxyl group is alkylated with a suitable alkyl halide such as 1-iodoethane, fluoro-2-iodoethane, etc. n. For example, a compound of formula (IB) (as well as a compound of formula (I)) wherein R ² is 4-hydroxyquinoline reacts with fluoro-2-iodoethane; a suitable base such as Cs ₂ CO ₃ , K ₂ CO ₃ , etc.: in a suitable solvent such as N,N-dimethylformamide to give a compound of formula (IA) (and also a compound of formula (I)), where R ² is 4-(2-fluoroethoxy)quinoline.

A compound of formula (IB) (and also a compound of formula (I)), where R ² is quinoline, is oxidized to an N-oxide compound of formula (IB) (and also a compound of formula (I)) using m-chloroperoxybenzoic acid ( m - CPBA) in a suitable solvent such as DCM, chloroform, etc. at temperatures ranging from 0 ºC to room temperature for a period of 30 minutes to 1 hour.

The compound of formula (IB) (as well as the compound of formula (I)) wherein R ² is a bromo-substituted quinoline is subjected to tritiation under conditions known to those skilled in the art. For example, (4-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone is reacted with Pd/C in a suitable solvent (MeOH, etc.), in the presence of gaseous tritium at a pressure of 1 atm. to obtain ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl-4-t) methanone.

A compound of formula (IB) (and also a compound of formula (I)) wherein R ² is heteroaryl substituted with a reactive functional group such as Br is reacted under catalytic halogenation and dehalogenation reaction conditions such as Pd/C and hydrogen gas , under conditions known to those skilled in the art.

SCHEME 15

According to CHART 15, a compound of formula (I) is prepared from a compound of formula (XXXV) in three steps. In the first step, removal of the BOC protecting group as previously described, followed by amide bond coupling and subsequent Suzuki coupling as previously described, affords a compound of formula (I).

SCHEME 16

In accordance with CHART 16, the compound of formula (XXXVIII) is obtained by the method described in JOC 2002, 67, 3479-3486, where PG is BOC. A ketoester compound of formula (XXXVIII) is reacted with commercially available or synthetically produced methylhydrazine in an inert solvent such as toluene and the like at a temperature of about 100° C. to give a compound of formula (XXXIX) wherein PG is BOC.

The preparation of a compound of formula (XXIX) with a sulfonate-based substitutable group such as trifluoromethanesulfonyl (triflate) is carried out by reaction with a triflating agent such as trifluoromethanesulfonic anhydride (Tf ₂ O), a base such as triethylamine (TEA), pyridine, etc. etc., in a suitable solvent such as DCM, etc. Milder triflating agents, such as N-phenylbis(trifluoromethanesulfonimide) (Tf ₂ NPh), a base such as TEA, DIEA, etc., in a suitable solvent such as DCM, etc.; are used to improve selectivity to give compounds of formula (XLa) and (XLb) where PG is BOC. Single enantiomers were isolated by purification (XLa) and (XLb) using chiral SFC.

SCHEME 17

According to CHART 17, a single enantiomeric compound of formula (XLa) (as well as XLb or a racemic mixture) is coupled with a suitably substituted commercially available or synthetically produced alkyl. cycloalkyl, aryl or heteroaryl boric acid, a boronate ester, and the like, in the presence of a palladium-based catalyst under the Suzuki coupling conditions previously described to form a compound of formula (XLI). Removal of the protecting groups is carried out in accordance with the previously described methods. Subsequent amide coupling of a compound of formula (XLII) with a suitably substituted commercially available or synthetically produced acid affords a compound of formula (II).

Compounds of formula (I) (as well as formulas (IA), (IB), (IC), (ID) or (II)) can be converted to the corresponding salts using methods known to those skilled in the art. For example, treatment of an amine of formula (I) with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et ₂ O, CH ₂ Cl ₂ , THF, MeOH, chloroform, or isopropanol makes it possible to obtain the corresponding salt form. In an alternative embodiment, trifluoroacetic or formic acid salts are obtained by purifying compounds under reversed-phase HPLC conditions. Crystalline forms of pharmaceutically acceptable salts of compounds of formula (I) (as well as formulas (IA), (IB), (IC), (ID) or (II)) can be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non-polar solvents (including mixtures of non-polar solvents).

If the compounds according to the present invention have at least one chiral center, they can accordingly exist as enantiomers. Where compounds have two or more chiral centers, they may additionally exist as diastereomers. It should be understood that all such isomers and mixtures thereof are within the scope of the present invention.

Compounds obtained in accordance with the schemes described above, can be obtained in the form of individual forms, such as individual enantiomers, by form-specific synthesis or by resolution. Compounds obtained in accordance with the schemes described above, in an alternative embodiment, can be obtained in the form of mixtures of different forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. When preparing racemic and non-racemic mixtures of enantiomers, individual enantiomers can be isolated using conventional separation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, conversion to diastereomeric adducts, biotransformation, or enzymatic transformation. In the preparation of regioisomeric or diastereomeric mixtures, the individual isomers may, if necessary, be obtained by conventional methods such as chromatography or crystallization.

The following specific examples further illustrate the present invention and various preferred embodiments.

EXAMPLES

Unless otherwise indicated, the following experimental and analytical protocols were used to prepare the compounds described in the examples below and the corresponding analytical data.

Unless otherwise noted, the reaction mixtures were stirred on a magnetic stirrer at room temperature (room temp.) in a nitrogen atmosphere. If the solutions were "dry", this essentially used a drying agent such as Na ₂ SO ₄ or MgSO ₄ . If the mixtures, solutions and extracts were "concentrated", then they were usually concentrated on a rotary evaporator under reduced pressure. Reactions under microwave conditions were carried out in a Biotage initiator or a Discover CEM (Microwave Reactor) instrument.

Normal phase silica gel chromatography (PCC) was performed on silica gel (SiO ₂ ) using pre-filled cartridges.

Preparative reverse phase high performance liquid chromatography (RP-HPLC) was performed with one of:

METHOD A - Agilent HPLC systems with Xterra Prep RP18 column (5 µM, 30×100 or 50×150 mm) or XBridge C18 OBD columns (5 µM, 30×100 or 50×150 mm); mobile phase 5% ACN in 20 mM NH ₄ OH, incubation for 2 min followed by a gradient of 5-99% ACN over 15 min, then incubation at 99% ACN for 5 min; flow rate 40 or 80 ml/min;

or

METHOD B - Shimadzu LC-8A series HPLC systems with Inertsil ODS-3 column (3 µm, 30×100 mm, T=45°C), mobile phase 5% ACN in H ₂ O (both with 0.05% TFA) , holding for 1 min followed by a gradient of 5-99% ACN over 6 min, then holding at 99% ACN for 3 min; flow rate 80 ml/min;

or

METHOD C Shimadzu LC-8A series HPLC system with XBridge C18 OBD column (5 µm, 50×100 mm), mobile phase 5% ACN in H ₂ O (both with 0.05% TFA) held for 1 min followed by gradient 5-99% ACN for 14 min, subsequently maintained at 99% ACN for 10 min with a flow rate of 80 ml/min;

or

METHOD D - Gilson HPLC systems with XBridge C18 column (5 µm, 100×50 mm), mobile phase 5-99% ACN in 20 mM NH ₄ OH for 10 min, subsequently held at 99% ACN for 2 min, speed flow 80 ml/min.

METHOD E: Agilent HPLC system with Gemini-NX C18 column (5 μM, 30×100 mm) and mobile phase 0-90% ACN in 10 mM (NH ₄ )HCO ₃ for 16 min at a flow rate of 30 ml/min Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on either a Jasco preparative SFC system, an APS 1010 system from Berger instruments, or an SFC-PICLAB-PREP 200 system (PIC SOLUTION, Avignon, France). The separation was carried out at 100-150 bar with a flow rate in the range of 40-60 ml/min. The column was heated to a temperature of 35 to 40°C.

Unless otherwise noted, mass spectra (MS) were obtained on an Agilent 1100 Series MSD analyzer using electrospray ionization (ESI) in positive mode. The calculated (calc.) weight corresponds to the exact weight.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. For multiplicity, the following designations are used: s=singlet, d=doublet, t=triplet, k=quartet, m=multiplet, br. = wide. It should be understood that for compounds containing an exchangeable proton, said proton may or may not be visible in the NMR spectrum, depending on the choice of solvent used to plot the NMR spectrum and the concentration of the compound in solution.

Chemical element names were created using ChemDraw Ultra 17.1 software (CambridgeSoft Corp., Cambridge, Massachusetts, USA) or OEMetaChem V1.4.0.4 (Open Eye).

.

Compounds designated R* or S* are enantiomerically pure compounds for which the absolute configuration has not been determined.

Intermediate 1: racemic (5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

Stage A: racemic tert-Butyl (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-epimincycloocta[c]pyrazole-10-carboxylate . To solutionracemic-9-(tert-butyl) 3-ethyl (1S,5R)-2-oxo-9-azabicyclo [3.3.1] nonane-3,9-dicarboxylate (2.5 g, 8.4 mmol) in toluene (30.0 ml ) was added methylhydrazine (0.66 ml, 12.6 mmol) and the resulting mixture was heated at a temperature of 110 ºC for 3 hours. After cooling to room. temp., the solvent was concentrated in vacuo and the crude residue was purified (FCC, SiO₂; 0-10% MeOH/DCM) to give the title compound as an oil (2.3 g, 91% yield). MS (EMI): mass calculated for C₁₅H₂₃N₃O_3, 293.1; obtained m/z, 294.1 [M+H]⁺.

Stage B: racemic tert-Butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole-10-carboxylate. To solutionracemic tert-butyl (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-epimincycloocta[c]pyrazole-10-carboxylate (2.0 g, 6.8 mmol) in dichloromethane (DCM) (30.0 mL) was added N,N-diisopropylethylamine (DIEA/DIPEA/Hunig's base) (1.3 mL, 7.5 mmol) followed by 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.7 g, 7.5 mmol). The reaction mixture was stirred at rt. pace. for 5 h, the solvent was concentratedin a vacuum and the crude residue was purified (FCC, SiO₂; 0-20 EtOAc/hexanes at 220 nm) to give the title compound as an oil (2.5 g, 86% yield). MS (EMI): mass calculated for C₁₆H₂₂F₃N₃O₅S_, 425.1; obtained m/z, 369.9 [M+2H-tert-butyl]⁺.

Stage C: racemic tert-Butyl (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10-carboxylate. Solutionracemictert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole-10-carboxylate (750 mg, 1.8 mmol), phenylboronic acid (645 mg, 5.3 mmol), potassium phosphate (1.1 g, 5.3 mmol) and 1,1'-ferrocendyl-bis(diphenylphosphine) (dppf) (60 mg, 0.1 mmol) in dioxane (6.0 ml) was degassed with nitrogen for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl₂(dppf)) (195 mg, 0.3 mmol) and the resulting mixture was degassed with nitrogen for an additional period of 10 minutes. The reaction mixture was heated in a microwave reactor at 140 ºC for 30 minutes. After cooling to rt, the crude mixture was diluted with brine and extracted using DCM (x3). The combined organic extracts were dried over Na₂SO₄, concentrated in vacuo and purified (FCC, SiO₂; 0-50% EtOAc/hexanes) to give the product as a white solid (605 mg, 97% yield). MS (EMI): mass calculated for C₂₁H₂₇N₃O₂, 353.2; obtained m/z, 354.1 [M+H]⁺.

Stage D racemic (5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole. To solutionracemictert-butyl (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole-10-carboxylate in dichloromethane (DCM) (2.0 ml) was added trifluoroacetic acid (2.0 ml) and the mixture was stirred at room temperature for 1 h. The solvent was concentratedin a vacuumto give the title compound as a white solid (475 g, 95% yield). MS (EMI): mass calculated for C₁₃H₁₅N_3, 253.1; obtained m/z, 254.1 [M+H]⁺.

Intermediate 2: tert -Butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole-10-carboxylate.

Method A

Step A: ( 4Z )-9-Oxabicyclo[6.1.0]non-4-ene. To a solution of 1,5-cyclooctadiene (125 g, 116 mmol) in tetrahydrofuran (175 mL) was added dropwise a solution of 3-chloroperoxybenzoic acid ( m- CPBA) (55%, 300 g, 956 mmol) in chloroform (1.75 L ) and the reaction mixture was stirred at room temperature for 42 hours. The reaction mixture was washed with 20% sodium bisulfite (4×1 L), saturated sodium bicarbonate solution (4×1 L) and brine (2×1 L). The organic layer was dried over sodium sulfate, filtered and evaporated. The mixture was distilled under vacuum (b.o. = 40 ºC at a pressure of 2 mmHg) to obtain the title compound (74.2 g, 51% yield) as a colorless liquid. MS (ESI): mass calculated for C ₈ H ₁₂ O _- 124.1; the resulting m/z, 123.0 [M−H] ⁻ .

Step B: (1S,8S,Z)-8-(((R)-1-Phenylethyl)amino)cyclooct-4-en-1-ol. ( R )-(+)-α-methylbenzylamine (77 ml, 604 mmol, 0.95 g/ml) and 1.2 -epoxy-5-cyclooctene (50 g, 403 mmol) in distilled tetrahydrofuran (300 ml). The reaction mixture was stirred in a sealed tube at 100°C for 48 h, poured into water (500 ml) and the volatiles were evaporated. The aqueous layer was extracted with dichloromethane (3×500 ml), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (120 g, imp.) as a yellow oil. The reaction was repeated with an amount of 99 g (798 mmol). The crude products from both reactions were combined and converted to the hydrochloride salt over 2 batches. Hydrogen chloride (3.88 M in diethyl ether, 82 ml, 318 mmol) was added to 20 g of the crude product. The separated phase was collected and the first batch (3.34 g, 11.8 mmol, 14%) was isolated as a white crystalline solid. To the remaining amount of the crude product (280 g, 114 mmol) in ethyl acetate (560 ml) was added hydrogen chloride (3.88 M in diethyl ether, 560 ml, 2173 mmol). The suspension was stirred at room temperature for 30 min and the precipitated phase was collected. The solid was suspended in ethyl acetate saturated with water (5.6 L) and stirred at 50° C. for 30 min. After cooling to room temperature, the precipitated phase was collected and a second batch (78 g, 277 mmol, 24% yield) was isolated as a white crystalline solid. MS ( _ESI ): mass calculated for C ₁₆ H ₂₃ NO - 245.2; obtained m/z, m/z=246.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.18 (m, 6H), 4.33-4.09 (m, 2H), 3.88 (br. s, 4H), 3.42 (s, 1H), 3.02-2.82 (m, 1H), 2.05-1.85 (m, 2H), 1.79-1.60 (m, 2H), 1.50 (d , J=6.8 Hz, 2H), 1.38-1.27 (m, 2H)

Step C: (1S,2S,5R)-9-((R)-1-phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol. To a solution of mercury(II) chloride (104 g, 383 mmol) in tetrahydrofuran (750 ml) and water (320 ml) was added a solution of (1S,8S, Z)-8-[[(1 R )-1-phenylethyl]amino ]cyclooct-4-en-1-ol (98.0 g, 348 mmol) in tetrahydrofuran (350 ml) and sodium hydroxide (3 M, 116 ml, 348 mmol) and the reaction mixture was stirred at room temperature for 1 day. To the reaction mixture were added sodium hydroxide (3 M, 280 ml, 840 mmol) and a solution of sodium borohydride (13.0 g, 344 mmol) in sodium hydroxide (3 M, 70 ml, 210 mmol) at 0°C, then the reaction mixture stirred at room temperature for 1 day to give the title compound (98 g) which was used in the next step without further purification. LCMS: 58%, t _R =2.019 min, m/z=246.1 [M+H] ⁺ .

Step D: tert-Butyl (1S,2S,5R)-2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate. A mixture of (1 R ,2 S ,5 R )-9-[(1 R )-1-phenylethyl]-9-azabicyclo[3.3.1]nonan-4-ol (98.0 g, crude) and 10% palladium per carbon (42.5 g) in methanol (2.5 L) was stirred at room temperature for 2 h in a hydrogen atmosphere. Di- tert -butyl dicarbonate (175 g, 802 mmol) and triethylamine (56 ml, 402 mmol) were added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered with a ^Celite® pad; and the ^Celite® pad was washed with methanol (2×500 ml). The combined filtrates were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate. The residue was purified by silica gel gradient column chromatography eluting with heptane/ethyl acetate (100:0 → 3:1) to give the first batch of the title compound (43.4 g, 180 mmol, 44% yield) as a yellow oil. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 4.94-4.87 (m, 1H), 4.08-3.87 (m, 2H), 3.66-3.53 (m, 1H ), 1.96-1.31 (m, 10H), 1.39 (s, 9H).

+116.0° (c 0,110, MeOH). МС (ИЭР): масса, рассчитанная для C₁₃H₂₁NO_3, 239.2; полученное m/z, 262,1 [M+Na]⁺. ¹H ЯМР (500 МГц, ДМСО-d ₆) δ 4,49-4,35 (м, 1H), 4,34-4,23 (м, 1H), 2,43-2,24 (м, 3H), 1,83-1,74 (м, 1H), 1,71-1,56 (м, 2H), 1,57-1,33 (м, 4H), 1,43, 1,39 (с, 9H).Step E: tert -Butyl (1R,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate. To a solution of oxalyl chloride (12.9 ml, 152 mmol) in dichloromethane (560 ml) was added dimethyl sulfoxide (21.5 ml, 303 mmol) dropwise at -78°C. To the reaction mixture was added a solution of tert -butyl (1 R ,2 S ,5 R )-2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (24.5 g, 102 mmol) in dichloromethane (140 ml ) and the reaction mixture was stirred at -78°C for 30 min. Triethylamine (TEA) (85 ml, 61 mmol) was added, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with water (3×300 ml), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with heptane/ethyl acetate (4:1) to give the title compound (19.5 g, 82 mmol, 80% yield) as a white crystalline solid.

+116.0° (c 0.110, MeOH). MS (ESI): mass calculated for C ₁₃ H ₂₁ NO _3, 239.2; obtained m/z, 262.1 [M+Na] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 4.49-4.35 (m, 1H), 4.34-4.23 (m, 1H), 2.43-2.24 (m, 3H ), 1.83-1.74 (m, 1H), 1.71-1.56 (m, 2H), 1.57-1.33 (m, 4H), 1.43, 1.39 (s , 9H).

−45,0° (c 0,185, MeOH). МС (ИЭР): масса, рассчитанная для C₁₆H₂₅NO_5, 311.2; полученное m/z, 256,1 [M+2H−трет-Бутил]⁺. ¹H ЯМР (300 МГц, ДМСО-d ₆) δ 11,83 (с, 1H), 4,52-4,37 (м, 1H), 4,36-4,25 (м, 1H), 4,20 (кв, J=7,1 Гц, 2H), 2,66-2,49 (м, 1H), 2.09 (д, J=16,5 Гц, 1H), 1,76-1,45 (м, 6H), 1,39 (с, 9H), 1,24 (т, J=7,1 Гц, 3H).Step F: 9-(tert-Butyl) 3-ethyl (1S,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-3,9-dicarboxylate. Bis _ _ _ lithium (trimethylsilyl)amide (LiHMDS) (1 M in tetrahydrofuran, 41.2 ml, 41.2 mmol) at -78°C and the reaction mixture was stirred at -78°C for 30 min. A solution of ethyl cyanoformate (4.4 ml, 44.5 mmol) in distilled tetrahydrofuran (20 ml) was added to the reaction mixture, and the reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated ammonium chloride (200 ml). The aqueous layer was extracted with dichloromethane (2×200 ml). The combined organic layers were washed with water (2×150 ml), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with a mixture of heptane and ethyl acetate (4:1) to give the title compound (5.5 g, 18 mmol, 51% yield) as a pale yellow oil.

−45.0° (c 0.185, MeOH). MS (ESI): mass calculated for C ₁₆ H ₂₅ NO _5, 311.2; obtained m/z, 256.1 [M+2H− tert -Butyl] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 11.83 (s, 1H), 4.52-4.37 (m, 1H), 4.36-4.25 (m, 1H), 4, 20 (q, J =7.1 Hz, 2H), 2.66-2.49 (m, 1H), 2.09 (d, J =16.5 Hz, 1H), 1.76-1.45 (m , 6H), 1.39 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H).

Step G: tert-Butyl (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-epimincycloocta[c]pyrazole- 10-carboxylate . To a mixture of 9-(tert-butyl) 3-ethyl (1S,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-3,9-dicarboxylate (20.4 g, 65.5 mmol) in acetic acid (AcOH) (260 ml) was added methylhydrazine (5.2 ml, 99.3 mmol, 0.88 g/ml) and the reaction mixture was stirred at 80°C for 8 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica gel with eluting with a mixture of ethyl acetate and methanol (10:1) to give the title compound (15.4 g, 52.5 mmol, 80% yield). MS (ESI): mass calculated for C ₁₅ H ₂₃ N ₃ O _3, 293.2; obtained m/z, 294.2 [M+H] ⁺ .

+10,0° (c 0,15, MeOH).Step H: tert-Butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carboxylate . To a solution of tert-butyl (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-epimincycloocta[c]pyrazole-10 -carboxylate (20.0 g, 68.2 mmol) in dichloromethane (300 mL) was added N,N -diisopropylethylamine (13 mL, 75.1 mmol) and N - phenylbis (trifluoromethanesulfonimide) (26.8 g, 75 .0 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated sodium bicarbonate (2×200 ml), 10% potassium bisulfate (2×200 ml) and brine (1×200 ml), dried sodium sulfate, filtered and evaporated. The residue was purified by silica gel gradient column chromatography eluting with a mixture of heptane and ethyl acetate (6:1 → 4:1). The residue was taken up in ethyl acetate (100 ml) and evaporated. Less pure fractions were combined and evaporated. The residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate (3×150 ml), dried with sodium sulfate, filtered and evaporated. The products were combined to give the title compound (16.4 g, 39 mmol, 56% yield) as a colorless oil. MS (ESI): mass calculated for C ₁₆ H ₂₂ F ₃ N ₃ O ₅ S _- 425.1; obtained m/z, 370.1 [M+2H-tert-butyl] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 5.06 (d, J =18.9 Hz, 1H), 4.48 (d, J =31.6 Hz, 1H), 3.73 (s , 3H), 2.84 (dd, J = 16.3, 7.4 Hz, 1H), 2.44 (d, J = 16.3 Hz, 1H), 1.78-1.61 (m, 3H), 1.59-1.41(m, 2H), 1.38(s, 9H), 1.27-1.16(m, 1H). Optical rotation:

+10.0° (c 0.15, MeOH).

Method B

The title compound was obtained by purifying racemic tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole-10-carboxylate by chiral SFC (step B, intermediate 1) using stationary phase: Lux Cellulose-2 5 μm 250*30 mm, mobile phase: 85% CO ₂ , 15% iPrOH ( single enantiomer; retention time 0.93 min). MS (ESI): mass calculated for C ₁₆ H ₂₂ F ₃ N ₃ O ₅ S - 425.1; obtained m/z, 370.0 [M+2H-tert-butyl]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 5.06 (d, J =18.9 Hz, 1H), 4.48 (d, J =31.6 Hz, 1H), 3.73 (s , 3H), 2.84 (dd, J = 16.3, 7.4 Hz, 1H), 2.44 (d, J = 16.3 Hz, 1H), 1.78-1.61 (m, 3H), 1.59-1.41(m, 2H), 1.38(s, 9H), 1.27-1.16(m, 1H).

Intermediate 3: tert -Butyl (5S,9R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole-10-carboxylate.

The title compound was obtained by the previously mentioned purification of intermediate 2 (method B) with chiral SFC, this intermediate being used to give the title compound (single enantiomer; retention time 0.48 min). MS (ESI): mass calculated for C ₁₆ H ₂₂ F ₃ N ₃ O ₅ S _, 425.1; obtained m/z, 370.0 [M+2H-tert-butyl] ⁺ .

Intermediate 4: racemic (5R,9S)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1 using (3-fluorophenyl)boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ FN _3, 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Intermediate 5: racemic (5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for intermediate 1 using (4-fluorophenyl)boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ FN _3, 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Intermediate 6: racemic (5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for intermediate 1 using (3-chlorophenyl)boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ ClN _3, 287.1; obtained m/z, 288.1 [M+H] ⁺ .

Intermediate 7: racemic -(5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1, using (3,5-difluorophenyl)boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ ClN ₃ - 289.1; obtained m/z, 290.1 [M+H] ⁺ .

Intermediate 8: racemic -(5R,9S)-3-(3,4-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1, using (3,4-difluorophenyl)boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ ClN ₃ - 289.1; obtained m/z, 290.1 [M+H] ⁺ .

Intermediate 9: racemic (5R,9S)-2-Methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1 using (5-(trifluoromethyl)thiophen-2-yl)boronic acid in place of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ ClN _3, - 327.1; obtained m/z, 328.1 [M+H] ⁺ .

Intermediate 10: racemic -(5R,9S)-3-(3-(Difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for intermediate 1, using (3-(difluoromethyl)-4-fluorophenyl) boronic acid instead of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₆ H ₁₈ ClN ₃ - 327.1; obtained m/z, 328.1 [M+H] ⁺ .

Intermediate 11: racemic (5R,9S)-2-Cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for Intermediate 1 using cyclopropylhydrazine hydrochloride in place of methylhydrazine in step A and (3-fluorophenyl)boronic acid in place of phenylboronic acid in step C. MS (ESI): mass calculated for C ₁₈ H ₂₀ FN _{3 ,} 297.1; obtained m/z, 298.1 [M+H] ⁺ .

Intermediate 12: (5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

Step A: tert-Butyl (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole-10-carboxylate . A solution of tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole-10-carboxylate (intermediate 2) (500 mg, 1.2 mmol), (3,5-difluorophenyl)boronic acid (223 mg, 1.4 mmol), chloro(2-dicyclohexylphosphino) -2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2) (93 mg, 0 ,12 mmol) and sat. aq. a solution of Na ₂ CO ₃ (8.0 ml) in dioxane (2.0 ml). The vial was evacuated and degassed with N ₂ (x3), after which it was capped and sealed. The mixture was heated in a microwave reactor at a temperature of 110°C for 30 minutes. After cooling to rt, the crude mixture was diluted with brine and extracted using DCM (x3). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated in vacuo and purified (FCC, SiO ₂ ; 0-100% EtOAc/hexanes) to give the product as a white solid (356 mg, 78% yield). MS (ESI): mass calculated for C ₂₁ H ₂₅ F ₂ N ₃ O ₂ , 389.1; obtained m/z, 334.0 [M+2H-tert-butyl] ⁺ .

Step B: (5R,9S)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole. To a solution of tert-butyl (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-carboxylate in DCM (2.0 ml) was added trifluoroacetic acid (2.0 ml) and the mixture was stirred at room temperature for 1 h. 100×4.6 mm), mobile phase 10-100% ACN in 20 mM NH ₄ OH to give the title compound as a white solid (225 mg, 86% yield). MS (ESI): mass calculated for C ₁₆ H ₁₇ F ₂ N _3, 289.1; resulting m/z, 290.1[M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.36-7.28 (m, 1H), 7.28-7.20 (m, 2H), 3.95 (t, J =3.3 Hz, 1H), 3.78 (s, 3H), 2.86 (dd, J =16.1, 7.3 Hz, 1H), 2.34 (d, J =16.1 Hz, 2H), 1.86-1.64 (m, 2H), 1.62-1.44 (m, 2H), 1.40-1.21 (m, 2H).

Intermediate 13: (5R,9S)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-fluorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H ₁₈ FN ₃ - 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Intermediate 14: (5R,9S)-3-(3-Chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-chlorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H _18Cl FN ₃ - 287.1; obtained m/z, 288.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.59-7.57 (m, 1H), 7.57-7.54 (m, 1H), 7.54-7.51 (m, 1H ), 7.48-7.44 (m, 1H), 4.43-4.36 (m, 1H), 3.79 (s, 3H), 3.68-3.61 (m, 1H), 2.97 (dd, J =16.4, 7.4 Hz, 1H), 2.55 (d, J =16.4 Hz, 1H), 1.97-1.81 (m, 2H), 1 .74-1.65 (m, 1H), 1.65-1.56 (m, 1H), 1.47-1.39 (m, 1H), 1.37-1.25 (m, 1H) .

Intermediate 15: (5R,9S)-3-(3-Fluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-fluoro-5-methoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₂₀ FN _{3 O} - 301.1; obtained m/z, 302.1 [M+H] ⁺ .

Intermediate 16: (5R,9S)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₁₇ F ₄ N ₃ - 339.1; obtained m/z, 340.1 [M+H] ⁺ .

Intermediate 17: (5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-chloro-5-methoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₂₀ ClN _{3 O} - 317.1; obtained m/z, 318.1 [M+H] ⁺ .

Intermediate 18: (5R,9S)-3-(3-Chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3-chloro-4-methoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₂₀ ClN ₃ O _, 317.1; the resulting m/z is 318.1 [M+H] ⁺ .

Intermediate 19: (5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3,5-dichlorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H ₁₇ Cl ₂ N ₃ - 321.1; obtained m/z, 322.1 [M+H] ⁺ .

Intermediate 20: (5R,9S)-3-(4-Chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (4-chloro-3-fluorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H ₁₇ ClFN _3, 305.1; obtained m/z, 306.1 [M+H] ⁺ .

Intermediate 21: (5R,9S)-3-(3,4-Difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3,4-difluoro-5-methoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₁₉ F ₂ N _{3 O} - 319.1; obtained m/z, 320.1 [M+H] ⁺ .

Intermediate 22: (5R,9S)-3-(3,5-Difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3,5-difluoro-4-methoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₇ H ₁₉ F ₂ N _{3 O} - 319.1; obtained m/z, 320.1 [M+H] ⁺ .

Intermediate 23: (5R,9S)-3-(3,5-Dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3,5-dimethoxyphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₈ H ₂₃ N ₃ O ₂ - 313.1; obtained m/z, 314.1 [M+H] ⁺ .

Intermediate 24: (5R,9S)-3-(3,4-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (3,4-difluorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H ₁₇ F ₂ N _3, - - 289.1; obtained m/z, 290.1 [M+H] ⁺ .

Intermediate 25: (5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole.

The title compound was prepared in a manner similar to that described for intermediate 12 using (3,4,5-trifluorophenyl)boronic acid in place of (3,5-difluorophenyl)boronic acid in step A using conventional or microwave heating. MS (ESI): mass calculated for C ₁₆ H ₁₆ F ₃ N ₃ - 307.1; obtained m/z, 308.1 [M+H] ⁺ .

Intermediate 26: (5S,9R)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1 using tert-butyl (5S,9R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10-carboxylate (intermediate 3) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazole (Step C, Intermediate 1). MS (ESI): mass calculated for C ₁₆ H ₁₉ N ₃ - 253.1; obtained m/z, 254.1 [M+H] ⁺ .

Intermediate 27: (5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1 using tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10-carboxylate (intermediate 2) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazole (Step C, Intermediate 1). MS (ESI): mass calculated for C ₁₆ H ₁₉ N ₃ - 253.1; obtained m/z, 254.1 [M+H] ⁺ .

Intermediate 28: (5S,9R)-3-(3-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for Intermediate 1 using (3-fluorophenyl)boronic acid in place of phenylboronic acid in step C and t-butyl (5S,9R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy )-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10-carboxylate (intermediate 3) instead of racemic (5R,9S)-2-methyl-3- phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (step C, intermediate 1). MS (ESI): mass calculated for C ₁₆ H ₁₈ FN ₃ - 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Intermediate 29: (5S,9R)-3-(3,5-Difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 1, using (3,5-difluorophenyl)boronic acid in place of phenylboronic acid in step C and tert-butyl (5S,9R)-2-methyl-3-(((trifluoromethyl)sulfonyl )oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10-carboxylate (intermediate 3) instead of racemic (5R,9S)-2-methyl- 3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (step C, intermediate 1). MS (ESI): mass calculated for C ₁₆ H ₁₇ F ₂ N ₃ - 289.1; obtained m/z, 290.1 [M+H] ⁺ .

Intermediate 30: (5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using (4-fluorophenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₆ H ₁₈ FN _3, 271.1; the resulting m/z is 272.1 [M+H] ⁺ .

Intermediate 31: (5R,9S)-3-Cyclopropyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole.

The title compound was prepared in a manner analogous to that described for intermediate 12, using cyclopropylboronic acid instead of (3,5-difluorophenyl)boronic acid. MS (ESI): mass calculated for C ₁₃ H ₁₉ N ₃ - 217.1; obtained m/z, 218.1 [M+H] ⁺ .

Intermediate 32: (5R,9S)-2-methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole.

The title compound was prepared in a manner similar to that described for intermediate 12 using methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole instead of (3,5- difluorophenyl)-boronic acid. MS (ESI): mass calculated for C ₁₉ H ₂₂ N ₄ - 306.1; obtained m/z, 307.1 [M+H] ⁺ .

Intermediate 33:2-methylquinoxaline-6-carboxylic acid.

To a solution of 3,4-diaminobenzoic acid (500 mg, 3.3 mmol) in ethanol (4.0 ml) was added 2-oxopropanal (0.45 ml, 6.6 mmol) and the mixture was refluxed at 80 ºC for within 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude mixture was used without purification. MS (ESI): mass calculated for C ₁₀ H ₈ N ₂ O ₂ - 188.0, obtained m/z, 189.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.38 (s, 1H), 8.96 (s, 1H), 8.62-8.49 (m, 1H), 8.31-8, 19 (m, 1H), 8.17-7.95 (m, 1H), 2.75 (d, J = 1.6 Hz, 3H).

Intermediate 34: racemic (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole.

Stage A: racemic tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9 -carboxylate. The title compound was prepared in a manner similar to that described for Intermediate 1, Steps A-B using 8-(tert-butyl) 3-ethyl 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (Intermediate 35, product of step E) instead ofracemic-9-(tert-butyl) 3-ethyl (1S,5R)-2-oxo-9-azabicyclo [3.3.1] nonane-3,9-dicarboxylate in step A. MS(ESI): mass calculated for C₁₅H₂₀F₃N₃O₅S_, - 411.1; obtained m/z, 356.0 [M+2H-tert-butyl]⁺.

Stage B: racemic (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole. The title compound was prepared in a manner analogous to that of intermediate 12, steps A-B usingracemictert-Butyl(5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9 -carboxylate instead of tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta [c]pyrazole-10-carboxylate (intermediate 2) and phenylboronic acid instead of (3,5-difluorophenyl)boronic acid in step A. MS (ESI): mass calculated for C₁₅H₁₇N_3, - 239.1; obtained m/z, 240.1 [M+H]⁺.

Intermediate 35: tert -butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c ]pyrazole-9-carboxylate.

Step A: ethyl 5-formyl-1H-pyrrole-2-carboxylate. To a cooled (0 ºC) solution of dichloroethane (DCE) (250 ml) and POCl ₃ (18.7 ml, 201 mmol) was slowly added N, N -dimethylformamide (DMF) (17.7 ml, 230 mmol), this suspension was stirred at 0 ºC for 15 minutes. Then a solution of ethyl 1H-pyrrole-2-carboxylate (20 g, 144 mmol) dissolved in dichloroethane (DCE) (50 ml) was added to the reaction mixture and stirred at 0 ºC for 30 min, warming to room temperature overnight . The completed reaction was cooled to 0 ºC and 50 ml of sodium acetate trihydrate solution (~43 g) was added. The resulting mixture was heated to 75 ºC for 30 min and then cooled to room temperature. The aqueous layer was extracted with methyl tert -butyl ether (MTBE), washed with aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification (FCC, eluting with 0-10% EtOAc in hexanes) afforded the title compound (18.1 g, 75%). MS (ESI): mass calculated for C ₈ H ₉ NO ₃ - 167.1; obtained m/z, 168.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.04-9.67 (s, 1H), 9.74-9.59 (s, 1H), 7.02-6.86 (d, J =2 .5 Hz, 2H), 4.49-4.30 (m, 2H), 1.45-1.31 (m, 2H).

Step B: ethyl-(E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate . To a chilled (0°C) solution of NaH (8.7 g, 217 mmol) in THF (200 ml) was added triethylphosphonate acetate (61.7 g, 234 mmol). The reaction mixture was stirred at 0°C for 3 hours, then ethyl 5-formyl-1H-pyrrole-2-carboxylate (27.9 g, 167 mmol) was added. The reaction mixture was stirred at rt. pace. during the night. The reaction mixture was quenched with aqueous NH ₄ Cl (200 ml) and extracted into Et ₂ O (x 3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was recrystallized from 10% EtOAc in hexanes) to give the title compound (39.5 g, 99.8%). MS (ESI): mass calculated for C ₁₂ H ₁₅ NO ₄ - 237.1; obtained m/z, 238.1 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.93 (s, 1H), 7.56 (d, J =16.0 Hz, 1H), 6.98-6.81 (m, 1H), 6 .63-6.43 (m, 1H), 6.32 (d, J = 16.0 Hz, 1H), 4.39 (c, J = 7.1 Hz, 2H), 4.25 (c, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H).

Step C: ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate. Ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrol-2-carboxylate (39.5 g, 167 mmol), rhodium was added to the flask on an Aclunia column (27.4 g, 13.3 mmol), suspended in acetic acid (80 ml), evacuated and refilled with N ₂ . Then, an elastic balloon with H ₂ was placed on the flask, the air was pumped out and filled twice with H ₂ . The reaction mixture was stirred at room temperature for 48 hours. The crude reaction mixture was passed through ^Celite® , washed with DCM, then concentrated under reduced pressure. Water (400 ml) was added to the reaction mixture and the reaction mixture was extracted into DCM (x3). The organic layers were combined, washed with aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give the title product as a colored oil (38.6 g, 95%). MS (ESI): mass calculated for C ₁₂ H ₂₁ NO ₄ - 243.1; obtained m/z, 244.1 [M+H] ⁺ .

Step D: 1-(tert-butyl) 2-ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate. In a solution of ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate (38.6 g, 158 mmol) and Boc anhydride (di-tert-butyl decarbonate) (38 g, 175 mmol) in DCM (317 ml) was added slowly TEA (44.1 ml, 317 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 ml), washed with water, brine, dried over Na₂SO₄, filtered and concentrated to give the title product (54.8 g, 100.6%). MS (EMI): mass calculated for C₁₇H₂₉NO₆, - 343.2; m/z obtained - 244.1 [M+2H-CO₂tBu]⁺.

Step E: 8-(tert-butyl)-3-ethyl-2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate. Solution of 1-(tert-butyl) 2-ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate (54.8 g, 160 mmol) in THF (1.3 L) and tert-butoxide potassium (KOtBu) (21.5 g, 191 mmol) was heated at 60 ºC for 3 hours. The reaction mixture was cooled and concentrated under reduced pressure. The crude product was resuspended in DCM (800 ml) and washed with saturated NH ₄ Cl solution. The aqueous layer was extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (FCC, SiO ₂ , eluting with 0-10% EtOAc in hexanes) afforded the title compound (37.8 g, 79.7%). MS (ESI): mass calculated for C ₁₅ H ₂₃ NO ₅ - 297.2; the resulting m/z is 242.1 [M+2H-tBu] ⁺ .

Step F: Racemic tert-butyl 2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydro-5,8-epimincyclohepta[c]pyrazole-9-carboxylate. To a solution of 8-(tert-butyl) 3-ethyl 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate (1.76 g, 5.9 mmol) in toluene (33 ml) was added methylhydrazine (467 ml). The resulting mixture was heated at 110 ºC for 2 hours. The cooled reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , eluting with 0-10% MeOH in DCM) gave the title compound as a clear oil. MS (ESI): mass calculated for C ₁₄ H ₂₁ N ₃ O ₃ - 279.2; the resulting m/z is 280.2 [M+1] ⁺ .

Step G: tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazole-9-carboxylate and tert-butyl (5S,8R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazole-9-carboxylate . To a solution of racemic tert-butyl-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydro-5,8-epimincyclohept[c]pyrazole-9-carboxylate (9.48 g, 34 mmol) in DCM (152 mL) was added N- phenylbis (trifluoromethanesulfonimide) (13.5 g, 37 mmol) followed by DIEA (6.4 mL, 37 mmol). The resulting solution was stirred at room temperature for 18 hours. The completed reaction mixture was concentrated under reduced pressure. Purification (FCC, SiO ₂ , eluting with 0-20% EtOAc in hexanes) provided the title racemic mixture of compounds (11.2 g, 80%). MS (ESI): mass calculated for C ₁₅ H ₂₀ F ₃ N ₃ O ₅ S - 411.1; obtained m/z, 356.0 [M+2H-tert-butyl] ⁺ .

Single enantiomers were isolated by chiral SFC purification of racemic tert-butyl-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohept[ c]pyrazole-9-carboxylate using stationary phase: Chiralpak IC 5 µm, 250*30 mm, mobile phase: 93% CO ₂ , 7% iPrOH to give tert-butyl-( 5R , 8S )-2-methyl -3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9-carboxylate (one enantiomer; retention time 1.05 min ) MS (ESI): mass calculated for C ₁₅ H ₂₀ F ₃ N ₃ O ₅ S - 411.1; obtained m/z, 356.0 [M+2H-tert-butyl] ⁺ and

intermediate 104: tert-butyl ( 5S , 8R )-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazole-9-carboxylate (one enantiomer; retention time 1.13 min) MS (ESI): mass calculated for C ₁₅ H ₂₀ F ₃ N ₃ O _5S - 411.1; obtained m/z, 356.0 [M+2H-tert-butyl] ⁺ .

Intermediate 36: 8-bromoquinoline-6-carboxylic acid.

Glycerol (1.75 g, 19.0 mmol), 4-nitrobenzoic acid (391 mg, 234 mmol), boric acid (215 mg, 3.48 mmol) and iron(II) sulfate heptahydrate (234 mg, 0.842 mmol) and the reaction mixture was stirred at 140°C for 42 hours. The reaction mixture was cooled to room temperature and brought to pH to 10 with 10% sodium hydroxide. The aqueous layer was extracted with ethyl acetate (2×100 ml) and the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (150 mg, 25% yield) as a yellow powder. MS (ESI): mass calculated for C ₁₀ H ₆ BrNO ₂ - 251.0; obtained m/z, 252.0 [M+H] ⁺ .

Intermediate 37: 1-(3-chlorophenyl)-1,2,4-triazole-3-carboxylic acid.

Step A: methyl 1-(3-chlorophenyl)-1,2,4-triazole-3-carboxylate. To a mixture of methyl-1 H -1,2,4-triazole-5-carboxylate (300 mg, 2.36 mmol), (3-chlorophenyl)boronic acid (370 mg, 2.37 mmol) and copper(II) acetate (429 mg, 2.36 mmol) in dichloromethane (5 ml) was added pyridine (570 μl, 7.08 mmol) and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered through a plate of Celite ^® and the filtrate was washed with 10% potassium bisulfate (1×5 ml), saturated sodium bicarbonate (1×5 ml) and brine (3×5 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting residue was triturated with diethyl ether (5 ml) to give the title compound (120 mg, 21% yield) as a white powder. MS (ESI): mass calculated for C ₁₀ H ₈ ClN ₃ O ₂ - 237.0; obtained m/z, 238.1 [M+H] ⁺ .

Step B: 1-(3-chlorophenyl)-1,2,4-triazole-3-carboxylic acid. To a solution of methyl 1-(3-chlorophenyl)-1,2,4-triazole-3-carboxylate (120 mg, 0.505 mmol) in 1,4-dioxane (1 ml) was added aqueous sodium hydroxide solution (500 μl, 1. 00 mmol, 2 M) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 5 with 6M hydrochloric acid, and the precipitate was collected to give the title compound (99 mg, 87% yield) as a white powder. MS (ESI): mass calculated for C ₉ H ₆ ClN ₃ O ₂ - 223.0; obtained m/z, 224.1 [M+H] ⁺ .

Intermediate 38: 1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid.

The title compound was prepared analogously to intermediate 37 using (3-(trifluoromethyl)phenyl)boronic acid instead of (3-chlorophenyl)boronic acid. MS (IER): mass calculated for C₁₀H₆F₃N₃O₂, - 257.0; obtained m/z, 258.1 [M+H]⁺.

Intermediate 39: 1-(2-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid.

The title compound was prepared analogously to intermediate 37 using (2-fluorophenyl)boronic acid instead of (3-chlorophenyl)boronic acid. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 40: 5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid.

The title compound was prepared in a manner similar to that described for intermediate 37 using (3-(trifluoromethyl)phenyl)boronic acid in place of (3-chlorophenyl)boronic acid and methyl 5-methyl-1 H-1,2,4-triazole-3- carboxylate instead of methyl-1 H -1,2,4-triazole-5-carboxylate. MS (ESI): mass calculated for C ₁₁ H ₈ N ₃ F ₃ N ₃ O ₂ - 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Intermediate 41: 1-(3-methoxyphenyl)-1,2,4-triazole-3-carboxylic acid.

The title compound was prepared in a manner analogous to that described for intermediate 37 using (3-methoxyphenyl)boronic acid instead of (3-chlorophenyl)boronic acid. MS (EMI): mass calculated for C₁₀H₉N₃O₃-219.1; obtained m/z, 220.1 [M+H]⁺.

Intermediate 42: 1-(2-methoxyphenyl)-1,2,4-triazole-3-carboxylic acid.

The title compound was prepared in a manner analogous to that described for intermediate 37 using (2-methoxyphenyl)boronic acid instead of (3-chlorophenyl)boronic acid. MS (EMI): mass calculated for C₁₀H₉N₃O₃, - 219.1; obtained m/z, 220.1 [M+H]⁺.

Intermediate 43: 2-(1H-imidazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 37 using (2-(methoxycarbonyl)phenyl)boronic acid in place of (3-chlorophenyl)boronic acid and imidazole in place of methyl- 1H -1,2,4-triazole-5-carboxylate . MS (ESI): mass calculated for C ₁₀ H ₈ N ₂ O ₂ - 188.1; obtained m/z, 189.1 [M+H] ⁺ .

Intermediate 44: 3-[3-(trifluoromethyl)pyrazol-1-yl]benzoic acid.

A mixture of 3-iodobenzoic acid (300 mg, 1.21 mmol), 3-(trifluoromethyl)pyrazole (247 mg, 1.82 mmol), cesium carbonate (670 mg, 2.06 mmol), trans - N, N ′- dimethylcyclohexane-1,2-diamine (32 µl, 0.203 mmol) and copper(I) iodide (25 mg, 0.131 mmol) in N,N -dimethylformamide (1.25 ml) were stirred at 100°C for 30 min, then at 140°C for 70 min under microwave irradiation. The reaction mixture was taken up in water (5 ml), acidified to pH 3 with 1 M hydrochloric acid and extracted with ethyl acetate (3×5 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC (method E) to give the title compound (140 mg, 45% yield) as a tan powder. MS (ESI): mass calculated for C ₁₁ H ₇ F ₃ N ₂ O ₂ - 256.0; obtained m/z, 257.1 [M+H] ⁺ .

Intermediate 45: 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-5-(trifluoromethyl)benzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.1 [M+H] ⁺ .

Intermediate 46: 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-5-methoxybenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.1 [M+H] ⁺ .

Intermediate 47: 3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-3-methoxybenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.1 [M+H] ⁺ .

Intermediate 48: 3-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-3-methoxybenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.1 [M+H] ⁺ .

Intermediate 49: 2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₂ - 189.1; obtained m/z, 190.1 [M+H] ⁺ .

Intermediate 50: 2-(1H-1,2,3-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₂ - 189.1; obtained m/z, 190.1 [M+H] ⁺ .

Intermediate 51: 3-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 1,2,3-triazole instead of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₂ - 189.1; obtained m/z, 190.1 [M+H] ⁺ .

Intermediate 52: 2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-5-(trifluoromethyl)benzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.0 [M+H] ⁺ .

Intermediate 53: 2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodobenzoic acid in place of 3-iodobenzoic acid and 3-trifluoromethyl)-1H-1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.1 [M+H] ⁺ .

Intermediate 54: 3-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 3-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 55: 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 4-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 56: 5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 5-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 57: 4-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-4-methylbenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ - 203.1; obtained m/z, 202.1 [M+H] ^- .

Intermediate 58: 5-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-5-methylbenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ - 203.1; obtained m/z, 204.1 [M+H] ⁺ .

Intermediate 59: 3-[4-(trifluoromethyl)pyrazol-1-yl]benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44 using 4-(trifluoromethyl)pyrazole instead of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₁ H ₇ F ₃ N ₂ O ₂ - 256.0; obtained m/z, 257.1 [M+H] ⁺ .

Intermediate 60: 3-(4-fluoro-1H-pyrazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44 using 4-fluoropyrazole instead of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₇ F ₁ N ₂ O ₂ - 206.0; obtained m/z, 207.1 [M+H] ⁺ .

Intermediate 61: 3-(4-methoxy-1H-pyrazol-1-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44 using 4-methoxypyrazole instead of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₁ H ₁₀ N ₂ O ₃ - 218.1; obtained m/z, 219.1 [M+H] ⁺ .

Intermediate 62: 5-methoxy-1-phenyl-1,2,4-triazole-3-carboxylic acid.

Step A: ethyl ( 2Z )-2-amino-2-(phenylhydrazono)acetate. To a solution of ethyl 2-amino-2-thioxoacetate (615 mg, 4.62 mmol) in a mixture of toluene (10 ml) and acetic acid (1 ml) was added phenylhydrazine (455 μl, 4.62 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1 M sodium carbonate (20 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with 1 M sodium carbonate (2×10 ml) and brine (1×10 ml), dried over sodium sulfate, filtered and evaporated to give the title compound (652 mg) as a yellow oil which was used directly on next stage. MS (ESI): mass calculated for C ₁₀ H ₁₃ N ₃ O ₂ - 207.1; obtained m/z, 208.1 [M+H] ⁺ .

Step B: ethyl 5-oxo-1-phenyl- 4H -1,2,4-triazole-3-carboxylate. Triphosgene (860 mg, 2.90 mmol) was added to a solution of ethyl-( 2Z )-2-amino-2-(phenylhydrazono)acetate (600 mg, crude) in distilled tetrahydrofuran (20 ml) at 0°C. The reaction mixture was stirred at 0° C. for 2 h, then at room temperature for 18 h. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (2×10 ml), dried over sodium sulfate, filtered and evaporated. Purification (FCC, SiO ₂ , n -heptane:ethyl acetate (100:0 → 50:50) gave the title compound (295 mg, 43% yield) as a white powder. MS (ESI): mass calculated for C ₁₁ H ₁₁ N ₃ O ₃ - 233.1 obtained m/z, 234.1 [M+H] ⁺ .

Step C: ethyl 5-methoxy-1-phenyl-1,2,4-triazole-3-carboxylate. Trimethyloxonium tetrafluoroborate (34 mg, 0.232 mmol ) at 0 °C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with 1 M sodium carbonate (10 ml) and was extracted with dichloromethane (2×10 ml). The combined organic layers were washed with brine (2×10 ml), dried over sodium sulfate, filtered and evaporated. Purification (FCC, SiO ₂ , n -heptane:ethyl acetate (100:0 → 50:50) gave the title compound (155 mg, 56% yield) as a pale yellow powder. MS (ESI): mass calculated for C ₁₂ H ₁₃ N ₃ O ₃ - 247.1 obtained m/z, 248.1 [M+H] ⁺ .

Stage D: 5-methoxy-1-phenyl-1,2,4-triazole-3-carboxylic acid. Sodium hydroxide (1 M, 1 ml, 1.00 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (3 ml) and the aqueous layer was acidified to pH 5 with 2 M hydrochloric acid and extracted with ethyl acetate (2×2 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (113 mg, 84% yield) as a white powder. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.1 [M+H] ⁺ .

Intermediate 63: ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole.

The title compound was prepared in a manner similar to that of intermediate 12, using (3-fluoro-5-methylphenyl)boronic acid instead of (3,5-difluorophenyl)boronic acid in step A. MS (ESI): mass calculated for C ₁₇ H ₂₀ FN ₃ , - 285.2; obtained m/z, 286.1 [M+H] ⁺ .

Intermediate 64: 3-fluoro-5-pyrazol-1-yl-benzoic acid.

Mixture of methyl 3-bromo-5-fluorobenzoate (300 mg, 1.29 mmol), pyrazole (132 mg, 1.94 mmol), cesium carbonate (713 mg, 2.19 mmol), trans -N,N'- dimethylcyclohexane -1,2-diamine (35 µl, 0.222 mmol, 0.902 g/ml) and copper(I) iodide (25 mg, 0.131 mmol) in N,N -dimethylformamide (1 ml) were stirred at 140°C for 120 min under microwave irradiation. The reaction mixture was diluted with ethyl acetate (5 ml) and water (5 ml). The aqueous layer was acidified to pH 3 with 1M hydrochloric acid. The precipitate was collected and washed with water (2×5 ml) to give the title compound (245 mg, 1.19 mmol, 92%) as a tan powder.

MS (ESI): mass calculated for C ₁₀ H ₇ FN ₂ O ₂ - 206.1; obtained m/z, 207.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.56 (br. s., 1H), 8.67 (d, J =2.6 Hz, 1H), 8.28-8.25 (m , 1H), 8.03 (dt, J = 10.1, 2.3 Hz, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.61-7.56 (m, 1H), 6.62-6.59 (m, 1H).

Intermediate 65: 5-methoxy-2-(1H-1,2,4-triazol-1-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 2-iodo-5-methoxybenzoic acid in place of 3-iodobenzoic acid and 1,2,4-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.2 [M+H] ⁺ .

Intermediate 66: 2-[4-(trifluoromethyl)triazol-2-yl]benzoic acid.

Stage A: ethyl 3-benzyl-5-(trifluoromethyl)triazole-4-carboxylate and ethyl 1-benzyl-5-(trifluoromethyl)triazole-4-carboxylate. Ethyl 4,4,4-trifluoro-2-butinoate (3.0 g, 18.1 mmol) was added to a solution of azidomethylbenzene (1.2 g, 9.01 mmol) in toluene (40 ml). The reaction mixture was stirred at 115° C. for 16 h and evaporated to give a mixture of the title compounds (2.65 g, 8.86 mmol, 98%) as a yellow oil. MS (EMI): mass calculated for C₁₃H₁₂F₃N₃O₂, - 299.1; obtained m/z, 300.1 [M+H]⁺.

Stage B: 3-benzyl-5-(trifluoromethyl)triazole-4-carboxylic acid and 1-benzyl-5-(trifluoromethyl)triazole-4-carboxylic acid . To a mixture of ethyl 3-benzyl-5-(trifluoromethyl)triazole-4-carboxylate and ethyl 1-benzyl-5-(trifluoromethyl)triazole-4-carboxylate (2.65 g, 8.86 mmol) in 1,4- dioxane (14 ml) and water (14 ml) was added sodium hydroxide (720 mg, 18 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with 6 M hydrochloric acid (3 ml) and evaporated. The residue was taken up in water (10 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was triturated with diisopropyl ether to give the first crop of a mixture of the title compounds (680 mg, 2.51 mmol, 28%) as a white powder.

The triturating solvent was evaporated to give a second crop of a mixture of the title compounds (670 mg, 2.47 mmol, 28%) as a white powder. MS (ESI): mass calculated for C ₁₁ H ₈ F ₃ N ₃ O ₂ - 271.1; obtained m/z, 272.1 [M+H] ⁺ .

Step C: 1-benzyl-4-(trifluoromethyl)triazole and 1-benzyl-5-(trifluoromethyl)triazole . The carbonate silver (305 mg, 1.11 mmol) and acetic acid (36 µl, 0.629 mmol, 1.049 g/ml). The reaction mixture was stirred at 120° C. for 18 h and acidified to pH 3 with 1 M aqueous hydrochloric acid. The mixture was diluted in water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water (3×25 ml), dried over magnesium sulfate, filtered and evaporated to give a mixture of the title compounds (300 mg, 1.32 mmol, 36%) as a yellow powder. MS (ESI): mass calculated for C ₁₀ H ₈ F ₃ N ₃ O ₃ - 227.1; obtained m/z, 228.1 [M+H] ⁺ .

Step D: 4-(trifluoromethyl)-1 H -triazole. Selcat-Q-6 10 % palladium on carbon (351 mg, 0.33 mmol) and hydrogen chloride (4.2 M in 1,4-dioxane, 2.36 ml, 9.91 mmol). The reaction mixture was stirred at room temperature for 78 h under hydrogen atmosphere (1 bar) to give the title compound (35 ml, 0.094 M stock solution) as a pale yellow liquid.

Step E: 2-[4-(trifluoromethyl)triazol-2-yl]benzoic acid . A mixture of 2-iodobenzoic acid (200 mg, 0.806 mmol), 4-(trifluoromethyl) -1H -triazole (0.094 M stock solution in 1,4-dioxane, 11 mL, 1.034 mmol), cesium carbonate (445 mg, 1.366 mmol ), trans - N, N '-dimethylcyclohexane-1,2-diamine (22 μl, 0.140 mmol) and copper (I) iodide (15 mg, 0.079 mmol) in N, N -dimethylformamide (5 ml) was stirred at 140 ° C for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, filtered and washed with 1,4-dioxane (5 ml). The combined filtrates were evaporated. The reaction was repeated twice on a scale of 50 and 72 mg. The crude products were combined and purified by preparative HPLC (method E) to give the title compound (44 mg, 0.171 mmol, 13%) as a pale yellow oil and 2-[4-(trifluoromethyl)triazol-1-yl] benzoic acid (intermediate 67) (27 mg, 0.105 mmol, 8%) as a pale yellow oil. MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.40 (br. s, 1 H), 8.72 (s, 1 H), 7.91 (d, J =7.3 Hz, 1 H ), 7.85-7.78 (m, 2 H), 7.78-7.64 (m, 1 H).

Intermediate 67: 2-[4-(trifluoromethyl)triazol-1-yl]benzoic acid.

The title compound was isolated from intermediate 66, step E.

MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.1 [M+H] ⁺ . ¹ H NMR ( 300 MHz, DMSO- d ₆ ) δ 13.33 (br. s, 1 H), 9.36 (s, 1 H), 8.04 (d, J = 7.4 Hz, 1 H ), 7.90-7.64 (m, 3 H).

Intermediate 68: 3-fluoro-5-(4H-1,2,4-triazol-4-yl)benzoic acid.

Step A: methyl 3-fluoro-5-(1,2,4-triazol-4-yl)benzoate. To a solution of methyl 3-amino-5-fluorobenzoate (250 mg, 1.48 mmol) in pyridine (8 ml) was added 1,2-diformylhydrazine (325 mg, 3.69 mmol) and triethylamine (1 ml, 7.16 mmol ). Chlorotrimethylsilane (375 µl, 2.96 mmol) was added dropwise to the mixture. The reaction mixture was stirred at 100°C for 16 h and evaporated. The residue was diluted with dichloromethane (8 ml) and water (10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml). The combined organic layers were washed with 10% potassium bisulfate (1×15 ml) and 1 M sodium hydroxide (1×15 ml), dried with sodium sulfate, filtered and evaporated to give the title compound (131 mg, 0.592 mmol, 40%) in the form of a white powder. MS (ESI): mass calculated for C ₁₀ H ₈ FN ₃ O ₂ - 221.1; obtained m/z, 222.1 [M+H] ⁺ .

Step B: 3-fluoro-5-(1,2,4-triazol-4-yl)benzoic acid. Sodium hydroxide was added to a solution of methyl 3-fluoro-5-(1,2,4-triazol-4-yl)benzoate (130 mg, 0.588 mmol) in 1,4-dioxane (1 ml) and water (1 ml). (48 mg, 1.20 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with 6 M hydrochloric acid (0.20 ml). The precipitate was collected and washed with water (1×1 ml) to give the title compound (80 mg, 0.386 mmol, 65%) as a white powder. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 69: 4-fluoro-3-(4H-1,2,4-triazol-4-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 3-amino-4-fluorobenzoate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ S, - 207.0; found m/z, 206.0 [MH] ^- .

Intermediate 70: 3-methyl-5-(4H-1,2,4-triazol-4-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 3-amino-5-methylbenzoate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ S, - 203.1; obtained m/z, 204.1 [M+H] ⁺ .

Intermediate 71: 2-methyl-3-(4H-1,2,4-triazol-4-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 3-amino-2-methylbenzoate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ S, - 203.1; obtained m/z, 204.1 [M+H] ⁺ .

Intermediate 72: 4-methyl-3-(4H-1,2,4-triazol-4-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 3-amino-4-methylbenzoate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ S, - 203.1 ; obtained m/z, 204.1 [M+H] ⁺ .

Intermediate 73: 2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodobenzoic acid in place of 3-iodobenzoic acid and 4-methyl-2H-1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ - 203.1; obtained m/z, 204.1 [M+H] ⁺ .

Intermediate 74: 4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 4-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 75: 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44 using 3-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.1 [M+H] ⁺ .

Intermediate 76: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-5-methylbenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ - 203.1; obtained m/z, 204.2 [M+H] ⁺ .

Intermediate 77: 2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)benzoic acid.

The title compound was prepared in a manner similar to that described for intermediate 44, using 2-iodo-3-(trifluoromethyl)benzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₁₀ H ₆ F ₃ N ₃ O ₂ - 257.0; obtained m/z, 258.1 [M+H] ⁺ .

Intermediate 78: 4-(1H-pyrazol-1-yl)picolinic acid.

The title compound was prepared in a manner similar to that described for intermediate 64, using methyl 4-iodopicolinate instead of methyl 3-bromo-5-fluorobenzoate. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₂ - 189.1; obtained m/z, 190.1 [M+H] ⁺ .

Intermediate 79: indolizine-7-carboxylic acid.

The title compound was prepared in a manner similar to that described for intermediate 66, step B, using methyl indolizine-7-carboxylate instead of ethyl 3-benzyl-5-(trifluoromethyl)triazole-4-carboxylate. MS (ESI): mass calculated for C ₉ H ₇ NO ₂ - 161.1; obtained m/z, 162.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.73 (br. s, 1 H), 8.29 (d, J = 7.2 Hz, 1 H), 8.16-8.09 ( m, 1 H), 7.78-7.69 (m, 1 H), 6.94 (dd, J =7.3, 1.8 Hz, 1 H), 6.88 (dd, J =4 .0, 2.6 Hz, 1 H), 6.78-6.71 (m, 1 H).

Intermediate 80: 2-(1H-pyrazol-1-yl)isonicotinic acid.

The title compound was prepared in a manner similar to that described for intermediate 64, using methyl 2-iodisonicotinate instead of methyl 3-bromo-5-fluorobenzoate. MS (ESI): mass calculated for C ₉ H ₇ N ₃ O ₂ - 189.1; obtained m/z, 190.1 [M+H] ⁺ .

Intermediate 81: 4-methoxy-5-(1H-pyrazol-1-yl)nicotinic acid.

Step A: methyl 4-hydroxypyridine-3-carboxylate . To a mixture of 4-hydroxynicotinic acid (2.09 g, 15 mmol) in methanol (41 ml, 101 mmol, 0.792 g/ml) was added sulfuric acid (80 μl, 1.5 mmol, 1.84 g/ml). The reaction mixture was stirred at 65°C for 16 hours. The reaction mixture was neutralized with saturated sodium carbonate (3 ml) and the precipitate was collected to give the title compound (1.98 g, 12.9 mmol, 86%) as a powder of dirty white. MS (ESI): mass calculated for C ₇ H ₇ NO ₃ - 153.0; obtained m/z, 154.1 [M+H] ⁺ .

Stage B: methyl 4-hydroxy-5-iodopyridine-3-carboxylate . To a suspension of methyl 4-hydroxypyridine-3-carboxylate (1.11 g, 7.25 mmol) in acetonitrile (5 ml) and acetic acid (3 ml) was added N -iodosuccinimide (1.63 g, 7.24 mmol) and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was evaporated. The residue was diluted with acetone (10 mL) and the precipitate was collected to give the title compound (828 mg, 2.97 mmol, 41%) as an off-white powder. MS (ESI): mass calculated for C ₇ H ₆ INO ₃ - 278.9; obtained m/z, 280.0 [M+H] ⁺ .

Stage C: methyl 5-iodo-4-methoxypyridine-3-carboxylate . To a suspension of methyl 4-hydroxy-5-iodopyridine-3-carboxylate (811 mg, 2.91 mmol) in dichloromethane (15 ml) was added trimethyloxonium tetrafluoroborate (1075 mg, 7.25 mmol). The reaction mixture was stirred at room temperature for 20 hours. Trimethyloxonium tetrafluoroborate (1075 mg, 7.25 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (40 ml). The aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (2 x 20 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give the title compound (260 mg, 0.887 mmol, 30%) as an off-white powder. MS (ESI): mass calculated for C ₈ H ₈ INO ₃ - 293.0; obtained m/z, 294.0 [M+H]+.

Stage D: 4-methoxy-5-pyrazol-1-yl-pyridine-3-carboxylic acid . Pyrazole (116 mg, 1.70 mmol), copper(I) oxide (5.0 mg , 0.0349 mmol) and cesium carbonate (222 mg, 0.681 mmol). The reaction mixture was stirred at 110°C for 40 h under argon. The reaction mixture was purified by preparative HPLC (method E) to give the title compound (15 mg, 0.068 mmol, 20%) as an off-white powder. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₃ - 219.1; obtained m/z, 220.2 [M+H] ⁺ .

Intermediate 82: 4-(1H-pyrazol-1-yl)nicotinic acid.

Stage A: methyl 4-pyrazol-1-ylpyridine-3-carboxylate . Mixture of 4-bromo-nicotinic acid methyl ester hydrobromide (220 mg, 0.741 mmol), pyrazole (76 mg, 1.12 mmol), cesium carbonate (725 mg, 2.23 mmol), trans -N,N'- dimethylcyclo - n- hexane-1,2-diamine (20 µl, 0.127 mmol, 0.902 µg/ml) and copper(I) iodide (14 mg, 0.0735 mmol) in N, N -dimethylformamide (2 ml) was stirred at 140° C for 20 min under microwave irradiation. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound (60 mg, 0.295 mmol, 39%) as a yellow oil. MS (ESI): mass calculated for C ₁₀ H ₉ N ₃ O ₂ - 203.1; obtained m/z, 204.2 [M+H] ⁺ .

Step B: 4-pyrazol-1-ylpyridine-3-carboxylic acid . To a mixture of methyl 4-pyrazol-1-ylpyridine-3-carboxylate (60 mg, 0.295 mmol) in water (800 μl) and 1,4-dioxane (800 μl) was added sodium hydroxide (30 mg, 0.75 mmol). The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was quenched with 6 M hydrochloric acid (0.15 ml) and evaporated to give the title compound (80 mg) as a crude white powder. The title compound was used in its crude form without further purification.

Intermediate 83: 6-methyl-3-(1H-1,2,4-triazol-1-yl)picolinic acid.

Step A: 6-methyl-3-nitro-pyridine-2-carbonitrile. Zinc cyanide (749 mg, 6.378 mmol) and tetrakis (triphenylphosphine)palladium(0 ) (1004 mg, 0.869 mmol). The reaction mixture was stirred at 80° C. for 22 hours under argon and evaporated under reduced pressure. The reaction was repeated on the same scale. The crude products were combined and purified by silica gel gradient column chromatography eluting with n -heptane:ethyl acetate (100:00 → 70:30) to give the title compound (700 mg, 4.29 mmol, 37%) in yellow oil.

MS (ESI): mass calculated for C ₇ H ₅ N ₃ O ₂ - 163.0; obtained m/z, 164.1 [M+H] ⁺ .

Stage B: 3-amino-6-methylpyridine-2-carbonitrile . Iron (548 mg, 9.81 mmol) was added to a solution of 6-methyl-3-nitropyridine-2-carbonitrile (640 mg, 3.92 mmol) in acetic acid (10 ml) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (20 ml) and filtered through a pad of ^Celite® . ^Celite® was washed with dichloromethane (3 x 10 ml). The combined filtrates were evaporated and the residue was taken up in water (15 ml), adjusted to pH 9 with saturated sodium carbonate (5 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give the title compound (451 mg, 3.39 mmol, 86%) as an orange powder. MS (ESI): mass calculated for C ₇ H ₇ N ₃ - 133.1; the resulting m/z is 134.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.20 (d, J =8.6 Hz, 1H), 7.14 (d, J =8.7 Hz, 1H), 6.03 (br s, 2H), 2.29 (s, 3H).

Step C: 3-iodo-6-methylpyridine-2-carbonitrile . To a suspension of 3-amino-6-methylpyridine-2-carbonitrile (750 mg, 5.63 mmol) in water (10 ml) was added hydrochloric acid (6 M, 5.6 ml, 33.6 mmol) and the mixture was cooled to 0 °C An aqueous solution of sodium nitrite (2 M, 4.2 mL, 8.4 mmol) was added dropwise over 5 min at 0°C and the reaction mixture was stirred at 0°C for 30 min. An aqueous solution of potassium iodide (2 M, 6.2 ml, 12.4 mmol) was added dropwise over 10 min, maintaining the temperature in the range of 0-5°C. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was diluted with saturated aqueous sodium carbonate (5 ml) and was extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel gradient column chromatography eluting with n -heptane-ethyl acetate (9:1 → 4:1) to give the title compound (925 mg, 3.79 mmol, 67%) as a dirty white powder. MS (ESI): mass calculated for C ₇ H ₅ IN ₂ - 244.0; obtained m/z, 245.0 [M+H] ⁺ .

Step D: 6-methyl-3-(1,2,4-triazol-1-yl)pyridine-2-carbonitrile . To a solution of 3-iodo-6-methylpyridine-2-carbonitrile (250 mg, 1.02 mmol) and 1,2,4-triazole (106 mg, 1.53 mmol) in N, N -dimethylformamide (1.5 ml ) were added cesium carbonate (567 mg, 1.74 mmol), trans - N, N' -dimethylcyclohexane-1,2-diamine (28 µl, 0.178 mmol, 0.902 g/ml) and copper(I) iodide (20 mg, 0.105 mmol). The reaction mixture was stirred at 140°C for 40 min under microwave irradiation and poured into water (8 ml). The mixture was extracted with ethyl acetate (3×10 ml) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound (50 mg, 0.270 mmol, 26%) as a pale yellow powder.

MS (ESI): mass calculated for C ₉ H ₇ N ₅ - 185.1; obtained m/z, 186.2 [M+H] ⁺ .

Stage E: 6-Methyl-3-(1,2,4-triazol-1-yl)pyridine-2-carboxylic acid . To a mixture of 6-methyl-3-(1,2,4-triazol-1-yl)pyridine-2-carbonitrile (50 mg, 0.27 mmol) in water (675 µl) and 1,4-dioxane (675 µl ) sodium hydroxide (27 mg, 0.675 mmol) was added. The reaction mixture was stirred at 60°C for 1 h, then at 80°C for 23 h. The reaction mixture was quenched with 6 M hydrochloric acid (0.115 ml) and evaporated to give the title compound (88 mg, crude) in as a pale yellow powder containing approx. 35 wt.% sodium chloride. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₂ - 204.1; obtained m/z, 161.1 [M+2H−CO ₂ ] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.92 (s, 1H), 8.16 (s, 1H), 7.84 (d, J =8.2 Hz, 1H), 7.49 -7.34 (m, 1H), 7.30 (d, J = 8.2 Hz, 1H), 2.50-2.47 (m, 3H).

Intermediate 84: 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid.

The title compound was prepared in a manner similar to that described for intermediate 83 using pyrazole instead of 1,2,4-triazole in step D. MS (ESI): mass calculated for C ₁₀ H ₉ FN ₃ O ₂ - 203.1; obtained m/z, 202.1 [M+H] ^- .

Intermediate 85: 3-2H-1,2,3-triazol-2-yl)picolinic acid.

The title compound was prepared in a manner similar to that described for intermediate 83, step DE, using 3-bromopicolinonitrile in place of 3-iodo-6-methylpyridine-2-carbonitrile, using 1 H-1,2,3-triazole in place of 1,2,4- triazole; and using traditional heating instead of microwave. MS (ESI): mass calculated for C ₈ H ₆ N ₄ O ₂ - 190.1; obtained m/z, 191.1 [M+H] ⁺ .

Intermediate 86: 6-methyl-4-(2H-1,2,3-triazol-2-yl)picolinic acid.

Stage A: 4-amino-6-methylpyridine-2-carbonitrile . To a solution of 6-methyl-4-nitropyridine-2-carbonitrile (1.0 g, 6.13 mmol) in acetic acid (20 ml) was added iron (856 mg, 15.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of ^Celite® and ^Celite® was washed with ethyl acetate (3×50 ml). The combined filtrates were washed with saturated sodium carbonate solution (3×30 ml) and brine (1×30 ml). The organic layer was dried over magnesium sulfate, filtered and evaporated to give the title compound (760 mg, 5.71 mmol, 93%) as a tan powder. MS (ESI): mass calculated for C ₇ H ₇ N ₃ - 133.1; m/z obtained, 134.2 [M+H] ⁺ .

Step B: 4-iodo-6-methylpyridine-2-carbonitrile . To a suspension of 4-amino-6-methylpyridine-2-carbonitrile (650 mg, 4.88 mmol) in water (7 ml) was added hydrochloric acid (6 M, 4.89 ml, 29.3 mmol) and the mixture was cooled to 0 °C Sodium nitrite (2 M, 3.66 ml, 7.32 mmol) was added dropwise to the mixture over 1 min at 0°C and the reaction mixture was stirred at 0°C for 30 min. A 2 M potassium iodide aqueous solution (5.37 ml, 10.7 mmol) was added dropwise to the reaction mixture over 1 min at 0°C. The reaction mixture was stirred at 0°C for 30 min. The reaction mixture was quenched with saturated sodium carbonate solution (50 ml) and was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n -hexane:ethyl acetate (4:1) to give the title compound (320 mg, 1.31 mmol, 27%) as a yellow powder. MS (ESI): mass calculated for C ₇ H ₅ IN ₂ - 244.0; m/z obtained, 245.0 [M+H] ⁺ .

Step C: 6-methyl-4-(2H-1,2,3-triazol-2-yl)picolinic acid . The title compound was prepared in a manner similar to that described for intermediate 83 using 4-iodo-6-methylpyridine-2-carbonitrile in place of 3-iodo-6-methylpyridine-2-carbonitrile in step D using conventional instead of microwave heating. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₂ - 204.1; m/z obtained, 205.1 [M+H] ⁺ .

Intermediate 87: 4-(4H- 1,2,4-triazol-4-yl)picolinic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 4-aminopyridine-2-carboxylate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₈ H ₆ N ₄ O ₂ - 190.1; obtained m/z, 191.1 [M+H] ⁺ .

Intermediate 88: 5-(4H-1,2,4-triazol-4-yl)nicotinic acid.

The title compound was prepared in a manner similar to that described for intermediate 68 using methyl 5-aminonicotinate instead of methyl 3-amino-5-fluorobenzoate in step A. MS (ESI): mass calculated for C ₈ H ₆ N ₄ O ₂ , - 190.1; obtained m/z, 191.1 [M+H] ⁺ .

Intermediate 89: 6-methyl-4-(4H-1,2,4-triazol-4-yl)picolinic acid.

Stage A: 4-amino-6-methylpyridine-2-carbonitrile . To a solution of 6-methyl-4-nitropyridine-2-carbonitrile (1.0 g, 6.13 mmol) in acetic acid (20 ml) was added iron powder (3.08 g, 55.2 mmol) at 50°C and the reaction mixture was stirred at 50°C for 30 min, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n -heptane:ethyl acetate (1:1) to give the title compound (160 mg, 1.20 mmol, 19%) as a white powder.

Step B: 6-methyl-4-(1,2,4-triazol-4-yl)pyridine-2-carbonitrile . To a solution of 4-amino-6-methylpyridine-2-carbonitrile (150 mg, 1.13 mmol) in pyridine (5 ml) was added 1,2-diformylhydrazine (248 mg, 2.82 mmol) and triethylamine (786 µl, 5 .63 mmol). Chlorotrimethylsilane (1.43 ml, 11.3 mmol) was added dropwise to the mixture and the reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered and evaporated, and the residue was purified by silica gel column chromatography, eluting with chloroform: methanol (10:1) to give the title compound (65 mg, 0.351 mmol, 31%) as a white powder. MS (ESI): mass calculated for C ₉ H ₇ N ₅ - 185.1; obtained m/z, 186.1 [M+H] ⁺ .

Step C: 6-methyl-4-(1,2,4-triazol-4-yl)pyridine-2-carboxylic acid hydrochloride . To a mixture of 6-methyl-4-(1,2,4-triazol-4-yl)pyridine-2-carbonitrile (50 mg, 0.270 mmol) in water (600 µl) and 1,4-dioxane (600 µl) was added sodium hydroxide (50 mg, 1.25 mmol). The reaction mixture was stirred at 80° C. for 1 hour. The reaction was quenched with 6 M hydrochloric acid (0.3 ml) and the mixture was evaporated. The residue was triturated with water (1 ml) to give the title compound (21 mg, 0.087 mmol, 32%) as a white powder. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₂ - 204.1; obtained m/z, 205.1 [M+H] ⁺ .

Intermediate 90: 5-(triazol-2-yl)pyridine-3-carboxylic acid.

Step A: 5-(triazol-2-yl)pyridine-3-carboxylic acid and 5-(triazol-1-yl)pyridine-3-carboxylic acid . A mixture of methyl 5-iodopyridine-3-carboxylate (200 mg, 0.76 mmol), 1 H -1,2,3-triazole (80 mg, 1.16 mmol), cesium carbonate (420 mg, 1.29 mmol) , trans- N,N'- dimethylcyclohexane-1,2-diamine (20 µL, 0.127 mmol, 0.902 g/mL) and copper(I) iodide (20 mg, 0.105 mmol) in N, N -dimethylformamide (2 mL) stirred at 140° C. for 3 hours. The reaction mixture was filtered and the filtrate was evaporated to give a mixture of the title compounds (320 mg, imp.) as a brown powder. MS (ESI): mass calculated for C ₈ H ₆ N ₄ O ₂ - 190.1; m/z obtained, 189.2 [M+H] ^- .

Step B: methyl 5-(triazol-2-yl)pyridine-3-carboxylate and methyl 5-(triazol-1-yl)pyridine-3-carboxylate . To a suspension of the crude acid mixture (320 mg, 1.68 mmol) in dry tetrahydrofuran (5 ml) was added 1.0 M ethereal diazomethane (5 ml, 5 mmol, 1 M). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with water (1×5 ml), dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC to give methyl 5-(triazol-2-yl)pyridine-3-carboxylate (11 mg, 0.054 mmol, 3%) as a white powder. MS: m/z 205.1 [M+H] ⁺ .

Fractions from the same preparative HPLC (method E) were collected to give methyl 5-(triazol-1-yl)pyridine-3-carboxylate (8 mg, 0.039 mmol, 2%) as a white powder. MS (ESI): mass calculated for C ₉ H ₈ N ₄ O ₂ - 204.1; m/z obtained, 205.1 [M+H] ⁺ .

Step C: 5-(triazol-2-yl)pyridine-3-carboxylic acid . To a solution of methyl 5-(triazol-2-yl)pyridine-3-carboxylate (11 mg, 0.0539 mmol) in 1,4-dioxane (500 µl) was added sodium hydroxide solution (6 mg, 0.15 mmol) in water (130 µl). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 4 with 1 M hydrochloric acid (100 μl). The mixture was evaporated to give the title compound (18 mg, 0.095 mmol, imp.) as a light brown powder. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.82 (br. s, 1H), 9.45 (d, J =2.5 Hz, 1H), 9.10 (d, J =1, 7 Hz, 1H), 8.76-8.71 (m, 1H), 8.27 (s, 2H).

Intermediate 91: 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylic acid.

Step A: ethyl 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylate . Lithium diisopropylamide (LDA) (2.0 M in THF/heptane/ethylbenzene) (0.30 ml, 0.60 mmol) and the mixture was stirred at -78°C for 30 min, after which a solution of N-fluorodibenzenesulfonimide (NFSI) (187 mg, 0.60 mmol) was added in THF (0.5 ml). The reaction mixture was kept at -78°C for an additional 30 minutes, the cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was quenched using saturated aqueous NH ₄ Cl and then diluted with EtOAc and H ₂ O. The layers were separated and the aqueous layer was extracted with EtOAc (× 3). The combined organic layers were then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo . The crude residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give a yellow solid (33.5 mg, 61% yield). MS (ESI): mass calculated for C ₈ H ₁₁ FN ₂ O ₂ - 186.1; obtained m/z, 187.1 [M+H] ⁺ . ¹ H NMR (400 MHz, chloroform- d ) δ 4.29 (k, J = 7.1 Hz, 2 H), 3.67 (s, 3 H), 2.38 (s, 3 H), 1 .34 (t, J = 7.1 Hz, 3 H).

Step B: 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylic acid. A solution of ethyl 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylate (9.7 mg, 52.1 µmol) in 37% HCl aqueous solution (1.62 ml) was heated to 110°C for 3 h, after which it was cooled to room temperature and diluted with H ₂ O. The mixture was carefully neutralized with 10 N aqueous NaH solution and then was extracted with ethyl acetate (× 3). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a yellow solid which was used in the next step without further purification. MS (ESI): mass calculated for C ₆ H ₇ FN ₂ O ₂ - 158.0; obtained m/z, 159.1 [M+H] ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ) δ 3.68 (d, J =1.5 Hz, 3 H), 2.34 (s, 3 H).

Intermediate 92: 1-cyclopropyl-5-methyl-pyrazole-4-carboxylic acid.

Step A: ethyl 1-cyclopropyl-5-methyl-pyrazole-4-carboxylate and ethyl 2-cyclopropyl-5-methyl-pyrazole-4-carboxylate . To a solution of ethyl 3-methyl- 1H -pyrazole-4-carboxylate (1.55 g, 10.1 mmol) in 1,2-dichloroethane (60 ml) was added cyclopropylboronic acid (1.73 g, 20.1 mmol) , copper(II) acetate (3.65 g, 20.1 mmol), potassium carbonate (278 g, 20.1 mmol) and 2,2'-bipyridine (3.14 g, 20.1 mmol). The reaction mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with water (100 ml) and extracted with chloroform (2×60 ml). The combined organic layers were washed with brine (1×10 ml), dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel gradient column chromatography eluting with n -heptane-ethyl acetate (20:1 → 1:1) to give a 60:40 mixture of the title compounds (290 mg, 1.493 mmol, 15%) in form of a colorless liquid.

Ethyl 1-cyclopropyl-5-methyl-pyrazole-4-carboxylate. MS (EMI): mass calculated for C₁₀H₁₄N₂O₂, - 194.1; obtained m/z, 195.2 [M+H]⁺. 1 H NMR (300 MHz, DMSO-d ₆) δ 7.69 (s, 1 H), 4.20 (k,J= 6.8 Hz, 2 H), 3.64-3.48 (m, 1 H), 2.57 (s, 3 H), 1.26 (t,J= 7.1 Hz, 3 H), 1.13-1.03 (m, 4 H).

Fractions from the same column were collected and purified by silica gel column chromatography eluting with n -heptane-ethyl acetate (100:1 → 1:1) to give pure ethyl 2-cyclopropyl-5-methyl-pyrazole-4- carboxylate (90 mg, 0.463 mmol, 5%) as a colorless liquid.

MS (ESI): mass calculated for C ₁₀ H ₁₄ N ₂ O ₂ - 194.1; obtained m/z, 195.2 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.21 (s, 1H), 4.18 (q, J =7.1 Hz, 2H), 3.74-3.66 (m, 1H) , 2.30 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.09-1.01 (m, 2H), 0.96-0.90 (m, 2H ).

Stage B: 1-cyclopropyl-5-methyl-pyrazole-4-carboxylic acid . To a mixture of ethyl 1-cyclopropyl-5-methyl-pyrazole-4-carboxylate and ethyl 2-cyclopropyl-5-methyl-pyrazole-4-carboxylate (260 mg, 1.34 mmol) in water (1.5 ml) and 1,4-dioxane (1.5 ml) was added sodium hydroxide (120 mg, 3 mmol). The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was evaporated. The residue was dissolved in water (2 ml) and acidified to pH 4 with 1 M hydrochloric acid. The precipitate was collected to give the title compound (35 mg, 0.211 mmol, 16%) as a white powder. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₂ - 166.1; obtained m/z, 167.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.19 (br. s, 1H), 7.65 (s, 1H), 3.59-3.50 (m, 1H), 2.55 ( s, 3H), 1.08-0.98 (m, 4H). The structure was confirmed by nuclear Overhauser effect spectroscopy.

Intermediate 93: 1-cyclopropyl-3-methyl-pyrazole-4-carboxylic acid.

To a mixture of ethyl 2-cyclopropyl-5-methyl-pyrazole-4-carboxylate (intermediate 92, step A) (70 mg, 0.36 mmol) in water (1 ml) and 1,4-dioxane (1 ml) sodium hydroxide (32 mg, 0.80 mmol) was added. The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water (2 ml). The mixture was acidified to pH 4 with 1M hydrochloric acid. The precipitate was collected to give the title compound (25 mg, 0.150 mmol, 42%) as a white powder. MS (ESI): mass calculated for C ₈ H ₁₀ N ₂ O ₂ - 166.1; m/z obtained, 167.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.11 (br. s, 1H), 8.14 (s, 1H), 3.78-3.58 (m, 1H), 2.28 ( s, 3H), 1.14-0.80 (m, 4H). The structure was confirmed by nuclear Overhauser effect spectroscopy.

Intermediate 94: 1-Methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid.

Stage A: 4-iodine-1-methylpyrazolo[3,4- b ]pyridine. To a solution of 4-iodine-1H-pyrazolo[3,4-b]pyridine (405 mg, 1.65 mmol) inN, N-dimethylformamide (4 ml) was added sodium hydride (60% in mineral oil, 80 mg, 2.0 mmol) at 0°C and the reaction mixture was stirred at 0°C for 15 min. Iodomethane (115 μl, 1.85 mmol, 2.28 g/ml) was added to the reaction mixture and the reaction mixture was stirred at 0° C. for 45 minutes. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×15 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting withn-heptane:ethyl acetate (9:1) to give the title compound (200 mg, 0.772 mmol, 47%) as a white powder. MS (EMI): mass calculated for C₇H₆IN₃, - 259.0; obtained m/z, 260.0 [M+H]⁺.

Step B: 1-methylpyrazolo[3,4- b ]pyridine-4-carbonitrile.

Copper(I) cyanide (62 mg, 0.692 mmol) was added to a solution of 4-iodo-1-methylpyrazolo[3,4- b ]pyridine (150 mg, 0.579 mmol) in dimethyl sulfoxide (1.5 ml). The reaction mixture was stirred at 120° C. for 20 h under argon and poured into water (15 ml). The precipitate was collected to give the crude title compound (165 mg) as an orange powder. MS (ESI): mass calculated for C ₈ H ₆ N ₄ - 158.1; obtained m/z, 157.1 [M+H] ^- .

Step C: 1-methylpyrazolo[3,4- b ]pyridine-4-carboxylic acid. To a mixture of 1-methylpyrazolo[3,4-b]pyridine-4-carbonitrile (150 mg, 0.948 mmol) in water (1 ml) and 1,4-dioxane (1 ml) sodium hydroxide (1 M, 960 μl, 0.96 mmol) was added. The reaction mixture was stirred at 80°C for 20 h and filtered. The filtrate was diluted in water (5 ml) and extracted with ethyl acetate (2 x 5 ml). The aqueous layer was acidified to pH 4 with 1M hydrochloric acid. The precipitate was collected to give the title compound (35 mg, 0.198 mmol, 21%) as a tan powder. MS (EMI): mass calculated for C₈H₇N₃O₂, - 177.1; obtained m/z, 178.1 [M+H]⁺.

Intermediate 95: 7-methylimidazo[1,2-a]pyridine-5-carboxylic acid.

Step A: 7-methylimidazo[1,2- a ]pyridine-5-carbonitrile. To a solution of 5-bromo-7-methylimidazo[1,2-a]pyridine (300 mg, 1.42 mmol) in dimethyl sulfoxide (3 ml) copper(I) cyanide (152 mg, 1.70 mmol) was added. The reaction mixture was stirred at 120°C for 20 hours. Copper(I) iodide (54 mg, 0.284 mmol) was added to the reaction mixture. The reaction mixture was stirred at 120° C. for 20 hours. The reaction mixture was poured into water (20 ml). The precipitate was collected and triturated with warm chloroform (3 x 20 ml). The filtrate was evaporated to give the title compound (103 mg, 0.655 mmol, 46%) as a tan powder. MS (EMI): mass calculated for C₉H₇N₃, - 157.1; obtained m/z, 158.1 [M+H]⁺.

Step B: 7-methylimidazo[1,2- a ]pyridine-5-carboxylic acid. To a mixture of 7-methylimidazo[1,2-a]pyridine-5-carbonitrile (93 mg, 0.592 mmol) in water (1.5 ml) and 1,4-dioxane (1.5 ml) was added sodium hydroxide (59 mg, 1.48 mmol). The reaction mixture was stirred at 50° C. for 1 hour. The mixture was acidified to pH 4 with 1 M hydrochloric acid. The mixture was evaporated. The residue was triturated with methanol (2×3 ml) and the filtrate was evaporated to give the title compound (120 mg, imp.) as a pale yellow powder. MS (EMI): mass calculated for C₉H₈N₂O₂, - 176.1; obtained m/z, 177.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d ₆) δ 8.86 (d,J=2.0 Hz, 1H), 8.16-8.09 (m, 1H), 8.00-7.96 (m, 1H), 7.96-7.93 (m, 1H), 3, 72-3.17 (m, 1H), 2.54 (s, 3H).

Intermediate 96: Potassium 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate.

To a solution of ethyl 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (100 mg, 0.5 mmol) in THF (4.0 ml) was added potassium trimethylsilanylate (92.4 mg, 0.72 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and washed with THF to give the title compound as a white solid, which was used in the next step without purification. MS (ESI): mass calculated for C ₈ H ₄ FKN ₂ O ₂ - 218.0; obtained m/z, 181.1 [M-K+2H] ⁺ .

Intermediate 97: Potassium 2,7-dimethylimidazo[1,2-b]pyridazine-3-carboxylate.

Step A: Ethyl 2,7-dimethylimidazo[1,2-b]pyridazine-3-carboxylate . Ethyl 2-chloro-3-oxobutanoate (2.3 ml , 2.7 mmol) and the mixture was heated to 90° C. for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, the organic layer was washed with water (x2). The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. Purification by flash chromatography (SiO ₂ ; 0-100% EtOAc/hexanes) afforded the title compound as a white solid (86.4 mg, 20% yield). MS (ESI): mass calculated for C ₁₁ H ₁₃ N ₃ O ₂ - 219.1, obtained m/z - 220.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.57 (d, J =2.1 Hz, 1H), 7.98-7.90 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.60 (s, 3H), 2.41 (d, J =1.2 Hz, 3H), 1.34 (t, J =7.1 Hz, 3H).

Step B: Potassium 2,7-dimethylimidazo[1,2-b]pyridazine-3-carboxylate . The title compound was prepared in a manner similar to that described for intermediate 96 using ethyl 2,7-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (Step A) in place of ethyl 7-fluoroimidazo[1,2-a]- pyridine-3-carboxylate and stirring the reaction mixture at 60°C instead of room temperature. MS (ESI): mass calculated for C ₉ H ₈ KN ₃ O ₂ - 229.0; obtained m/z, 192.0 [M-K+2H] ⁺ .

Intermediate 98: Potassium 2,5,8-trimethylimidazo[1,2-a]pyrazine-3-carboxylate.

The title compound was prepared in a manner similar to that described for intermediate 97 using 3,6-dimethylpyrazin-2-amine instead of 5-methylpyridazin-3-amine in step A. MS (ESI): mass calculated for C ₁₀ H ₁₀ KN ₃ O ₂ , - 243.0; obtained m/z, 206.1 [M-K+2H] ⁺ .

Intermediate 99: Sodium 3-methylimidazo[1,5-a]pyrazine-1-carboxylate.

To a solution of methyl 3-methylimidazo[1,5-a]pyrazine-1-carboxylate (53 mg, 0.28 mmol) in ethanol (3.0 ml) was added a solution of sodium hydroxide (33 mg, 0.83 mmol) in water (1.0 ml). The resulting mixture was stirred at 80° C. for 16 hours. The reaction mixture was then filtered and washed with ethyl acetate to give the title compound as a white solid, which was used in the next step without purification. MS (ESI): mass calculated for C ₈ H ₆ N ₃ NaO ₂ - 199.0, obtained m/z - 178.1 [M-Na+2H] ⁺ .

Intermediate 100: 2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid.

Step A: ethyl 2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylate. A solution of 1-aminopyridin-1-ium (1 g, 10.5 mmol) in DMF (10 ml) was cooled to 0 ºC in an ice bath and ethyl 4,4,4-trifluorobut-2-inoate (1.5 ml , 10.5 mmol) followed by the addition of TEA (1.5 ml, 10.5 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (2.39 g, 10.5 mmol ). The resulting mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ºC in an ice bath and 2,3-dichloro-5,6-dicyano-p-benzoquinone (2.39 g, 10.5 mmol) was added, which was stirred overnight while warming to room temperature. The reaction mixture was poured into water and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified (FCC, SiO ₂ ; 0-30% EtOAc/hexanes) to give the title compound (220 mg, 8%) . MS (ESI): mass calculated for C ₁₁ H ₉ F ₃ N ₂ O ₂ - 258.0; obtained m/z, 259.0 [M+H] ⁺ .

Step B: 2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid.

LiOH ₍ 82 mg, 3.4 mmol). The resulting solution was stirred at room temperature. during the night. The completed reaction was concentrated and taken up in water. The reaction mixture was acidified with 1N HCl and extracted with EtOAc (3x). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound, which was then taken up without further purification (216 mg, 100%). MS (ESI): mass calculated for C ₉ H ₅ F ₃ N ₂ O ₂ - 230.0; obtained m/z, 231.0 [M+H] ⁺ .

Intermediate 101: lithium-quinoxaline-6-carboxylic-2,3- d ₂ acid.

Stage A: methyl 2,3-dihydroxyquinoxaline-6-carboxylate . A solution of methyl 3,4-diaminobenzoate (1.0 g, 6.0 mmol) in diethyl oxalate (20.0 ml) was heated to 140° C. in an oil bath for 16 h. The resulting mixture was cooled to room temperature and the solids were collected filtration, then dried under vacuum to give the title compound as a yellow solid (780 mg, 60% yield). MS (ESI): mass calculated for C ₁₀ H ₈ N ₂ O ₄ - 220.1, obtained m/z, 221.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.10 (d, J =74.3 Hz, 2H), 7.78-7.62 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 3.84 (s, 3H).

Stage B: methyl 2,3-dichloroquinoxaline-6-carboxylate . To a solution of methyl 2,3-dihydroxyquinoxaline-6-carboxylate (590 mg, 2.7 mmol) in toluene (16.0 ml) was added thionyl chloride (3.8 ml, 53.6 mmol) followed by N,N-dimethylformamide (0.25 ml, 3.2 mmol). The resulting solution was heated to reflux for 3 hours. After cooling the mixture, the solvent was concentrated in vacuo and triturated with ethyl acetate. The resulting brown solid was filtered and dried in vacuo to give the title compound (308 mg, 45% yield). MS (ESI): mass calculated for C ₁₀ H ₆ Cl ₂ N ₂ O ₂ - 257.1; obtained m/z, 257.9 [M+H] ⁺ .

Stage C: methylquinoxaline-6-carboxylate-2,3- d ₂ . To a solution of methyl 2,3-dichloroquinoxaline-6-carboxylate (208 mg, 0.81 mmol) in THF (16.0 ml) was added PdCl₂(dppf) (30 mg, 0.04 mmol), N¹, N¹, N², N²-tetramethylethane-1,2-diamine (0.21 ml, 1.37 mmol) and sodium borodeuteride (68 mg, 1.62 mmol). The mixture was degassed with nitrogen and then stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (x2). The combined organic extracts were dried over Na₂SO₄ and concentrated. Purification by flash chromatography (SiO₂; 0-100% EtOAc/hexanes) gave the title compound as a white solid (72.5 mg, 47% yield). MS (EMI): mass calculated for C₁₀H₆ D₂N₂O₂, - 190.2; obtained m/z, 191.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d ₆) δ 8.65 (dd,J=1.9, 0.6 Hz, 1H), 8.33 (dd,J= 8.7, 1.9 Hz, 1H), 8.23 (dd,J=8.7, 0.6 Hz, 1H), 3.97 (s, 3H).

Stage D: quinoxaline-6-lithium-2,3-carboxylate d2 to a solution of methylquinoxaline-6-carboxylate-2,3-d ₂ (68 mg, 0.36 mmol) in THF (2.4 ml) was added a solution of lithium hydroxide (17.0 mg, 0.72 mmol) in water (1.0 ml). The mixture was stirred at room temperature for 1 hour, then concentrated to give the title compound as a white solid, which was further used in the next step without purification (quantitative). MS (EMI): mass calculated for C₉H₃ D₂ LiN₂O₂, - 182.1; obtained m/z, 177.1 [M+H]⁺.

Intermediate 102: lithium-quinoxaline-6-carboxylic-2- d acid.

The title compound was prepared analogously to intermediate 101 using ethyl 2-oxoacetate and ethanol instead of diethyl oxalate and the reaction mixture was stirred at room temperature instead of heating in step A. MS (ESI): mass calculated for C ₉ H ₄ DLiN ₂ O ₂ , - 181.1, obtained m/z, 175.9 [M-Li+2 H] ⁺ .

Intermediate 103: Potassium 2,6,6-trimethyl-6,7-dihydro-4H-pyrazole[5,1-c][1,4]oxazine-3-carboxylate.

Stage A: 6,6-dimethylmorpholine-3-carboxylic acid . Trifluoroacetic acid (6.0 ml) was added to a solution of 4-(tert-butyl)3-methyl-6,6-dimethylmorpholine-3,4-dicarboxylate (5 g, 18.3 mmol) in DCM (18.3 ml) and stirred the reaction mixture at room temperature for 2 h. Concentrate the solvent, dissolve the crude residue in methanol (MeOH) (9.2 ml) followed by the addition of sodium hydroxide (3.0 g, 73.2 mmol) in water. The solvent was concentrated using a rotary evaporator and the crude product was used in the next step without purification. MS (ESI): mass calculated for C ₇ H ₁₃ NO ₃ - 159.1, obtained m/z, 160.2 [M+H] ⁺ .

Step B: 6,6-dimethyl-6,7-dihydro-4H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8-ium-3-olate. To a solution of 6,6-dimethylmorpholine-3-carboxylic acid (2.9 g, 18.3 mmol) in water (1.8 ml, 95.2 mmol) was added sodium nitrite (1.9 g, 27.4 mmol) and hydrochloric acid (37% aqueous solution) (1.24 ml, 14.8 mmol). The resulting mixture was stirred at room temperature for 16 hours, then diluted with water and extracted 3 times with a mixture of 20% isopropyl alcohol and chloroform. The combined organic extracts were dried over anhydrous Na ₂ SO 4 and concentrated in vacuo. The crude residue was then dissolved in acetonitrile (7.5 ml) followed by the addition of 2,2,2-trifluoroacetic anhydride (1.5 ml, 11.1 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with potassium carbonate (2.0 g, 14.8 mmol), water was added and filtered to give the title compound as a crystalline precipitate, extracted 3 times with 20% iPrOH/chloroform. The solid was used in the next step without further purification. MS (ESI): mass calculated for C ₇ H ₁₂ N ₂ O ₄ - 170.2; obtained m/z, 171.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 4.6 (s, 2H) 4.3 (s, 2H) 1.3 (s, 6H).

Step C: Ethyl 2,6,6-trimethyl-6,7-dihydro-4H-pyrazole[5,1-c][1,4]oxazine-3-carboxylate:

To a solution of 6,6-dimethyl-6,7-dihydro-4H- [1,2,3] oxadiazolo[4,3-c] [1,4]oxazin-8-ium-3-olate (200 mg, 1 .2 mmol) in xylene (4.0 mL) was added ethyl but-2-inoate (0.28 mL, 2.4 mmol) and the mixture was stirred at 145° C. for 16 h. The solvent was concentrated and purified by flash chromatography (SiO ₂ ; 0-100% EtOAc/hexanes) to give the title compound as the main regioisomer (91 mg, 33% yield). MS (ESI): mass calculated for C ₁₂ H ₁₈ N ₂ O ₃ - 238.3; obtained m/z, 239.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 4.88 (s, 2H), 4.17 (q, J =7.1 Hz, 2H), 3.89 (s, 2H), 2.32 (s, 3H), 1.28 (s, 1H), 1.27-1.24 (m, 8H).

Step D: Potassium 2,6,6-trimethyl-6,7-dihydro-4H-pyrazole[5,1-c][1,4]oxazine-3-carboxylate: The title compound was prepared in a manner analogous to that described for Intermediate 96 , using ethyl 2,6,6-trimethyl-6,7-dihydro-4H-pyrazole[5,1-c] [1,4] oxazine-3-carboxylate (step C) instead of ethyl 7-fluoroimidazo[1 ,2-a] pyridine-3-carboxylate and the reaction mixture was stirred at 60°C for 24 h rather than at room temperature. MS (ESI): mass calculated for C ₁₀ H ₁₃ KN ₂ O ₃ - 248.1; obtained m/z, 211.1 [M-K+2H] ⁺ .

Intermediate 104: tert -Butyl (5S,8R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c ]pyrazole-9-carboxylate.

The title compound was obtained from the same chiral SFC purification of racemic tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazole-9-carboxylate (intermediate 35) used to prepare the title compound (one enantiomer; retention time 1.13 min). MS (ESI): mass calculated for C ₁₅ H ₂₀ F ₃ N ₃ O ₅ S - 411.1; obtained m/z, 356.0 [M+2H-tert-butyl] ⁺ .

Intermediate 105: (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2 ,2,2-trifluoroacetate.

Stage A: tert -butyl (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9- carboxylate.Microwave bottle withtert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9-carboxylate (intermediate 35) (500 mg, 1.22 mmol), (3,4,5-trifluorophenyl)boronic acid (257 mg, 1.46 mmol), sodium carbonate (386 mg, 3.65 mmol) and XPhos Pd G2 (96 mg, 0.12 mmol) in 1,4-dioxane (17 ml) and water (2 ml) was purged with N₂ within 5 min. The resulting mixture was heated in a microwave reactor for 30 minutes at a temperature of 110 ºC. The completed reaction was diluted with water and extracted into DCM (3x). The combined organics were dried over Na₂SO₄, filtered, concentrated under reduced pressure and purified (FCC, SiO₂; 0-30% EtOAc/hexanes) to give the title compound (465 mg, 97%). MS (EMI): mass calculated for C₂₀H₂₂F₃N₃O₂, - 393.2; obtained m/z, 338.0 [M+2H-tert-butyl]⁺.

Step B: (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2, 2,2-trifluoroacetate . To a solution of tert-butyl (5 R ,8 S )-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohept[c ]pyrazole-9-carboxylate (950 mg, 2.42 mmol) in DCM (10 mL) trifluoroacetic acid (TFA) (3.5 mL, 45.8 mmol) was added and stirred at room temperature for 30 min. The complete reaction was concentrated and used further without further purification (983 mg, 100%). MS (ESI): mass calculated for C ₁₅ H ₁₄ F ₃ N ₃ - 293.3; obtained m/z, 294.0 [M+H]+.

Intermediate 106: (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2,2,2-trifluoroacetate.

The title compound was prepared in a manner analogous to that of intermediate 105 using phenylboronic acid in place of (3,4,5-trifluorophenyl)boronic acid in step A. MS (ESI): mass calculated for C ₁₅ H ₁₇ N ₃ - 239, 1; obtained m/z, 240.1 [M+H] ⁺ .

Intermediate 107: (5R,8S)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate 2,2,2-trifluoroacetate.

To a solution of tert -butyl (5 R ,8 S )-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c ]pyrazole-9-carboxylate (intermediate 104) (235 mg, 0.571 mmol) in DCM (5 ml) was added with TFA (0.85 ml, 11.07 mmol) and stirred at room temperature for 30 min. The complete reaction was concentrated and used further without further purification (177 mg, 100%). MS (ESI): mass calculated for C ₁₀ H ₁₂ F ₃ N ₃ O ₃ S - 311.1; obtained m/z, 312.0 [M+H] ⁺ .

Intermediate 108: (5R,8S)-9-(3-methoxybenzoyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yltrifluoromethanesulfonate.

Into a solution of (5 R ,8 S )-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate 2,2,2-trifluoroacetate ( intermediate 107) (90 mg, 0.289 mmol), 3-methoxybenzoic acid (58 mg, 0.379 mmol) and HATU (330 mg, 0.867 mmol) in DMF (11 ml) was added DIEA (200 μl, 1.16 mmol). The resulting solution was stirred at room temperature. during the night. The complete reaction was diluted with water and extracted into DCM (x2), the combined organics were dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified (FCC, SiO ₂ ; 0-10% MeOH/DCM) to give the title compound (62 mg, 48%). MS (ESI): mass calculated for C ₁₈ H ₁₈ F ₃ N ₃ O ₅ S - 445.1; obtained m/z, 446.0 [M+H] ⁺ .

Intermediate 109: (5R,8S)-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5,6,7,8-hexahydro-5, 8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate.

The title compound was prepared in a manner similar to intermediate 108 using 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid in place of 3-methoxybenzoic acid. MS (ESI): mass calculated for C ₁₈ H ₂₀ F ₃ N ₅ O ₄ S - 459.1; obtained m/z, 460.0 [M+H] ⁺ .

Intermediate 110: (5R,8S)-2-methyl-9-(quinoline-6-carbonyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-3- yl trifluoromethanesulfonate.

The title compound was prepared in a manner similar to that described for intermediate 108, using quinoline-6-carboxylic acid instead of 3-methoxybenzoic acid. MS (ESI): mass calculated for C ₁₈ H ₁₇ F ₃ N ₄ O ₄ S - 466.1; obtained m/z, 467.0 [M+H] ⁺ .

Intermediate 111: (5S,8R)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2 ,2,2-trifluoroacetate.

The title compound was prepared in a manner similar to that described for intermediate 105 using tert -butyl (5S,8R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazole-9-carboxylate instead of (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazole 2,2,2-trifluoroacetate in step A. MS (ESI): mass calculated for C ₁₅ H ₁₄ F ₃ N ₃ - 293.3; obtained m/z10 294.1 [M+H] ⁺ .

Intermediate 112: 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

The title compound was prepared in a manner analogous to that described for intermediate 44, using 5-fluoro-2-iodobenzoic acid in place of 3-iodobenzoic acid and 1,2,3-triazole in place of 3-(trifluoromethyl)pyrazole. MS (ESI): mass calculated for C ₉ H ₆ FN ₃ O ₂ - 207.0; obtained m/z, 208.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 13.34 (br. s, 1H), 8.05 (s, 2H), 7.78 (dd, J =8.8, 4.9 Hz, 1H), 7.59 (dd, J =8.6, 2.9 Hz, 1H), 7.55 (td, J =8.4, 3.0 Hz, 1H).

Example 1 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone.

To a solution of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) (25 mg, 0.01 mmol) in DCM (2.0 mL) was added 1-[bis(dimethylamino)methylene]-1H - 1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU ) (45 mg, 0.12 mmol) followed by N,N-diisopropylethylamine (DIPEA or DIEA) (0.05 ml, 0.3 mmol) and quinoline-6-carboxylic acid (18.8 mg, 0.11 mmol) and the mixture was stirred for 1 h at room temperature. The reaction mixture was then diluted with water and extracted with DCM (x2). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC on an XBridge C18 column (5 μm, 100×4.6 mm), mobile phase 10-100% ACN in 20 mM NH ₄ OH to give the title compound as a white solid (16, 2 mg, 40% yield. MS ( _ESI ): mass calculated for C ₂₆ H ₂₄ N ₄ O - 408.2; the resulting m/z is 409.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.07-8.89 (m, 1H), 8.48 (d, J =8.4 Hz, 1H), 8.20-8.02 (m, 2H), 7.88-7.73 (m, 1H), 7.68-7.39 (m, 6H), 5.17-4.81 (m, 1H), 4.11 (s , 1H), 3.76 (d, J = 40.8 Hz, 3H), 3.23-2.93 (m, 1H), 2.49-2.31 (m, 1H), 2.14- 1.38 (m, 6H).

Example 2 quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-cyclopropyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole (intermediate 31) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole ( intermediate connection 1). MS (ESI): mass calculated for C ₂₃ H ₂₄ N ₄ O - 372.2; the resulting m/z is 373.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): δ 9.07-8.81 (m, 1H), 8.56-8.40 (m, 1H), 8.16-7.93 (m, 2H), 7.83-7.50(m, 2H), 5.69-5.56(m, 1H), 4.78-4.57(m, 1H), 3.81-3.69( m, 3H), 3.40-3.38 (m, 2H), 1.92-1.22 (m, 7H), 0.97-0.85 (m, 2H), 0.80-0, 60 (m, 2H).

Example 3 Racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ ClN ₃ O ₂ - 421.1; obtained m/z, 422.1 [M+H] ⁺ .

Example 4 (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole (intermediate 27) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole ( intermediate 1) and 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ ClN ₃ O ₂ - 421.1; obtained m/z, 422.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.56-7.30 (m, 6H), 7.24-7.16 (m, 1H), 7.10-6.62 (m, 1H ), 5.82-5.67 (m, 1H), 3.92-3.86 (m, 3H), 3.85-3.66 (m, 4H), 3.14-2.67 (m , 1H), 2.38 (dd, J =19.2, 16.0 Hz, 1H), 1.95-1.34 (m, 6H).

Example 5 (2-chloro-3-methoxyphenyl) ((5S,9R)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5S,9R)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole (intermediate 26) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole ( intermediate 1) and 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ ClN ₃ O ₂ - 421.1; obtained m/z, 422.1 [M+H] ⁺ .

Example 6 Racemic (2-(1H-1,2,4-Triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 2-(1 H-1,2,4-triazol-1-yl)-benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ N ₆ O - 424.2; the resulting m/z is 425.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.02-8.64 (m, 1H), 8.49-8.23 (m, 1H), 7.75-7.39 (m, 9H ), 5.64 (s, 1H), 3.86-3.58 (m, 4H), 3.08-2.77 (m, 1H), 2.35 (dd, J =16.2, 8 .4 Hz, 1H), 1.80-1.28 (m, 6H).

Example 7 Racemic (3-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 3-(4H-1,2,4-triazol-4-yl)-benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ N ₆ O - 424.2; the resulting m/z is 425.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.21 (d, J =1.1 Hz, 2H), 7.93-7.76 (m, 2H), 7.71-7.59 ( m, 1H), 7.58-7.35 (m, 6H), 5.79-5.68 (m, 1H), 4.03 (td, J = 7.0, 6.6, 4.6 Hz, 1H), 3.76 (d, J =40.0 Hz, 3H), 3.11-2.92 (m, 1H), 2.47-2.33 (m, 1H), 1.96 -1.33 (m, 6H).

Example 8 Racemic (4-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-(1 H-1,2,4-triazol-1-yl)-benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ N ₆ O - 424.2; obtained m/z, 425.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.39 (s, 1H), 8.26 (d, J =2.7 Hz, 1H), 8.08-7.88 (m, 2H) , 7.77-7.60(m, 1H), 7.58-7.32(m, 6H), 5.74(s, 1H), 4.06(s, 1H), 3.86-3 .68 (m, 3H), 3.24-2.88 (m, 1H), 2.42 (d, J =16.2 Hz, 1H), 2.02-1.40 (m, 6H).

Example 9 Racemic (3-(1H-imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 3-(1H-imidazol-1-yl)-benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ N ₅ O - 423.2; obtained m/z, 424.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35 (dd, J =3.0, 1.8 Hz, 1H), 7.90-7.31 (m, 10H), 7.11 ( dd, J =3.1, 1.9 Hz, 1H), 5.74 (s, 1H), 4.04 (s, 1H), 3.83-3.67 (m, 3H), 3.19 -2.90 (m, 1H), 2.40 (d, J =16.1 Hz, 1H), 2.03-1.36 (m, 6H).

Example 10 Racemic (1-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₀ H ₂₂ N ₆ O - 362.2; obtained m/z, 363.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.58 (dd, J =21.7, 0.7 Hz, 1H), 7.61-7.35 (m, 5H), 5.55 ( d, J = 172.8 Hz, 1H), 5.07-4.44 (m, 1H), 3.95-3.87 (m, 3H), 3.81-3.70 (m, 3H) , 3.17-2.89 (m, 1H), 2.47-2.28 (m, 1H), 1.93-1.36 (m, 6H).

Example 11 Racemic (5-chloro-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₂₂ ClN ₅ O - 395.2; obtained m/z, 396.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.74 (s, 1H), 7.57-7.37 (m, 5H), 5.73-5.56 (m, 1H), 4, 33-4.18 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.14-2.93 (m, 1H), 2.65-2.31 ( m, 1H), 2.07-1.55 (m, 4H), 1.56-1.30 (m, 2H).

Example 12 Racemic (5-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 5-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₅ N ₅ O ₂ - 391.2; obtained m/z, 392.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.56-7.46 (m, 4H), 7.46-7.40 (m, 2H), 5.69-5.58 (m, 1H ), 4.47-4.35 (m, 1H), 3.92 (s, 3H), 3.77 (s, 3H), 3.59 (s, 3H), 3.14-3.04 ( m, 1H), 2.50-2.41 (m, 1H), 1.85-1.57 (m, 4H), 1.54-1.34 (m, 2H).

Example 13 Racemic (4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₁ BrF ₃ N ₅ O - 507.1; obtained m/z, 508.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.60-7.38 (m, 5H), 5.75 (d, J =18.7 Hz, 1H), 4.04-3.71 ( m, 6H), 3.31-2.85 (m, 2H), 2.64-2.52 (m, 1H), 2.05-1.32 (m, 6H).

Example 14 Racemic (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-chloroquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₇ N ₅ O - 401.2; obtained m/z, 402.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.55-7.30 (m, 6H), 5.72 (d, J =26.3 Hz, 1H), 4.94 (d, J =32.7 Hz, 1H), 3.88-3.79 (m, 3H), 3.81-3.68 (m, 3H), 3.11-2.88 (m, 1H), 2, 46-2.28(m, 1H), 1.88-1.36(m, 7H), 0.96-0.78(m, 2H), 0.65-0.33(m, 2H).

Example 15 Racemic ((5R,9S)-2-Methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( 1-phenyl-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ N ₆ O - 424.2; obtained m/z, 425.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.41 (d, J =18.5 Hz, 1H), 7.96-7.79 (m, 2H), 7.64-7.56 ( m, 2H), 7.55-7.40 (m, 6H), 5.57 (d, J =203.7 Hz, 1H), 5.10-4.52 (m, 1H), 3.76 (d, J = 29.6 Hz, 3H), 3.18-2.96 (m, 1H), 2.56 (d, J = 16.2 Hz, 1H), 2.06-1.39 ( m, 6H).

Example 16 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( 1-phenyl-1H-pyrazol-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-phenyl-1H-pyrazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ N ₅ O - 423.2; obtained m/z, 424.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.60 (dd, J =13.8, 2.5 Hz, 1H), 7.95-7.79 (m, 2H), 7.62- 7.30 (m, 8H), 6.84 (dd, J =2.5, 1.4 Hz, 1H), 6.03-5.68 (m, 1H), 5.19-5.01 ( m, 1H), 3.85-3.62 (m, 3H), 3.15-3.01 (m, 1H), 2.57-2.53 (m, 1H), 1.91-1, 38 (m, 6H).

Example 17 Racemic (5-methoxy-1-phenyl-1H-pyrazol-3-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 5-methoxy-1-phenyl-1H-pyrazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₇ N ₅ O ₂ - 453.2; obtained m/z, 454.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.74-7.57 (m, 2H), 7.58-7.30 (m, 8H), 6.22 (s, 1H), 6, 10-5.71 (m, 1H), 5.12 (d, J = 72.4 Hz, 1H), 4.00-3.92 (m, 3H), 3.81-3.65 (m, 3H), 3.14-2.96 (m, 1H), 2.07-1.38 (m, 7H).

Example 18 Racemic (1-methyl-1H-indol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-methyl-1H-indole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₆ N ₄ O - 410.2; the resulting m/z is 411.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.57-7.38 (m, 6 H), 7.27-7.14 (m, 1 H), 6.98 (d, J =7 .0 Hz, 1 H), 6.32 (d, J = 23.4 Hz, 1 H), 5.78 (d, J = 21.0 Hz, 1 H), 4.14-3.76 ( m, 6 H), 3.69 (s, 1 H), 3.22-2.78 (m, 2 H), 2.31 (d, J =16.1 Hz, 1 H), 2.02 -1.33 (m, 6H).

Example 19 Racemic (5-chloro-1H-indol-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 5-chloro-1H-indole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ ClN ₄ O - 430.1; the resulting m/z is 431.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.48-11.13 (m, 1H), 7.82-7.61 (m, 1H), 7.57-7.37 (m, 5H ), 7.18 (d, J = 63.8 Hz, 1H), 6.60-6.42 (m, 1H), 5.92-5.67 (m, 1H), 5.21-4, 45 (m, 1H), 3.85-3.68 (m, 3H), 3.24-2.73 (m, 2H), 2.45-2.32 (m, 1H), 2.04- 1.27 (m, 6H).

Example 20 Racemic (7-methyl-1H-indazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 7-methyl-1H-indazole-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ N ₅ O - 411.2; obtained m/z, 412.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.32 (s, 1H), 8.14 (d, J =10.6 Hz, 1H), 7.70-7.39 (m, 6H) , 7.18 (s, 1H), 5.70 (s, 1H), 4.96 (d, J =20.3 Hz, 1H), 4.19 (s, 1H), 3.75 (d, J = 36.8 Hz, 3H), 3.23-2.92 (m, 2H), 2.41 (d, J = 16.3 Hz, 1H), 2.07-1.31 (m, 7H ).

Example 21 Racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ N ₅ O - 411.2; obtained m/z, 412.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (dd, J =11.6, 4.8 Hz, 1 H), 7.63-7.34 (m, 5 H), 7, 03 (dd, J =18.7, 4.8 Hz, 1 H), 6.35 (dd, J =36.5, 3.5 Hz, 1 H), 5.81 (s, 1 H), 5.19-4.53(m, 1H), 3.97-3.65(m, 6H), 3.22-2.78(m, 2H), 2.34(d, J = 16.1 Hz, 1 H), 2.04-1.34 (m, 6 H).

Example 22 Racemic (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ ClN ₅ O - 431.1; the resulting m/z is 432.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.37-7.86 (m, 1H), 7.76-7.62 (m, 1H), 7.59-7.32 (m, 5H ), 6.68-6.43 (m, 1H), 5.80 (d, J =41.6 Hz, 1H), 4.15-3.83 (m, 1H), 3.82-3, 69 (m, 3H), 3.20-2.85 (m, 2H), 2.48-2.16 (m, 1H), 2.00-1.32 (m, 6H).

Example 23 Racemic (4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ FN ₅ O - 415.1; obtained m/z, 416.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.23 (s, 1H), 8.21 (s, 1H), 7.69-7.36 (m, 6H), 6.71-6, 42 (m, 1H), 4.89 (d, J = 172.2 Hz, 1H), 4.00 (s, 1H), 3.76 (d, J = 29.1 Hz, 3H), 3, 16-2.82 (m, 1H), 2.41 (d, J =16.3 Hz, 1H), 2.00-1.32 (m, 6H).

Example 24 Racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ N ₅ O - 411.2; obtained m/z, 412.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.34 (dd, J =4.6, 1.6 Hz, 1 H), 8.16-7.91 (m, 2 H), 7, 48 (dd, J =38.4, 4.5 Hz, 5 H), 7.21 (dd, J =7.9, 4.6 Hz, 1 H), 4.78 (s, 1 H), 3.87 (s, 3 H), 3.76 (s, 3 H), 3.27-3.07 (m, 2 H), 2.49-2.39 (m, 1 H), 2, 05-1.36 (m, 6H).

Example 25 Racemic [1,2,4]triazolo[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using [1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ N ₆ O - 398.1; obtained m/z, 399.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.66-8.42 (m, 1H), 8.00-7.63 (m, 2H), 7.58-7.06 (m, 6H ), 5.85-5.09 (m, 1H), 3.76 (d, J = 37.5 Hz, 4H), 3.06-2.79 (m, 1H), 2.36 (d, J = 16.1 Hz, 1H), 2.08-1.33 (m, 6H).

Example 26: Racemic ((5R,8S)-2-Methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl) (quinolin- 6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole (intermediate 34) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₅ H ₂₂ N ₄ O - 394.1; obtained m/z, 395.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.98 (s, 1H), 8.57-8.40 (m, 1H), 8.28-8.02 (m, 2H), 7, 94-7.37(m, 7H), 5.56-5.40(m, 1H), 4.50-4.32(m, 1H), 3.85-3.65(m, 3H), 3.14-2.84 (m, 1H), 2.43-1.56 (m, 5H).

Example 27 Racemic (4-chloroquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-chloroquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ ClN ₄ O - 442.1; obtained m/z, 443.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (dd, J =9.4, 4.7 Hz, 1 H), 8.27-8.15 (m, 2 H), 7, 99-7.81 (m, 2 H), 7.55-7.40 (m, 5 H), 5.77 (d, J =8.5 Hz, 1 H), 4.96 (d, J = 96.1 Hz, 1 H), 3.86-3.67 (m, 3 H), 3.23-2.85 (m, 1 H), 2.43 (d, J = 16.2 Hz , 1 H), 1.90-1.41 (m, 6 H).

Example 28 Racemic (4-hydroxyquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 4-hydroxyquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ N ₄ O ₂ - 424.2; obtained m/z, 425.2 [M+H] ⁺ . ¹ H-NMR (500 MHz, DMSO- d ₆ ) δ 11.94 (s, 1H), 8.14-7.89 (m, 2H), 7.74-7.42 (m, 6H), 6 .16-6.02 (m, 1H), 4.93 (d, J = 74.9 Hz, 1H), 4.12 (s, 1H), 3.81-3.67 (m, 3H), 3.30-2.83 (m, 2H), 2.47-2.33 (m, 1H), 2.00-1.36 (m, 6H).

Example 29 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-5-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using quinoxaline-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ N ₅ O - 409.1; obtained m/z, 410.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.10-8.86 (m, 2 H), 8.24-8.04 (m, 1 H), 8.04-7.67 (m , 2 H), 7.61-7.36 (m, 5 H), 5.98-5.73 (m, 1 H), 3.81 (d, J =3.8 Hz, 2 H), 3.71-3.49 (m, 2 H), 3.22-2.62 (m, 1 H), 2.25 (dd, J = 33.8, 15.9 Hz, 1 H), 2 .03-1.33 (m, 6 H).

Example 30 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ N ₅ O - 409.2; obtained m/z, 410.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.11-8.97 (m, 2H), 8.28-8.04 (m, 2H), 7.97-7.83 (m, 1H ), 7.61-7.36 (m, 5H), 5.77 (d, J =13.7 Hz, 1H), 3.76 (d, J =44.7 Hz, 3H), 3.25 -2.95 (m, 2H), 2.40 (d, J =16.2 Hz, 1H), 2.03-1.40 (m, 6H).

Example 31 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinozalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using quinosaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ N ₅ O - 409.2; obtained m/z, 410.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.71 (d, J =9.5 Hz, 1H), 9.37 (d, J =12.6 Hz, 1H), 8.31-8 .22 (m, 1H), 8.19-7.95 (m, 2H), 7.57-7.41 (m, 5H), 5.77 (d, J = 5.6 Hz, 1H), 3.76 (d, J = 50.8 Hz, 3H), 3.20-3.01 (m, 2H), 2.47-2.34 (m, 1H), 2.04-1.41 ( m, 6H).

Example 32 Racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (2-(trifluoromethyl)-1,8-naphthyridin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1, using 2-(trifluoromethyl)-1,8-naphthyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O - 477.2; obtained m/z, 478.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.40-8.60 (m, 3H), 794-7.81 (m, 1H), 7.65-7.38 (m, 5H), 5.83 (s, 1H), 4.10-3.92 (m, 1H), 3.92-3.68 (m, 3H), 3.30-3.04 (m, 1H), 2, 45-2.26 (m, 1H), 2.07-1.34 (m, 6H).

Example 33 Racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(4-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 5) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1) and 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₃ O ₂ - 439.1; obtained m/z, 440.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.69-7.30 (m, 5H), 7.26-6.59 (m, 2H), 5.90-5.55 (m, 1H ), 5.17-4.37 (m, 1H), 3.96-3.86 (m, 3H), 3.81-3.65 (m, 3H), 3.15-2.73 (m , 1H), 2.36 (t, J =16.9 Hz, 1H), 1.98-1.26 (m, 6H).

Example 34 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 30) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (intermediate 30) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ FN ₆ O - 442.1; the resulting m/z is 443.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.16 (d, J =12.8 Hz, 1H), 8.03-7.74 (m, 2H), 7.72-7.11 ( m, 7H), 5.71-4.94 (m, 1H), 4.57-4.25 (m, 1H), 3.86-3.52 (m, 3H), 3.14-2, 78 (m, 1H), 2.43-2.13 (m, 1H), 1.91-1.12 (m, 6H).

Example 35 Racemic (1,4-dimethyl-1H-pyrazol-3-yl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 5) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1) and 1,3-dimethyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₄ FN ₅ O - 393.2; the resulting m/z is 394.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.64-7.44 (m, 3H), 7.41-7.28 (m, 2H), 5.78-5.67 (m, 1H ), 4.80-4.68 (m, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.06-2.88 (m, 1H), 2.51- 2.37 (m, 1H), 2.03 (s, 3H), 1.94-1.54 (m, 4H), 1.55-1.31 (m, 2H).

Example 36 ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 30) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ FN ₆ O - 430.1; the resulting m/z is 431.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.67-8.37 (m, 1H), 7.63-7.49 (m, 2H), 7.43-7.26 (m, 4H ), 6.36-6.21 (m, 1H), 5.26-5.07 (m, 1H), 4.24-4.09 (m, 3H), 3.84-3.64 (m , 3H), 3.17-2.99 (m, 1H), 2.64-2.54 (m, 1H), 2.11-1.42 (m, 6H).

Example 37 Racemic ((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 5) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ FN ₄ O - 426.2; obtained m/z, 427.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.08-8.86 (m, 1H), 8.58-8.43 (m, 1H), 8.20-8.02 (m, 2H ), 7.87-7.71 (m, 1H), 7.69-7.51 (m, 3H), 7.44-7.27 (m, 2H), 5.82-5.03 (m , 1H), 4.86-4.06 (m, 1H), 3.86-3.62 (m, 3H), 3.21-2.96 (m, 1H), 2.40 (d, J =16.2 Hz, 1H), 2.12-1.37 (m, 6H).

Example 38 ((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 30) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ FN ₄ O - 426.1; obtained m/z, 427.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.01-8.92 (m, 1H), 8.54-8.42 (m, 1H), 8.21-8.03 (m, 2H ), 7.81-7.54 (m, 4H), 7.47-7.21 (m, 2H), 5.82-5.65 (m, 1H), 4.14-4.05 (m , 1H), 3.78-3.67 (m, 3H), 3.19-2.94 (m, 1H), 2.40 (d, J =16.2 Hz, 1H), 2.10- 1.26 (m, 6H).

Example 39 Racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(3-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 4) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ ClFN ₃ O ₂ - 439.1; obtained m/z, 440.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.63-7.50 (m, 1H), 7.47-7.12 (m, 5H), 7.11-6.55 (m, 1H ), 5.77 (d, J = 8.5 Hz, 1H), 3.95-3.85 (m, 3H), 3.82-3.65 (m, 4H), 3.16-2, 76 (m, 1H), 2.40 (dd, J =23.1, 16.1 Hz, 1H), 2.00-1.32 (m, 6H).

Example 40 Racemic ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) (1-phenyl-1 H-1,2,4-triazol-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 4) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1) and 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ FN ₆ O - 442.1; obtained m/z, 443.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.41 (d, J =12.7 Hz, 1H), 7.95-7.83 (m, 2H), 7.66-7.24 ( m, 7H), 5.57 (d, J =160.3 Hz, 1H), 5.12-4.55 (m, 1H), 3.78 (d, J =23.3 Hz, 3H), 3.20-2.97 (m, 1H), 2.61-2.55 (m, 1H), 2.15-1.38 (m, 6H).

Example 41 ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (furo[3,2-b]pyridin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 13) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and furol[3,2-b]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ FN ₄ O ₂ - 416.1; obtained m/z, 417.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.63-8.41 (m, 2H), 8.23-8.06 (m, 1H), 7.62-7.18 (m, 5H ), 5.80-5.02 (m, 1H), 4.88-4.00 (m, 1H), 3.78 (d, J =39.0 Hz, 3H), 3.15-3, 03 (m, 1H), 2.40 (d, J =16.2 Hz, 1H), 2.05-1.38 (m, 6H).

Example 42 Racemic ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 4) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ FN ₄ O - 426.1; the resulting m/z is 427.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.06-8.93 (m, 1 H), 8.48 (d, J =8.3 Hz, 1 H), 8.08 (dd, J = 7.2, 3.8 Hz, 2 H), 7.85-7.70 (m, 1 H), 7.67-7.51 (m, 2 H), 7.51-7.20 (m, 3 H), 5.76 (d, J =5.9 Hz, 1 H), 4.24-4.05 (m, 1 H), 3.78 (d, J =40.8 Hz , 3 H), 3.22-3.02 (m, 1 H), 2.44 (d, J =16.1 Hz, 1 H), 2.11-1.37 (m, 6 H).

Example 43 ((5S,9R)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5S,9R)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 28) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ FN ₄ O - 426.2; the resulting m/z is 427.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.09 -8.91 (m, 1H), 8.56 -8.43 (m, 1H), 8.18 -7.99 (m, 2H ), 7.84 -7.66 (m, 1H), 7.66 -7.50 (m, 2H), 7.50 -7.24 (m, 3H), 5.77 (s, 1H), 4.12 (d, J =6.5 Hz, 1H), 3.78 (d, J =51.1 Hz, 3H), 3.25-2.88 (m, 1H), 2.47-2 .32 (m, 1H), 2.11 -1.38 (m, 6H).

Example 44 ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 13) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ FN ₄ O - 426.2; the resulting m/z is 427.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.04-8.90 (m, 1H), 8.57-8.37 (m, 1H), 8.19-8.05 (m, 2H ), 7.88-7.70 (m, 1H), 7.68-7.52 (m, 2H), 7.50-7.23 (m, 3H), 5.77 (s, 1H), 4.12 (s, 1H), 3.88-3.68 (m, 3H), 3.17-2.99 (m, 1H), 2.48-2.38 (m, 1H), 2. 06-1.39 (m, 6H).

Example 45 Racemic ((5R,9S)-2-cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner similar to that described in Example 1 using racemic (5R,9S)-2-cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 11) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₈ H ₂₅ FN ₄ O - 452.2; the resulting m/z is 453.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.05-8.82 (m, 1H), 8.48 (d, J =8.5 Hz, 1H), 8.17-7.98 ( m, 2H), 7.85-7.69 (m, 1H), 7.69-7.40 (m, 4H), 7.39-7.18 (m, 1H), 5.76-5, 73 (m, 1H), 3.83-3.58 (m, 1H), 3.22-2.93 (m, 2H), 2.42 (d, J =16.4 Hz, 1H), 2 .10-1.36 (m, 6H), 1.10-0.74 (m, 4H).

Example 46 (3-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 3-(1H-1,2,4-triazol-1-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ ClN ₆ O - 458.2; the resulting m/z is 459.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.38 (s, 1 H), 8.26 (s, 1 H), 7.99-7.94 (m, 1 H), 7.94 -7.91(m, 1H), 7.71-7.59(m, 2H), 7.59-7.38(m, 4H), 5.77-5.70(m, 1 H), 4.11-4.02 (m, 1 H), 3.80 (s, 3 H), 3.01 (dd, J = 16.2, 7.4 Hz, 1 H), 2, 43 (d, J =16.2 Hz, 1 H), 2.03-1.36 (m, 6 H).

Example 47 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 3-(1H-pyrazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ ClN ₅ O - 457.2; the resulting m/z is 458.2 [M+H] ⁺ . ¹ H NMR (500 MHz, methanol-d4) δ 8.15-7.84 (m, 2 H), 7.76-7.69 (m, 1 H), 7.67-7.58 (m, 1 H), 7.57-7.45 (m, 4 H), 7.45-7.39 (m, 1 H), 7.30-7.24 (m, 1 H), 5.94- 5.88, 5.05-5.00 (m, 1 H), 5.22-5.15, 4.30-4.22 (m, 1 H), 3.84, 3.77 (s, 3 H), 3.19, 3.01 (dd, J =16.4, 7.4 Hz, 1 H), 2.60, 2.50 (d, J =16.3 Hz, 1 H), 2.18-1.49 (m, 6 H).

Example 48 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 3-(1H-pyrazol-1-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ ClN ₅ O - 457.2; the resulting m/z is 458.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.69-8.52 (m, 1 H), 8.03-7.92 (m, 1 H), 7.91-7.82 (m , 1 H), 7.81-7.74 (m, 1 H), 7.68-7.44 (m, 5 H), 7.39-7.24 (m, 1 H), 6.63 -6.50 (m, 1 H), 5.81 -5.66 (m, 1 H), 4.15-4.00 (m, 1 H), 3.80 (s, 3 H), 2 .99 (dd, J =16.2, 7.3 Hz, 1 H), 2.43 (d, J =17.3 Hz, 1 H), 2.08-1.35 (m, 6 H) .

Example 49 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 3-(1H-tetrazol-1-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ ClN ₇ O - 459.2; the resulting m/z is 460.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.15 (s, 1 H), 8.05-8.00 (m, 1 H), 7.99-7.94 (m, 1 H) , 7.73 (t, J = 7.9 Hz, 1 H), 7.64-7.59 (m, 2 H), 7.59-7.47 (m, 3 H), 5.78- 5.69 (m, 1 H), 4.11-4.02 (m, 1 H), 3.81 (s, 3 H), 3.03 (dd, J =16.2, 7.4 Hz , 1 H), 2.43 (d, J =16.2 Hz, 1 H), 2.08-1.37 (m, 6 H).

Example 50 (2-chloro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 2-chloro 5-[1,2,4]triazol-4-yl-benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ Cl ₂ N ₆ O - 492.1; the resulting m/z is 493.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.19 (s, 2H), 7.90-7.69 (m, 3H), 7.64-7.45 (m, 4H), 5, 84-5.80 (m, 1H), 3.87 -3.78 (m, 1H), 3.81 (s, 3H), 3.13 -2.89 (m, 1H), 2.51 - 2.37 (m, 1H), 2.00 -1.36 (m, 6H).

Example 51 (4-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 4-(4H-1,2,4-triazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ ClN ₆ O - 458.2; the resulting m/z is 459.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.20-9.15 (m, 2 H), 7.80-7.75 (m, 2 H), 7.66-7.60 (m , 2 H), 7.60-7.47 (m, 4 H), 5.76-5.67 (m, 1 H), 4.08-3.99 (m, 1 H), 3.80 (s, 3 H), 3.04 (dd, J =16.0, 7.0 Hz, 1 H), 2.42 (d, J =16.1 Hz, 1 H), 2.07-1 .31 (m, 6 H).

Example 52 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-isopropyl-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-isopropyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₅ ClN ₆ O - 424.2; the resulting m/z is 425.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.64 (s, 1 H), 7.63-7.57 (m, 1 H), 7.57-7.43 (m, 3 H) , 5.76-5.69 (m, 1 H), 4.71-4.60 (m, 1 H), 4.54-4.48 (m, 1 H), 3.78 (s, 3 H), 2.99 (dd, J = 15.8, 7.4 Hz, 1 H), 2.57-2.46 (m, 1 H), 2.07-1.54 (m, 4 H ), 1.54 -1.38 (m, 2 H), 1.45 (d, J =6.7 Hz, 6 H).

Example 53 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (Intermediate 1) and 1-(2-fluorophenyl-1H-1,2,4-triazole-3-carboxylic acid (Intermediate 39) instead of quinoline-6-carboxylic acid. MS (ESI): mass, calculated for C ₂₅ H ₂₂ ClFN ₆ O - 476.2, m/z obtained - 477.2 [M+H] ^{+ 1} H NMR (500 MHz, DMSO- d ₆ ) δ 9.13 (d, J =2.2 Hz, 1 H), 7.89-7.80 (m, 1 H), 7.64-7.40 (m, 7 H), 5.80-5.75 (m, 1 H ), 4.59-4.49 (m, 1 H), 3.79 (s, 3 H), 3.07-2.97 (m, 1 H), 2.53 (d, J =16, 4 Hz, 1 H), 2.04-1.38 (m, 6 H).

Example 54 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-(pyridin-2-yl)-1 H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ ClN ₇ O - 459.2; the resulting m/z is 460.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.47 (s, 1H), 8.64-8.53 (m, 1H), 8.15-8.06 (m, 1H), 7, 92-7.85 (m, 1H), 7.64-7.59 (m, 1H), 7.58-7.45 (m, 4H), 5.81-5.75 (m, 1H), 4.60-4.53(m, 1H), 3.80(s, 3H), 3.13-3.00(m, 1H), 2.55-2.49(m, 1H), 2, 06-1.40 (m, 6H).

Example 55 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-(3-fluorophenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ ClFN ₆ O - 476.2, m/z obtained - 477.2 [M+H] ^{+ 1} H NMR (500 MHz, DMSO- d ₆ ) δ 9.43 (s, 1H), 7.86 -7.79(m, 1H), 7.79-7.72(m, 1H), 7.69-7.58(m, 2H), 7.58-7.46(m, 3H), 7 .36-7.28(m, 1H), 5.80-5.73(m, 1H), 4.58-4.48(m, 1H), 3.79(s, 3H), 3.12 -2.97(m, 1H), 2.56-2.48(m, 1H), 1.93-1.39(m, 6H).

Example 56 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-(3-chlorophenyl)-1,2,4-triazole-3-carboxylic acid (intermediate 37) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ Cl ₂ N ₆ O - 492.1; the resulting m/z is 493.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.44 (s, 1 H), 8.08-8.00 (m, 1 H), 7.91-7.83 (m, 1 H) , 7.63 (t, J = 8.2 Hz, 1 H), 7.63-7.59 (m, 1 H), 7.58-7.46 (m, 4 H), 5.80- 5.74(m, 1H), 4.58-4.50(m, 1H), 3.79(s, 3H), 3.11-2.99(m, 1H), 2.55 -2.50(m, 1H), 2.07-1.35(m, 6H).

Example 57 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₃ ClF ₃ N ₅ O - 525.2; the resulting m/z is 526.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.12 (s, 1H), 7.66-7.44 (m, 9H), 5.78-5.71 (m, 1H), 4, 21-4.11 (m, 1H), 3.80 (s, 3H), 3.04 (dd, J =16.2, 7.4 Hz, 1H), 2.51-2.44 (m, 1H), 1.94-1.37 (m, 6H).

Example 58 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (Intermediate 1) and 5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid (Intermediate 40) instead of quinoline-6-carboxylic acid . MS (ESI): mass calculated for C ₂₇ H ₂₄ ClF ₃ N ₆ O - 540.2; the resulting m/z is 541.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.05-8.02 (m, 1H), 8.00-7.96 (m, 1H), 7.95-7.90 (m, 1H ), 7.88-7.84 (m, 1H), 7.61-7.58 (m, 1H), 7.57-7.45 (m, 3H), 5.78-5.72 (m , 1H), 4.67-4.59 (m, 1H), 3.79 (s, 3H), 3.09-2.97 (m, 1H), 2.60-2.42 (m, 1H ), 2.53 (s, 3H), 1.98-1.59 (m, 4H), 1.58-1.41 (m, 2H).

Example 59 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid (intermediate 38) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ ClF ₃ N ₆ O - 526.2; the resulting m/z is 527.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.53 (s, 1H), 8.29-8.24 (m, 1H), 8.24-8.18 (m, 1H), 7, 89-7.79 (m, 2H), 7.63-7.59 (m, 1H), 7.57-7.45 (m, 3H), 5.81-5.74 (m, 1H), 4.57-4.50(m, 1H), 3.80(s, 3H), 3.13-2.98(m, 1H), 2.57-2.47(m, 1H), 2, 07-1.40 (m, 6H).

Example 60 (1-benzyl-1 H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ ClN ₆ O - 472.2; the resulting m/z is 473.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.75 (s, 1H), 7.61-7.56 (m, 1H), 7.56-7.49 (m, 2H), 7, 49-7.43(m, 1H), 7.43-7.27(m, 5H), 5.73-5.68(m, 1H), 5.45(s, 2H), 4.48- 4.42 (m, 1H), 3.77 (s, 3 H), 2.94 (dd, J =16.0, 7.4 Hz, 1H), 2.46 (d, J =16.2 Hz, 1H), 1.96-1.37 (m, 6H).

Example 61 Benzo[d]isoxazol-3-yl((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and benzo[d]isoxazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ ClN ₄ O ₂ - 432.1; obtained m/z, 433.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.93-7.90 (m, 1 H), 7.88-7.85 (m, 1 H), 7.78-7.72 (m , 1 H), 7.62-7.59 (m, 1 H), 7.58-7.45 (m, 4 H), 5.93-5.80 (m, 1 H), 4.65 -4.51 (m, 1 H), 3.80 (s, 3 H), 3.01 (dd, J =16.2, 7.3 Hz, 1 H), 2.54 (d, J = 16.1 Hz, 1 H), 2.02-1.68 (m, 4 H), 1.59-1.41 (m, 2 H).

Example 62 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-methyl-1H-indazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 1-methyl-1H-indazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ ClN ₅ O - 445.2; the resulting m/z is 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.00-7.94 (m, 1 H), 7.72 (dd, J =12.9, 8.5 Hz, 1 H), 7, 63-7.57(m, 1H), 7.57-7.42(m, 4H), 7.27-7.21(m, 1H), 5.88-5.80(m, 1 H), 5.39-5.31 (m, 1 H), 4.10 (s, 3 H), 3.79 (s, 3 H), 3.14-3.03 (m, 1 H ), 2.56 (dd, J =16.2, 11.7 Hz, 1 H), 2.10-1.62 (m, 4 H), 1.57-1.42 (m, 2 H) .

Example 63 Racemic ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 6) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₃ ClN ₄ O - 442.1; the resulting m/z is 443.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04-8.89 (m, 1 H), 8.48 (d, J =8.3 Hz, 1 H), 8.18-7, 99(m, 2H), 7.85-7.46(m, 6H), 5.77(s, 1H), 3.77(s, 3H), 3.21-2.95( m, 2 H), 2.44 (d, J =16.2 Hz, 1 H), 2.07-1.38 (m, 6 H).

Example 64 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5.9 -epimincycloocta[c]pyrazole (intermediate 14) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ ClN ₅ O - 443.1; the resulting m/z is 444.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.09-8.95 (m, 2H), 8.25-8.01 (m, 2H), 7.93-7.78 (m, 1H ), 7.68-7.43 (m, 4H), 5.77 (d, J =14.8 Hz, 1H), 4.08 (d, J =5.7 Hz, 1H), 3.84 -3.66 (m, 3H), 3.16-2.98 (m, 1H), 2.41 (d, J =16.2 Hz, 1H), 2.04-1.39 (m, 6H ).

Example 65 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(4-(2-fluoroethoxy)quinolin-6-yl)methanone.

Stage A: ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole -10-yl)(4-hydroxyquinolin-6-yl)methanone. To a solution of 4-hydroxyquinoline-6-carboxylic acid (70 mg, 0.37 mmol); (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 12 ), trifluoroacetic acid (100 mg, 0.25 mmol) and HATU (141 mg, 0.37 mmol) in DCM (1.6 ml) was added triethylamine (0.10 ml, 0.74 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and loaded directly onto a silica gel (12 g) column and eluted with a gradient of 0 to 20% MeOH/DCM to give a yellow oil (80 mg, 70% yield). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O ₂ - 460.2; obtained m/z, 461.1 [M+H] ⁺ .

Step B: ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(4-(2-fluoroethoxy)quinolin-6-yl)methanone. ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole-10 solution -yl)(4-hydroxyquinolin-6-yl)methanone (80 mg, 0.17 mmol) in dimethylformamide (DMF) (0.7 ml) was treated with 1-fluoro-2-iodoethane (45 mg, 0.26 mmol) and cesium carbonate (113 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 16 hours and then diluted with water. The solids were filtered and purified on a silica gel (4 g) column with methanol (MeOH) in dichloromethane (DCM) (1 to 5% gradient) to give the title compound as a white solid (21 mg, 24% yield). . MS (ESI): mass calculated for C ₂₈ H ₂₅ F ₃ N ₄ O ₂ - 506.2; obtained m/z, 507.2 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ) δ 8.81 (d, J =5.3, 1.1 Hz, 1 H), 8.41 (dd, J =9.2, 1.9 Hz, 1 H), 8.08 (dd, J =8.6, 4.2 Hz, 1 H), 7.77 (td, J =8.9, 2.0 Hz, 1 H), 6.98-6.84 ( m, 3 H), 6.78 (dd, J = 5.2, 1.4 Hz, 1 H), 6.06 and 5.12 (s, 1 H), 5.30 and 4.28 (m , 1 H), 4.95-4.86 (m, 2 H), 4.49-4.41 (m, 2 H), 3.89 and 3.80 (s, 3 H), 3.31 -3.28 and 3.10-3.04 (m, 1 H), 2.54 and 2.44 (d, J = 16.2 Hz, 1 H), 2.13-1.99 (m, 1 H), 1.94-1.73 (m, 3 H), 1.68-1.51 (m, 2 H).

Example 66 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(3-(2-fluoroethoxy)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 65 using 3-hydroxybenzoic acid in place of 4-hydroxyquinoline-6-carboxylic acid in step A. MS (ESI): mass calculated for C ₂₅ H ₂₄ F ₃ N ₃ O ₂ , - 455.2; obtained m/z, 456.2 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ 7.34-7.30 (m, 1H), 7.02-6.96 (m, 3H), 6.91-6.82 (m, 3H), 5, 98 and 5.05 (m, 1H), 5.21 and 4.22 (m, 1H), 4.80-4.69 (m, 2H), 4.25-4.19 (m, 2H) 3 .85 and 3.79 (s, 3H), 3.23-3.19 and 2.97-2.91 (m, 1H), 2.44 (dd, J = 36.7, 16.3 Hz, 1H), 2.01-1.68 (m, 3H), 1.63-1.47 (3H).

Example 67 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(3-(2-(fluoro-18F)ethoxy)phenyl)methanone.

Step A: 2-(3-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole-10-carbonyl)phenoxy)ethyl 4-methylbenzenesulfonate . The title compound was prepared in a manner analogous to that described in Example 65, Step B, using ethylene ditosylate instead of 1-fluoro-2-iodoethane. MS (ESI): mass calculated for C ₃₂ H ₃₁ F ₂ N ₃ SO ₅ - 607.2, obtained m/z - 608.2 [M+H] ⁺ .

Stage B: ((5 R ,9 S )-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazol-10-yl)(3- (2-(fluoro- ¹⁸ F)ethoxy)phenyl)methanone. [¹⁸ F]fluoride in a transport bottle manufactured by PETNET Solutions Inc. (San Diego, California, USA) was transferred and captured on an ion exchange cartridge. It was then eluted into the reaction vessel (RV1) of the Synthra RNPlus ® module using potassium carbonate solution (0.75 mg) and Kryptofix 222 (7.2 mg) in 0.8 ml acetonitrile/water (6/2, v/v). about.). After evaporation of the solvent under vacuum in a stream of nitrogen at 85°C, anhydrous CH₃CN (0.5 ml). This process was repeated and the temperature was raised to 110°C for 3.5 minutes. The reaction flask was then cooled to 70°C, after which a solution of 3.0 mg of 2-(3-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole-10-carbonyl)phenoxy)ethyl 4-methylbenzenesulfonate in 0.7 ml anhydrous acetonitrile (MeCN/ACN). The reaction mixture was heated at 110°C for 10 min. The reactor was cooled to 40°C, diluted with water (4.3 ml) and the contents were transferred to the HPLC injector circuit for purification. Purification was performed by HPLC using an Eclipse XDB-C18 semi-preparative column (5 µm, 9.4 mm x 250 mm) with 10 mM NH₄OAc and MeCN (45:55 v/v) at a flow rate of 4 ml/min with UV detection at 254 nm. The purified radiolabeled solution was diluted with 30 ml of water and passed through a SepPak Light C-18 cartridge. The C-18 cartridge was additionally washed with 10 ml of water, after which 0.5 ml of ethanol was used to elute the marker. The labeled solution was further diluted with 4.5 ml of saline. The finished composition contains 10% ethanol suitable for intravenous injection (IV).

Example 68 Racemic (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₂ N ₆ O - 460.1; obtained m/z, 461.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.16 (d, J =11.4 Hz, 1H), 8.00-7.74 (m, 1H), 7.70-7.49 ( m, 3H), 7.46-7.13 (m, 4H), 5.69 (d, J =3.2 Hz, 1H), 3.97-3.62 (m, 4H), 3.22 -2.87(m, 1H), 2.43-2.21(m, 1H), 1.90-1.27(m, 6H).

Example 69 (2-(1H-1,2,4-triazol-5-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-(1H-1,2,4-triazol-5-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₂ N ₆ O - 460.1; obtained m/z, 461.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.60-7.82 (m, 2 H), 7.72-6.80 (m, 6 H), 5.75 (d, J =3 .3 Hz, 1 H), 4.35 (d, J = 82.0 Hz, 1 H), 3.89-3.55 (m, 4 H), 3.11-2.78 (m, 1 H), 2.38 (dd, J =44.8, 15.9 Hz, 1 H), 2.17-1.27 (m, 6 H).

Example 70 (2-(5-chloro-1H-1,2,4-triazol-3-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-(3-chloro-1H-1,2,4-triazol-5-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ ClF ₂ N ₆ O - 494.1; the resulting m/z is 495.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 15.00-14.33 (m, 1H), 7.90-7.00 (m, 7H), 5.76-5.63 (m, 1H ), 3.79 (s, 3H), 3.79-3.68 (m, 1H), 3.00-2.86 (m, 1H), 2.58-2.42 (m, 1H), 2.25-1.16 (m, 6H).

Example 71 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(3-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-(1-methyl-1H-pyrazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₅ F ₂ N ₅ O - 473.2; the resulting m/z is 474.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.23 (s, 1H), 7.93-(s, 1H), 7.72-7.61 (m, 1H), 7.61-7 .56 (m, 1H), 7.49-7.27 (m, 4H), 7.26-7.17 (m, 1H), 5.81-5.64 (m, 1H), 4.16 -3.99 (m, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.06-2.94 (m, 1H), 2.51-2.36 (m , 1H), 2.06-1.30 (m, 6H).

Example 72 (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-(4H-1,2,4-triazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₂ N ₆ O - 460.1; obtained m/z, 461.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.20 (d, J =4.4 Hz, 2H), 7.91-7.74 (m, 2H), 7.73-7.58 ( m, 1H), 7.51-7.28 (m, 4H), 5.73 (d, J =3.5 Hz, 1H), 4.05 (t, J =6.2 Hz, 1H), 3.85-3.69 (m, 3H), 3.15-2.98 (m, 1H), 2.44 (d, J =16.2 Hz, 1H), 2.08-1.37 ( m, 6H).

Example 73 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₂ N ₆ O - 474.2; the resulting m/z is 475.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.11 (s, 1H), 7.86-6.95 (m, 7H), 5.74-5.61 (m, 1H), 3, 94-3.77 (m, 1H), 3.82 (s, 3H), 3.03-2.85 (m, 1H), 2.49-2.31 (m, 4H), 1.95- 1.13 (m, 6H).

Example 74 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid [WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.1; the resulting m/z is 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.18 (d, J = 8.2 Hz, 1 H), 7.86-7.43 (m, 3 H), 7.35 (t, J =9.0Hz, 4H), 5.51(s, 1H), 3.95(s, 1H), 3.81(s, 3H), 3.06(dd, J =16 .3, 7.5 Hz, 1 H), 2.47-2.33 (m, 1 H), 1.86-1.26 (m, 6 H).

Example 75 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-fluoro-2-(oxazol-2-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O ₂ - 471.2; obtained m/z, 472.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.51-8.16 (m, 1H), 7.75-7.57 (m, 1H), 7.60-7.13 (m, 6H ), 5.72-5.58 (m, 1H), 3.82 (s, 3H), 3.92-3.63 (m, 1H), 3.19-2.77 (m, 1H), 2.52-2.31 (m, 1H), 1.97-1.22 (m, 6H).

Example 76 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(2-(pyrimidin-2-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(pyrimidin-2-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O ₂ - 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.51-8.16 (m, 1H), 7.75-7.57 (m, 1H), 7.60-7.13 (m, 6H ), 5.72-5.58 (m, 1H), 3.82 (s, 3H), 3.92-3.63 (m, 1H), 3.19-2.77 (m, 1H), 2.52-2.31 (m, 1H), 1.97-1.22 (m, 6H).

Example 77 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(5-methoxy-1-methyl-1H-pyrazol-4-yl)-methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₃ F ₂ N ₅ O ₂ - 427.2; obtained m/z, 428.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.47 (s, 1H), 7.41-7.18 (m, 3H), 5.73-5.53 (m, 1H), 4, 51-4.31(m, 1H), 3.93(s, 3H), 3.81(s, 3H), 3.59(s, 3H), 3.26-3.10(m, 1H) , 2.51-2.35 (m, 1H), 2.05-1.23 (m, 6H).

Example 78 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-ethyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₅ N ₅ O - 479.2; the resulting m/z is 480.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.37-7.27 (m, 3 H), 7.17-7.13 (m, 1 H), 5.75-5.70 (m , 1 H), 4.92-4.85 (m, 1 H), 4.29 (k, J = 7.2 Hz, 2 H), 3.81 (s, 3 H), 3.13- 3.00(m, 1H), 2.61-2.52(m, 1H), 1.88-1.61(m, 4H), 1.55-1.43(m, 2H ), 1.41 (t, J = 7.2 Hz, 3 H).

Example 79 Racemic (5-cyclopropyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₃ F ₂ N ₅ O - 423.2; the resulting m/z is 424.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 12.68-12.55 (m, 1H), 7.60-7.39 (m, 1H), 7.39-7.24 (m, 3H ), 5.77-5.55 (m, 1H), 4.44-4.24 (m, 1H), 3.89-3.69 (m, 3H), 3.14-2.99 (m , 1H), 2.17-1.54 (m, 5H), 1.54-1.34 (m, 2H), 1.01-0.67 (m, 4H).

Example 80 Racemic (5-cyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl--1-(2-hydroxyethyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₇ F ₂ N ₅ O ₂ - 467.2; obtained m/z, 468.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.45 (s, 1H), 7.37-7.25 (m, 3H), 5.72-5.66 (m, 1H), 4, 91-4.85 (m, 1H), 4.25-4.14 (m, 3H), 3.85-3.73 (m, 5H), 3.08-2.96 (m, 1H), 2.47-2.40 (m, 1H), 1.96-1.30 (m, 7H), 0.96-0.81 (m, 2H), 0.71-0.57 (m, 2H ).

Example 81 Racemic (3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl- 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-cyclopropyl-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ F ₅ N ₅ O - 505.2; the resulting m/z is 506.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.62 (s, 1 H), 7.37-7.25 (m, 3 H), 5.75-5.66 (m, 1 H) , 5.14 (k, J = 9.0 Hz, 2 H), 4.11-4.02 (m, 1 H), 3.82 (s, 3 H), 3.08-2.98 ( m, 1 H), 2.49-2.42 (m, 1 H), 1.95-1.33 (m, 7 H), 1.03-0.85 (m, 2 H), 0, 76-0.63 (m, 2H).

Example 82 Racemic (5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₉ H ₂₇ F ₂ N ₅ O - 499.2; the resulting m/z is 500.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.74 (s, 1H), 7.71-7.60 (m, 2H), 7.59-7.50 (m, 2H), 7, 49-7.41(m, 1H), 7.41-7.24(m, 3H), 5.82-5.65(m, 1H), 4.40-4.18(m, 1H), 3.83 (s, 3H), 3.22-2.99 (m, 1H), 2.51-2.35 (m, 1H), 2.11-1.27 (m, 7H), 0. 92-0.67 (m, 2H), 0.65-0.42 (m, 2H).

Example 83 Racemic (5-cyclopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₃₀ H ₂₆ F ₅ N ₅ O - 567.2; obtained m/z, 568.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.09-7.99 (m, 2H), 7.86-7.75 (m, 3H), 7.41-7.24 (m, 3H ), 5.78-5.71 (m, 1H), 4.38-4.29 (m, 1H), 3.83 (s, 3H), 3.15-3.03 (m, 1H), 2.51-2.43 (m, 1H), 2.15-2.03 (m, 1H), 1.88-1.57 (m, 4H), 1.55-1.37 (m, 2H ), 0.90-0.74 (m, 2H), 0.62-0.45 (m, 2H).

Example 84 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methyl-1-phenyl-1 H-1,2,4-triazol-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methyl-1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₂ N ₆ O - 474.2; obtained m/z, 475.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.69-7.49 (m, 5H), 7.37-7.27 (m, 3H), 5.77-5.73 (m, 1H ), 4.71-4.64 (m, 1H), 3.81 (s, 3H), 3.10-2.98 (m, 1H), 2.62-2.54 (m, 1H), 2.52 (s, 3H), 1.89-1.67 (m, 4H), 1.57-1.40 (m, 2H).

Example 85 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O - 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.75-7.65 (m, 2H), 7.49-7.39 (m, 2H), 7.37-7.26 (m, 3H ), 5.77-5.72 (m, 1H), 4.69-4.63 (m, 1H), 3.81 (s, 3H), 3.12-2.97 (m, 1H), 2.62-2.53(m, 1H), 2.47(s, 3H), 1.88-1.66(m, 4H), 1.56-1.38(m, 2H).

Example 86 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-ethyl-1-phenyl-1 H-1,2,4-triazol-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-ethyl-1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₆ F ₂ N ₆ O - 488.2; obtained m/z, 489.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.66-7.50 (m, 5H), 7.38-7.27 (m, 3H), 5.79-5.71 (m, 1H ), 4.70-4.61 (m, 1H), 3.81 (s, 3H), 3.11-2.98 (m, 1H), 2.88-2.77 (m, 2H), 2.62-2.55 (m, 1H), 2.02-1.39 (m, 6H), 1.22 (t, J = 7.6 Hz, 3H).

Example 87 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(2-fluoropyridin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-fluoroisonicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₉ F ₃ N ₄ O - 412.2; obtained m/z, 413.2 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ) δ 8.30 (d, J =5.0 Hz, 1H), 7.19 (m, 1H), 6.94 (m, 1H), 6.91-6.84 ( m, 3H), 5.97 and 4.85 (m, 1H), 5.21 and 4.03 (m, 1H), 3.85 and 3.81 (s, 3H), 3.23-3, 18 and 2.95-2.90 (m, 1H), 2.46 (dd, J =23.1, 16.3 Hz, 1H), 2.01-1.93 (m, 1H), 1, 91-1.82(m, 1H), 1.80-1.73(m, 1H), 1.63-1.50(3H).

Example 88 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(5-methoxypyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 5-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₂ N ₄ O ₂ - 424.2; obtained m/z, 425.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.38 (d, J =2.9 Hz, 1H), 8.22 (d, J =1.6 Hz, 1H), 7.46-7 .40 (m, 1H), 7.39-7.25 (m, 3H), 5.78-5.64 (m, 1H), 4.08-3.95 (m, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.17-3.00 (m, 1H), 2.40 (d, J =16.4 Hz, 1H), 2.08-1, 30 (m, 6H).

Example 89 (5-Aminopyridin-2-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (4 R,9 S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1) and 5-aminopicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₁ F ₂ N ₅ O - 409.2; obtained m/z, 410.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.86-7.78 (m, 1H), 7.39-7.21 (m, 4H), 6.94-6.88 (m, 1H ), 5.72 (s, 2H), 5.67-5.60 (m, 1H), 4.76-4.67 (m, 1H), 3.78 (s, 3H), 3.10- 2.89 (m, 1H), 2.67-2.31 (m, 1H), 2.14-1.31 (m, 6H).

Example 90 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(5-methoxybenzofuran-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 5-methoxybenzofuran-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₂ N ₃ O ₃ - 463.2; the resulting m/z is 464.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.59-7.53 (m, 1H), 7.43-7.28 (m, 4H), 7.24-7.17 (m, 1H ), 7.09-7.02 (m, 1H), 5.76-5.60 (m, 1H), 4.88-4.69 (m, 1H), 3.89-3.68 (m , 6H), 3.32-3.02 (m, 1H), 2.60 (d, J = 16.3 Hz, 1H), 1.95-1.61 (m, 4H), 1.61- 1.35 (m, 2H).

Example 91 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (2-methylbenzo[d]oxazol-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 2-methylbenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₂ N ₄ O ₂ - 448.1; obtained m/z, 449.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.81-7.69 (m, 2H), 7.45-7.29 (m, 4H), 5.72 (d, J= 3.1 Hz, 1H), 4.16-4.01 (m, 1H), 3.87-3.73 (m, 3H), 3.17-3.02 (m, 1H), 2.66-2, 57 (m, 3H), 2.48-2.37 (m, 1H), 1.99-1.38 (m, 6H).

Example 92 (2-Aminobenzo[d]oxazol-6-yl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro -2 H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole (intermediate 1) and 2-aminobenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₂ N ₅ O ₂ - 449.1; obtained m/z, 450.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.28-9.08 (m, 1H), 8.75 (dd, J =16.4, 5.9 Hz, 1H), 8.40- 8.24 (m, 1H), 8.08-7.90 (m, 1H), 7.81-7.63 (m, 1H), 7.41-7.24 (m, 3H), 5. 97-5.09 (m, 1H), 3.95-3.66 (m, 4H), 2.99-2.63 (m, 1H), 2.45 (d, J = 16.2 Hz, 1H), 2.08-1.40 (m, 6H).

Example 93 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (furo[3,2-b]pyridin-2-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and furol[3,2-b]pyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₂ N ₄ O ₂ - 434.1; obtained m/z, 435.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.67-8.53 (m, 1H), 8.16 (t, J =8.7 Hz, 1H), 7.64-7.27 (m, 5H), 5.76-5.37(m, 1H), 5.03-4.62(m, 1H), 3.89-3.74(m, 3H), 3.19-3.03( m, 1H), 2.65-2.54 (m, 1H), 2.12-1.45 (m, 6H).

Example 94 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(furo[3,2-c]pyridin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and furol[3,2-c]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₂ N ₄ O ₂ - 434.2; the resulting m/z is 435.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.47 (d, J =5.7 Hz, 1H), 8.24-8.12 (m, 1H), 7.82-7.76 ( m, 1H), 7.41-7.23 (m, 3H), 7.10-7.03 (m, 1H), 5.89-5.76 (m, 1H), 4.36-4, 21 (m, 1H), 3.83 (s, 3H), 2.99 (dd, J =16.1, 7.4 Hz, 1H), 2.59-2.36 (m, 1H), 2 .03-1.35 (m, 6H).

Example 95 10-yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ F ₂ N ₆ O - 448.1; the resulting m/z is 449.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.68-8.59 (m, 1H), 8.48-8.35 (m, 1H), 7.40-7.27 (m, 4H ), 6.09 (d, J =247.3 Hz, 1H), 5.55-5.09 (m, 1H), 4.21-4.08 (m, 3H), 3.89-3, 74 (m, 3H), 3.21-3.05 (m, 1H), 2.61 (dd, J =16.2, 7.8 Hz, 1H), 2.06-1.48 (m, 6H).

Example 96 Racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 7) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.2; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.08-8.78 (m, 1H), 8.48 (d, J =8.4 Hz, 1H), 8.18-8.00 ( m, 2H), 7.88-7.55 (m, 2H), 7.45-7.25 (m, 3H), 5.76 (s, 1H), 3.87-3.66 (m, 3H), 3.29-2.87 (m, 2H), 2.46 (d, J =16.1 Hz, 1H), 2.12-1.34 (m, 6H).

Example 97 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.2; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04-8.92 (m, 1H), 8.55-8.42 (m, 1H), 8.17-8.04 (m, 2H ), 7.87-7.55 (m, 2H), 7.45-7.24 (m, 3H), 5.83-5.70 (m, 1H), 4.18-4.05 (m , 1H), 3.89-3.69 (m, 3H), 3.21-3.06 (m, 1H), 2.47 (d, J =16.3 Hz, 1H), 2.09- 1.41 (m, 6H).

Example 98 ((5S,9R)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5S,9R)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 29) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.2; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04-8.92 (m, 1H), 8.55-8.42 (m, 1H), 8.17-8.04 (m, 2H ), 7.87-7.55 (m, 2H), 7.45-7.24 (m, 3H), 5.83-5.70 (m, 1H), 4.18-4.05 (m , 1H), 3.89-3.69 (m, 3H), 3.21-3.06 (m, 1H), 2.47 (d, J =16.3 Hz, 1H), 2.09- 1.41 (m, 6H).

Example 99 10-yl) (isoquinolin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and isoquinoline-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.2; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.44-9.28 (m, 1H), 8.27-8.05 (m, 3H), 7.92-7.71 (m, 2H ), 7.40-7.27 (m, 3H), 5.80 (s, 1H), 4.36-4.04 (m, 1H), 3.88-3.72 (m, 3H), 3.15-2.97 (m, 1H), 2.49-2.31 (m, 1H), 2.08-1.43 (m, 6H).

Example 100 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and isoquinoline-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.2; the resulting m/z is 445.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.02-8.93 (m, 1H), 8.49-8.41 (m, 1H), 8.08 (d, J =8.4 Hz, 1H), 8.04-8.00 (m, 1H), 7.67-7.54 (m, 2H), 7.40-7.26 (m, 3H), 5.82-5, 73 (m, 1H), 4.15-4.03 (m, 1H), 3.84 (s, 3H), 3.06 (dd, J =16.2, 7.3 Hz, 1H), 2 .44 (d, J =16.2 Hz, 1H), 2.07-1.36 (m, 6H).

Example 101 (4-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 4-bromoquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ BrF ₂ N ₄ O - 522.1; the resulting m/z is 523.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.81 (dd, J =9.0, 4.6 Hz, 1H), 8.21-7.98 (m, 3H), 7.95- 7.80 (m, 1H), 7.43-7.23 (m, 3H), 5.77 (s, 1H), 4.10 (s, 1H), 3.92-3.71 (m, 3H), 3.22-2.98(m, 1H), 2.46(s, 1H), 2.03-1.43(m, 6H).

Example 102 (3-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-bromoquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ BrF ₂ N ₄ O - 522.1; the resulting m/z is 523.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.01 (d, J =2.4 Hz, 1H), 8.84-8.82 (m, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.07-8.04 (m, 1H), 7.84 (dd, J =8.6, 1.9 Hz, 1H), 7.40-7.28 (m , 3H), 5.81-5.69 (m, 1H), 4.13-4.05 (m, 1H), 3.84 (s, 3H), 3.09 (dd, J =16.3 , 7.4 Hz, 1H), 2.50-2.43 (m, 1H), 2.12-1.33 (m, 6H).

Example 103 (8-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and 8-bromoquinoline-6-carboxylic acid (Intermediate 1) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ BrF ₂ N ₄ O - 522.1; the resulting m/z is 523.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.16-8.99 (m, 1H), 8.60-8.48 (m, 1H), 8.21-8.03 (m, 2H ), 7.81-7.62 (m, 1H), 7.44-7.23 (m, 3H), 5.83-5.68 (m, 1H), 4.25-4.07 (m , 1H), 3.85 (s, 3H), 3.22-2.97 (m, 1H), 2.66-2.37 (m, 1H), 2.13-1.30 (m, 6H ).

Example 104 (2-chloroquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-chloroquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ ClF ₂ N ₄ O - 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.55 (d, J =8.7 Hz, 1H), 8.16 (d, J =1.9 Hz, 1H), 8.02 (d , J = 8.7 Hz, 1H), 7.86 (dd, J = 8.6, 1.9 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.40 -7.27 (m, 3H), 5.81-5.71 (m, 1H), 4.13-4.04 (m, 1H), 3.84 (s, 3H), 3.10 (dd , J =16.6, 7.4 Hz, 1H), 2.46 (d, J =16.0 Hz, 1H), 2.08-1.35 (m, 6H).

Example 105 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(8-fluoroquinolin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 8-fluoroquinoline-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O - 462.2; obtained m/z, 463.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.12-8.98 (m, 1H), 8.46-8.36 (m, 1H), 7.83-7.47 (m, 3H ), 7.42-7.26 (m, 3H), 5.96-5.84 (m, 1H), 3.84 (s, 3H), 3.80-3.63 (m, 1H), 3.10-2.95(m, 1H), 2.66-2.35(m, 1H), 2.13-1.66(m, 2H), 1.64-1.30(m, 4H ).

Example 106 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(8-fluoroquinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 8-fluoroquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O - 462.2; obtained m/z, 463.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.02 (dd, J =4.2, 1.6 Hz, 1H), 8.57-8.52 (m, 1H), 7.95- 7.92 (m, 1H), 7.70 (dd, J =8.3, 4.2 Hz, 1H), 7.67 (dd, J =10.9, 1.7 Hz, 1H), 7 .39-7.30 (m, 3H), 5.79-5.70 (m, 1H), 4.18-4.09 (m, 1H), 3.84 (s, 3H), 3.10 (dd, J =16.1, 7.4 Hz, 1H), 2.45 (d, J =16.2 Hz, 1H), 1.98-1.67 (m, 3H), 1.64- 1.37 (m, 3H).

Example 107 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(2-(trifluoromethyl)quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-(trifluoromethyl)quinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₁ F ₅ N ₄ O - 512.2; obtained m/z, 513.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.87-8.79 (m, 1H), 8.29-8.24 (m, 1H), 8.24 (d, J =8.7 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.7, 1.9 Hz, 1H), 7.41-7.29 (m , 3H), 5.84-5.72 (m, 1H), 4.14-4.03 (m, 1H), 3.85 (s, 3H), 3.10 (dd, J =16.4 , 7.6 Hz, 1H), 2.50-2.42 (m, 1H), 2.09-1.34 (m, 6H).

Example 108 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(8-hydroxyquinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 8-hydroxyquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O ₂ - 460.2; obtained m/z, 461.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 10.37-10.05 (m, 1H), 9.01-8.81 (m, 1H), 8.47-8.34 (m, 1H ), 7.69-7.55 (m, 1H), 7.50-7.41 (m, 1H), 7.39-7.27 (m, 3H), 7.12-7.01 (m , 1H), 5.84-5.65(m, 1H), 4.24-4.00(m, 1H), 3.84(s, 3H), 3.23-2.94(m, 1H ), 2.56-2.39 (m, 1H), 2.09-1.26 (m, 6H).

Example 109 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(5-methoxyquinolin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 5-methoxyquinoline-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₄ F ₂ N ₄ O ₂ - 474.2; obtained m/z, 475.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.94 (d, J =2.2 Hz, 1H), 8.53 (d, J =2.2 Hz, 1H), 7.79-7 .74 (m, 1H), 7.69-7.61 (m, 1H), 7.40-7.29 (m, 3H), 7.19-7.11 (m, 1H), 5.82 -5.71(m, 1H), 4.18-4.09(m, 1H), 4.01(s, 3H), 3.84(s, 3H), 3.07(dd, J =16 .2, 7.4 Hz, 1H), 2.44 (d, J =16.4 Hz, 1H), 2.07-1.38 (m, 6H).

Example 110 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(8-nitroquinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 8-nitroquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₂ N ₅ O ₃ - 489.2; obtained m/z, 490.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.18-9.03 (m, 1H), 8.75-8.59 (m, 1H), 8.45-8.28 (m, 2H ), 7.81 (dd, J = 8.4, 4.3 Hz, 1H), 7.44-7.22 (m, 3H), 5.82-5.68 (m, 1H), 4, 23-4.07 (m, 1H), 3.85 (s, 3H), 3.13 (dd, J = 16.3, 7.3 Hz, 1H), 2.58-2.37 (m, 1H), 2.20-1.31 (m, 6H).

Example 111 (8-aminoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 8-aminoquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₂ N ₅ O - 459.2; obtained m/z, 460.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.77 (dd, J =4.2, 1.7 Hz, 1H), 8.30-8.23 (m, 1H), 7.51 ( dd, J = 8.3, 4.1 Hz, 1H), 7.39-7.29 (m, 3H), 7.11 (d, J = 1.7 Hz, 1H), 6.82 (d , J = 1.7 Hz, 1H), 6.10 (s, 2H), 5.76-5.68 (m, 1H), 4.24-4.15 (m, 1H), 3.84 ( s, 3H), 3.02 (dd, J =16.2, 7.4 Hz, 1H), 2.55-2.44 (m, 1H), 2.02-1.31 (m, 6H) .

Example 112 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (quinazolin-7-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and quinazoline-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.70 (dd, J =6.2, 0.9 Hz, 1H), 9.37 (d, J =6.4 Hz, 1H), 8 .36-8.22 (m, 1H), 8.10-7.67 (m, 2H), 7.43-7.27 (m, 3H), 5.78 (d, J = 3.5 Hz , 1H), 4.13-3.92 (m, 1H), 3.88-3.73 (m, 3H), 3.16-3.01 (m, 1H), 2.42 (d, J =16.2 Hz, 1H), 2.06-1.38 (m, 6H).

Example 113 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.03 (d, J =7.5 Hz, 2H), 8.24-8.05 (m, 2H), 7.95-7.77 ( m, 1H), 7.46-7.30 (m, 3H), 5.80 (d, J = 3.2 Hz, 1H), 4.09 (t, J = 5.8 Hz, 1H), 3.90-3.71 (m, 3H), 3.22-3.00 (m, 1H), 2.44 (d, J =16.2 Hz, 1H), 2.00-1.35 ( m, 6H).

Example 114 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinazolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and quinazoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.70 (s, 1H), 9.36 (s, 1H), 8.28-8.22 (m, 1H), 8.14-8, 04 (m, 2H), 7.41-7.28 (m, 3H), 5.82-5.72 (m, 1H), 4.14-4.06 (m, 1H), 3.85 ( s, 3H), 3.10 (dd, J =16.5, 7.6 Hz, 1H), 2.50-2.43 (m, 1H), 2.11-1.35 (m, 6H) .

Example 115 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(2-methylquinoxalin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-methylquinoxaline-6-carboxylic acid (intermediate 33) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₂ N ₅ O - 459.2; obtained m/z, 460.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.92 (s, 1H), 8.20-7.90 (m, 2H), 7.88-7.70 (m, 1H), 7, 46-7.23(m, 3H), 5.86-5.66(m, 1H), 4.16-3.96(m, 1H), 3.84(s, 3H), 3.25- 2.99 (m, 1H), 2.73 (s, 3H), 2.53-2.34 (m, 1H), 2.06-1.31 (m, 6H).

Example 116 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (7-fluoroquinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 7-fluoroquinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O - 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.10-8.88 (m, 2H), 8.41-7.85 (m, 2H), 7.43-7.24 (m, 3H ), 5.83 (s, 1H), 3.97 (s, 1H), 3.88-3.72 (m, 3H), 3.16-2.84 (m, 1H), 2.47- 2.32 (m, 1H), 1.99-1.34 (m, 6H).

Example 117 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (1,6-naphthyridin-5-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,6-naphthyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.24-9.09 (m, 1H), 8.75 (dd, J =16.4, 5.9 Hz, 1H), 8.42- 8.23 (m, 1H), 8.07-7.93 (m, 1H), 7.79-7.66 (m, 1H), 7.41-7.22 (m, 3H), 5. 98-5.21 (m, 1H), 3.91-3.62 (m, 4H), 2.95-2.63 (m, 1H), 2.48-2.35 (m, 1H), 2.07-1.40 (m, 6H).

Example 118 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1,8-naphthyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,8-naphthyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.16 (dd, J =4.2, 2.0 Hz, 1H), 9.13 (d, J =2.4 Hz, 1H), 8 .60 (d, J = 2.4 Hz, 1H), 8.59-8.57 (m, 1H), 7.72 (dd, J = 8.1, 4.2 Hz, 1H), 7, 41-7.27(m, 3H), 5.83-5.75(m, 1H), 4.21-4.12(m, 1H), 3.85(s, 3H), 3.16( dd, J = 16.3, 7.4 Hz, 1H), 2.52-2.42 (m, 1H), 2.12-1.37 (m, 6H).

Example 119 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1,8-naphthyridin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,8-naphthyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; obtained m/z, 446.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.30-9.01 (m, 2H), 8.51-8.33 (m, 1H), 7.85-7.54 (m, 2H ), 7.45-7.18 (m, 3H), 5.97-5.83 (m, 1H), 3.85 (s, 3H), 3.81-3.61 (m, 1H), 3.15-2.95 (m, 1H), 2.38 (d, J =16.3 Hz, 1H), 2.20-1.31 (m, 6H).

Example 120 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1,7-naphthyridin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,7-naphthyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; the resulting m/z is 446.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.56-9.41 (m, 1H), 9.16-9.05 (m, 1H), 8.79-8.61 (m, 1H ), 8.02-7.71 (m, 1H), 7.48-7.17 (m, 4H), 5.96-5.84 (m, 1H), 3.85 (s, 3H), 3.84-3.60(m, 1H), 3.25-2.94(m, 1H), 2.44-2.29(m, 1H), 2.18-1.35(m, 6H ).

Example 121 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1,6-naphthyridin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,6-naphthyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; the resulting m/z is 446.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.45-8.70 (m, 3H), 8.10-7.94 (m, 1H), 7.73-7.60 (m, 1H ), 7.42-7.29 (m, 3H), 5.99-5.84 (m, 1H), 3.85 (s, 3H), 3.83-3.61 (m, 1H), 3.27-3.01 (m, 1H), 2.41 (d, J =16.2 Hz, 1H), 2.17-1.34 (m, 6H).

Example 122 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (1,5-naphthyridin-2-yl) methanone

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1,5-naphthyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.2; the resulting m/z is 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.18-9.02 (m, 1H), 8.61-8.45 (m, 2H), 7.99-7.78 (m, 2H ), 7.42-7.28 (m, 3H), 5.81 (s, 1H), 4.34-4.10 (m, 1H), 3.90-3.70 (m, 3H), 3.16-3.07 (m, 1H), 2.47 (d, J =5.7 Hz, 1H), 2.14-1.43 (m, 6H).

Example 123 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole-10-carbonyl)-1-(2-fluoroethyl)quinoline-4(1H)-one.

The title compound was obtained as a by-product obtained during purification in example 65, stage B. MS (ESI): weight calculated for C ₂₈ H ₂₅ F ₃ N ₄ O ₂ - 506.2; obtained m/z, 507.2 [M+H] ⁺ . ¹ H NMR (CDCl ₃ ): δ 8.50 (dd, J =18.7, 2.1 Hz, 1H), 7.73 (dd, J =30.2, 8.8, 2.1 Hz, 1H), 7.54 (dd, J =7.8, 0.7 Hz, 1H), 7.37 (dd, J =11.7, 8.8 Hz, 1H), 6.91-6.82 (m, 3H), 6.27 (d, J = 7.8 Hz, 1H), 5.99 and 5.01 (s, 1H), 5.20 and 4.27 (m, 1H), 4, 82-4.72 (m, 2H), 4.45-4.40 (m, 2H), 3.86 and 3.76 (s, 3H), 3.27-3.19 and 3.05-3 .00 (m, 1H), 2.46 (dd, J = 33.9, 16.3 Hz, 1H), 2.12-1.94 (m, 1H), 1.94-1.67 (m , 3H), 1.64-1.51 (m, 2H).

Example 124 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole-10-carbonyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₂ N ₄ O ₃ - 478.2; the resulting m/z is 479.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.40-7.27 (m, 3H), 7.22-7.15 (m, 1H), 7.11-6.99 (m, 2H ), 5.73-5.60 (m, 1H), 4.70 (s, 2H), 4.21-4.08 (m, 1H), 3.82 (s, 3H), 3.30- 3.25 (m, 3H), 3.03 (dd, J =16.0, 7.2 Hz, 1H), 2.45 (d, J =16.6 Hz, 1H), 2.08-1 .31 (m, 6H).

Example 125 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₂ N ₅ O ₂ - 465.2; the resulting m/z is 466.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.85-7.71 (m, 1H), 7.41-7.26 (m, 3H), 7.01-6.89 (m, 1H ), 5.67-5.50 (m, 1H), 4.34-4.22 (m, 1H), 4.24-4.19 (m, 2H), 3.88-3.71 (m , 3H), 3.54-3.44 (m, 2H), 3.18-2.99 (m, 1H), 3.07 (s, 3H), 2.55-2.38 (m, 1H ), 2.01-1.32 (m, 6H).

Example 126 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 24) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₂ N ₆ O - 460.1; obtained m/z, 461.1 [M+H] ⁺ . ¹ H NMR (600 MHz, Chloroform- d ) δ 12.91 (d, J =13.3 Hz, 1H), 12.75-12.58 (m, 1H), 12.58-11.63 (m , 7H), 10.60-10.28 (m, 1H), 9.36-8.96 (m, 1H), 8.65-8.35 (m, 3H), 7.87-7.61 (m, 1H), 7.19-6.84 (m, 1H), 6.68-5.89 (m, 6H).

Example 127 Racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 8) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.1; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.03-8.91 (m, 1H), 8.56-8.40 (m, 1H), 8.19-8.00 (m, 2H ), 7.86-7.56 (m, 4H), 7.42 (d, J = 9.2 Hz, 1H), 5.76 (d, J = 3.6 Hz, 1H), 4.11 (s, 1H), 3.87-3.66 (m, 3H), 3.09 (ddd, J =32.8, 16.2, 7.4 Hz, 1H), 2.48-2.34 (m, 1H), 2.10-1.40 (m, 6H).

Example 128 ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2 H-5 ,9-epimincycloocta[c]pyrazole (intermediate 24) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9- epiminecycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O - 444.1; the resulting m/z is 445.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.05-8.91 (m, 1H), 8.55-8.39 (m, 1H), 8.16-7.98 (m, 2H ), 7.82-7.56 (m, 4H), 7.41 (s, 1H), 5.86-5.68 (m, 1H), 4.19-4.02 (m, 1H), 3.87-3.68 (m, 3H), 3.16-2.98 (m, 1H), 2.48-2.32 (m, 1H), 2.05-1.41 (m, 6H ).

Example 129 Racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 8) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₂ N ₅ O - 445.1; the resulting m/z is 446.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.12-8.94 (m, 2H), 8.27-8.02 (m, 2H), 7.95-7.67 (m, 2H ), 7.66-7.38 (m, 2H), 5.78 (s, 1H), 4.08 (s, 1H), 3.87-3.65 (m, 3H), 3.21- 3.01 (m, 1H), 2.47-2.27 (m, 1H), 2.07-1.34 (m, 6H).

Example 130 ((5R,9S)-3-(3-fluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluoro5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 15) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ FN ₅ O ₂ - 457.1; obtained m/z, 458.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 7.1 Hz, 2H), 8.28-7.80 (m, 3H), 7.08-6.80 ( m, 3H), 5.88-5.71 (m, 1H), 4.16-3.97 (m, 1H), 3.93-3.64 (m, 6H), 3.19-3, 00 (m, 1H), 2.47-2.33 (m, 1H), 2.05-1.36 (m, 6H).

Example 131 ((5R,9S)-3-(4-chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(4-chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 20) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ ClFN ₅ O - 461.1; the resulting m/z is 462.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.02 (d, J =12.1 Hz, 2H), 8.26-8.04 (m, 2H), 7.93-7.66 ( m, 2H), 7.60-7.31 (m, 2H), 5.85-5.75 (m, 1H), 4.10-3.97 (m, 1H), 3.74-3, 64 (m, 3H), 3.07-2.83 (m, 1H), 2.39-2.27 (m, 1H), 2.05-1.37 (m, 6H).

Example 132 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 18) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ ClN ₅ O ₂ - 473.1; obtained m/z, 474.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.11-8.95 (m, 2H), 8.26-7.97 (m, 2H), 7.95-7.78 (m, 1H ), 7.50-7.21 (m, 2H), 7.16-7.01 (m, 1H), 5.79 (s, 1H), 4.21-3.97 (m, 1H), 3.96-3.86 (m, 3H), 3.65-3.54 (m, 3H), 2.98-2.71 (m, 1H), 2.40-2.17 (m, 1H ), 2.06-1.40 (m, 6H).

Example 133 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 18) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ ClN ₆ O ₂ - 488.1; obtained m/z, 489.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.36-7.69 (m, 3H), 7.71-6.77 (m, 6H), 5.77-5.52 (m, 1H ), 4.60-4.26(m, 1H), 3.96-3.84(m, 3H), 3.79-3.58(m, 3H), 3.07-2.85(m , 1H), 2.43-2.30 (m, 1H), 1.94-1.11 (m, 6H).

Example 134 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 18) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ ClN ₆ O ₂ - 476.1; obtained m/z, 477.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.71-8.59 (m, 1H), 8.50-8.26 (m, 1H), 7.62-7.48 (m, 1H ), 7.46-7.37 (m, 1H), 7.38-7.31 (m, 1H), 7.26 (dd, J =8.6, 6.4 Hz, 1H), 6, 36-5.77(m, 1H), 5.49-5.02(m, 1H), 4.21-4.07(m, 3H), 3.96-3.88(m, 3H), 3.79-3.69 (m, 3H), 3.15-2.99 (m, 1H), 2.57-2.52 (m, 1H), 2.05-1.46 (m, 6H ).

Example 135 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 18) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₇ H ₂₅ ClN ₄ O ₂ - 472.1; obtained m/z, 473.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.01-8.91 (m, 1H), 8.47 (d, J =8.3 Hz, 1H), 8.15-8.01 ( m, 2H), 7.82-7.71 (m, 1H), 7.66-7.54 (m, 2H), 7.53-7.41 (m, 1H), 7.27 (t, J = 9.6 Hz, 1H), 4.14-4.05 (m, 1H), 3.94-3.89 (m, 4H), 3.82-3.62 (m, 3H), 3 .14-2.95 (m, 1H), 2.40 (d, J =15.9 Hz, 1H), 2.04-1.40 (m, 6H).

Example 136 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylbenzo[d]oxazol-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole

(intermediate 17) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 2-methylbenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ ClN ₄ O ₃ - 476.1; obtained m/z, 477.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.86-7.66 (m, 2H), 7.46-7.27 (m, 1H), 7.22-6.96 (m, 3H ), 5.79-5.61 (m, 1H), 4.15-3.95 (m, 1H), 3.92-3.60 (m, 6H), 3.15-2.94 (m , 1H), 2.64 (d, J =6.7 Hz, 3H), 2.38 (d, J =16.0 Hz, 1H), 2.00-1.33 (m, 6H).

Example 137 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 17) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₇ H ₂₅ ClN ₄ O ₂ - 472.1; obtained m/z, 473.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04-8.87 (m, 1H), 8.48 (d, J =8.4 Hz, 1H), 8.15-8.03 ( m, 2H), 7.85-7.51 (m, 2H), 7.23-6.93 (m, 3H), 5.81-5.63 (m, 1H), 4.19-4, 06 (m, 1H), 3.89-3.70 (m, 6H), 3.11-2.96 (m, 1H), 2.43 (d, J =16.2 Hz, 1H), 2 .06-1.40 (m, 6H).

Example 138 ((5R,9S)-3-(3-Chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinoxalin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole

(intermediate 17) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ ClN ₅ O ₂ - 473.1; obtained m/z, 474.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.09-8.99 (m, 2H), 8.26-8.01 (m, 2H), 7.97-7.77 (m, 1H ), 7.24-6.96 (m, 3H), 5.86-5.70 (m, 1H), 4.16-3.95 (m, 1H), 3.91-3.64 (m , 6H), 3.20-2.94 (m, 1H), 2.41 (d, J =16.0 Hz, 1H), 2.04-1.37 (m, 6H).

Example 139 10-yl)(2-methylbenzo[d]oxazol-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 23) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 2-methylbenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₈ N ₄ O ₄ - 472.2; obtained m/z, 473.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.81-7.65 (m, 2H), 7.45-7.27 (m, 1H), 6.70-6.52 (m, 3H ), 5.82-5.52 (m, 1H), 4.09-3.98 (m, 1H), 3.90-3.66 (m, 9H), 3.15-2.93 (m , 1H), 2.64 (d, J = 8.4 Hz, 3H), 2.37 (d, J = 16.0 Hz, 1H), 1.98-1.37 (m, 6H).

Example 140 ((5R,9S)-3-(3,5-Dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(quinoxalin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 23) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₇ N ₅ O ₃ - 469.2; obtained m/z, 470.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.12-8.95 (m, 2H), 8.27-8.02 (m, 2H), 7.96-7.73 (m, 1H ), 6.72-6.43 (m, 3H), 5.83-5.63 (m, 1H), 4.14-4.00 (m, 1H), 3.84-3.69 (m , 9H), 3.22-2.92 (m, 1H), 2.40 (d, J =15.9 Hz, 1H), 2.04-1.37 (m, 6H).

Example 141 (3-(4H-1,2,4Triazol-4-yl)phenyl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 3-(4H-1,2,4-triazol-4-yl) benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ Cl ₂ N ₆ O - 492.1; obtained m/z, 493.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.20 (d, J =6.2 Hz, 2H), 7.90-7.33 (m, 7H), 5.83-5.62 ( m, 1H), 4.14-3.98 (m, 1H), 3.85-3.70 (m, 3H), 3.11-2.95 (m, 1H), 2.44 (d, J = 16.1 Hz, 1H), 2.06-1.40 (m, 6H).

Example 142 10-yl)(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ Cl ₂ N ₅ O ₂ - 497.1; obtained m/z, 498.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.87-7.55 (m, 4H), 6.94 (d, J =51.0 Hz, 1H), 5.72-5.49 ( m, 1H), 4.27 (s, 1H), 4.22 (t, J =4.4 Hz, 2H), 3.85-3.69 (m, 3H), 3.49 (t, J =4.4 Hz, 2H), 3.18-2.95 (m, 4H), 2.41 (d, J =16.1 Hz, 1H), 2.02-1.34 (m, 6H) .

Example 143 10-yl)(5-methoxy-1-methyl-1H-pyrazol-4-yl)-methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₃ Cl ₂ N ₅ O ₂ - 492.1; obtained m/z, 493.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.76-7.59 (m, 3H), 7.42 (d, J =75.0 Hz, 1H), 5.70-5.56 ( m, 1H), 4.54-4.31 (m, 1H), 4.00-3.71 (m, 6H), 3.64-3.57 (m, 3H), 3.20-2, 96 (m, 1H), 2.50-2.35 (m, 1H), 1.96-1.36 (m, 6H).

Example 144 (5-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₅ Cl ₂ N ₅ O - 469.1; obtained m/z, 470.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.80-7.56 (m, 3H), 7.37 (d, J =75.0 Hz, 1H), 5.73-5.58 ( m, 1H), 4.28-4.04 (m, 1H), 3.88-3.73 (m, 6H), 3.06-2.94 (m, 1H), 2.42 (d, J = 16.1 Hz, 1H), 1.92-1.37 (m, 7H), 0.95-0.42 (m, 4H).

Example 145 10-yl)(1-phenyl-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ Cl ₂ N ₆ O - 492.1; obtained m/z, 493.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.42 (d, J =15.2 Hz, 1H), 7.97-7.80 (m, 2H), 7.78-7.39 ( m, 6H), 5.92-5.69 (m, 1H), 4.77-4.31 (m, 1H), 3.86-3.66 (m, 3H), 3.13-2, 98 (m, 1H), 2.58 (dd, J =31.4, 16.1 Hz, 1H), 2.02-1.43 (m, 6H).

Example 146 10-yl)(5-methoxypyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ Cl ₂ N ₄ O ₂ - 456.1; obtained m/z, 457.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.46-8.32 (m, 1H), 8.27-8.10 (m, 1H), 7.77-7.58 (m, 3H ), 7.47-7.30 (m, 1H), 5.80-5.62 (m, 1H), 4.04-3.98 (m, 1H), 3.88-3.69 (m , 6H), 3.13-2.96 (m, 1H), 2.42 (d, J =16.1 Hz, 1H), 2.01-1.36 (m, 6H).

Example 147 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ Cl ₂ N ₇ O - 507.1; obtained m/z, 508.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.23 (dd, J =9.6, 8.4 Hz, 1H), 8.04 (d, J =41.6 Hz, 2H), 7 .72-7.47 (m, 4H), 5.73-5.52 (m, 1H), 3.91-3.84 (m, 1H), 3.83-3.66 (m, 3H) , 2.90-2.67 (m, 1H), 2.59-2.52 (m, 3H), 2.46-2.35 (m, 1H), 1.94-1.30 (m, 6H).

Example 148 10-yl)(2-methylbenzo[d]oxazol-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and 2-methylbenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ Cl ₂ N ₄ O ₂ - 480.1; obtained m/z, 481.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.83-7.60 (m, 5H), 7.45-7.27 (m, 1H), 5.75-5.57 (m, 1H ), 4.11-3.96 (m, 1H), 3.84-3.67 (m, 3H), 3.15-2.99 (m, 1H), 2.64 (d, 3H), 2.40 (d, J =16.0 Hz, 1H), 2.03-1.39 (m, 6H).

Example 149 10-yl)(furo[3,2-b]pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and furo[3,2-b]pyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ Cl ₂ N ₄ O ₂ - 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.63 (dd, J =13.0, 4.6 Hz, 1H), 8.23-8.10 (m, 1H), 7.79- 7.39 (m, 5H), 5.78-5.35 (m, 1H), 5.06-4.66 (m, 1H), 3.87-3.70 (m, 3H), 3. 30-3.03 (m, 1H), 2.65-2.56 (m, 1H), 2.12-1.45 (m, 6H).

Example 150 ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(imidazo[1,5-a]pyridin-8-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,5-a]pyridine-8-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ Cl ₂ N ₅ O - 465.1; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.53-8.29 (m, 2H), 7.74-7.55 (m, 3H), 7.24 (d, J =54.5 Hz, 1H), 6.83-6.64 (m, 2H), 5.82-5.61 (m, 1H), 4.11-3.93 (m, 1H), 3.85-3, 67 (m, 3H), 3.19-2.90 (m, 1H), 2.45-2.33 (m, 1H), 2.01-1.36 (m, 6H).

Example 151 10-yl)(imidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ Cl ₂ N ₅ O - 465.1; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.00-8.81 (m, 1H), 8.06 (s, 1H), 7.77-7.59 (m, 4H), 7, 49-7.40(m, 1H), 7.17-6.98(m, 1H), 5.68(s, 1H), 4.92(s, 1H), 3.80(s, 3H) , 3.28-3.05 (m, 1H), 2.55 (d, J =16.2 Hz, 1H), 2.07-1.44 (m, 6H).

Example 152: ((5R,9S)-3-(3,5-Dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole (intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₂ Cl ₂ N ₄ O - 476.1; obtained m/z, 477.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.04-8.86 (m, 1H), 8.52-8.34 (m, 1H), 8.13-7.99 (m, 2H ), 7.83-7.48 (m, 5H), 5.83-5.59 (m, 1H), 4.18-3.98 (m, 1H), 3.84-3.71 (m , 3H), 3.12-2.97 (m, 1H), 2.45 (d, J =16.1 Hz, 1H), 2.04-1.40 (m, 6H).

Example 153 10-yl)(quinoxalin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole

(intermediate 19) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ Cl ₂ N ₅ O - 477.1; obtained m/z, 478.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.13-8.90 (m, 2H), 8.28-8.00 (m, 2H), 7.97-7.44 (m, 4H ), 5.86-5.68 (m, 1H), 4.14-3.99 (m, 1H), 3.88-3.68 (m, 3H), 3.17-3.01 (m , 1H), 2.47-2.31 (m, 1H), 2.04-1.40 (m, 6H).

Example 154 Racemic -((5R,9S)-3-(3-(Difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic -(5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 10) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₇ H ₂₃ F ₃ N ₄ O, 476.1; obtained m/z, 477.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.08-8.88 (m, 1H), 8.48 (t, J =7.9 Hz, 1H), 8.18-8.02 ( m, 2H), 7.87-7.71 (m, 3H), 7.66-7.48 (m, 2H), 7.43-7.05 (m, 1H), 5.77 (s, 1H), 4.13 (s, 1H), 3.88-3.65 (m, 3H), 3.17-2.97 (m, 1H), 2.43 (d, J =16.1 Hz , 1H), 2.07-1.42 (m, 6H).

Example 155 Racemic -((5R,9S)-3-(3-(Difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epimincycloocta[c]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic -(5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 10) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O - 477.1; obtained m/z, 478.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.11-8.90 (m, 2H), 8.27-8.01 (m, 2H), 7.97-7.72 (m, 3H ), 7.64-7.46 (m, 1H), 7.39-7.07 (m, 1H), 5.79 (s, 1H), 4.09 (t, J = 5.7 Hz, 1H), 3.83-3.63 (m, 3H), 3.22-2.89 (m, 1H), 2.40 (d, J =16.1 Hz, 1H), 2.06-1 .34 (m, 6H).

Example 156 ((5R,9S)-3-(3-Fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazole (intermediate 16) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₄ N ₅ O, 495.2; obtained m/z, 496.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.11-8.88 (m, 2H), 8.26-8.00 (m, 2H), 7.94-7.67 (m, 4H ), 5.79 (s, 1H), 4.09 (s, 1H), 3.89-3.71 (m, 3H), 3.14-3.03 (m, 1H), 2.49- 2.37 (m, 1H), 2.02-1.31 (m, 6H).

Example 157 (3-Chloro-5-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-chloro-5-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ ClF ₃ N ₃ O ₂ - 475.1; obtained m/z, 476.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.58 (t, J =7.8 Hz, 2H), 7.19-6.78 (m, 3H), 5.67 (s, 1H) , 4.00 (s, 1H), 3.86-3.66 (m, 6H), 3.05-2.91 (m, 1H), 2.45-2.39 (m, 1H), 1 .96-1.32 (m, 6H).

Example 158 N-(3-Methoxy-5-((5 R,9 S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazole-10-carbonyl) phenyl)acetamide,

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-acetamido-5-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₃ N ₄ O ₃ - 498.1; obtained m/z, 499.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.12-9.96 (m, 1H), 7.66-7.43 (m, 2H), 7.39-7.14 (m, 2H ), 6.64-6.47 (m, 1H), 5.83-5.55 (m, 1H), 4.15-3.96 (m, 1H), 3.86-3.64 (m , 6H), 3.12-2.90 (m, 1H), 2.48-2.30 (m, 1H), 2.04 (d, J =2.2 Hz, 3H), 1.96- 1.35 (m, 6H).

Example 159 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-(4H-1,2,4-triazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.20 (d, J =5.7 Hz, 2H), 7.93-7.74 (m, 2H), 7.74-7.58 ( m, 3H), 7.54-7.35 (m, 1H), 5.79-5.64 (m, 1H), 4.08-3.94 (m, 1H), 3.87-3, 70 (m, 3H), 3.11-2.97 (m, 1H), 2.47-2.34 (m, 1H), 2.05-1.35 (m, 6H).

Example 160 (2-(4H-1,2,4-Triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(4H-1,2,4-triazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMF- d ₇ ) δ 9.33-8.96 (m, 1H), 8.56 (s, 2H), 8.17-7.78 (m, 5H), 6, 15-5.99 (m, 1H), 4.88-4.63 (m, 1H), 4.20-4.06 (m, 3H), 3.51-3.21 (m, 1H), 2.81-2.62 (m, 1H), 2.27-1.63 (m, 6H).

Example 161 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 54) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.01-8.90 (m, 1H), 8.38-8.25 (m, 1H), 7.77-7.29 (m, 5H ), 5.58-5.49 (m, 1H), 3.95-3.84 (m, 1H), 3.79 (s, 3H), 3.13-2.95 (m, 1H), 2.40-2.24 (m, 1H), 1.96-1.18 (m, 6H).

Example 162 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 55) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.02-8.94 (m, 1H), 8.32-8.24 (m, 1H), 7.89-7.33 (m, 5H ), 5.68-5.57 (m, 1H), 3.87-3.65 (m, 1H), 3.80 (s, 3H), 2.97 (dd, J =16.3.7 .2 Hz, 1H), 2.42-2.33 (m, 1H), 1.80-1.16 (m, 6H).

Example 163 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-fluoro-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 56) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.91-8.85 (m, 1H), 8.30-8.22 (m, 1H), 7.81-7.75 (m, 1H ), 7.65-7.39 (m, 4H), 5.63-5.56 (m, 1H), 3.86-3.76 (m, 1H), 3.80 (s, 3H), 3.04 (dd, J =16.0, 7.4 Hz, 1H), 2.42-2.25 (m, 1H), 1.83-1.18 (m, 6H).

Example 164 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 57) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O - 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.96-8.83 (m, 1H), 8.29-8.20 (m, 1H), 7.68-7.29 (m, 5H ), 5.67-5.57 (m, 1H), 3.86-3.77 (m, 1H), 3.79 (s, 3H), 2.95 (dd, J =16.0.7 .0 Hz, 1H), 2.42 (s, 3H), 2.45-2.24 (m, 1H), 1.77-0.97 (m, 6H).

Example 165 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methyl-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 58) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.85 (s, 1H), 8.23 (s, 1H), 7.68-7.52 (m, 3H), 7.48-7, 36 (m, 2H), 5.66-5.59 (m, 1H), 3.80 (s, 3H), 3.70-3.63 (m, 1H), 2.99-2.86 ( m, 1H), 2.39 (s, 3H), 2.46-2.22 (m, 1H), 1.92-1.17 (m, 6H).

Example 166 )-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 52) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O - 546.2; obtained m/z, 547.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.09-9.04 (m, 1H), 8.39-8.30 (m, 1H), 8.12-7.81 (m, 3H ), 7.66-7.52 (m, 1H), 7.54-7.36 (m, 1H), 5.71-5.62 (m, 1H), 3.80 (s, 3H), 3.84-3.70 (m, 1H), 2.97-2.79 (m, 1H), 2.45-2.21 (m, 1H), 1.88-1.19 (m, 6H ).

Example 167 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 53) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O, 546.2; obtained m/z, 547.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.34-9.30 (m, 1H), 7.87-7.82 (m, 1H), 7.77-7.57 (m, 3H ), 7.56-7.51 (m, 1H), 7.41-7.31 (m, 1H), 5.60-5.55 (m, 1H), 4.01-3.92 (m , 1H), 3.80 (s, 3H), 3.11 (dd, J = 16.3, 7.5 Hz, 1H), 2.46-2.40 (m, 1H), 1.95- 1.29 (m, 6H).

Example 168 (2-(1H-Imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(1H-imidazol-1-yl)benzoic acid (Intermediate 43) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O - 477.2; obtained m/z, 478.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.15-6.58 (m, 9H), 5.75-5.63 (m, 1H), 3.78 (s, 3H), 3, 66-3.53(m, 1H), 2.86-2.69(m, 1H), 2.39-2.23(m, 1H), 1.93-1.03(m, 6H).

Example 169 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₄ N ₅ O - 495.1; obtained m/z, 496.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.18-7.82 (m, 1H), 7.73-7.28 (m, 6H), 6.65-6.48 (m, 1H ), 5.74-5.55 (m, 1H), 3.86-3.72 (m, 4H), 3.01-2.82 (m, 1H), 2.38-2.22 (m , 1H), 1.70-1.15 (m, 6H).

Example 170 (3-(1-Methyl-1H-pyrazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-(1-methyl-1H-pyrazol-4-yl)benzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₄ F ₃ N ₅ O - 491.1; obtained m/z, 492.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.23 (d, J =7.4 Hz, 1H), 7.93 (dd, J =12.6, 0.8 Hz, 1H), 7 .74-7.53(m, 4H), 7.49-7.38(m, 1H), 7.22-7.09(m, 1H), 5.80-5.65(m, 1H) , 4.12-4.00 (m, 1H), 3.88-3.71 (m, 6H), 3.13-2.95 (m, 1H), 2.47-2.36 (m, 1H), 2.01-1.39 (m, 6H).

Example 171 (3-(4-Fluoro-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-(4-fluoro-1H-pyrazol-1-yl)benzoic acid (intermediate 60) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₄ N ₅ O, 495.2; obtained m/z, 496.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.79 (d, J =4.4 Hz, 1H), 7.95-7.89 (m, 1H), 7.89-7.84 ( m, 1H), 7.83-7.77 (m, 1H), 7.64-7.53 (m, 3H), 7.38-7.32 (m, 1H), 5.76-5, 70 (m, 1H), 4.10-4.03 (m, 1H), 3.81 (s, 3H), 2.99 (dd, J =16.2, 7.3 Hz, 1H), 2 .44 (d, J =16.3 Hz, 1H), 2.00-1.65 (m, 3H), 1.60 (d, J =13.2 Hz, 1H), 1.56-1, 38 (m, 2H).

Example 172 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-[4-(trifluoromethyl)pyrazol-1-yl]benzoic acid (Intermediate 59) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₁ F ₆ N ₅ O - 545.2; obtained m/z, 546.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.31-9.26 (m, 1H), 8.26-8.22 (m, 1H), 8.04-8.00 (m, 1H ), 7.96-7.94 (m, 1H), 7.68-7.54 (m, 3H), 7.46-7.41 (m, 1H), 5.76-5.71 (m , 1H), 4.09-4.02 (m, 1H), 3.82 (s, 3H), 3.01 (dd, J = 16.2, 7.4 Hz, 1H), 2.46- 2.40 (m, 1H), 2.03-1.38 (m, 6H).

Example 173 (3-(4-Methoxy-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-(4-methoxy-1H-pyrazol-1-yl)benzoic acid (Intermediate 61) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₄ F ₃ N ₅ O ₂ - 507.2; obtained m/z, 508.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.40 (s, 1H), 7.92-7.86 (m, 1H), 7.82-7.78 (m, 1H), 7, 64-7.51 (m, 3H), 7.57 (s, 1H), 7.31-7.25 (m, 1H), 5.76-5.70 (m, 1H), 4.09- 4.04 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.01 (dd, J =16.2, 7.3 Hz, 1H), 2.44 (d, J =16.2 Hz, 1H), 1.99-1.37 (m, 6H).

Example 174 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-[3-(trifluoromethyl)pyrazol-1-yl]benzoic acid (intermediate 44) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₁ F ₆ N ₅ O - 545.2; obtained m/z, 546.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.88-8.78 (m, 1H), 8.07-7.97 (m, 1H), 7.95-7.83 (m, 1H ), 7.72-7.53 (m, 3H), 7.50-7.42 (m, 1H), 7.12-7.03 (m, 1H), 5.78-5.68 (m , 1H), 4.15-4.01 (m, 1H), 3.82 (s, 3H), 3.03 (dd, J = 16.1, 7.3 Hz, 1H), 2.59- 2.36 (m, 1H), 2.05-1.38 (m, 6H).

Example 175 (3-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 51) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.15 (s, 2H), 8.13-8.09 (m, 1H), 8.02-7.98 (m, 1H), 7, 70-7.55 (m, 3H), 7.49-7.44 (m, 1H), 5.73-5.69 (m, 1H), 4.12-4.06 (m, 1H), 3.80 (s, 3H), 2.99 (dd, J =16.3, 7.4 Hz, 1H), 2.44 (d, J =16.3 Hz, 1H), 1.98-1 .35 (m, 6H).

Example 176 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid [obtained according to the procedure described in the Patent Cooperation Treaty, Patent publication WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.1; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.17 (d, J =15.0 Hz, 1H), 8.03-7.86 (m, 1H), 7.79-6.98 ( m, 5H), 5.65 (s, 1H), 4.41 (d, J =132.8 Hz, 1H), 3.93-3.60 (m, 3H), 3.11-2.94 (m, 1H), 2.43-2.29 (m, 1H), 1.94-1.23 (m, 6H).

Example 177 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid [WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O - 492.1; obtained m/z, 493.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.11 (d, J =7.4 Hz, 1H), 7.79-7.36 (m, 5H), 7.35-6.89 ( m, 1H), 5.53-5.43 (m, 1H), 3.98-3.86 (m, 1H), 3.82-3.69 (m, 3H), 3.08-2, 97 (m, 1H), 2.39 (d, J =16.0 Hz, 1H), 2.19-2.05 (m, 3H), 1.96-1.26 (m, 6H).

Example 178 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 47) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.01 (s, 2H), 7.65-7.53 (m, 3H), 7.38-7.28 (m, 1H), 7, 03-6.96(m, 1H), 5.42(s, 1H), 3.95-3.88(m, 1H), 3.78(s, 3H), 3.76(s, 3H) , 2.99 (dd, J =16.1, 7.3 Hz, 1H), 2.38 (d, J =16.0 Hz, 1H), 1.97-1.21 (m, 6H).

Example 179 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid [WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.16 (d, J =14.0 Hz, 1H), 7.89-6.79 (m, 6H), 5.65 (s, 1H) , 4.57-4.24 (m, 1H), 3.94-3.51 (m, 6H), 3.13-2.91 (m, 1H), 2.43-2.25 (m, 1H), 1.91-1.17 (m, 6H).

Example 180 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 46) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.10 (d, J =5.0 Hz, 1H), 7.88-7.72 (m, 1H), 7.71-7.37 ( m, 3H), 7.25-7.13 (m, 1H), 6.91 (d, J =2.8 Hz, 1H), 5.70-5.60 (m, 1H), 3.89 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.02-2.90 (m, 1H), 2.40-2.22 (m, 1H), 1.98-1.20 (m, 6H).

Example 181: (2-(2H-1,2,3-Triazol-2-yl)-3-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl )-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)benzoic acid (Intermediate 77) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O - 546.2; obtained m/z, 547.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.29-8.15 (m, 1H), 8.24-8.23 (m, 1H), 7.97-7.79 (m, 1H ), 7.86-7.84 (m, 1H), 7.69-7.53 (m, 3H), 5.73-5.67 (m, 1H), 3.91-3.71 (m , 1H), 3.81 (s, 3H), 3.05-2.93 (m, 1H), 2.42-2.34 (m, 1H), 1.98-1.60 (m, 2H ), 1.59-1.17 (m, 4H).

Example 182 )-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 45) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O - 546.2; obtained m/z, 547.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.27-8.25 (m, 1H), 8.23-8.10 (m, 1H), 8.08-7.96 (m, 1H ), 7.89-7.85 (m, 1H), 7.79-7.74 (m, 1H), 7.65-7.51 (m, 2H), 5.76-5.65 (m , 1H), 3.86-3.72 (m, 1H), 3.81 (s, 3H), 2.96-2.83 (m, 1H), 2.46-2.29 (m, 1H ), 2.11-1.20 (m, 6H).

Example 183 (2-(1H-1,2,3-Triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 50) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.51-8.46 (m, 1H), 7.99-7.94 (m, 1H), 7.74-7.55 (m, 5H ), 7.54-7.42 (m, 1H), 5.63-5.58 (m, 1H), 3.87-3.73 (m, 1H), 3.79 (s, 3H), 2.97 (dd, J =16.1, 7.3 Hz, 1H), 2.42-2.31 (m, 1H), 1.81-1.20 (m, 6H).

Example 184 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 48) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.32-8.27 (m, 1H), 7.90-7.85 (m, 1H), 7.65-7.44 (m, 3H ), 7.40-7.31 (m, 1H), 7.07-7.01 (m, 1H), 5.47-5.40 (m, 1H), 3.99-3.93 (m , 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.02 (dd, J = 16.2, 7.3 Hz, 1H), 2.39 (d, J = 16.0 Hz, 1H), 1.92-1.19 (m, 6H).

Example 185 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.73-7.39 (m, 3H), 5.69-5.10 (m, 1H), 4.99-4.36 (m, 1H ), 4.17-3.95(m, 2H), 3.79(s, 3H), 3.22-3.04(m, 1H), 2.92-2.69(m, 2H), 2.46-2.36(m, 1H), 2.03-1.90(m, 2H), 1.83-1.33(m, 8H).

Example 186 (3,4-Dihydro-2H-pyrano[3,2-b]pyridin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3,4-dihydro-2H-pyrano[3,2-b]pyridine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₃ N ₄ O ₂ - 468.1; obtained m/z, 469.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.18-7.97 (m, 1H), 7.65-7.41 (m, 2H), 7.24-6.72 (m, 1H ), 5.81-5.63 (m, 1H), 4.33-3.99 (m, 2H), 3.88-3.67 (m, 4H), 3.09-2.95 (m , 1H), 2.93-2.81 (m, 2H), 2.43-2.27 (m, 1H), 2.12-1.90 (m, 2H), 1.85-1.27 (m, 6H).

Example 187 -trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS ( EMI): mass calculated for C ₂₃ H ₂₂ F ₃ N ₅ O ₂ - 457.1, obtained m/z, 458.1 [M+H] ^{+ .1} H NMR (600 MHz, DMSO- d ₆ ) δ 7.61-7.35 (m, 3H), 5.54 (s, 1H), 5.15-4.73 (m, 1H), 4.38 (s, 2H), 4.09 (s , 2H), 3.85-3.65 (m, 3H), 3.02 (s, 1H), 2.48-2.35 (m, 1H), 2.19 (s, 2H), 2, 00-1.36 (m, 6H).

Example 188 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and (R/S)6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid instead of quinoline -6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O ₂ - 471.1; obtained m/z, 472.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.63-7.40 (m, 3H), 5.53 (s, 1H), 5.13-4.73 (m, 1H), 4, 46-3.94 (m, 4H), 3.86-3.65 (m, 4H), 3.15-2.91 (m, 1H), 2.44-2.30 (m, 1H), 2.03-1.37 (m, 6H), 1.02 (s, 3H).

Example 189 -trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₃ N ₅ O ₂ - 457.1; obtained m/z, 458.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.64-7.45 (m, 2H), 5.75 (d, J =9.3 Hz, 1H), 5.71-5.57 ( m, 1H), 5.07-4.91 (m, 1H), 4.37-4.25 (m, 2H), 4.19-4.03 (m, 2H), 3.82-3, 71 (m, 3H), 3.08-2.91 (m, 1H), 2.63-2.52 (m, 1H), 2.26-2.13 (m, 2H), 1.93- 1.39 (m, 6H).

Example 190 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₉ F ₆ N ₅ O - 483.1; obtained m/z, 484.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.80 (s, 1H), 7.65-7.51 (m, 2H), 5.76-5.66 (m, 1H), 4, 09-3.94 (m, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 2.97 (dd, J =15.8, 7.3 Hz, 1H), 2 .61-2.33 (m, 1H), 1.85-1.31 (m, 6H).

Example 191 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₆ N ₅ O - 525.2; obtained m/z, 526.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.78 (s, 1H), 7.63-7.54 (m, 2H), 5.81-5.55 (m, 1H), 4, 01-3.87 (m, 1H), 3.81-3.76 (m, 3H), 3.07-2.89 (m, 1H), 2.46-2.40 (m, 1H), 1.79-1.67 (m, 3H), 1.63 (s, 9H), 1.45 (t, J =19.0 Hz, 3H).

Example 192 (5-Ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-phenyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₅ F ₃ N ₆ O - 506.2; obtained m/z, 507.2 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.66-7.50 (m, 7H), 5.80-5.40 (m, 1H), 5.10-4.62 (m, 1H ), 3.83-3.70 (m, 3H), 3.12-2.94 (m, 1H), 2.90-2.75 (m, 2H), 2.62-2.53 (m , 1H), 1.99-1.42 (m, 6H), 1.29-1.14 (m, 3H).

Example 193 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₁ F ₆ N ₅ O - 545.2; obtained m/z, 546.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.66-7.52 (m, 7H), 7.42 (s, 1H), 5.78-5.73 (m, 1H), 5, 01-4.94 (m, 1H), 3.79 (s, 3H), 3.09-2.99 (m, 1H), 2.61-2.53 (m, 1H), 1.99- 1.39 (m, 6H).

Example 194 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1-phenyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-phenyl-5-(trifluoromethyl)-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O - 546.2; obtained m/z, 547.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.70-7.62 (m, 7H), 5.77-5.73 (m, 1H), 4.69-4.63 (m, 1H ), 3.80 (s, 3H), 2.99 (dd, J =16.1, 7.4 Hz, 1H), 2.60 (d, J =16.1 Hz, 1H), 1.89 -1.69 (m, 4H), 1.56-1.39 (m, 2H).

Example 195 (5-Methoxy-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methoxy-1-phenyl-1,2,4-triazole-3-carboxylic acid (Intermediate 1) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.72-7.65 (m, 2H), 7.63-7.49 (m, 4H), 7.44-7.37 (m, 1H ), 5.72-5.69 (m, 1H), 4.75-4.69 (m, 1H), 4.13 (s, 3H), 3.78 (s, 3H), 3.05- 2.99 (m, 1H), 2.56 (d, J =16.2 Hz, 1H), 1.86-1.38 (m, 6H).

Example 196 (1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-(3-fluorophenyl)-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.45 (s, 1H), 7.83-7.72 (m, 2H), 7.71-7.51 (m, 3H), 7, 39-7.26(m, 1H), 5.80-5.72(m, 1H), 4.61-4.50(m, 1H), 3.81(s, 3H), 3.09- 2.98 (m, 1H), 2.60-2.43 (m, 1H), 2.04-1.58 (m, 4H), 1.56-1.38 (m, 2H).

Example 197 trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₄ N ₆ O - 510.1; obtained m/z, 511.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.75-7.67 (m, 2H), 7.64-7.55 (m, 2H), 7.52-7.37 (m, 2H ), 5.79-5.39 (m, 1H), 5.11-4.57 (m, 1H), 3.84-3.73 (m, 3H), 3.09-2.97 (m , 1H), 2.65-2.53 (m, 1H), 2.50-2.46 (m, 3H), 1.98-1.37 (m, 6H).

Example 198 (1-(2-Methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 1-(2-methoxyphenyl)-1,2,4-triazole-3-carboxylic acid (Intermediate 1) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.04 (s, 1H), 7.66 (dd, J =7.9, 1.6 Hz, 1H), 7.63-7.55 ( m, 2H), 7.54-7.44 (m, 1H), 7.38-7.31 (m, 1H), 7.20-7.09 (m, 1H), 5.80-5, 72 (m, 1H), 4.64-4.52 (m, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.08-2.96 (m, 1H) , 2.64-2.42(m, 1H), 2.02-1.57(m, 4H), 1.57-1.38(m, 2H).

Example 199 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 1-(3-methoxyphenyl)-1,2,4-triazole-3-carboxylic acid (Intermediate 41) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.41 (s, 1H), 7.68-7.55 (m, 2H), 7.54-7.41 (m, 3H), 7, 08-6.99 (m, 1H), 5.80-5.72 (m, 1H), 4.61-4.51 (m, 1H), 3.85 (s, 3H), 3.80 ( s, 3H), 3.10-2.98 (m, 1H), 2.60-2.43 (m, 1H), 2.08-1.37 (m, 6H).

Example 200 (4-Methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₃ N ₄ O ₂ - 442.2; obtained m/z, 443.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.58-8.46 (m, 1H), 8.25-8.17 (m, 1H), 7.65-7.50 (m, 2H ), 7.27-7.08 (m, 1H), 5.80-5.71 (m, 1H), 4.01-3.92 (m, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 2.93-2.79 (m, 1H), 2.42-2.30 (m, 1H), 1.96-1.31 (m, 6H).

Example 201 (6-Methoxypyridin-2-yl) ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxypicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₃ N ₄ O ₂ - 442.2; obtained m/z, 443.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 7.88-7.70 (m, 1H), 7.63-7.46 (m, 2H), 7.16 (d, J =7.2 Hz, 1H), 7.00-6.85(m, 1H), 5.81-5.58(m, 1H), 4.35-4.20(m, 1H), 3.91-3, 70 (m, 6H), 3.12-2.91 (m, 1H), 2.65-2.51 (m, 1H), 2.10-1.38 (m, 6H).

Example 202 (4-Methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxypicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₃ N ₄ O ₂ - 442.2; obtained m/z, 443.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.38 (d, J =5.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.12-7.09 ( m, 1H), 7.04 (dd, J =5.8, 2.6 Hz, 1H), 5.74-5.70 (m, 1H), 4.20-4.15 (m, 1H) , 3.86 (s, 3H), 3.80 (s, 3H), 2.98 (dd, J =16.0, 7.3 Hz, 1H), 2.45 (d, J =16.0 Hz, 1H), 1.90-1.37 (m, 6H).

Example 203 (5-Methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxypicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₃ N ₄ O ₂ - 442.2; obtained m/z, 443.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.26 (d, J =2.7 Hz, 1H), 7.62-7.52 (m, 3H), 7.50-7.44 ( m, 1H), 5.73-5.67 (m, 1H), 4.43-4.38 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3 .08-2.96 (m, 1H), 2.57-2.41 (m, 1H), 2.03-1.35 (m, 6H).

Example 204 (6-Methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₃ N ₄ O ₂ - 442.2; obtained m/z, 443.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.28 (s, 1H), 7.81-7.74 (m, 1H), 7.65-7.52 (m, 2H), 6, 92-6.83(m, 1H), 5.70-5.60(m, 1H), 4.15-4.08(m, 1H), 3.88(s, 3H), 3.79( s, 3H), 3.10 (dd, J =16.4, 7.4 Hz, 1H), 2.40 (d, J =16.2 Hz, 1H), 2.00-1.35 (m , 6H).

Example 205 (5-Isopropoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-isopropoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₅ F ₃ N ₄ O ₂ , 470.1; obtained m/z, 471.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.34 (dd, J =13.5, 2.8 Hz, 1H), 8.13 (dd, J =50.4, 1.7 Hz, 1H), 7.69-7.58(m, 2H), 7.48-7.28(m, 1H), 5.81-5.60(m, 1H), 4.83-4.68( m, 1H), 4.04-3.95 (m, 1H), 3.85-3.72 (m, 3H), 3.14-2.93 (m, 1H), 2.47-2, 35 (m, 1H), 2.00-1.40 (m, 6H), 1.29 (dd, J =5.9, 1.3 Hz, 6H).

Example 206 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-(trifluoromethoxy)pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(trifluoromethoxy)picolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₆ N ₄ O ₂ - 496.1; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.25-8.10 (m, 1H), 7.71-7.37 (m, 4H), 5.75-5.60 (m, 1H ), 4.26-4.09 (m, 1H), 3.83-3.67 (m, 3H), 3.15-2.88 (m, 1H), 2.68-2.52 (m , 1H), 2.09-1.38 (m, 6H).

Example 207 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-(trifluoromethoxy)pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-(trifluoromethoxy)picolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₆ N ₄ O ₂ - 496.1; obtained m/z, 497.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.80-8.51 (m, 1H), 8.10-7.99 (m, 1H), 7.86-7.69 (m, 1H ), 7.66-7.47 (m, 2H), 5.88-5.59 (m, 1H), 4.27-4.04 (m, 1H), 3.85-3.66 (m , 3H), 3.12-2.95 (m, 1H), 2.68-2.52 (m, 1H), 2.08-1.34 (m, 6H).

Example 208 6-((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl) picolinonitrile,

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-cyanopicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.13-8.86 (m, 1H), 8.54-8.23 (m, 1H), 7.86-7.70 (m, 1H ), 7.69-7.50 (m, 2H), 5.89-5.50 (m, 1H), 4.15-3.96 (m, 1H), 3.89-3.69 (m , 3H), 3.13-2.91(m, 1H), 2.48-2.37(m, 1H), 1.95-1.42(m, 6H).

Example 209 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₁₈ F ₃ N ₅ O - 413.1; obtained m/z, 414.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.86 (d, J =1.5 Hz, 1H), 8.77 (dd, J =7.5, 2.6 Hz, 1H), 8 .73-8.65 (m, 1H), 7.67-7.52 (m, 2H), 5.80-5.70 (m, 1H), 4.27-4.16 (m, 1H) , 3.81 (s, 3H), 3.04 (dd, J =15.9, 7.3 Hz, 1H), 2.60-2.38 (m, 1H), 2.09-1.31 (m, 6H).

Example 210 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrimidin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrimidine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₁₈ F ₃ N ₅ O - 413.1; obtained m/z, 414.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.24 (d, J =1.4 Hz, 1H), 8.97 (d, J =5.1 Hz, 1H), 7.69 (dd , J = 5.1, 1.5 Hz, 1H), 7.62-7.55 (m, 2H), 5.74-5.69 (m, 1H), 4.11-4.05 (m , 1H), 3.80 (s, 3H), 2.99 (dd, J = 16.1, 7.4 Hz, 1H), 2.56-2.38 (m, 1H), 1.91- 1.42 (m, 6H).

Example 211 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyridazin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyridazine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₁₈ F ₃ N ₅ O - 413.1; obtained m/z, 414.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.41-9.31 (m, 1H), 9.34-9.31 (m, 1H), 7.77 (dd, J =5.2 , 2.3 Hz, 1H), 7.66-7.53 (m, 2H), 5.77-5.67 (m, 1H), 3.97-3.88 (m, 1H), 3, 81 (s, 3H), 3.10 (dd, J =16.4, 7.4 Hz, 1H), 2.42 (d, J =16.5 Hz, 1H), 2.07-1.31 (m, 6H).

Example 212 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrimidin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrimidine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₁₈ F ₃ N ₅ O, 413.1; obtained m/z, 414.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.30 (s, 1H), 8.93 (s, 2H), 7.68-7.51 (m, 2H), 5.77-5, 66 (m, 1H), 4.04 (d, J =6.5 Hz, 1H), 3.82 (s, 3H), 3.16 (dd, J =16.3, 7.3 Hz, 1H ), 2.42 (d, J =16.5 Hz, 1H), 2.09-1.34 (m, 6H).

Example 213 (5-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-(1H-pyrazol-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 9.23 (d, J =2.8 Hz, 1H), 8.70 (d, J =2.5 Hz, 1H), 8.61-8 .54 (m, 1H), 8.32-8.26 (m, 1H), 7.90-7.80 (m, 1H), 7.68-7.51 (m, 2H), 6.68 -6.55(m, 1H), 5.81-5.68(m, 1H), 4.14-4.03(m, 1H), 3.82(s, 3H), 3.17-3 .00 (m, 1H), 2.49-2.37 (m, 1H), 2.07-1.38 (m, 6H).

Example 214 (6-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(1H-pyrazol-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.79-8.32 (m, 2H), 8.19-7.83 (m, 4H), 7.78-7.28 (m, 2H ), 6.67-6.49 (m, 1H), 4.25-4.11 (m, 1H), 3.83-3.73 (m, 3H), 3.19-3.03 (m , 1H), 2.44 (d, J =16.3 Hz, 1H), 2.11-1.28 (m, 6H).

Example 215 (6-(1H-Pyrrol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(1H-pyrrol-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O - 477.1; obtained m/z, 478.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.71-8.42 (m, 2H), 8.24-7.76 (m, 3H), 7.72-7.42 (m, 2H ), 7.16 (d, J = 1.3 Hz, 1H), 5.80-5.61 (m, 1H), 4.19-4.01 (m, 1H), 3.86-3, 71 (m, 4H), 3.20-3.04 (m, 1H), 2.42 (d, J =16.2 Hz, 1H), 2.06-1.36 (m, 6H).

Example 216 (6-(1H-Imidazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(1H-imidazol-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.63-8.46 (m, 2H), 8.12-7.87 (m, 3H), 7.61 (dt, J =10.4 , 9.6, 6.5 Hz, 2H), 7.16 (d, J = 1.2 Hz, 1H), 5.85-5.63 (m, 1H), 4.17-3.99 ( m, 1H), 3.88-3.53 (m, 3H), 3.17-3.06 (m, 1H), 2.43 (d, J =16.2 Hz, 1H), 2.07 -1.37 (m, 6H).

Example 217 (6-Methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3.4.5 -trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid [WO2016040789] instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₇ O - 493.1; obtained m/z, 494.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.23 (dd, J =9.3, 8.4 Hz, 1H), 8.12-7.93 (m, 2H), 7.65- 7.47 (m, 3H), 5.75-5.58 (m, 1H), 3.89-3.84 (m, 1H), 3.82-3.69 (m, 3H), 3. 11-2.75 (m, 1H), 2.57-2.53 (m, 3H), 2.47-2.42 (m, 1H), 2.02-1.34 (m, 6H).

Example 218 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-(pyrrolidin-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₆ F ₃ N ₅ O - 481.2; obtained m/z, 482.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.01 (dd, J =11.6, 2.8 Hz, 1H), 7.89-7.71 (m, 1H), 7.68- 7.52 (m, 2H), 6.89-6.74 (m, 1H), 5.73-5.60 (m, 1H), 4.10-4.00 (m, 1H), 3. 85-3.69 (m, 3H), 3.31-3.22 (m, 4H), 3.11-2.94 (m, 1H), 2.46-2.34 (m, 1H), 1.99-1.90 (m, 4H), 1.92-1.35 (m, 6H).

Example 219 1-(5-((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole-10-carbonyl) pyridin-3-yl) pyrrolidin-2-one,

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-(2-oxopyrrolidin-1-yl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₃ N ₅ O ₂ - 495.1; obtained m/z, 496.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 -8.80 (m, 1H), 8.44 -8.15 (m, 2H), 7.64 -7.44 (m, 2H ), 5.72 (s, 1H), 4.05 (s, 1H), 3.91 (t, J =7.0 Hz, 2H), 3.85-3.72 (m, 3H), 3 .27-3.00 (m, 2H), 2.57 (d, J = 20.3 Hz, 1H), 2.49 -2.40 (m, 1H), 2.16 -2.03 (m , 2H), 1.99 -1.35 (m, 6H).

Example 220 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-morpholinopyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-morpholinonicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₆ F ₃ N ₅ O ₂ - 497.2; obtained m/z, 498.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46-8.34 (m, 1H), 8.07-7.90 (m, 1H), 7.69-7.55 (m, 2H ), 7.41-7.16 (m, 1H), 5.76-5.61 (m, 1H), 4.12-3.96 (m, 1H), 3.83-3.71 (m , 6H), 3.27-3.15 (m, 5H), 3.14-2.89 (m, 1H), 2.47-2.32 (m, 1H), 2.02 -1.38 (m, 6H).

Example 221 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylindolizin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylindolizine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₄ O - 464.1; obtained m/z, 465.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.45-8.12 (m, 1H), 7.67-7.27 (m, 4H), 6.65 (s, 1H), 6, 29 (s, 1H), 5.73-5.53 (m, 1H), 4.43-4.13 (m, 1H), 3.87-3.70 (m, 3H), 3.15- 2.98 (m, 1H), 2.26 (s, 3H), 2.64-2.53 (m, 1H), 2.11-1.36 (m, 6H).

Example 222 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (2-methylbenzo[d]oxazol-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylbenzo[d]oxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₄ O ₂ - 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.79-7.68 (m, 2H), 7.61 (t, J =7.8 Hz, 2H), 7.47-7.29 ( m, 1H), 5.78-5.57 (m, 1H), 4.19-4.00 (m, 1H), 3.84-3.70 (m, 3H), 3.14-2, 99 (m, 1H), 2.64 (d, J =3.0 Hz, 3H), 2.39 (d, J =16.2 Hz, 1H), 2.02-1.36 (m, 6H ).

Example 223 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.1; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.90-8.71 (m, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.61 (t, J = 7.5 Hz, 2H), 7.50-7.39 (m, 1H), 7.12-6.92 (m, 1H), 5.75-5.33 (m, 1H), 5 .04-4.62 (m, 1H), 3.89-3.68 (m, 3H), 3.25-3.01 (m, 1H), 2.67-2.52 (m, 1H) , 2.07 -1.39 (m, 6H).

Example 224 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.1; obtained m/z, 466.0 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.66 (d, J =7.0 Hz, 1H), 8.21 (s, 1H), 7.72-7.54 (m, 3H) , 6.89 (dd, J =7.1, 1.9 Hz, 1H), 5.75-5.30 (m, 1H), 5.06-4.62 (m, 1H), 3.89 -3.69 (m, 3H), 3.25-3.10 (m, 1H), 2.59-2.52 (m, 1H), 2.45-2.31 (m, 3H), 2 .01-1.38 (m, 6H).

Example 225 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyridin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.74 (dd, J =14.5, 7.2 Hz, 1H), 8.12-7.99 (m, 1H), 7.78 ( d, J = 16.6 Hz, 1H), 7.67-7.56 (m, 2H), 6.94-6.62 (m, 2H), 5.76-5.55 (m, 1H) , 4.25-4.08 (m, 1H), 3.85-3.71 (m, 3H), 3.13-3.01 (m, 1H), 2.49-2.40 (m, 1H), 2.03-1.38 (m, 6H).

Example 226 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.20-7.90 (m, 1H), 7.85-7.72 (m, 1H), 7.65-7.44 (m, 2H ), 7.37-6.64 (m, 3H), 5.85-5.75 (m, 1H), 3.86-3.55 (m, 4H), 3.16-2.74 (m , 1H), 2.47-2.29 (m, 1H), 2.03-1.27 (m, 6H).

Example 227 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.79-8.62 (m, 1H), 7.81-7.64 (m, 1H), 7.58 (dd, J =8.7 , 6.6 Hz, 2H), 7.34-7.24 (m, 1H), 7.04-6.93 (m, 1H), 6.86 (dd, J =5.2, 0.9 Hz, 1H), 5.84-5.66 (m, 1H), 5.12-4.86 (m, 1H), 3.83-3.68 (m, 3H), 3.13-3, 01 (m, 1H), 2.64-2.53 (m, 1H), 1.99-1.42 (m, 6H).

Example 228 Imidazo[1,2-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.93-7.45 (m, 5H), 7.39-7.16 (m, 1H), 7.09-6.88 (m, 1H ), 5.87-5.64 (m, 1H), 4.12-3.98 (m, 1H), 3.86-3.68 (m, 3H), 3.17-2.98 (m , 1H), 2.47-2.37 (m, 1H), 2.13-1.34 (m, 6H).

Example 229 Imidazo[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,5-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.35-8.05 (m, 1H), 7.74-7.43 (m, 4H), 6.91-6.62 (m, 2H ), 5.88-5.63 (m, 1H), 4.30-4.06 (m, 1H), 3.87-3.65 (m, 3H), 3.18-2.98 (m , 1H), 2.76-2.52 (m, 1H), 2.15-1.34 (m, 6H).

Example 230: Imidazo[1,5-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,5-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.59-8.48 (m, 1H), 8.46-8.36 (m, 1H), 7.67-7.52 (m, 3H ), 7.45-7.36(m, 1H), 6.83-6.74(m, 1H), 5.70-5.57(m, 1H), 4.34-4.20(m , 1H), 3.80 (s, 3H), 3.12-3.02 (m, 1H), 2.60-2.40 (m, 1H), 1.92-1.32 (m, 6H ).

Example 231 Imidazo[1,2-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 8.85-8.71 (m, 1H), 8.06-7.90 (m, 1H), 7.72-7.53 (m, 4H ), 7.35-7.12 (m, 1H), 5.74-5.57 (m, 1H), 4.38-4.17 (m, 1H), 3.82 (s, 3H), 3.10 (dd, J =16.3, 7.4 Hz, 1H), 2.65-2.36 (m, 1H), 2.13-1.32 (m, 6H).

Example 232: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-methylimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-methylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.1; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.79 (dd, J =7.0, 0.9 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J = 8.8, 6.7 Hz, 2H), 7.50-7.42 (m, 1H), 6.93 (dd, J =7.2, 1.7 Hz, 1H), 5.66 (s , 1H), 4.92 (s, 1H), 3.80 (s, 3H), 3.17 (s, 1H), 2.60-2.53 (m, 1H), 2.44-2, 31 (m, 3H), 2.03-1.42 (m, 6H).

Example 233 (1-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.1; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.33 (dd, J =13.1, 4.7 Hz, 1H), 7.68-7.49 (m, 3H), 7.09- 6.92 (m, 1H), 6.47-6.29 (m, 1H), 5.88-5.77 (m, 1H), 4.61-4.49 (m, 1H), 3. 88-3.76 (m, 6H), 3.22-2.80 (m, 1H), 2.37 (d, J =16.1 Hz, 1H), 2.03-1.34 (m, 6H).

Example 234: (1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.1; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.34 (dd, J =4.6, 1.6 Hz, 1H), 7.95 (s, 2H), 7.61 (t, J = 7.6 Hz, 2H), 7.20 (dd, J = 7.9, 4.6 Hz, 1H), 5.79-5.43 (m, 1H), 4.95-4.64 (m , 1H), 3.90-3.71 (m, 6H), 3.21-3.06 (m, 1H), 2.58-2.51 (m, 1H), 2.03-1.37 (m, 6H).

Example 235 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrrolo[1,2-b]pyridazin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and (pyrrolo[1,2-b]pyridazine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O, - 451.2 obtained m/z, 452.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 8.39-8.26 (m, 1H), 8.15 (d, J =9.2 Hz, 1H), 7.89 (d, J =2.9 Hz, 1H), 7.68-7.49 (m, 2H), 7.08 (s , 1H), 6.97-6.81 (m, 1H), 5.71-5.34 (m, 1H), 4.91-4.62 (m, 1H), 3.84-3.68 (m, 3H), 3.26-3.03 (m, 1H), 2.67 (s, 1H), 2.07-1.39 (m, 6H).

Example 236: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrrolo[1,2-a]pyrazin-8-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrrolo[1,2-a]pyrazine-8-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O, 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.01 (s, 1H), 8.37 (dd, J =4.8, 1.5 Hz, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.71-7.57 (m, 3H), 7.11 (s, 1H), 5.79-5.22 (m, 1H), 5.09-4.42 (m, 1H), 3.79 (s, 3H), 3.25-3.09 (m, 1H), 2.64-2.51 (m, 1H), 2.06-1.35 (m , 6H).

Example 237 (4-Methoxy-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxy-1-methyl-1H-indazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₃ N ₅ O ₂ , 495.2; obtained m/z, 496.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.67-7.51 (m, 2H), 7.42-7.29 (m, 1H), 7.20 (dd, J =11.3 , 8.4 Hz, 1H), 6.57 (dd, J = 12.5, 7.7 Hz, 1H), 5.87-5.68 (m, 1H), 4.61-4.42 ( m, 1H), 4.06-3.93 (m, 3H), 3.83-3.59 (m, 6H), 3.13-2.68 (m, 1H), 2.47-2, 37 (m, 1H), 1.99-1.28 (m, 6H).

Example 238: (1-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O, 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.74-8.61 (m, 1H), 8.49-8.33 (m, 1H), 7.66-7.52 (m, 2H ), 7.35 (dd, J = 8.1, 4.5 Hz, 1H), 6.41-5.78 (m, 1H), 5.54-5.08 (m, 1H), 4, 14 (d, J =17.8 Hz, 3H), 3.78 (d, J =20.9 Hz, 3H), 3.21-3.04 (m, 1H), 2.64-2.55 (m, 1H), 2.03-1.45 (m, 6H).

Example 239 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-b]pyridazin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-b]pyridazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.67-8.26 (m, 3H), 7.63 (s, 2H), 7.39 (dd, J =9.1, 4.4 Hz, 1H), 5.78-5.29 (m, 1H), 5.04-4.55 (m, 1H), 3.90-3.62 (m, 3H), 3.30-3, 03 (m, 1H), 2.66-2.52 (m, 1H), 2.14-1.37 (m, 6H).

Example 240: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyrimidin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrimidine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.25-9.07 (m, 1H), 8.70-8.53 (m, 1H), 7.67-7.54 (m, 2H ), 7.20-7.10 (m, 1H), 7.02-6.85 (m, 1H), 5.83-5.58 (m, 1H), 5.12-4.66 (m , 1H), 3.85-3.70 (m, 3H), 3.14-3.02 (m, 1H), 2.60 (d, J = 16.3 Hz, 1H), 2.03- 1.31 (m, 6H).

Example 241 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O - 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.30-9.03 (m, 1H), 8.82-8.62 (m, 1H), 8.41 (d, J =16.9 Hz, 1H), 7.57 (dd, J =8.6, 6.6 Hz, 2H), 7.27-6.96 (m, 1H), 5.82-5.57 (m, 1H) , 4.52-4.00 (m, 1H), 3.88-3.64 (m, 3H), 3.16-3.02 (m, 1H), 2.42-2.25 (m, 1H), 1.97-1.41 (m, 6H).

Example 242: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O, 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.06 (d, J = 20.2 Hz, 1H), 8.69 -8.56 (m, 1H), 8.32 (d, J = 17.3 Hz, 1H), 7.57 (dd, J = 8.7, 6.6 Hz, 2H), 5.78 -5.61 (m, 1H), 4.53 -4.29 (m , 1H), 3.86 -3.63 (m, 3H), 3.20 -3.03 (m, 1H), 2.47 -2.40 (m, 1H), 2.38 -2.27 (m, 3H), 1.93 -1.39 (m, 6H).

Example 243 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrimidine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.32-9.09 (m, 1H), 8.32 (dd, J =19.6, 2.3 Hz, 1H), 7.66- 7.44 (m, 2H), 7.15 (dd, J =13.8, 7.1 Hz, 1H), 6.89-6.73 (m, 1H), 5.98-5.60 ( m, 1H), 4.44-3.96 (m, 1H), 3.87-3.71 (m, 3H), 3.16-2.98 (m, 1H), 2.66-2, 52 (m, 1H), 2.04-1.43 (m, 6H).

Example 244: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(pyrazolo[1,5-a]pyrazin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.40-9.17 (m, 1H), 8.90 (dd, J =4.8, 1.5 Hz, 1H), 8.47 ( s, 1H), 8.14-8.00 (m, 1H), 7.62 (s, 2H), 5.79-5.29 (m, 1H), 5.12-4.59 (m, 1H), 3.92-3.71 (m, 3H), 3.21-2.94 (m, 1H), 2.70-2.51 (m, 1H), 2.04-1.39 ( m, 6H).

Example 245 Imidazo[1,2-b]pyridazin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-b]pyridazine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.44-8.33 (m, 1H), 8.30-8.18 (m, 1H), 7.90 (dd, J =12.9 , 1.3 Hz, 1H), 7.68-7.55 (m, 2H), 7.34 (dd, J = 15.1, 9.4 Hz, 1H), 5.82-5.63 ( m, 1H), 4.43-4.20 (m, 1H), 3.86-3.70 (m, 3H), 3.14-3.02 (m, 1H), 2.77-2, 54 (m, 1H), 2.04-1.42 (m, 6H).

Example 246 Imidazo[1,2-b]pyridazin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-b]pyridazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.62 (dd, J =4.4, 1.6 Hz, 1H), 8.22 (d, J =9.4 Hz, 1H), 8 .00 (d, J = 36.2 Hz, 1H), 7.64-7.51 (m, 2H), 7.41-7.22 (m, 1H), 5.90-5.62 (m , 1H), 4.24-4.02 (m, 1H), 3.89-3.58 (m, 3H), 3.16-3.03 (m, 1H), 2.49-2.37 (m, 1H), 1.96-1.37 (m, 6H).

Example 247 [1,2,4]Triazolo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and [1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.2; obtained m/z, 453.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.05-8.99 (m, 1H), 8.59-8.56 (m, 1H), 7.94-7.88 (m, 1H ), 7.65-7.55 (m, 2H), 7.28-7.17 (m, 1H), 5.74-5.66 (m, 1H), 4.11-4.03 (m , 1H), 3.80 (s, 3H), 3.14-3.02 (m, 1H), 2.39 (d, J =16.3 Hz, 1H), 2.04-1.32 ( m, 6H).

Example 248: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O, 466.1; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.62-8.18 (m, 3H), 7.61-7.39 (m, 2H), 5.86-5.54 (m, 1H ), 4.72-4.35 (m, 1H), 3.96-3.65 (m, 6H), 3.14-3.03 (m, 1H), 2.48-2.27 (m , 1H), 1.95-1.36 (m, 6H).

Example 249 Imidazo[1,2-a]pyrimidin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O, 452.1; obtained m/z, 453.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.26 (dd, J =6.9, 2.0 Hz, 1H), 8.70 (dd, J =4.1, 2.0 Hz, 1H), 8.32-8.03 (m, 1H), 7.76-7.53 (m, 2H), 7.23 (dd, J =6.9, 4.1 Hz, 1H), 5 .80-5.58 (m, 1H), 5.04-4.82 (m, 1H), 3.86-3.70 (m, 3H), 3.21-3.08 (m, 1H) , 2.70-2.54 (m, 1H), 1.90-1.18 (m, 6H).

Example 250: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinolin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoline-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O, 462.1; obtained m/z, 463.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.06-8.83 (m, 1H), 8.17-7.05 (m, 7H), 6.02-5.78 (m, 1H ), 4.45-4.02 (m, 1H), 3.85-3.68 (m, 3H), 3.08-2.60 (m, 1H), 2.37 (d, J =16 .1 Hz, 1H), 2.10-1.32 (m, 6H).

Example 251 Isoquinolin-1-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and isoquinoline-1-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O, 462.1; obtained m/z, 463.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.51 (dd, J =15.5, 5.6 Hz, 1H), 8.17-8.02 (m, 1H), 7.99- 7.49 (m, 6H), 5.99-5.73 (m, 1H), 3.87-3.70 (m, 3H), 3.69-3.56 (m, 1H), 2, 86-2.75 (m, 1H), 2.47-2.37 (m, 1H), 2.09-1.37 (m, 6H).

Example 252: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O, 462.1; obtained m/z, 463.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.97 (dd, J =4.2, 1.7 Hz, 1H), 8.48 (d, J =8.4 Hz, 1H), 8 .14-8.00 (m, 2H), 7.82-7.51 (m, 4H), 5.87-5.69 (m, 1H), 4.22-4.04 (m, 1H) , 3.87-3.70 (m, 3H), 3.15-3.03 (m, 1H), 2.47-2.40 (m, 1H), 2.00-1.37 (m, 6H).

Example 253 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinolin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoline-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O, 462.1; obtained m/z, 463.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.05-8.86 (m, 1H), 8.53-8.40 (m, 1H), 8.16-7.88 (m, 2H ), 7.74-7.52 (m, 4H), 5.83-5.66 (m, 1H), 4.18-4.01 (m, 1H), 3.86-3.69 (m , 3H), 3.14-2.96 (m, 1H), 2.46-2.30 (m, 1H), 2.03-1.38 (m, 6H).

Example 254: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinazolin-4-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinazoline-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.33 (d, J =18.1 Hz, 1H), 8.33-7.38 (m, 6H), 5.99-5.78 ( m, 1H), 4.19-4.02 (m, 1H), 3.86-3.65 (m, 3H), 2.93-2.79 (m, 1H), 2.45-2, 37 (m, 1H), 2.05-1.46 (m, 6H).

Example 255 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.07-8.96 (m, 2H), 8.25-7.99 (m, 2H), 7.93-7.79 (m, 1H ), 7.64-7.52 (m, 2H), 5.81-5.74 (m, 1H), 4.08 (s, 1H), 3.86-3.70 (m, 3H), 3.19-2.99 (m, 1H), 2.41 (d, J =16.1 Hz, 1H), 2.05-1.38 (m, 6H).

Example 256: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylquinoxalin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-methylquinoxaline-6-carboxylic acid (Intermediate 33) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O, 477.1; obtained m/z, 478.0 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.98-8.87 (m, 1H), 8.14-7.59 (m, 5H), 5.83-5.69 (m, 1H ), 4.17-4.02 (m, 1H), 3.84-3.68 (m, 3H), 3.16-3.02 (m, 1H), 2.81-2.69 (m , 3H), 2.47-2.38 (m, 1H), 1.99-1.42 (m, 6H).

Example 257 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinoxalin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.12 (d, J =4.4 Hz, 1H), 8.22-8.04 (m, 2H), 8.04-7.88 ( m, 2H), 7.69-7.43 (m, 2H), 5.89-5.57 (m, 1H), 4.52-4.30 (m, 1H), 3.89-3, 65 (m, 3H), 3.24-3.04 (m, 1H), 2.65 (d, J =16.3 Hz, 1H), 2.17-1.46 (m, 6H).

Example 258: Cinnolin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5.9 -epiminecycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and cinnoline-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.61-8.42 (m, 2H), 8.24-8.11 (m, 1H), 8.10-7.90 (m, 2H ), 7.68-7.45(m, 2H), 5.91-5.78(m, 1H), 4.32-4.11(m, 1H), 3.85-3.70(m , 3H), 3.19-3.02 (m, 1H), 2.49-2.39 (m, 1H), 2.09-1.44 (m, 6H).

Example 259 Cinnolin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazol-10-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and cinnoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.46 (dd, J =8.8, 5.8 Hz, 1H), 8.60-8.48 (m, 1H), 8.38- 8.27 (m, 1H), 8.21-8.08 (m, 1H), 8.00-7.85 (m, 1H), 7.65-7.54 (m, 2H), 5. 82-5.64 (m, 1H), 4.14-3.96 (m, 1H), 3.86-3.69 (m, 3H), 3.16-2.99 (m, 1H), 2.46-2.40 (m, 1H), 2.05-1.43 (m, 6H).

Example 260: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1,5-naphthyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,5-naphthyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.16-9.04 (m, 1H), 8.61-8.43 (m, 2H), 8.02-7.80 (m, 2H ), 7.70-7.52 (m, 2H), 5.85-5.76 (m, 1H), 4.32-4.13 (m, 1H), 3.86-3.70 (m , 3H), 3.16-3.07 (m, 1H), 2.75-2.56 (m, 1H), 2.16-1.42 (m, 6H).

Example 261 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1,5-naphthyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,5-naphthyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.16-8.94 (m, 2H), 8.54-8.28 (m, 2H), 7.96-7.79 (m, 1H ), 7.71-7.50(m, 2H), 5.84-5.73(m, 1H), 4.23-4.08(m, 1H), 3.88-3.73(m , 3H), 3.20-3.06 (m, 1H), 2.46-2.31 (m, 1H), 2.06-1.37 (m, 6H).

Example 262: ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1,6-naphthyridin-8-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,6-naphthyridine-8-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₃ N ₅ O, 463.1; obtained m/z, 464.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.54-9.39 (m, 1H), 9.27-8.37 (m, 3H), 7.88-7.44 (m, 3H ), 6.02-5.77 (m, 1H), 4.38-3.98 (m, 1H), 3.88-3.69 (m, 3H), 3.18-2.89 (m , 1H), 2.45-2.22 (m, 1H), 2.06-1.32 (m, 6H).

Example 263 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4, 5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9- epiminecycloocta[c]pyrazole (intermediate 22) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₂ N ₆ O ₂ , 490.1; obtained m/z, 491.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.16 (d, J =13.2 Hz, 1H), 8.03-7.72 (m, 2H), 7.70-7.39 ( m, 3H), 7.31-6.89 (m, 2H), 5.74-5.61 (m, 1H), 4.56-4.26 (m, 1H), 4.00-3, 85 (m, 3H), 3.85-3.60 (m, 3H), 3.15-2.88 (m, 1H), 2.46-2.35 (m, 1H), 1.90- 1.19 (m, 6H).

Example 264: ((5R,9S)-3-(3,5-Difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9- epiminecycloocta[c]pyrazole (intermediate 22) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ F ₂ N ₆ O ₂ , 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.69-8.54 (m, 1H), 8.47-8.32 (m, 1H), 7.42-7.29 (m, 3H ), 6.36-6.25 (m, 1H), 5.17-5.08 (m, 1H), 4.19-4.10 (m, 3H), 4.01-3.96 (m , 3H), 3.82-3.73 (m, 3H), 3.15-3.08 (m, 1H), 2.63-2.55 (m, 1H), 2.02-1.41 (m, 6H).

Example 265 ((5R,9S)-3-(3,5-Difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9- epiminecycloocta[c]pyrazole (intermediate 22) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₇ H ₂₄ F ₂ N ₄ O ₂ , 474.2; obtained m/z, 475.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (d, J =4.5 Hz, 1H), 8.48 (d, J =8.3 Hz, 1H), 8.19-8 .04 (m, 2H), 7.85-7.56 (m, 2H), 7.39 (t, J = 8.6 Hz, 2H), 5.87-5.69 (m, 1H), 4.16-4.09 (m, 1H), 4.01-3.96 (m, 3H), 3.84-3.79 (m, 3H), 2.49-2.40 (m, 1H ), 1.94-1.40 (m, 7H).

Example 266: (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4, 5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazole (intermediate 21) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₂ N ₆ O ₂ - 490.1; obtained m/z, 491.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 8.16 (d, J =13.2 Hz, 1H), 8.03-7.72 (m, 2H), 7.70-7.39 ( m, 3H), 7.31-6.89 (m, 2H), 5.74-5.61 (m, 1H), 4.56-4.26 (m, 1H), 4.00-3, 85 (m, 3H), 3.85-3.60 (m, 3H), 3.15-2.88 (m, 1H), 2.46-2.35 (m, 1H), 1.90- 1.19 (m, 6H).

Example 267 ((5R,9S)-3-(3,4-Difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazole (intermediate 21) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₄ F ₂ N ₆ O ₂ - 478.1; obtained m/z, 479.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.69-8.58 (m, 1H), 8.47-8.37 (m, 1H), 7.39-7.32 (m, 1H ), 7.25-7.07 (m, 2H), 6.37-6.23 (m, 1H), 5.26-5.06 (m, 1H), 4.20-4.10 (m , 3H), 3.96-3.90 (m, 3H), 3.83-3.74 (m, 3H), 3.18-3.07 (m, 1H), 2.65-2.55 (m, 1H), 2.08-1.35 (m, 6H).

Example 268: ((5R,9S)-3-(3,4-Difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazole (intermediate 21) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₇ H ₂₄ F ₂ N ₄ O ₂ , -474.1; obtained m/z, 475.1 [M+H] ⁺ . ¹ H NMR (600 MHz, DMSO- d ₆ ) δ 9.05-8.93 (m, 1H), 8.47 (t, J =7.8 Hz, 1H), 8.15-8.01 ( m, 2H), 7.86-7.56 (m, 2H), 7.32-7.07 (m, 2H), 5.76 (s, 1H), 4.12 (s, 1H), 3 .97-3.93 (m, 3H), 3.84-3.73 (m, 3H), 3.22-3.02 (m, 1H), 2.43 (d, J = 16.1 Hz , 1H), 2.05-1.42 (m, 6H).

Example 269 ((5R,9S)-2-Methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9- epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate 32) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₉ H ₂₇ N ₅ O, 461.2; obtained m/z, 462.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.06-8.89 (m, 1H), 8.48 (dd, J =17.5, 8.2 Hz, 1H), 8.16- 8.03 (m, 2H), 7.82-7.71 (m, 1H), 7.68-7.47 (m, 3H), 7.29-7.05 (m, 2H), 6, 70 (s, 1H), 5.88-5.68 (m, 1H), 4.16-4.06 (m, 1H), 3.81-3.56 (m, 6H), 2.98- 2.82 (m, 1H), 2.40-2.30 (m, 1H), 2.00-1.46 (m, 6H).

Example 270 Racemic -((5R,9S)-2-Methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using racemic (5R,9S)-2-methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9- hexahydro-2 H-5,9-epimincycloocta[c]pyrazole (intermediate 9) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5,9-epimincycloocta[c]pyrazole (Intermediate 1). MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₄ OS - 482.1; obtained m/z, 483.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.03-8.91 (m, 1H), 8.55-8.37 (m, 1H), 8.15-8.02 (m, 2H ), 7.90-7.45 (m, 4H), 5.77 (s, 1H), 4.17 (s, 1H), 3.99-3.80 (m, 3H), 3.26- 2.98 (m, 1H), 2.65 (dd, J =69.0, 16.4 Hz, 1H), 2.11-1.33 (m, 6H).

Example 271 (4-Methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ F ₃ N ₃ O ₂ - 441.2; obtained m/z, 442.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.65-7.54 (m, 2H), 7.43-7.37 (m, 2H), 7.04-6.94 (m, 2H ), 5.71 -5.59 (m, 1H), 4.22 -4.06 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.12 - 2.96 (m, 1H), 2.42 (d, J =16.2 Hz, 1H), 1.99-1.32 (m, 6H).

Example 272 (2-Fluoro-4-methylphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-fluoro-4-methylbenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₄ N ₃ O - 443.2; obtained m/z, 444.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.62-7.50 (m, 2H), 7.37-7.09 (m, 1H), 7.14-7.08 (m, 1H ), 7.08 -7.04 (m, 1H), 5.78 -5.64 (m, 1H), 3.92 -3.81 (m, 1H), 3.77 (s, 3H), 2.83 (dd, J =16.1, 7.4 Hz, 1H), 2.51 -2.43 (m, 1H), 2.32 (s, 3H), 1.90 -1.29 ( m, 6H).

Example 273: (2-Fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-fluoro-4-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₄ N ₃ O ₂ , 459.2; obtained m/z, 460.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.67-7.48 (m, 2H), 7.31 (s, 1H), 7.02-6.74 (m, 2H), 5, 83 -5.59 (m, 1H), 5.08-4.57 (m, 1H), 3.85-3.70 (m, 6H), 3.22 -2.80 (m, 1H), 2.49 -2.42 (m, 1H), 1.88 -1.31 (m, 6H).

Example 274 (3-Fluoro-5-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-fluoro-5-pyrazol-1-yl-benzoic acid (Intermediate 64) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₄ N ₅ O, 495.2; obtained m/z, 496.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.64 (d, J =2.6 Hz, 1H), 7.84-7.80 (m, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.74 -7.71 (m, 1H), 7.61 -7.53 (m, 2H), 7.21 -7.16 (m, 1H), 6.59 -6.55 (m, 1H), 5.70 -5.67 (m, 1H), 4.06 -4.00 (m, 1H), 3.79 (s, 3H), 2.99 (dd , J = 16.2, 7.4 Hz, 1H), 2.41 (d, J = 16.1 Hz, 1H), 1.98 -1.35 (m, 6H).

Example 275 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-fluoro-5-(4H-1,2,4-triazol-4-yl)benzoic acid (Intermediate 68) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 9.25 (s, 2H), 7.91-7.82 (m, 1H), 7.72-7.65 (m, 1H), 7. 63-7.53(m, 2H), 7.42-7.33(m, 1H), 5.74-5.67(m, 1H), 4.06-3.97(m, 1H), 3.82 (s, 3H), 3.05 (dd, J =16.4, 7.2 Hz, 1H), 2.42 (d, J =16.5 Hz, 1H), 2.09-1 .35 (m, 6H).

Example 276 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-fluoro-3-(4H-1,2,4-triazol-4-yl)benzoic acid (Intermediate 69) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.98 (s, 2H), 7.89-7.72 (m, 1H), 7.69-7.45 (m, 4H), 5, 70 (s, 1H), 4.10 (d, J =6.7 Hz, 1H), 3.81 (s, 3H), 3.12-2.97 (m, 1H), 2.59-2 .37 (m, 1H), 2.07-1.35 (m, 6H).

Example 277 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(4-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-methyl-3-(4H-1,2,4-triazol-4-yl)benzoic acid (Intermediate 72) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.84 (s, 2H), 7.63-7.38 (m, 5H), 5.73-5.64 (m, 1H), 4, 15 -4.08 (m, 1H), 3.80 (s, 3H), 3.03 (dd, J =16.5, 7.4 Hz, 1H), 2.44 (d, J =16, 3 Hz, 1H), 2.18 (s, 3H), 1.91-1.38 (m, 6H).

Example 278 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methyl-5-(4H-1,2,4-triazol-4-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-methyl-5-(4H-1,2,4-triazol-4-yl)benzoic acid (Intermediate 70) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 9.17 (s, 2H), 7.73-7.65 (m, 1H), 7.64-7.49 (m, 3H), 7. 32 -7.25 (m, 1H), 5.77 -5.64 (m, 1H), 4.11 -3.99 (m, 1H), 3.82 (s, 3H), 3.01 ( dd, J = 15.5, 7.1 Hz, 1H), 2.66 -2.36 (m, 1H), 2.43 (s, 3H), 2.07 -1.33 (m, 6H) .

Example 279 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-methyl-3-(4H-1,2,4-triazol-4-yl)benzoic acid (Intermediate 71) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.83 (s, 2H), 7.68-7.30 (m, 5H), 5.85-5.75 (m, 1H), 3, 81 (s, 3H), 3.78 -3.70 (m, 1H), 3.43 -3.22 (m, 1H), 3.03 -2.81 (m, 1H), 2.10 ( s, 3H), 1.95 -1.31 (m, 6H).

Example 280 (2-(2H-1,2,3-Triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 49) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O, 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.12 (s, 2H), 7.90-7.86 (m, 1H), 7.66-7.36 (m, 5H), 5, 67 -5.63 (m, 1H), 3.88 -3.81 (m, 1H), 3.78 (s, 3H), 2.95 (dd, J = 16.3, 7.6 Hz, 1H), 2.35 (d, J =16.1 Hz, 1H), 1.88-1.19 (m, 6H).

Example 281 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 74) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.25-8.14 (m, 1H), 7.89-7.28 (m, 6H), 5.73-5.62 (m, 1H ), 3.92 -3.76 (m, 1H), 3.81 (s, 3H), 3.03 -2.91 (m, 1H), 2.42 -2.34 (m, 1H), 1.94 -1.17 (m, 6H).

Example 282 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 75) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.17 (s, 1H), 7.75-7.31 (m, 6H), 5.55-5.47 (m, 1H), 3, 98 -3.91 (m, 1H), 3.79 (s, 3H), 3.04 (dd, J =16.2, 7.2 Hz, 1H), 2.41 (d, J =16, 2 Hz, 1H), 1.89 -1.27 (m, 6H).

Example 283 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 112) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₄ N ₆ O - 496.2; obtained m/z, 497.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) : 8.12 (s, 2H), 7.91 (dd, J =9.0, 4.9 Hz, 1H), 7.61 -7.55 ( m, 1H), 7.55-7.30 (m, 3H), 5.65-5.60 (m, 1H), 3.88-3.83 (m, 1H), 3.78 (s, 3H), 3.02 (dd, J =16.1, 7.2 Hz, 1H), 2.33 (d, J =16.0 Hz, 1H), 1.82 -1.19 (m, 6H ).

Example 284 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 76) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.11 (s, 2H), 7.84-7.31 (m, 5H), 5.73-5.58 (m, 1H), 3, 92 -3.81 (m, 1H), 3.81 (s, 3H), 2.99 -2.87 (m, 1H), 2.39 (s, 3H), 2.45 -2.22 ( m, 1H), 1.91 -1.10 (m, 6H).

Example 285 )-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)benzoic acid (Intermediate 77) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O, 546.2; obtained m/z, 547.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.17 (s, 2H), 8.12-7.39 (m, 5H), 5.51-5.38 (m, 1H), 3, 95 -3.84 (m, 1H), 3.79 (s, 3H), 3.14 -2.98 (m, 1H), 2.63 -2.33 (m, 1H), 2.05 - 1.20 (m, 6H).

Example 286 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 73) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O, 492.2; obtained m/z, 493.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.88 (s, 1H), 7.90-7.77 (m, 1H), 7.62-7.55 (m, 2H), 7. 46 -7.41 (m, 1H), 7.62 -7.32 (m, 2H), 5.70 -5.64 (m, 1H), 3.90 -3.84 (m, 1H), 3.78 (s, 3H), 3.00 -2.93 (m, 1H), 2.50 -2.42 (m, 1H), 2.33 (s, 3H), 1.91 -1, 18 (m, 6H).

Example 287 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-[4-(trifluoromethyl)triazol-2-yl]benzoic acid (Intermediate 66) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O, 546.2; obtained m/z, 547.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.79 (s, 1H), 7.95-7.91 (m, 1H), 7.73-7.65 (m, 2H), 7. 64 -7.56 (m, 2H), 7.51 -7.46 (m, 1H), 5.62 -5.57 (m, 1H), 4.02 -3.94 (m, 1H), 3.78 (s, 3H), 3.14 -3.01 (m, 1H), 2.42 (d, J =16.3 Hz, 1H), 1.90 -1.30 (m, 6H) .

Example 288 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methoxy-2-(1H-1,2,4-triazol-1-yl)benzoic acid (Intermediate 65) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ , 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.75 (s, 1H), 8.18 (s, 1H), 7.59 (d, J =8.7 Hz, 1H), 7.59 -7.53 (m, 2H), 7.15 (dd, J =8.9, 2.8 Hz, 1H), 6.95 (d, J =2.8 Hz, 1H), 5.60 - 5.55(m, 1H), 3.81(s, 3H), 3.76(s, 3H), 3.81-3.74(m, 1H), 2.94(dd, J =16, 1, 7.2 Hz, 1H), 2.34 (d, J =16.1 Hz, 1H), 1.77-1.19 (m, 6H).

Example 289 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-[4-(trifluoromethyl)triazol-1-yl]benzoic acid (Intermediate 67) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₀ F ₆ N ₆ O, 546.2; obtained m/z, 547.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 9.35 (s, 1H), 7.83-7.77 (m, 1H), 7.75-7.68 (m, 2H), 7. 63 -7.54 (m, 2H), 7.45 -7.28 (m, 1H), 5.62 -5.46 (m, 1H), 3.77 (s, 3H), 3.75 - 3.68 (m, 1H), 3.12 -2.97 (m, 1H), 2.40 (d, J = 16.3 Hz, 1H), 1.90 -1.21 (m, 6H) .

Example 290 (6-Isopropylpyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

Stage A:6-Isopropylpyrimidine-4-carboxylic acid, Sodium hydroxide (60 mg, 1.50 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was acidified until the pH was 3 with 6 M hydrochloric acid (0.25 ml), diluted with ethyl acetate (1 ml) and water ( 1 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×2 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (82 mg, 0.493 mmol, 65%) as a white powder, MS (ESI): mass calculated for C₈H₁₀N₂O₂, 166.1; obtained m/z, 167.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d ₆) δ 13.84 (br. s, 1H), 9.24 (s, 1H), 7.90 (s, 1H), 3.20 -3.04 (m, 1H), 1.26 (d,J=6.8Hz, 6H).

Step B: (6-Isopropylpyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone. The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-isopropylpyrimidine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O, 455.2; obtained m/z, 456.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 9.09 (d, J =1.3 Hz, 1H), 7.59-7.53 (m, 2H), 7.56 (s, 1H) , 5.74 -5.62 (m, 1H), 4.09 -3.99 (m, 1H), 3.78 (s, 3H), 3.08 -3.00 (m, 1H), 2 .95 (dd, J = 16.1, 7.3 Hz, 1H), 2.51 -2.41 (m, 1H), 1.87 -1.36 (m, 6H), 1.23 (d , J =6.9 Hz, 6H).

Example 291 (6-Methoxypyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxypyrimidine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₀ F ₃ N ₅ O ₂ , 443.2; obtained m/z, 444.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.84-8.79 (m, 1H), 7.70-7.47 (m, 2H), 7.14-7.07 (m, 1H ), 5.76 -5.63 (m, 1H), 4.11 -4.02 (m, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 3.15 - 2.89 (m, 1H), 2.65-2.34 (m, 1H), 2.01-1.33 (m, 6H).

Example 292 hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(dimethylamino)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O, 455.2; obtained m/z, 456.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.22-8.16 (m, 1H), 7.65-7.45 (m, 3H), 6.62 (d, J =8.8 Hz, 1H), 5.67 -5.46 (m, 1H), 4.32 -4.14 (m, 1H), 3.77 (s, 3H), 3.15 -2.98 (m, 1H), 3.04 (s, 6H), 2.40 (d, J =16.3 Hz, 1H), 1.99-1.29 (m, 6H).

Example 293 (5-Methoxy-4-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxy-4-methylnicotinic acid hydrochloride instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ F ₃ N ₄ O ₂ , 456.2; obtained m/z, 457.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.40-8.26 (m, 2H), 7.71-7.48 (m, 2H), 5.89-5.69 (m, 1H ), 3.94 (s, 3H), 3.81 (s, 3H), 3.85 -3.63 (m, 1H), 3.18 -2.94 (m, 1H), 2.41 - 2.32 (m, 1H), 2.18 (s, 3H), 2.02-1.29 (m, 6H).

Example 294 (6-Methoxy-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxy-5-methylnicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ F ₃ N ₄ O ₂ , 456.2; obtained m/z, 457.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.11-8.07 (m, 1H), 7.64-7.52 (m, 3H), 5.66-5.60 (m, 1H ), 4.16 -4.09 (m, 1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.08 (dd, J = 16.1, 7.3 Hz, 1H), 2.39 (d, J =16.3 Hz, 1H), 2.15 (s, 3H), 1.87-1.32 (m, 6H).

Example 295 (5-Fluoro-6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-fluoro-6-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ F ₄ N ₄ O ₂ , 460.2; obtained m/z, 461.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.08 (d, J =1.9 Hz, 1H), 7.77 (dd, J =10.7, 1.9 Hz, 1H), 7 .63 -7.52 (m, 2H), 5.66 -5.59 (m, 1H), 4.15 -4.06 (m, 1H), 3.96 (s, 3H), 3.78 (s, 3H), 3.10 (dd, J =16.3, 7.4 Hz, 1H), 2.38 (d, J =16.3 Hz, 1H), 1.88 -1.30 ( m, 6H).

Example 296 (5-Fluoro-2-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-fluoro-2-methoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ F ₄ N ₄ O ₂ , 460.2; obtained m/z, 461.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.28-8.17 (m, 2H), 7.61-7.46 (m, 2H), 5.75-5.64 (m, 1H ), 3.77 (s, 3H), 3.80-3.69 (m, 4H), 2.91-2.79 (m, 1H), 2.51-2.42 (m, 1H), 1.95 -1.29 (m, 6H).

Example 297 (5,6-Dimethoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5,6-dimethoxynicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ F ₃ N ₄ O ₃ , 472.2; obtained m/z, 473.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.80-7.76 (m, 1H), 7.62-7.53 (m, 2H), 7.30-7.26 (m, 1H ), 5.67 -5.61 (m, 1H), 4.19 -4.12 (m, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.78 ( s, 3H), 3.06 (dd, J =16.0, 7.4 Hz, 1H), 2.39 (d, J =16.2 Hz, 1H), 2.00 -1.34 (m , 6H).

Example 298 (5,6-Dimethoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5,6-dimethoxypicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ F ₃ N ₄ O ₃ , 472.2; obtained m/z, 473.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.61 -7.48 (m, 2H), 7.34 (d, J =8.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 5.69 -5.63 (m, 1H), 4.63 -4.55 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H ), 3.76 (s, 3H), 3.03 -2.94 (m, 1H), 2.58 -2.44 (m, 1H), 1.86 -1.70 (m, 2H), 1.68 -1.52 (m, 2H), 1.52 -1.35 (m, 2H).

Example 299 (3-Chloro-2-methoxypyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-chloro-2-methoxyisonicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ ClF ₃ N ₄ O ₂ , 476.1; obtained m/z, 477.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.17 (d, J =5.1 Hz, 1H), 7.72-7.43 (m, 2H), 6.99 (d, J = 5.0 Hz, 1H), 5.81 -5.65 (m, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 3.85 -3.69 (m, 1H ), 2.99 -2.81 (m, 1H), 2.63 -2.33 (m, 1H), 1.98 -1.31 (m, 6H).

Example 300 (5-Chloro-6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-chloro-6-methoxypicolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ ClF ₃ N ₄ O ₂ - 476.1; obtained m/z, 477.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.05-7.95 (m, 1H), 7.67-7.46 (m, 2H), 7.22 (d, J =7.8 Hz, 1H), 5.77 -5.61 (m, 1H), 4.45 -4.26 (m, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3 .13 -2.92 (m, 1H), 2.65 -2.35 (m, 1H), 1.95-1.27 (m, 6H).

Example 301 (4-Chloro-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-chloro-2-methylnicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ ClF ₃ N ₄ O - 460.1; obtained m/z, 461.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.48-8.44 (m, 1H), 7.63-7.42 (m, 3H), 5.85-5.82 (m, 1H ), 3.80 (s, 3H), 3.82-3.75 (m, 1H), 2.95 (dd, J =16.2, 7.5 Hz, 1H), 2.56-2, 46 (m, 1H), 2.26 (s, 3H), 1.92-1.35 (m, 6H).

Example 302 (4-Chloro-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-chloro-5-methylnicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ ClF ₃ N ₄ O - 460.1; obtained m/z, 461.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.57-8.55 (m, 1H), 8.34-8.29 (m, 1H), 7.63-7.55 (m, 2H ), 5.79-5.75 (m, 1H), 3.78 (s, 3H), 3.75-3.69 (m, 1H), 3.00-2.93 (m, 1H), 2.36 (s, 3H), 2.40-2.29 (m, 1H), 1.96-1.27 (m, 6H).

Example 303 (3-Chloro-5-fluoropyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-chloro-5-fluoroisonicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₇ ClF ₄ N ₄ O - 464.1; obtained m/z, 465.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.70-8.69 (m, 1H), 8.69-8.68 (m, 1H), 7.63-7.52 (m, 2H ), 5.80 -5.75 (m, 1H), 3.94 -3.86 (m, 1H), 3.80 (s, 3H), 2.79 (dd, J =16.3.7 .3 Hz, 1H), 2.58-2.45 (m, 1H), 1.89-1.61 (m, 4H), 1.56-1.36 (m, 2H).

Example 304 (6-Cyclopropyl-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-cyclopropyl-2-methylnicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₃ N ₄ O - 466.2; obtained m/z, 467.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.64-7.49 (m, 3H), 7.14-7.01 (m, 1H), 5.77-5.71 (m, 1H ), 3.78 (s, 3H), 3.81-3.70 (m, 1H), 2.96-2.75 (m, 1H), 2.53 (d, J = 16.3 Hz, 1H), 2.41-2.36 (m, 3H), 2.10-2.03 (m, 1H), 1.86-1.28 (m, 6H), 0.98-0.82 ( m, 4H).

Example 305 1-(5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5.9 -epimincycloocta[c]pyrazole-10-carbonyl)pyridin-2-yl)cyclopropan-1-carbonitrile,

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(1-cyanocyclopropyl)nicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O, 477.2; the resulting m/z, - 478.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.56 (d, J =2.1 Hz, 1H), 7.89 (dd, J =8.1, 2.3 Hz, 1H), 7 .65-7.53 (m, 3H), 5.72-5.61 (m, 1H), 4.03-3.95 (m, 1H), 3.78 (s, 3H), 3.11 -3.01(m, 1H), 2.38(d, J =16.3Hz, 1H), 1.89-1.78(m, 4H), 1.77-1.32(m, 6H ).

Example 306 (2-(1H-Pyrazol-1-yl)pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(1H-pyrazol-1-yl)isonicotinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O, 478.2; the resulting m/z, - 479.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) : 8.63-8.61 (m, 1H), 8.53 (d, J =5.0 Hz, 1H), 7.85-7.81 ( m, 2H), 7.63-7.54 (m, 2H), 7.36 (dd, J =5.1, 1.4 Hz, 1H), 6.60-6.57 (m, 1H) , 5.73-5.68 (m, 1H), 4.01-3.96 (m, 1H), 3.79 (s, 3H), 2.97 (dd, J =16.3, 7, 4 Hz, 1H), 2.43 (d, J =16.3 Hz, 1H), 1.95-1.33 (m, 6H).

Example 307 (4-(1H-Pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-(1H-pyrazol-1-yl)picolinic acid (Intermediate 78) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.88-8.74 (m, 1H), 8.64 (d, J =5.6 Hz, 1H), 8.07-8.02 ( m, 1H), 8.02-7.94 (m, 1H), 7.93-7.83 (m, 1H), 7.68-7.45 (m, 2H), 6.74-6, 57 (m, 1H), 5.82-5.69 (m, 1H), 4.30-4.16 (m, 1H), 3.81 (s, 3H), 3.14-2.91 ( m, 1H), 2.67-2.36 (m, 1H), 2.06-1.30 (m, 6H).

Example 308 (4-(1H-Pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-(1H-pyrazol-1-yl)nicotinic acid (Intermediate 82) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O - 478.2; obtained m/z, 479.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.70 (d, J =5.6 Hz, 1H), 8.50-8.46 (m, 1H), 8.42 (d, J = 2.6 Hz, 1H), 7.86 (d, J =1.6 Hz, 1H), 7.79 (d, J =5.5 Hz, 1H), 7.63-7.54 (m, 2H), 6.65-6.62(m, 1H), 5.76-5.70(m, 1H), 3.78(s, 3H), 3.75-3.67(m, 1H) , 2.97 (dd, J =16.3, 7.4 Hz, 1H), 2.29 (d, J =16.1 Hz, 1H), 1.93-1.17 (m, 6H).

Example 309 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-(1H-pyrazol-1-yl)picolinic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₆ O, 478.2; the resulting m/z, - 479.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.59-8.56 (m, 1H), 8.17-8.07 (m, 1H), 8.06-7.97 (m, 1H ), 7.87-7.83 (m, 1H), 7.68-7.46 (m, 3H), 6.61-6.54 (m, 1H), 5.80-5.71 (m , 1H), 4.32-4.21(m, 1H), 3.81(s, 3H), 3.09-2.97(m, 1H), 2.56-2.38(m, 1H ), 1.96-1.37 (m, 6H).

Example 310 (6-Methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4, 5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid (Intermediate 84) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O - 492.2; obtained m/z, 493.3 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d): 7.98 (d, J =2.5 Hz, 1H), 7.93-7.88 (m, 1H), 7.72-7.67 (m , 1H), 7.34-7.32 (m, 1H), 7.00-6.90 (m, 2H), 6.39-6.35 (m, 1H), 6.02-5.97 (m, 1H), 3.81 (s, 3H), 3.87-3.65 (m, 1H), 2.63 (s, 3H), 2.65-2.57 (m, 1H), 2.17 (d, J =16.1 Hz, 1H), 2.00-1.31 (m, 6H).

Example 311 (4-Methoxy-5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4, 5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-methoxy-5-(1H-pyrazol-1-yl)nicotinic acid (Intermediate 81) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₆ O ₂ - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.73 (d, J =2.3 Hz, 1H), 8.41 (d, J =2.3 Hz, 1H), 7.91-7 .87 (m, 1H), 7.69-7.66 (m, 1H), 7.59-7.51 (m, 2H), 6.46-6.43 (m, 1H), 5.74 -5.70 (m, 1H), 4.07-4.01 (m, 1H), 3.80 (s, 6H), 2.98 (dd, J =16.2, 7.4 Hz, 1H ), 2.48-2.43 (m, 1H), 1.85-1.57 (m, 3H), 1.51-1.32 (m, 3H).

Example 312 -trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 6-methyl-3-(1H-1,2,4-triazol-1-yl)picolinic acid (Intermediate 83) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₇ O - 493.2; obtained m/z, 494.2 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d): 8.61 (s, 1H), 8.07 (s, 1H), 7.89 (d, J =8.3 Hz, 1H), 7.38 ( d, J = 8.3 Hz, 1H), 7.00-6.91 (m, 2H), 6.00-5.95 (m, 1H), 3.82 (s, 3H), 3.80 -3.73 (m, 1H), 2.71 (dd, J =16.3, 7.2 Hz, 1H), 2.66 (s, 3H), 2.25 (d, J =16.0 Hz, 1H), 2.01-1.35 (m, 6H).

Example 313 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-(4H-1,2,4-triazol-4-yl)nicotinic acid (Intermediate 88) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₇ O - 479.2; obtained m/z, 480.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 9.25 (s, 2H), 9.10 (d, J =2.6 Hz, 1H), 8.69 (d, J =1.7 Hz , 1H), 8.27 (s, 1H), 7.65-7.54 (m, 2H), 5.77-5.72 (m, 1H), 4.11-4.00 (m, 1H ), 3.82 (s, 3H), 3.15-3.04 (m, 1H), 2.44 (d, J = 16.3 Hz, 1H), 2.11-1.37 (m, 6H).

Example 314 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 4-(4H-1,2,4-triazol-4-yl)picolinic acid (Intermediate 87) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₇ O - 479.2; obtained m/z, 480.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 9.41 (s, 2H), 8.74 (d, J =5.5 Hz, 1H), 8.06 (d, J =2.2 Hz , 1H), 7.93 (dd, J =5.5, 2.3 Hz, 1H), 7.62-7.53 (m, 2H), 5.81-5.73 (m, 1H), 4.19-4.10 (m, 1H), 3.81 (s, 3H), 3.01 (dd, J =15.8, 7.2 Hz, 1H), 2.53-2.44 ( m, 1H), 1.94-1.40 (m, 6H).

Example 315 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-methyl-4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 6-methyl-4-(4H-1,2,4-triazol-4-yl)picolinic acid (Intermediate 89) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₇ O - 493.2; obtained m/z, 494.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 9.38 (s, 2H), 7.95-7.77 (m, 2H), 7.66-7.48 (m, 2H), 5, 80-5.68 (m, 1H), 4.20-4.08 (m, 1H), 3.81 (s, 3H), 3.11-2.95 (m, 1H), 2.72- 2.58 (m, 1H), 2.56 (s, 3H), 2.12-1.33 (m, 6H).

Example 316 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-(triazol-2-yl)pyridine-3-carboxylic acid (Intermediate 90) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₇ O - 479.2; obtained m/z, 480.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 9.30 (d, J =2.5 Hz, 1H), 8.68 (d, J =1.9 Hz, 1H), 8.38-8 .33 (m, 1H), 8.23 (s, 2H), 7.63-7.54 (m, 2H), 5.75-5.69 (m, 1H), 4.12-4.04 (m, 1H), 3.79 (s, 3H), 3.06 (dd, J =16.3, 7.5 Hz, 1H), 2.41 (d, J =16.2 Hz, 1H) , 2.01-1.32 (m, 6H).

Example 317 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-(2H-1,2,3-triazol-2-yl)picolinic acid (Intermediate 85) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₇ O - 479.2; obtained m/z, 480.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.65 (dd, J =4.7, 1.4 Hz, 1H), 8.36 (dd, J =8.3, 1.5 Hz, 1H), 8.12 (s, 2H), 7.69 (dd, J =8.3, 4.7 Hz, 1H), 7.56-7.52 (m, 2H), 5.69-5 .65 (m, 1H), 3.89-3.84 (m, 1H), 3.81 (s, 3H), 2.80 (dd, J =15.9, 7.2 Hz, 1H), 2.44 (d, J =15.9 Hz, 1H), 1.96-1.34 (m, 6H).

Example 318 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-methyl-4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 6-methyl-4-(2H-1,2,3-triazol-2-yl)picolinic acid (Intermediate 86) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₇ O - 493.2; obtained m/z, 494.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.25 (s, 2H), 7.94 (d, J =1.9 Hz, 1H), 7.88 (d, J =1.9 Hz , 1H), 7.63-7.50 (m, 2H), 5.75-5.67 (m, 1H), 4.31-4.22 (m, 1H), 3.78 (s, 3H ), 3.00 (dd, J =16.0, 7.3 Hz, 1H), 2.57 (s, 3H), 2.49-2.41 (m, 1H), 1.92-1, 36 (m, 6H).

Example 319 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,5-dimethyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₂ F ₃ N ₅ O - 429.2; obtained m/z, 430.1 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform-d) δ 7.55-7.39 (m, 1H), 7.03-6.96 (m, 2H), 5.91 (br. s, 0.33H) , 5.34 (br.s, 0.55H), 5.15 (br.s, 0.57H), 4.58 (br.s, 0.36H), 3.85-3.74 (m, 6H), 3.23-2.91 (m, 1H), 2.51-2.31 (m, 4H), 2.06-1.44 (m, 6H).

Example 320 (5-Ethyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₄ F ₃ N ₅ O - 443.2; obtained m/z, 444.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.78 (s, 1H), 7.63-7.47 (m, 2H), 5.70-5.52 (m, 1H), 4, 44-4.26 (m, 1H), 3.76 (s, 3H), 3.75-3.70 (m, 3H), 3.10-2.93 (m, 1H), 2.64- 2.38 (m, 3H), 1.89-1.51 (m, 4H), 1.47-1.29 (m, 2H), 1.14-0.98 (m, 3H).

Example 321 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₄ F ₃ N ₅ O - 443.2; obtained m/z, 444.1 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform- d ) δ 6.99 (br.s, 2H), 5.93 (br.s, 0.31H), 5.20 (br.s, 0.60H), 4 .97 (br.s, 0.57H), 4.22 (br.s, 0.33H), 3.80 (s, 3H), 3.70 (s, 3H), 3.22-3.10 (m, 0.58H), 2.86 (br. s, 0.36H), 2.49-2.35 (m, 1.34H), 2.31-2.09 (m, 5.45H) , 2.02-1.39 (m, 6.35H).

Example 322 (5-Methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₂ F ₃ N ₅ O ₂ - 445.2; obtained m/z, 446.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.63-7.56 (m, 2H), 7.44 (s, 1H), 5.65-5.56 (m, 1H), 4, 43-4.36 (m, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.56 (s, 3H), 3.14 (dd, J =16.3, 7.5 Hz, 1H), 2.42 (d, J =16.4 Hz, 1H), 1.80-1.33 (m, 6H).

Example 323 (3-Methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₂ F ₃ N ₅ O ₂ - 445.2; obtained m/z, 446.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.76 (s, 1H), 7.60-7.46 (m, 2H), 5.60-5.46 (m, 1H), 4, 34-4.21(m, 1H), 3.79(s, 3H), 3.75(s, 3H), 3.67(s, 3H), 3.02-2.87(m, 1H) , 2.54-2.41 (m, 1H), 1.79-1.52 (m, 4H), 1.50-1.29 (m, 2H).

Example 324 (3-Fluoro-1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 3-fluoro-1,5-dimethyl-1H-pyrazole-4-carboxylic acid (Intermediate 91) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₁ F ₄ N ₅ O - 447.2; obtained m/z, 448.1 [M+H] ⁺ . ¹ H NMR (500 MHz, Chloroform- d ) δ 7.03-6.96 (m, 2H), 5.91 (br. s, 0.32H), 5.18-5.01 (m, 1, 20H), 4.30 (br. s, 0.32H), 3.81 (br. s, 3H), 3.68 (s, 3H), 3.24-2.92 (m, 1H), 2 .49-2.37 (m, 1H), 2.33-2.20 (m, 3H), 2.01-1.76 (m, 3.20H), 1.76-1.41 (m, 3H).

Example 325 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₂₀ F ₅ N ₅ O - 465.2; obtained m/z, 466.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 7.76 (s, 1H), 7.69-7.51 (m, 2H), 7.27 (t, J =52.6 Hz, 1H) , 5.76-5.57 (m, 1H), 4.36-4.20 (m, 1H), 3.98 (s, 3H), 3.80 (s, 3H), 3.14 (dd , J =16.3, 7.2 Hz, 1H), 2.69-2.32 (m, 1H), 2.01-1.30 (m, 6H).

Example 326 (1-Cyclopropyl-5-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 1-cyclopropyl-5-methyl-pyrazole-4-carboxylic acid (Intermediate 92) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.63-7.52 (m, 2H), 7.46 (s, 1H), 5.66-5.51 (m, 1H), 4, 46-4.27(m, 1H), 3.77(s, 3H), 3.55-3.46(m, 1H), 3.14-2.96(m, 1H), 2.45- 2.27 (m, 1H), 2.36 (s, 3H), 1.94-1.52 (m, 4H), 1.50-1.30 (m, 2H), 1.09-0, 94 (m, 4H).

Example 327 (1-Cyclopropyl-3-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 1-cyclopropyl-3-methyl-pyrazole-4-carboxylic acid (Intermediate 93) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.86 (s, 1H), 7.61-7.48 (m, 2H), 5.68-5.53 (m, 1H), 4, 42-4.22(m, 1H), 3.77(s, 3H), 3.70-3.58(m, 1H), 3.11-2.94(m, 1H), 2.57- 2.38 (m, 1H), 2.13 (s, 3H), 1.93-1.53 (m, 4H), 1.49-1.30 (m, 2H), 1.07-0, 97 (m, 2H), 0.94-0.85 (m, 2H).

Example 328 (3-Cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.75 (s, 1H), 7.61-7.47 (m, 2H), 5.70-5.56 (m, 1H), 4, 44-4.26(m, 1H), 3.76(s, 3H), 3.70(s, 3H), 3.07-2.93(m, 1H), 2.65-2.30( m, 1H), 2.00-1.54 (m, 5H), 1.50-1.29 (m, 2H), 0.84-0.64 (m, 4H).

Example 329 Indolizin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and indolizine-7-carboxylic acid (Intermediate 79) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₁ F ₃ N ₄ O - 450.2; obtained m/z, 451.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) : 8.29 (d, J =7.1 Hz, 1H), 7.73-7.45 (m, 4H), 6.90-6.74 ( m, 1H), 6.66-6.42 (m, 2H), 5.74-5.51 (m, 1H), 4.46-4.20 (m, 1H), 3.80 (s, 3H), 3.10 (dd, J =16.6, 7.4 Hz, 1H), 2.63-2.33 (m, 1H), 2.06-1.33 (m, 6H).

Example 330 (4-Fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ F ₄ N ₅ O - 469.2; obtained m/z, 470.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.68 (d, J =7.0 Hz, 1H), 8.20 (d, J =47.2 Hz, 1H), 7.60 (t , J = 7.8 Hz, 2H), 7.26 (dd, J = 10.6, 7.7 Hz, 1H), 7.01 (d, J = 6.3 Hz, 1H), 5.81 -5.65(m, 1H), 5.15-4.16(m, 1H), 3.84-3.65(m, 3H), 3.13-3.01(m, 1H), 2 .46-2.22 (m, 1H), 1.99-1.36 (m, 6H).

Example 331 (6-Fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ F ₄ N ₅ O - 469.1; obtained m/z, 470.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.18-9.08 (m, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.67-7, 47 (m, 3H), 5.75-5.34 (m, 1H), 5.04-4.62 (m, 1H), 3.79 (s, 3H), 3.23-3.02 ( m, 1H), 2.61-2.52 (m, 1H), 2.01-1.37 (m, 6H).

Example 332 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-methylpyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.30 (s, 1H), 7.77 (s, 1H), 7.60 (t, J =7.7 Hz, 2H), 7.38 (dd, J =8.9, 6.9 Hz, 1H), 7.04-6.93 (m, 1H), 5.77-5.33 (m, 1H), 5.04-4.51 (m, 1H), 3.79 (s, 3H), 3.25-3.12 (m, 1H), 2.72 (s, 3H), 2.59-2.51 (m, 1H), 2.05-1.36 (m, 6H).

Example 333 (4-Methoxypyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 4-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O ₂ - 481.2; obtained m/z, 482.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.34 (dd, J =9.4, 6.8 Hz, 1H), 7.98 (s, 1H), 7.65-7.51 ( m, 2H), 6.93-6.84 (m, 1H), 6.67 (dd, J =26.1, 7.7 Hz, 1H), 5.80-5.10 (m, 1H) , 4.64-3.91(m, 1H), 3.83-3.42(m, 6H), 3.14-2.72(m, 1H), 2.37(d, J =16, 0 Hz, 1H), 1.91-1.34 (m, 6H).

Example 334 (6-Methoxypyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O ₂ - 481.1; obtained m/z, 482.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.51 (dd, J =2.3, 0.8 Hz, 1H), 8.19 (s, 1H), 7.79 (d, J = 9.8 Hz, 1H), 7.61 (t, J =7.9 Hz, 2H), 7.23 (dd, J =9.6, 2.2 Hz, 1H), 5.77-5, 35 (m, 1H), 5.04-4.59 (m, 1H), 3.85 (s, 3H), 3.81-3.73 (m, 3H), 3.28-3.12 ( m, 2H), 2.00-1.38 (m, 6H).

Example 335 Imidazo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,5-a]pyridine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.51-8.43 (m, 1H), 8.42-8.31 (m, 1H), 7.72-7.54 (m, 3H ), 7.53-7.42(m, 1H), 6.74-6.55(m, 1H), 5.73-5.55(m, 1H), 4.43-4.13(m , 1H), 3.81 (s, 3H), 3.16-3.02 (m, 1H), 2.64-2.33 (m, 1H), 2.05-1.34 (m, 6H ).

Example 336 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methylimidazo[1,5-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methylimidazo[1,5-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.38 (s, 1H), 7.63-7.53 (m, 2H), 7.51 (d, J =9.1 Hz, 1H) , 7.47 (s, 1H), 6.62 (d, J =9.2 Hz, 1H), 5.77-5.72 (m, 1H), 3.98-3.93 (m, 1H ), 3.79 (s, 3H), 2.95 (dd, J =16.1, 7.3 Hz, 1H), 2.59 (s, 3H), 2.54 (dd, J =16, 3, 6.9 Hz, 1H), 1.90-1.32 (m, 6H).

Example 337 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methylimidazo[1,5-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methylimidazo[1,5-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.46-8.37 (m, 1H), 7.78-7.55 (m, 4H), 7.00-6.93 (m, 1H ), 5.72-5.66 (m, 1H), 4.25-4.17 (m, 1H), 3.82 (s, 3H), 3.11-3.04 (m, 1H), 2.74 (s, 3H), 2.57-2.40 (m, 1H), 1.93-1.37 (m, 6H).

Example 338 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methylimidazo[1,2-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methylimidazo[1,2-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.93-7.91 (m, 1H), 7.69-7.67 (m, 1H), 7.63-7.57 (m, 2H ), 7.57-7.45 (m, 1H), 7.07 (d, J =9.1 Hz, 1H), 5.80-5.72 (m, 1H), 3.96-3, 88 (m, 1H), 3.79 (s, 3H), 2.96 (dd, J =16.2, 7.3 Hz, 1H), 2.61 (s, 3H), 2.44-2 .35 (m, 1H), 1.94-1.52 (m, 4H), 1.51-1.33 (m, 2H).

Example 339 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-methylimidazo[1,2-a]pyridin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 7-methylimidazo[1,2-a]pyridine-5-carboxylic acid (Intermediate 95) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.70-7.50 (m, 3H), 7.58-7.53 (m, 1H), 7.47-7.44 (m, 1H ), 6.89-6.86 (m, 1H), 5.83-5.74 (m, 1H), 4.09-3.99 (m, 1H), 3.83 (s, 3H), 3.07-2.93 (m, 1H), 2.61-2.44 (m, 1H), 2.38 (s, 3H), 2.10-1.34 (m, 6H).

Example 340 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methylimidazo[1,2-a]pyridin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methylimidazo[1,2-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.71-7.61 (m, 2H), 7.61-7.52 (m, 1H), 7.47 (s, 1H), 7. 20 (dd, J =9.0, 6.8 Hz, 1H), 6.95 (dd, J =6.9, 1.2 Hz, 1H), 5.90-5.78 (m, 1H) , 4.27-4.11 (m, 1H), 3.83 (s, 3H), 3.21 (dd, J =16.1, 7.4 Hz, 1H), 2.55-2.39 (m, 1H), 2.13-1.37 (m, 6H), 1.92 (s, 3H).

Example 341 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methylimidazo[1,2-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methylimidazo[1,2-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.4 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.45-8.36 (m, 1H), 7.70-7.53 (m, 3H), 7.49-7.43 (m, 1H ), 7.30-7.10 (m, 1H), 5.78-5.65 and 5.09-4.92 (m, 1H), 4.31-4.19 and 3.86-3, 73 (m, 1H), 3.84 (s, 3H), 3.18-3.03 (m, 1H), 2.62-2.35 (m, 4H), 2.15-1.31 ( m, 6H).

Example 342 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-a]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.66 (s, 1H), 7.78-7.69 (m, 1H), 7.64-7.56 (m, 3H), 7. 52-7.42 (m, 1H), 5.71-5.61 (m, 1H), 4.30-4.19 (m, 1H), 3.81 (s, 3H), 3.09 ( dd, J =16.3, 7.4 Hz, 1H), 2.54-2.42 (m, 1H), 2.34 (s, 3H), 1.93-1.37 (m, 6H) .

Example 343 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-a]pyridin-5-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.64-7.49 (m, 4H), 7.22-7.17 (m, 1H), 6.96-6.91 (m, 1H ), 5.79-5.72 (m, 1H), 4.07-4.00 (m, 1H), 3.80 (s, 3H), 3.07-2.93 (m, 1H), 2.46-2.39 (m, 1H), 2.32 (s, 3H), 2.05-1.34 (m, 6H).

Example 344 Imidazo[1,2-a]pyridin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92-8.85 (m, 1H), 8.05 (s, 1H), 7.77-7.69 (m, 1H), 7, 62 (dd, J =8.8, 6.7 Hz, 2H), 7.50-7.37 (m, 1H), 7.12-7.05 (m, 1H), 5.74-5, 60 (m, 1H), 5.03-4.80 (m, 1H), 3.80 (s, 3H), 3.30-3.14 (m, 1H), 2.59-2.52 ( m, 1H), 2.05-1.43 (m, 6H).

Example 345 (7-Fluorimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and potassium 7-fluoroimidazo[1,2-a]pyridine-3-carboxylate (Intermediate 96) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ F ₄ N ₅ O - 469.2; obtained m/z, 470.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.93 (dd, J =7.7, 5.9 Hz, 1H), 8.05 (s, 1H), 7.70-7.53 ( m, 3H), 7.21-6.99 (m, 1H), 5.81-5.48 (m, 1H), 5.07-4.81 (m, 1H), 3.80 (s, 3H), 2.65-2.51 (m, 2H), 2.06-1.41 (m, 6H).

Example 346 (7-Chlorimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-chloroimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ ClF ₃ N ₅ O - 485.1; obtained m/z, 486.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.65-8.54 (m, 1H), 8.35 (dd, J =3.1, 0.8 Hz, 1H), 7.91- 7.77 (m, 1H), 7.63-7.50 (m, 2H), 7.15-7.01 (m, 1H), 5.81-5.57 (m, 1H), 3. 82-3.70 (m, 3H), 3.25-2.95 (m, 2H), 2.60-2.52 (m, 1H), 2.03-1.40 (m, 6H).

Example 347 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-a]pyridin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N _{5 O} - 465.5; obtained m/z, 467.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.39 (s, 1H), 7.67-7.51 (m, 3H), 7.41-7.27 (m, 1H), 6, 96 (t, J =6.9 Hz, 1H), 5.62-5.12 (m, 1H), 3.80 (s, 3H), 3.22-2.99 (m, 2H), 2 .37 (s, 3H), 2.01-1.35 (m, 7H).

Example 348 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₄ F ₃ N ₅ O - 479.2; obtained m/z, 480.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.28 (s, 1H), 7.59 (dd, J =8.7, 6.6 Hz, 2H), 7.40-7.27 ( m, 1H), 6.86-6.73 (m, 1H), 5.52-5.06 (m, 1H), 4.77-4.32 (m, 1H), 3.79 (s, 3H), 3.18-3.01 (m, 1H), 2.55 (s, 1H), 2.40-2.29 (m, 6H), 1.99-1.37 (m, 6H) .

Example 349 ((5R,9S)-3-(3-Fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 63) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₆ FN ₅ O - 443.2; obtained m/z, 444.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.39 (s, 1H), 7.61-7.51 (m, 1H), 7.40-7.30 (m, 1H), 7, 18 (d, J =10.3 Hz, 2H), 7.11 (d, J =9.8 Hz, 1H), 6.96 (t, J =6.8 Hz, 1H), 5.49- 4.80 (m, 1H) 3.78 (s, 3H), 3.22-2.91 (m, 2H), 2.63-2.52 (m, 1H), 2.41-2.30 (m, 6H), 1.95-1.37 (m, 6H).

Example 350 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and lithium 5-methylimidazo[1,2-a]pyridine-3-carboxylate instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.95 (s, 1H), 7.72-7.53 (m, 3H), 7.37 (dd, J =9.0, 6.8 Hz, 1H), 6.90 (d, J = 6.9 Hz, 1H), 5.83-5.69 (m, 1H), 5.13-4.52 (m, 1H), 3.88 -3.69 (m, 3H), 3.23-3.01 (m, 1H), 2.65-2.56 (m, 1H), 2.53-2.48 (m, 3H),1 .93-1.37 (m, 6H).

Example 351 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₁₉ F ₆ N ₅ O - 519.5; obtained m/z, 520.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.03 (d, J = 7.3 Hz, 1H), 8.29-8.16 (m, 2H), 7.63 (t, J = 7.7 Hz, 2H), 7.35 (dd, J = 7.4, 2.0 Hz, 1H), 5.81-5.48 (m, 1H), 5.07-4.72 (m , 1H), 3.81 (s, 3H), 2.63-2.54 (m, 1H), 2.07-1.92 (m, 1H), 1.91-1.41 (m, 6H ).

Example 352 (2-(Difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(difluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₀ F ₅ N ₅ O - 501.2; obtained m/z, 502.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.28 (d, J =174.0 Hz, 1H), 7.81-7.68 (m, 1H), 7.62-7.42 ( m, 3H), 7.36-6.89 (m, 2H), 5.75 (s, 1H), 5.35-4.45 (m, 1H), 3.79 (s, 3H), 3 .27-2.75 (m, 2H), 2.11-1.31 (m, 6H).

Example 353 (2-Methyl-2H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methyl-2H-indazole-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.73-7.55 (m, 3H), 7.35-7.13 (m, 2H), 5.78 (s, 1H), 5, 23-4.71 (m, 1H), 4.22-4.00 (m, 3H), 3.87-3.72 (m, 3H), 3.24-2.57 (m, 2H), 2.33-2.02 (m, 1H), 2.11-1.33 (m, 6H).

Example 354 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,7-dimethylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₃ N ₆ O - 480.2; obtained m/z, 481.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.61-7.53 (m, 2H), 7.03-7.01 (m, 1H), 6.56 (s, 1H), 5, 71-5.67 (m, 1H), 4.31-4.25 (m, 1H), 3.78 (s, 3H), 2.98 (dd, J =16.1, 7.3 Hz, 1H), 2.70 (s, 3H), 2.51-2.45 (m, 1H), 2.43 (s, 3H), 1.90-1.33 (m, 6H).

Example 355 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.43-8.34 (m, 1H), 8.30 (d, J =2.2 Hz, 1H), 7.67-7.52 ( m, 2H), 6.80 (d, J =2.3 Hz, 1H), 5.79-5.74 (m, 1H), 4.10-4.04 (m, 1H), 3.80 (s, 3H), 3.21-3.02 (m, 1H), 2.82-2.71 (m, 3H), 2.57 (d, J =16.3 Hz, 1H), 2, 01-1.30 (m, 6H).

Example 356 (5-Isopropyl-3-methylpyrazolo[1,5-a]pyrimidin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-isopropyl-3-methylpyrazolo[1,5-a]pyrimidine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₇ F ₃ N ₆ O - 508.2; obtained m/z, 509.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.15 (s, 1H), 7.61-7.50 (m, 2H), 6.98 (s, 1H), 5.75-5, 70 (m, 1H), 4.42-4.36 (m, 1H), 3.78 (s, 3H), 3.76-3.67 (m, 1H), 3.12-3.01 ( m, 1H), 2.52-2.42 (m, 1H), 2.26 (s, 3H), 1.93-1.41 (m, 6H), 1.36 (d, J =7, 1 Hz, 6H).

Example 357 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2,3,5-trimethylpyrazolo[1,5-a]pyrimidin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,3,5-trimethylpyrazolo[1,5-a]pyrimidine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₃ N ₆ O - 494.2; obtained m/z, 495.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.63-7.54 (m, 2H), 6.73 (s, 1H), 5.77-5.69 (m, 1H), 3, 79 (s, 3H), 3.68-3.62 (m, 1H), 2.90 (dd, J =16.3, 7.3 Hz, 1H), 2.55-2.45 (m, 3H), 2.40 (d, J =16.2 Hz, 1H), 2.33 (s, 3H), 2.16 (s, 3H), 1.97-1.67 (m, 3H), 1.59-1.30 (m, 3H).

Example 358 (7-Cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₅ F ₃ N ₆ O - 506.2; obtained m/z, 507.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 7.62-7.52 (m, 2H), 6.89 (s, 1H), 6.34 (s, 1H), 5.77-5, 72 (m, 1H), 3.79 (s, 3H), 3.78-3.65 (m, 1H), 2.92 (dd, J =16.7, 7.4 Hz, 1H), 2 .46-2.35 (m, 1H), 2.36 (s, 3H), 2.21-2.01 (m, 1H), 1.96-1.33 (m, 6H), 1.09 -0.97 (m, 4H).

Example 359 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epiminecycloocta[c]pyrazole (intermediate 1) and 2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.18-9.00 (m, 1H), 8.66-8.50 (m, 1H), 7.68-7.49 (m, 2H ), 7.19-6.91 (m, 1H), 5.88-5.00 (m, 1H), 4.94-4.13 (m, 1H), 3.91-3.67 (m , 3H), 3.15-2.94 (m, 1H), 2.47-2.30 (m, 4H), 1.92-1.34 (m, 6H).

Example 360 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylpyrazolo[1,5-b]pyridazin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylpyrazolo[1,5-b]pyridazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.46 (dd, J =4.5, 1.9 Hz, 1H), 8.06 (s, 1H), 7.59 (dd, J = 8.7, 6.6 Hz, 2H), 7.29 (dd, J =9.0, 4.5 Hz, 1H), 5.79-4.85 (m, 1H), 4.28-3 .94 (m, 1H), 3.80 (s, 3H), 3.21-2.66 (m, 2H), 2.42 (s, 3H), 2.00-1.35 (m, 6H ).

Example 361 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-a]pyrazin-8-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyrazine-8-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.53 (d, J =4.5 Hz, 1H), 7.96-7.92 (m, 1H), 7.79 (d, J = 4.5 Hz, 1H), 7.55-7.46 (m, 2H), 5.80-5.72 (m, 1H), 3.79 (s, 3H), 3.81-3.75 (m, 1H), 2.85 (dd, J =16.0, 7.4 Hz, 1H), 2.41-2.38 (m, 1H), 2.37 (s, 3H), 1, 92-1.68 (m, 3H), 1.56-1.35 (m, 3H).

Example 362 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2,5,8-trimethylimidazo[1,2-a]pyrazin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and potassium 2,5,8-trimethylimidazo[1,2-a]pyrazine-3-carboxylate (Intermediate 98) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₅ F ₃ N ₆ O - 494.2; obtained m/z, 495.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.71-7.48 (m, 3H), 5.89-5.74 (m, 0.5H), 5.25-4.65 (m , 1H), 4.26-4.09 (m, 0.5H), 3.88-3.64 (m, 3H), 3.27-2.78 (m, 2H), 2.73-2 .54 (m, 5H), 2.48-2.38 (m, 1H), 2.36-2.20 (m, 1H), 2.14-2.05 (m, 1H), 2.03 -1.97 (m, 1H), 1.92-1.40 (m, 6H).

Example 363 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.1 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.52 (d, J =4.4 Hz, 1H), 8.14-8.03 (m, 1H), 7.66-7.52 ( m, 2H), 7.33-7.20 (m, 1H), 5.82-5.07 (m, 1H), 4.60-3.99 (m, 1H), 3.85-3, 70 (m, 3H), 2.97-2.84 (m, 1H), 2.48-2.22 (m, 4H), 1.96-1.39 (m, 6H).

Example 364 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and potassium 2,7-dimethylimidazo[1,2-b]pyridazine-3-carboxylate (Intermediate 97) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₃ F ₃ N ₆ O - 480.2; obtained m/z, 481.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (d, J =2.0 Hz, 1H), 7.87 (d, J =10.7 Hz, 1H), 7.65-7 .50 (m, 2H), 5.85-5.70 (m, 1H), 5.16-4.49 (m, 1H), 3.82 (s, 3H), 3.74 (s, 1H ), 3.20-3.13 (m, 1H), 2.42-2.33 (m, 5H), 2.31-2.21 (m, 1H), 1.95-1.39 (m , 6H).

Example 365 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic -(5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.45 (s, 1H), 8.43-8.37 (m, 1H), 7.55-7.49 (m, 2H), 7. 21 (d, J = 4.8 Hz, 1H), 5.84-5.76 (m, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.77-3 .72 (m, 1H), 2.88 (dd, J =16.1, 7.3 Hz, 1H), 2.34 (d, J =15.9 Hz, 1H), 1.95-1, 65 (m, 3H), 1.55-1.29 (m, 3H).

Example 366 ((5R,9S)-2-Methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.2 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.51 (s, 1H), 8.44 (d, J =1.9 Hz, 1H), 8.13 (d, J =1.9 Hz , 1H), 7.65-7.54 (m, 2H), 5.74-5.67 (m, 1H), 4.11-4.03 (m, 1H), 3.85 (s, 3H ), 3.79 (s, 3H), 3.09 (dd, J =16.2, 7.4 Hz, 1H), 2.39-2.32 (m, 1H), 2.01-1, 32 (m, 6H).

Example 367 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.3 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ): 8.79 (s, 1H), 7.67 (d, J =3.5 Hz, 1H), 7.56-7.52 (m, 2H) , 6.54 (d, J =3.5 Hz, 1H), 5.80-5.76 (m, 1H), 4.06-4.00 (m, 1H), 3.82 (s, 3H ), 3.79 (s, 3H), 2.87 (dd, J =16.1, 7.3 Hz, 1H), 2.43 (d, J =16.1 Hz, 1H), 1.95 -1.35 (m, 6H).

Example 368 (1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and 1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (Intermediate 94) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.2 [M+H]+. ¹ H NMR (300 MHz, DMSO- d ₆ ): 8.64 (d, J =4.8 Hz, 1H), 8.16 (s, 1H), 7.71-7.50 (m, 2H) , 7.23 (d, J =4.6 Hz, 1H), 5.86-5.75 (m, 1H), 4.10 (s, 3H), 3.89-3.77 (m, 1H ), 3.82 (s, 3H), 2.92 (dd, J =16.3, 7.3 Hz, 1H), 2.39 (d, J =17.0 Hz, 1H), 2.09 -1.28 (m, 6H).

Example 369 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ F ₃ N ₇ O - 467.2; obtained m/z, 468.1 [M+H]+. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.08 (d, J =16.1 Hz, 1H), 8.35 (d, J =32.4 Hz, 1H), 7.69-7 .49 (m, 2H), 5.81 (s, 1H), 5.22-4.96 (m, 1H), 4.14-4.05 (m, 3H), 3.77 (d, J =33.1 Hz, 3H), 3.23-3.09 (m, 1H), 3.03-2.89 (m, 1H), 2.00-1.41 (m, 6H).

Example 370 [1,2,4]Triazolo[4,3-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and [1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O - 452.2; obtained m/z, 453.1 [M+H]+. ¹ H NMR (300 MHz, DMSO- d ₆ ): 9.32 (s, 1H), 8.68-8.59 (m, 1H), 7.89-7.81 (m, 1H), 7. 68-7.54 (m, 2H), 7.04-6.96 (m, 1H), 5.75-5.65 (m, 1H), 4.19-4.07 (m, 1H), 3.82 (s, 3H), 3.11 (dd, J =16.2, 7.4 Hz, 1H), 2.42 (d, J =16.9 Hz, 1H), 2.06-1 .36 (m, 6H).

Example 371 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(3-methylimidazo[1,5-a]pyrazin-1-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and sodium 3-methylimidazo[1,5-a]pyrazine-1-carboxylate (Intermediate 99) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ F ₃ N ₆ O - 466.2; obtained m/z, 467.1 [M+H]+. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 9.38 (s, 1H), 8.14 (s, 1H), 7.70 (d, J =5.1 Hz, 1H), 7.33 (t, J =7.3 Hz, 2H), 5.94 (s, 1H), 3.89-3.76 (m, 3H), 2.74 (d, J =12.1 Hz, 3H) , 2.61 (t, J =15.8 Hz, 1H), 2.30-1.51 (m, 8H).

Example 372 ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 63) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and quinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₅ FN ₄ O - 440.2; obtained m/z, 441.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.02-8.93 (m, 1H), 8.48 (d, J =8.3 Hz, 1H), 8.15-8.04 ( m, 2H), 7.83-7.68 (m, 1H), 7.65-7.52 (m, 1H), 7.25-7.04 (m, 3H), 5.82-5, 01 (m, 1H), 4.91-3.99 (m, 1H), 3.86-3.66 (m, 3H), 3.14-3.00 (m, 1H), 2.48- 2.31 (m, 4H), 2.07-1.36 (m, 6H).

Example 373 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(4-methylquinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 4-methylquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₃ F ₃ N ₄ O - 476.2; obtained m/z, 477.0 [M+H]+. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.82 (dd, J = 8.0, 4.4 Hz, 1H), 8.16-8.02 (m, 2H), 7.82- 7.66 (m, 1H), 7.66-7.39 (m, 3H), 5.83-4.82 (m, 1H), 4.17-4.01 (m, 1H), 3. 88-3.63 (m, 3H), 3.15-2.98 (m, 1H), 2.76-2.65 (m, 3H), 2.47-2.37 (m, 1H), 2.06-1.42 (m, 6H).

Example 374 10-yl)(2-hydroxyquinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole (intermediate 12) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole (intermediate 1) and 2-hydroxyquinoline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O ₂ - 460.5; obtained m/z, 461.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 11.99-11.80 (m, 1H), 8.01-7.93 (m, 1H), 7.77 (d, J =10.0 Hz, 1H), 7.54 (dd, J =25.0, 8.5 Hz, 1H), 7.39-7.27 (m, 4H), 6.55 (d, J =9.5 Hz , 1H), 5.75-5.61 (m, 1H), 5.05-4.78 (m, 1H), 3.89-3.70 (m, 3H), 3.19-3.04 (m, 1H), 2.49-2.43 (m, 1H), 2.04-1.40 (m, 6H).

Example 375 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazole-10-carbonyl) quinoline 1-oxide.

To an ice-cold solution of ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl)(quinolin-6-yl)methanone (Example 97, 150 mg, 0.34 mmol) in DCM (6.0 ml) was added in portions of meta -chloroperoxybenzoic acid (m-CPBA or m- CPBA) (87.4 mg, 0.51 mmol) at 0 ºC for 10 minutes and the mixture was slowly warmed to room temperature. After stirring for 1 h, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted with DCM (2x). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC on an XBridge C18 column (5 μm, 100×4.6 mm), mobile phase 10-100% ACN in 20 mM NH ₄ OH to give the title compound as a white solid (111 mg , 71% yield. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₂ N ₄ O ₂ - 460.5; obtained m/z, 461.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.68-8.52 (m, 2H), 8.18 (dd, J =11.0, 1.7 Hz, 1H), 8.03 ( dd, J =8.6, 4.5 Hz, 1H), 7.89-7.71(m, 1H), 7.59-7.49(m, 1H), 7.41-7.25( m, 3H), 5.84-4.72 (m, 2H), 3.80 (d, J =48.8 Hz, 3H), 3.20-3.03 (m, 1H), 2.46 (d, J =16.2 Hz, 1H), 2.06-1.37 (m, 6H).

Example 376 10-yl)(quinolin-6-yl-4-t) methanone.

(4-Bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone (Example 101, 10 mg, 0.02 mmol), methanol (1.5 ml) and Pd/C (8 mg, 0.008 mmol). The mixture was stirred at room temperature for 2 hours under a 1 atm tritium gas atmosphere. The solvent was removed in vacuo, the residue was taken up in ethanol and filtered. Unstable tritium was removed using a rotary evaporator (3x) and the crude material was purified on a HPLC-C-18 column using (gradient A=water and B=ACN: A->100% B over 60 min, UV=254 nM, flow=6 ml/min). The product was analyzed as having a specific activity=10.8 Ci/mmol and packaged in ethanol (1 mCi/ml). MS (ESI): mass calculated for C ₂₆ H ₂₁ TF ₂ N ₄ O - 446.2; obtained m/z, 446.9 [M+H]+.

Example 377 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(6-methylquinazolin-4-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 6-methylquinazoline-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N _{5 O} - 477.2; obtained m/z, 478.2 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.26 (d, J=18.2 Hz, 1H), 8.04-7.90 (m, 2H), 7.70-7.54 ( m, 3H), 5.97-4.30 (m, 3H), 3.77 (m, 2H), 2.87-2.60 (m, 1H), 2.52 (d, J=1, 0 Hz, 2H), 2.48-2.44 (m, 2H), 2.09-1.40 (m, 6H).

Example 378 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinoxalin-6-yl-2-d) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and lithium quinoxaline-6-carboxylic acid-2- d acid (Intermediate 102) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₁₉ DF ₃ N ₅ O - 464.2; obtained m/z, 465.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.09-8.99 (m, 1H), 8.20 (dd, J =14.5, 8.5 Hz, 1H), 8.09 ( dd, J =42.7, 1.9 Hz, 1H), 7.94-7.74(m, 1H), 7.66-7.55(m, 2H), 5.83-4.74( m, 1H), 4.16-4.03 (m, 1H), 3.86-3.66 (m, 3H), 3.18-3.04 (m, 1H), 2.45-2, 36 (m, 1H), 2.01-1.35 (m, 6H).

Example 379 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(quinoxalin-6-yl-2,3-d2) methanone.

.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and lithium quinoxaline-6-carboxylic acid-2,3- d ₂ acid (Intermediate 101) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₁₈ D ₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.0 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.20 (dd, J =14.4, 8.5 Hz, 1H), 8.09 (dd, J =42.7, 1.9 Hz, 1H), 7.95-7.77 (m, 1H), 7.67-7.55 (m, 2H), 5.81-5.75 and 5.16-4.79 (m, 1H), 4.14-4.04 (m, 1H), 3.85-3.72 (m, 3H), 3.15-3.00 (m, 1H), 2.48-2.33 (m, 1H ), 2.06-1.36 (m, 6H).

Example 380 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₆ F ₃ N ₅ O - 469.2; obtained m/z, 470.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.61 (d, J =54.4 Hz, 2H), 7.22 (s, 1H), 5.71-5.34 (m, 1H) , 4.89-4.52(m, 2H), 3.80(s, 3H), 2.87-2.52(m, 3H), 2.18-1.55(m, 8H), 1 .54-0.76 (m, 6H).

Example 381 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (intermediate 1) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.1 [M+H]+. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.70-7.53 (m, 2H), 7.20 (s, 1H), 5.72-5.36 (m, 1H), 4, 98-4.48 (m, 1H), 4.06 (dd, J =13.1, 6.9 Hz, 1H), 3.93 (s, 1H), 3.79 (s, 3H), 3 .29-2.93 (m, 2H), 2.84-2.71 (m, 2H), 1.94-1.69 (m, 6H), 1.69-1.59 (m, 2H) , 1.54-1.37 (m, 2H).

Example 382 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl)(2,6,6-trimethyl-6,7-dihydro-4H-pyrazol[5,1-c][1,4]oxazin-3-yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (intermediate 25) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazole (Intermediate 1) and potassium ) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₈ F ₃ N ₅ O ₂ - 499.2; obtained m/z, 500.1 [M+H]+. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.64-7.48 (m, 2H), 5.78-5.16 (m, 1H), 4.67 (t, J =15.9 Hz, 2H), 3.88 (s, 2H), 3.79 (s, 3H), 3.26-2.62 (m, 2H), 2.47 (s, 1H), 2.12 (s , 3H), 1.74 (d, J =33.5 Hz, 3H), 1.63-1.31 (m, 3H), 1.26 (d, J =2.6 Hz, 6H).

Example 383 (3-chlorophenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-chlorobenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₇ ClF ₃ N ₃ O - 431.1; obtained m/z, 432.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.27 (m, 4H), 7.02-6.88 (m, 2H), 5.84-3.96 (m, 2H), 3.78 (d, J= 21.8 Hz, 3H), 3.39-3.23 (m, 1H), 2.44-2.14 (m, 3H), 2.14-1.91 ( m, 1H), 1.76-1.59 (m, 1H).

Example 384 (3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ F ₃ N ₃ O ₂ - 427.2; obtained m/z, 428.1 [M+H]+. ¹ H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 1H), 7.15-6.91 (m, 5H), 5.80-5.13 (m, 1H), 5 .13-4.35 (m, 1H), 3.88-3.74 (m, 6H), 3.36-2.84 (m, 1H), 2.45-2.11 (m, 3H) , 2.11-1.93 (m, 1H), 1.74-1.59 (m, 1H).

Example 385 ((5R,8S)-3-(2,5-difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9- yl)(3-methoxyphenyl)methanone.

Microwave vial with ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-3 -yl trifluoromethanesulfonate (intermediate 108) (20 mg, 0.045 mmol), 2,5-difluorophenylboronic acid (9 mg, 0.054 mmol), sodium carbonate (14 mg, 0.135 mmol) and XPhos Pd G2 (4 mg, 0.005 mmol) in 1,4-dioxane (2 ml) and water (0.5 ml) were purged with N ₂ for 5 min. The resulting mixture was heated in a microwave reactor for 30 minutes at a temperature of 110 ºC. The completed reaction was diluted with water and extracted into DCM (x3). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification (reverse phase HPLC on an XBridge C18 column (5 mm, 100 x 4.6 mm), mobile phase 10-100% ACN in 20 mM NH ₄ OH) afforded the title compound (4.3 mg, 23%). MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₂ N ₃ O ₂ - 409.2; obtained m/z, 410.0 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.36-7.28 (m, 1H), 7.23-6.90 (m, 6H), 5.87-5.11 (m, 1H), 5.10-4.30(m, 1H), 3.81(s, 3H), 3.79-3.67(m, 3H), 3.31-2.83(m, 1H), 2, 45-2.11(m, 2H), 2.11-1.96(m, 1H), 1.78-1.64(m, 1H), 1.36-1.25(m, 1H).

Example 386 (3-methoxyphenyl)((5R,8S)-2-methyl-3-(2,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using 2,4,5-trifluorophenylboronic acid in place of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₀ F ₃ N ₃ O ₂ - 427.2; obtained m/z, 428.1 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34-7.27 (m, 2H), 7.20-7.04 (m, 2H), 7.04-6.93 (m, 2H), 5.77-5.11 (m, 1H), 5.09-4.34 (m, 1H), 3.81 (s, 3H), 3.77-3.67 (m, 4H), 3. 26-2.83(m, 1H), 2.38-1.96(m, 2H), 1.77-1.60(m, 1H), 1.36-1.21(m, 1H).

Example 387 ((5R,8S)-3-(2,3-difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole-9- yl)(3-methoxyphenyl)methanone.

The title compound was prepared in a manner similar to that described in Example 385 using 2,3-difluorophenylboronic acid instead of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₁ F ₂ N ₃ O ₂ - 409.2; obtained m/z, 410.1 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.33-7.27 (m, 2H), 7.23-7.14 (m, 1H), 7.12-6.99 (m, 3H), 6.99-6.94 (m, 1H), 5.79-5.12 (m, 1H), 5.10-4.32 (m, 1H), 3.81 (s, 3H), 3. 79-3.69 (m, 3H), 3.26-2.86 (m, 1H), 2.39-2.12 (m, 3H), 2.11-1.80 (m, 1H), 1.77-1.66 (m, 1H).

Example 388 (2,3-dimethoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8 -epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,3-dimethoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₂ F ₃ N ₃ O ₃ - 457.2; obtained m/z, 458.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.11-7.01 (m, 1H), 6.99-6.85 (m, 3H), 6.77 (s, 1H), 5.80- 5.13 (m, 1H), 4.73-4.09 (m, 1H), 3.94-3.82 (m, 6H), 3.82-3.71 (m, 3H), 3. 33-3.23 (m, 1H), 2.39-2.13 (m, 3H), 2.09-1.89 (m, 1H), 1.70-1.60 (m, 1H).

Example 389 (2-fluoro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-fluoro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₄ N ₃ O ₂ - 445.1; obtained m/z, 446.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.15-7.06 (m, 1H), 7.04-6.86 (m, 4H), 5.80-5.07 (m, 1H), 4.82-4.17(m, 1H), 3.95-3.87(m, 3H), 3.83-3.70(m, 3H), 3.34-2.80(m, 1H ), 2.40-2.21 (m, 3H), 2.08-1.95 (m, 1H), 1.69-1.60 (m, 1H).

Example 390 (2-chloro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-chloro-3-methoxybenzoic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ ClF ₃ N ₃ O ₂ - 461.1; obtained m/z, 462.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-6.67 (m, 5H), 5.85-5.06 (m, 1H), 4.67-3.84 (m, 4H), 3.77 (d, J = 23.6 Hz, 3H), 3.43-2.60 (m, 1H), 2.45-2.12 (m, 1H), 2.12-1.90 ( m, 1H), 1.60 (s, 3H).

Example 391 (6-methoxypyridin-2-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxypyridine-2-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₉ F ₃ N ₄ O ₂ - 428.1; obtained m/z, 429.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.70-7.63 (m, 1H), 7.56-7.45 (m, 1H), 7.00-6.91 (m, 2H), 6.86-6.80 (m, 1H), 6.16-5.73 (m, 1H), 5.42-5.14 (m, 1H), 4.03-3.92 (m, 3H ), 3.83-3.71 (m, 3H), 3.36-3.22 (m, 1H), 2.44-2.28 (m, 3H), 2.28-1.96 (m , 1H), 1.79-1.61 (m, 1H).

Example 392 (1,5-dimethyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7 ,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,5-dimethyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₂₀ F ₃ N ₅ O - 415.2; obtained m/z, 416.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 6.97 (dd, J =7.7, 6.3 Hz, 2H), 5.18 (d, J =55, 1 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.17 (s, 1H), 2.42 (s, 3H), 2.38-2.12 ( m, 3H), 2.03 (t, J =10.6 Hz, 1H), 1.67 (d, J =13.4 Hz, 1H).

Example 393 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3-fluoro-5-methylphenyl)-2-methyl-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using ( 5R , 8S )-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 109) instead of ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2, 4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 108) and (3-fluoro-5-methylphenyl)boronic acid instead of 2,5-difluorophenylboronic acid . MS (ESI): mass calculated for C ₂₄ H ₂₆ FN ₅ O - 419.2; obtained m/z, 420.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 6.97-6.87 (m, 2H), 6.83 (d, J =9.2 Hz, 1H), 5 .75-5.04 (m, 1H), 5.04-4.34 (m, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.31 (d, J =15.7 Hz, 1H), 2.41 (s, 3H), 2.38-1.93 (m, 4H), 1.83-1.60 (m, 2H), 0.94 (d, J = 38.0 Hz, 1H), 0.69 (s, 1H), 0.52 (s, 2H).

Example 394 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-finyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2,2,2 -trifluoroacetate (Intermediate 106) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate compound 1) and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₅ N ₅ O - 387.2; obtained m/z, 388.2 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57-7.38 (m, 4H), 7.32 (d, J= 7.1 Hz, 2H), 5.08 (s, 1H), 5 .03-4.36 (m, 1H), 3.98-3.82 (m, 3H), 3.77 (d, J= 5.3 Hz, 3H), 3.45-2.83 (m , 1H), 2.47-1.93 (m, 3H), 1.50-1.14 (m, 3H), 1.05-0.43 (m, 4H).

Example 395 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,4-difluorophenyl)-2-methyl-2,4,5,6,7 ,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using ( 5R , 8S )-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 109) instead of ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2, 4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 108) and 3,4-difluorophenylboronic acid instead of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₃ F ₂ N ₅ O - 423.2; obtained m/z, 424.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.32-7.21 (m, 1H), 7.13 (d, J =9.5 Hz, 1H), 7 .06 (s, 1H), 5.08 (s, 1H), 4.71 (d, J = 222.4 Hz, 1H), 3.88 (s, 3H), 3.76 (d, J = 10.9 Hz, 3H), 3.42-2.79 (m, 1H), 2.43-1.91 (m, 5H), 1.87-1.62 (m, 1H), 0.90 (s, 1H), 0.71 (s, 1H), 0.52 (s, 2H).

Example 396 ,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using ( 5R , 8S )-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 109) instead of ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2, 4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 108) and 2,4-difluorophenylboronic acid instead of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₃ F ₂ N ₅ O - 423.2; obtained m/z, 424.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.26-7.20 (m, 1H), 6.98 (q, J =10.9, 9.9 Hz, 2H), 5.07 (s, 1H), 4.98 (s, 1H), 3.87 (s, 3H), 3.67 (s, 3H), 3.32-1.93 (m, 5H ), 1.80-1.63 (m, 2H), 1.08-0.36 (m, 4H).

Example 397 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,5-difluorophenyl)-2-methyl-2,4,5,6,7 ,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using ( 5R , 8S )-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 109) instead of ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2, 4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 108) and 3,5-difluorophenylboronic acid instead of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₃ F ₂ N ₅ O - 423.2; obtained m/z, 424.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 6.85 (d, J =7.7 Hz, 3H), 5.04 (d, J =35.4 Hz, 1H ), 3.88 (s, 3H), 3.78 (s, 3H), 3.31 (d, J =16.1 Hz, 1H), 2.42-2.11 (m, 2H), 2 .04 (d, J = 23.5 Hz, 1H), 1.81-1.60 (m, 2H), 1.54 (s, 2H), 0.88 (d, J = 18.0 Hz, 1H), 0.70 (s, 1H), 0.52 (s, 2H).

Example 398 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(2,3,4-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 385 using ( 5R , 8S )-9-(5-cyclopropyl-1-methyl-1H-pyrazole-4-carbonyl)-2-methyl-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 109) instead of ( 5R , 8S )-9-(3-methoxybenzoyl)-2-methyl-2, 4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-3-yl trifluoromethanesulfonate (intermediate 108) and 2,3,4-trifluorophenylboronic acid instead of 2,5-difluorophenylboronic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₃ N ₅ O - 441.2; obtained m/z, 442.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.08 (t, J =8.1 Hz, 1H), 7.05-6.96 (m, 1H), 5 .38 (d, J = 243.7 Hz, 1H), 5.05-4.35 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 3.21 ( d, J = 15.8 Hz, 1H), 2.41-2.11 (m, 3H), 2.04 (d, J = 11.4 Hz, 1H), 1.80-1.61 (m , 2H), 0.93 (d, J =37.3 Hz, 1H), 0.65 (s, 1H), 0.49 (d, J =20.4 Hz, 2H).

Example 399 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₃ N ₅ O - 441.2; obtained m/z, 442.2 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.74-7.50 (m, 1H), 7.49-7.41 (m, 2H), 7.00-6.90 (m, 3H), 5.04 (d, J = 50.6 Hz, 1H), 4.28-4.13 (m, 1H), 3.88 (s, 3H), 3.76 (s, 3H), 3.28 (d, J =15.3 Hz, 1H), 2.32 (d, J =16.9 Hz, 2H), 2.24-2.13 (m, 1H), 2.01 (d, J = 11.9 Hz, 1H), 1.80-1.63 (m, 3H).

Example 400 9-yl)(2-methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₁ H ₁₇ F ₆ N ₅ O - 469.1; obtained m/z, 470.0 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.99-6.87 (m, 2H), 5.76-5.03 (m, 1H), 4.70-4.09 (m, 1H), 3.88-3.68 (m, 3H), 3.54-3.25 (m, 1H), 2.47-1.93 (m, 7H), 1.76-1.62 (m, 1H ).

Example 401 (1 H -indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and indole-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ F ₃ N ₄ O - 436.2; obtained m/z, 437.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.43 (s, 1H), 7.74 (d, J =7.9 Hz, 1H), 7.35 (d, J =7.3 Hz, 1H ), 7.11 (t, J = 7.7 Hz, 1H), 7.07-6.94 (m, 2H), 6.62-6.53 (m, 1H), 5.60 (s, 1H), 3.81 (s, 3H), 3.21 (s, 1H), 2.48-2.38 (m, 1H), 2.38-2.13 (m, 2H), 2.05 (t, J =10.1 Hz, 1H), 1.76-1.62 (m, 1H), 1.54 (s, 1H).

Example 402 (6-fluoro-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8 -hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-fluoro-1H-indole-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₈ F ₄ N ₄ O - 454.1; obtained m/z, 455.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.46-8.30 (m, 1H), 7.49-7.39 (m, 1H), 7.35-7.28 (m, 2H), 7.03-6.90(m, 2H), 6.56-6.49(m, 1H), 5.82-5.12(m, 1H), 4.93-4.23(m, 1H ), 3.86-3.68 (m, 3H), 3.36-2.80 (m, 1H), 2.43-2.18 (m, 3H), 2.11-1.92 (m , 1H), 1.72-1.60 (m, 1H).

Example 403 (2,3-dimethyl-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7 ,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,3-dimethyl-1H-indole-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₃ F ₃ N ₄ O - 464.2; obtained m/z, 465.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 7.56 (d, J =7.8 Hz, 1H), 7.26 (s, 2H), 7.10-7 .02 (m, 1H), 6.99 (t, J =6.9 Hz, 2H), 5.88-5.43 (m, 1H), 3.87-3.73 (m, 3H), 3.34-3.03 (m, 1H), 2.40 (d, J =15.3 Hz, 1H), 2.35 (s, 3H), 2.33-2.25 (m, 1H) , 2.25-2.21 (m, 3H), 2.18 (s, 1H), 2.03 (t, J =10.4 Hz, 1H), 1.74-1.60 (m, 1H ).

Example 404 (1H-indazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5 ,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1H-indazole-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.03 (s, 1H), 8.11 (s, 1H), 7.94-7.82 (m, 1H), 7.62-7.49 ( m, 1H), 7.23-7.14 (m, 1H), 7.07-6.89 (m, 2H), 5.53 (s, 1H), 5.38-4.96 (m, 1H), 3.81 (s, 3H), 3.32-3.12 (m, 1H), 2.50-2.39 (m, 1H), 2.39-2.16 (m, 2H) , 2.14-2.02 (m, 1H), 1.80-1.66 (m, 1H).

Example 405 (1H-benzo[d]imidazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8 -hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1H-benzimidazole-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.29 (s, 1H), 8.09 (s, 1H), 7.94 (d, J =8.0 Hz, 1H), 7.50 (d , J = 15.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.07-6.92 (m, 2H), 5.74-5.48 (m, 1H), 5.39-5.08 (m, 1H), 3.82 (s, 3H), 3.32-3.12 (m, 1H), 2.50-2.40 (m, 1H) , 2.40-2.15 (m, 2H), 2.15-2.01 (m, 1H), 1.81-1.64 (m, 1H).

Example 406 9-yl)(2-methylbenzo[d]oxazol-6-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methyl-1,3-benzoxazole-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ F ₃ N ₄ O ₂ - 452.1; obtained m/z, 453.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.72-7.59 (m, 2H), 7.43 (s, 1H), 6.99 (s, 2H), 5.19 (s, 1H) , 5.10-4.37(m, 1H), 3.79(s, 3H), 3.54-3.19(m, 1H), 2.67(s, 3H), 2.46-1 .92 (m, 4H), 1.75-1.63 (m, 1H).

Example 407 Furo[3,2-c]pyridin-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and furo[3,2-c]pyridine-4-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₇ F ₃ N ₄ O ₂ - 438.1; obtained m/z, 439.2 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.53-8.47 (m, 1H), 7.72-7.67 (m, 1H), 7.55-7.48 (m, 1H), 7.32-7.30(m, 1H), 7.01-6.92(m, 2H), 6.20-5.81(m, 1H), 5.38-5.22(m, 1H ), 3.85-3.71 (m, 3H), 3.40-3.27 (m, 1H), 2.46-2.19 (m, 3H), 2.12-1.99 (m , 1H), 1.78-1.64 (m, 1H).

Example 408 (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8 -hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2,2,2 -trifluoroacetate (Intermediate 106) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate compound 1) and 1-methyl-1H-pyrolo[2,3-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₃ N ₅ O - 397.2; obtained m/z, 398.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40-8.36 (m, 1H), 8.29-8.23 (m, 1H), 7.58 (s, 1H), 7.50- 7.44 (m, 2H), 7.44-7.37 (m, 1H), 7.36 (d, J =1.7 Hz, 1H), 7.35-7.32 (m, 1H) , 7.20-7.14 (m, 1H), 5.48 (s, 1H), 5.15 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.25 (s, 1H), 2.45-2.36 (m, 1H), 2.36-2.17 (m, 2H), 2.14-2.03 (m, 1H), 1, 77-1.64 (m, 1H).

Example 409 ,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.40-8.37 (m, 1H), 8.25-8.21 (m, 1H), 7.56 (s, 1H), 7.20- 7.15(m, 1H), 7.02-6.93(m, 2H), 5.46(s, 1H), 5.13(s, 1H), 3.92(s, 3H), 3 .80 (s, 3H), 3.22 (s, 1H), 2.42-2.22 (m, 3H), 2.12-2.03 (m, 1H), 1.74-1.63 (m, 1H).

Example 410 Imidazo[1,2-a]pyridin-5-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8 -hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and imidazole[1,2-a]pyridine-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.70 (d, J =1.3 Hz, 1H), 7.66-7.60 (m, 2H), 7 .29 (d, J =6.9 Hz, 1H), 6.99 (t, J =6.9 Hz, 2H), 5.15 (s, 2H), 3.80 (s, 3H), 3 .55-3.16 (m, 1H), 2.44-2.30 (m, 2H), 2.30-2.17 (m, 1H), 2.13-2.02 (m, 1H) , 1.78-1.66 (m, 1H).

Example 411 Imidazo[1,2-a]pyridin-3-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8 -hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c] pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1) and imidazole[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.19 (d, J =7.0 Hz, 1H), 8.02 (s, 1H), 7.72-7.64 (m, 1H), 7 .38-7.30(m, 1H), 7.02-6.90(m, 3H), 5.65(s, 1H), 5.18(s, 1H), 3.81(s, 3H ), 3.28-3.17 (m, 1H), 2.43 (d, J =15.3 Hz, 1H), 2.39-2.30 (m, 1H), 2.31-2, 19 (m, 1H), 2.16-2.05 (m, 1H), 1.79-1.68 (m, 1H).

Example 412 (2-chloroimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-chloroimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₇ ClF ₃ N ₅ O - 471.1; obtained m/z, 472.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63-8.57 (m, 1H), 7.60-7.54 (m, 1H), 7.38-7.30 (m, 1H), 7.02-6.93(m, 2H), 6.93-6.86(m, 1H), 5.37(s, 1H), 4.96(s, 1H), 3.76(s, 3H), 2.53-2.34 (m, 3H), 2.09 (t, J =9.4 Hz, 1H), 1.73 (t, J =7.6 Hz, 1H), 1, 62-1.42 (m, 1H).

Example 413 (7-methoxyimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 7-methoxyimidazo[1,2-A]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O ₂ - 467.2; obtained m/z, 468.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.04 (d, J =7.7 Hz, 1H), 7.91 (s, 1H), 7.00-6.95 (m, 2H), 6 .93 (d, J = 2.5 Hz, 1H), 6.66-6.61 (m, 1H), 5.63 (s, 1H), 5.16 (s, 1H), 3.88 ( s, 3H), 3.81 (s, 3H), 3.49 (d, J = 5.5 Hz, 1H), 3.26-3.16 (m, 1H), 2.48-2.04 (m, 3H), 1.77-1.66 (m, 1H).

Example 414 9-yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.1 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.58-8.52 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.21 (m, 1H), 7.01-6.91 (m, 2H), 6.84-6.77 (m, 1H), 5.19 (s, 1H), 4.95 (s, 1H), 3.78 (s, 3H), 3.36-3.11(m, 1H), 2.52(s, 3H), 2.45-2.32(m, 2H), 2.32-2.18(m, 1H) , 2.12-2.05 (m, 1H), 1.84-1.61 (m, 1H).

Example 415 (2,5-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5 ,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,5-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, J =6.9 Hz, 1H), 7.08-7.03 (m, 1H), 7.02-6.91 (m, 2H), 6.72 (t, J =6.9 Hz, 1H), 5.19 (s, 1H), 4.92 (s, 1H), 3.77 (s, 3H), 3.19 ( s, 1H), 2.65-2.58 (m, 3H), 2.54 (s, 3H), 2.46-2.18 (m, 3H), 2.13-1.99 (m, 1H), 1.79-1.65 (m, 1H).

Example 416 (2,6-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5 ,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c] pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2 H-5, 9-epimincycloocta[c]pyrazole (intermediate 1) and 2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38-8.32 (m, 1H), 7.49-7.40 (m, 1H), 7.14-7.07 (m, 1H), 7.03-6.90(m, 2H), 5.20(s, 1H), 4.95(s, 1H), 3.79(s, 3H), 3.30-3.10(m, 1H), 2.50 (s, 3H), 2.44-2.18 (m, 5H), 2.15-2.01 (m, 1H), 1.79-1.63 (m, 1H) , 1.55-1.38 (m, 1H).

Example 417 9-yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₅ O - 465.2; obtained m/z, 466.2 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.48-8.41 (m, 1H), 7.32-7.28 (m, 1H), 7.01-6.90 (m, 2H), 6.68-6.61(m, 1H), 5.19(s, 1H), 4.93(s, 1H), 3.78(s, 3H), 3.16(d, J =27, 4 Hz, 1H), 2.49 (s, 3H), 2.44-2.32 (m, 5H), 2.32-2.18 (m, 1H), 2.14-2.01 (m , 1H), 1.70 (d, J =13.3 Hz, 1H).

Example 418 (5-Chloro-2-methylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4 ,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-chloro-2-methyl-imidazo[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₉ ClF ₃ N ₅ O - 485.1; obtained m/z, 486.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.63-8.57 (m, 1H), 7.52-7.45 (m, 1H), 7.25-7.19 (m, 1H), 7.04-6.92 (m, 2H), 5.15 (s, 1H), 4.96 (s, 1H), 3.79 (s, 3H), 3.23 (s, 1H), 2 .51 (s, 3H), 2.49-2.33 (m, 2H), 2.33-2.19 (m, 1H), 2.15-2.03 (m, 1H), 1.81 -1.65 (m, 1H).

Example 419 5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(difluoromethyl)imidazole[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₈ F ₅ N ₅ O - 487.1; obtained m/z, 488.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (d, J =7.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.39-7.31 (m, 1H), 7.05-6.73 (m, 4H), 5.29 (d, J = 7.7 Hz, 1H), 4.88 (s, 1H), 3.77 (s, 3H), 3.08 (d, J = 48.6 Hz, 1H), 2.49-2.25 (m, 3H), 2.17-2.04 (m, 1H), 1.79-1.67 ( m, 1H).

Example 420 9-yl)(2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-(trifluoromethyl)imidazole[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₇ F ₆ N ₅ O - 505.1; obtained m/z, 506.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.72 (d, J =9.2 Hz, 1H), 7.37 (t, J =8.0 Hz, 1H ), 6.94 (s, 3H), 5.03 (s, 1H), 3.76 (s, 3H), 3.41 (s, 0H), 2.39 (s, 3H), 2.06 (d, J =14.3 Hz, 1H), 1.72 (s, 1H), 1.57 (s, 2H).

Example 421 2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl) methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 5-methyl-2-(trifluoromethyl)imidazole[1,2-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₁₉ F ₆ N ₅ O - 519.1; obtained m/z, 520.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.99 (s, 1H), 7.14 (s, 1H), 7.02-6.83 (m, 3H), 5.68-4.69 ( m, 1H), 3.78 (d, J =2.6 Hz, 3H), 3.22-3.00 (m, 1H), 2.65 (s, 3H), 2.52-1.98 (m, 4H), 1.84-1.66 (m, 1H), 1.42 (dd, J =30.7, 7.0 Hz, 1H).

Example 422 9-yl)(pyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₈ F ₃ N ₅ O - 437.1; obtained m/z, 438.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.51-8.47 (m, 1H), 8.18 (s, 1H), 8.11 (d, J =8.9 Hz, 1H), 7 .35-7.30 (m, 1H), 7.02-6.94 (m, 2H), 6.94-6.88 (m, 1H), 5.52 (s, 1H), 5.16 (s, 1H), 3.80 (s, 3H), 3.22 (s, 1H), 2.45-2.29 (m, 2H), 2.30-2.19 (m, 1H), 2.16-2.04 (m, 1H), 1.77-1.65 (m, 1H).

Example 423 9-yl)(2-methylpyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O - 451.2; obtained m/z, 452.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (dt, J =6.9, 1.1 Hz, 1H), 7.47 (d, J =8.8 Hz, 1H), 7.21 (ddd, J =8.9, 6.8, 1.1 Hz, 1H), 7.04-6.90 (m, 2H), 6.79 (td, J =6.9, 1.4 Hz , 1H), 3.78 (s, 3H), 3.76-3.67 (m, 1H), 3.23-3.14 (m, 2H), 2.80 (s, 1H), 2, 50 (s, 3H), 2.45-2.16 (m, 2H), 2.13-1.97 (m, 1H), 1.77-1.62 (m, 1H).

Example 424 (6-Methoxypyrazol[1,5-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₅ O ₂ - 467.2; obtained m/z, 468.0 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 8.08-8.05 (m, 1H), 8.02 (d, J =9.6 Hz, 1H), 7 .14-7.09(m, 1H), 7.01-6.93(m, 2H), 5.53(s, 1H), 5.15(s, 1H), 3.85(s, 3H ), 3.80 (s, 3H), 3.21 (d, J =15.3 Hz, 1H), 2.45-2.29 (m, 2H), 2.29-2.19 (m, 1H), 2.08 (t, J =10.6 Hz, 1H), 1.78-1.62 (m, 1H).

Example 425 9-yl)(2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (Intermediate 100) instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₇ F ₆ N ₅ O - 505.1; obtained m/z, 506.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J= 7.1 Hz, 1H), 7.34 (s, 2H), 7.08-6.86 (m, 3H), 6 .23-4.60 (m, 2H), 3.90-3.61 (m, 2H), 3.29-3.12 (m, 2H), 2.81 (s, 3H), 2.33 (d, J =36.2 Hz, 1H), 2.15-1.63 (m, 1H).

Example 426 9-yl)(pyrazolo[1,5-a]pyrazin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrazine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₇ F ₃ N ₆ O - 438.1; obtained m/z, 439.0 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.54 (s, 1H), 8.40 (dd, J =4.7, 1.5 Hz, 1H), 8.24 (s, 1H), 8 .03 (d, J =4.7 Hz, 1H), 6.98 (dd, J =7.7, 6.2 Hz, 2H), 5.57-5.10 (m, 2H), 3, 81 (s, 3H), 3.55-3.14 (m, 1H), 2.49-2.21 (m, 3H), 2.12 (t, J =10.5 Hz, 1H), 1 .81-1.67 (m, 1H).

Example 427 9-yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₂ H ₁₇ F ₃ N ₆ O - 438.1; obtained m/z, 439.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.72 (d, J =6.9 Hz, 1H), 8.65 (dd, J =4.1, 1.8 Hz, 1H), 8.42 (s, 1H), 7.05-6.91 (m, 3H), 5.44 (s, 1H), 5.10 (s, 1H), 3.75 (d, J = 17.4 Hz, 3H), 3.56-3.31 (m, 1H), 2.62-2.23 (m, 3H), 2.05 (t, J =9.7 Hz, 1H), 1.71 (dd , J =13.4, 7.6 Hz, 1H).

Example 428 9-yl)(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylimidazo[1,2-b]pyridazine-3-carboxylic acid hydrochloride instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O - 452.2; obtained m/z, 453.0 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.37-8.31 (m, 1H), 7.92-7.88 (m, 1H), 7.12-7.06 (m, 1H), 6.98 (s, 2H), 5.26-4.70 (m, 1H), 3.86-3.67 (m, 3H), 3.53-3.36 (m, 3H), 2, 64-2.44 (m, 2H), 2.44-2.31 (m, 3H), 2.15-1.62 (m, 2H).

Example 429 9-yl)(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O - 452.2; obtained m/z, 453.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J =7.0 Hz, 1H), 8.57-8.51 (m, 1H), 6.99 (d, J =6, 4 Hz, 2H), 6.89-6.81 (m, 1H), 5.12 (s, 2H), 3.89-3.31 (m, 6H), 2.54 (s, 3H), 2.35 (d, J =15.4 Hz, 1H), 2.02 (s, 1H), 1.68 (s, 1H).

Example 430 (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4 ,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₁₉ F ₃ N ₆ O - 452.2; obtained m/z, 453.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.71-8.59 (m, 1H), 8.60-8.52 (m, 1H), 7.24-7.19 (m, 1H), 7.00-6.89 (m, 2H), 6.72 (d, J =5.3 Hz, 1H), 5.88 (s, 1H), 4.26-4.17 (m, 3H) , 3.82-3.71 (m, 3H), 3.38-3.20 (m, 1H), 2.49-1.99 (m, 4H), 1.85-1.63 (m, 1H).

Example 431 ((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)(quinolin-6 -yl) methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2 ,2,2-trifluoroacetate (intermediate 106) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazole (intermediate 1). MS (ESI): mass calculated for C ₂₅ H ₂₂ N ₄ O - 394.2; obtained m/z, 395.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.01-8.94 (m, 1H), 8.20 (d, J =8.3 Hz, 1H), 8.14 (d, J =8, 7 Hz, 1H), 8.00 (s, 1H), 7.82 (d, J =8.8 Hz, 1H), 7.54-7.29 (m, 6H), 5.23 (s, 1H), 5.16-4.33(m, 1H), 3.81(s, 3H), 3.44-2.92(m, 1H), 2.53-2.14(m, 3H) , 2.16-1.95 (m, 1H), 1.74 (d, J =10.4 Hz, 1H).

Example 432 9-yl)(quinolin-8-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 8-quinolinecarboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₁₉ F ₃ N ₄ O - 448.2; obtained m/z, 449.1 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.95 (d, J =17.9 Hz, 1H), 8.22-8.11 (m, 1H), 7.91-7.81 (m, 1H ), 7.73-7.37 (m, 2H), 7.06-6.88 (m, 2H), 5.68 (d, J =237.4 Hz, 1H), 4.42 (d, J = 5.6 Hz, 1H), 3.82 (s, 1H), 3.71 (s, 3H), 3.47-2.71 (m, 1H), 2.60-1.96 (m , 3H), 1.86 (t, J =10.4 Hz, 1H), 1.77-1.64 (m, 1H).

Example 433 9-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5S,8R)-2-methyl-3-(3,4,5-trifluorophenyl-2,4,5,6,7,8-hexahydro-5,8 -epimincyclohepta[c]pyrazole 2,2,2-trifluoroacetate (intermediate 111) instead of (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazole (Intermediate 1) MS (ESI): mass calculated for C ₂₅ H ₁₉ F ₃ N ₄ O - 448.2, obtained m/z, 449.1 [M+H ]+ ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.04-8.92 (m, 1H), 8.19 (d, J =8.3 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.88-7.74 (m, 1H), 7.50-7.41 (m, 1H), 7.08-6, 90 (m, 2H), 5.86-5.14 (m, 1H), 5.17-4.38 (m, 1H), 3.80 (s, 3H), 3.41-2.84 ( m, 1H), 2.51-2.14 (m, 3H), 2.15-1.97 (m, 1H), 1.71 (d, J =11.2 Hz, 1H).

Example 434 9-yl)(quinolin-6-yl)methanone.

The title compound was prepared in a manner analogous to that described in Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl-2,4,5,6,7,8-hexahydro-5,8 -epimincyclohepta[c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazole (Intermediate 1) MS (ESI): mass calculated for C ₂₅ H ₁₉ F ₃ N ₄ O - 448.2, m/z obtained, 449.1 [M+ H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.02-8.94 (m, 1H), 8.19 (d, J =8.4 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.51-7.42 (m, 1H), 7, 08-6.93 (m, 2H), 5.23 (s, 1H), 5.09 (d, J =5.2 Hz, 1H), 3.80 (s, 3H), 3.41-2 .86 (m, 1H), 2.47-2.15 (m, 3H), 2.04 (t, J = 10.3 Hz, 1H), 1.71 (d, J = 11.3 Hz, 1H).

Example 435 (2,4-dimethylquinolin-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro -5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,4-dimethylquinoline-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₇ H ₂₃ F ₃ N ₄ O - 476.2; obtained m/z, 477.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.16-7.52 (m, 3H), 7.19 (s, 1H), 7.02-6.94 (m, 2H), 5.86- 5.16 (m, 1H), 5.12-4.47 (m, 1H), 3.90-3.70 (m, 3H), 3.43-2.91 (m, 1H), 2. 70 s, 3H), 2.68 (s, 3H), 2.42-2.20 (m, 3H), 2.11-1.95 (m, 1H), 1.75-1.62 (m , 1H).

Example 436 9-yl)(6-methylquinolin-8-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 6-methylquinoline-8-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₁ F ₃ N ₄ O - 462.2; obtained m/z, 463.2 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.86 (d, J =21.3 Hz, 1H), 8.15-7.97 (m, 1H), 7.66-7.33 (m, 3H), 7.07-6.88(m, 2H), 6.04-5.28(m, 1H), 4.48-4.36(m, 1H), 3.87-3.61( m, 3H), 3.46-3.26 (m, 1H), 2.62-2.34 (m, 5H), 2.28-2.01 (m, 1H), 1.94-1, 79 (m, 1H), 1.78-1.62 (m, 1H).

Example 437 9-yl)(quinoxalin-6-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and quinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₈ F ₃ N ₅ O - 449.1; obtained m/z, 450.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (s, 2H), 8.17 (d, J =12.7 Hz, 2H), 7.99-7.81 (m, 1H), 7 .08-6.92 (m, 2H), 5.51 (d, J =230.9 Hz, 1H), 4.75 (d, J =231.1 Hz, 1H), 3.93-3, 25 (m, 3H), 2.49-2.20 (m, 3H), 2.20-1.98 (m, 1H), 1.72 (s, 1H), 1.55 (s, 1H) .

Example 438 -5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,3-dimethylquinoxaline-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₆ H ₂₂ F ₃ N ₅ O - 477.2; obtained m/z, 478.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.13-7.98 (m, 2H), 7.85-7.71 (m, 1H), 7.03-6.94 (m, 2H), 5.49 (d, J = 341.1 Hz, 1H), 5.12-4.39 (m, 1H), 3.89-3.68 (m, 3H), 3.34 (d, J = 15.3 Hz, 1H), 2.85-2.68 (m, 6H), 2.48-2.21 (m, 3H), 2.15-1.96 (m, 1H), 1.79 -1.65 (m, 1H).

Example 439 -yl) methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazole 2,2,2 -trifluoroacetate (Intermediate 106) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole (intermediate compound 1) and quinoxaline-5-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₁ N ₅ O - 395.2; obtained m/z, 396.1 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.95-8.81 (m, 2H), 8.20-8.10 (m, 1H), 7.93-7.61 (m, 2H), 7.54-7.28 (m, 5H), 6.03-5.25 (m, 2H), 4.43 (d, J =5.6 Hz, 1H), 3.83 (s, 3H) , 3.52-2.70 (m, 1H), 2.52-2.31 (m, 1H), 2.33-2.07 (m, 1H), 2.01-1.86 (m, 1H), 1.80-1.66 (m, 1H).

Example 440 9-yl)(1,5-naphthyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 1,5-naphthyridine-3-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₁₈ F ₃ N ₅ O - 449.1; obtained m/z, 450.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 9.11-9.02 (m, 2H), 8.44 (s, 2H), 7.72 (s, 1H), 7.00 (s, 2H) , 5.22 (s, 1H), 5.04 (s, 1H), 3.77 (s, 4H), 3.35 (s, 1H), 2.50-2.24 (m, 2H), 2.16-2.02 (m, 1H), 1.74 (s, 1H).

Example 441 9-yl)(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₄ F ₃ N ₅ O - 455.2; obtained m/z, 456.0 [M+H]+. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.24 (s, 1H), 7.00-6.90 (m, 2H), 5.70-4.59 (m, 2H), 3.85- 3.70(m, 3H), 3.41-3.00(m, 1H), 3.00-2.86(m, 1H), 2.86-2.72(m, 1H), 2, 53-2.20 (m, 1H), 2.19-1.61 (m, 5H), 1.56 (s, 3H), 1.41-0.96 (m, 4H).

Example 442 9-yl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (Intermediate 1) and 5H,6H,7H,8H-imidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₃ H ₂₂ F ₃ N ₅ O - 441.2; obtained m/z, 442.1 [M+H]+. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 6.99-6.93 (m, 2H), 5.64-5.38 (m, 1H), 5.20- 4.90 (m, 1H), 4.43-4.02 (m, 2H), 3.80 (s, 3H), 3.15 (d, J =15.3 Hz, 1H), 2.90 (t, J =6.4 Hz, 2H), 2.43-2.33 (m, 1H), 2.29 (k, J =11.0 Hz, 1H), 2.20 (s, 1H) , 2.11-2.02 (m, 1H), 2.04-1.83 (m, 4H), 1.70-1.62 (m, 1H).

Example 443 Isochroman-7-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta [c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 3,4-dihydro-1H-2-benzopyran-7-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₅ H ₂₂ F ₃ N ₃ O ₂ - 453.2; obtained m/z, 454.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.20 (m, 1H), 7.19-7.08 (m, 2H), 7.04-6.91 (m, 2H), 5.22-5.10(m, 1H), 5.08-4.98(m, 1H), 4.77(s, 2H), 3.98(t, J =5.7Hz, 2H) , 3.79 (s, 3H), 3.34-3.18 (m, 1H), 2.88 (t, J =5.7 Hz, 2H), 2.43-2.07 (m, 3H ), 2.06-1.94 (m, 1H), 1.74-1.61 (m, 1H).

Example 444 5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone.

The title compound was prepared analogously to Example 1 using (5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazole 2,2,2-trifluoroacetate (intermediate 105) instead of racemic (5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9 -epimincycloocta[c]pyrazole (intermediate 1) and 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid instead of quinoline-6-carboxylic acid. MS (ESI): mass calculated for C ₂₄ H ₂₀ F ₃ N ₃ O ₃ - 455.1; obtained m/z, 456.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10-6.68 (m, 5H), 5.81-4.66 (m, 2H), 4.33-4.02 (m, 5H), 3.85-3.72(m, 3H), 3.56-2.73(m, 1H), 2.37-2.12(m, 2H), 2.12-1.88(m, 1H ), 1.73-1.59 (m, 1H).

BIOLOGICAL DATA

The assay used to measure MGL activity in vitro is based on the assay used for another serine hydrolase (FAAH) described in Wilson et al., 2003 (high throughput assay compatible with fatty acid amide hydrolase activity assay. Wilson SJ, Lovenberg TW, Barbier AJ Anal Biochem 2003 Jul 15;318(2):270-5.). The assay consists of combining endogenously expressed MGL from HeLa cells with test compounds, adding [glycerol- ^1,3-3H ]-oleoylglycerol, incubating for one hour, and then measuring the amount of cleaved [ ^1,3-3H ]-glycerol passing through through an activated carbon filter. The amount of degraded tritiated glycerol passing through the carbon filter is proportional to the activity of the MGL enzyme in a particular well/test conditions.

The standard conditions of this assay allow 300 nM [glycerol- ^1,3-3H ]-oleoylglycerol to be combined with human MGL from HeLa cells and test compounds for one hour, after which the reaction mixture is filtered through activated carbon and the tritium on stream is measured. The concentration of the test compound in the screening mode is 10 μM, while the highest concentration of the compound in the IC ₅₀ assays is determined empirically. MGL is the predominant hydrolase in HeLa cells/cell homogenates.

N / a - not investigated.

Table 4

No. approx. Connection name IR ₅₀ MGL (nM) 1 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6 -yl) methanone; 4.94 2 ((5R,9S)-3-cyclopropyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6- yl) methanone; 1625.92 3 racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; 0.78 4 (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; 0.26 5 (2-chloro-3-methoxyphenyl) ((5S,9R)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; 515.70 6 racemic (2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.49 7 racemic (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 20.36 8 racemic (4-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.92 9 racemic (3-(1H-imidazol-1-yl)phenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; 12.22 10 racemic (1-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 5999.29 eleven racemic (5-chloro-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 101.51 12 racemic (5-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 92.17 13 racemic (4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 543.63 14 racemic (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.00 15 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1-phenyl -1H-1,2,4-triazol-3-yl) methanone; 16.82 16 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1-phenyl -1H-pyrazol-3-yl) methanone; 8.75 17 racemic (5-methoxy-1-phenyl-1H-pyrazol-3-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl) methanone; 6.61 18 racemic (1-methyl-1H-indol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl)methanone; 0.26 19 racemic (5-chloro-1H-indol-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) methanone; 24.73 20 racemic (7-methyl-1H-indazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) methanone; 1.10 21 racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.29 22 racemic (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.30 23 racemic (4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.14 24 racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 15.65 25 racemic [1,2,4]triazol[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 95.52 26 racemic ((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl) (quinolin-6-yl ) methanone; 47.72 27 racemic (4-chloroquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; 1.62 28 racemic (4-hydroxyquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; 223.98 29 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-5 -yl) methanone; 9.36 thirty racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-6 -yl) methanone; 16.58 31 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinazolin-6 -yl) methanone; 132.10 32 racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)(2-( trifluoromethyl)-1,8-naphthyridin-3-yl) methanone; 1919.11 33 racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(4-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 7.85 34 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 11.66 35 racemic (1,4-dimethyl-1H-pyrazol-3-yl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3585.09 36 ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; 18.68 37 racemic ((5R,9S)-3-(4-Fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; 22.61 38 ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 8.63 39 racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(3-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 1.87 40 racemic-((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-phenyl-1H-1,2,4-triazol-3-yl) methanone; 10.44 41 ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( furo[3,2-b]pyridin-6-yl) methanone; 14.98 42 racemic ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; 2.30 43 ((5S,9R)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 1004.39 44 ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; 1.63 45 racemic ((5R,9S)-2-cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; 11.84 46 (3-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.50 47 (3-(1H-pyrazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.46 48 (3-(1H-pyrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.27 49 (3-(1H-tetrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; 5.10 50 (2-chloro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 44.32 51 (4-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2220.75 52 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-isopropyl-1H-1,2,4-triazol-3-yl)methanone; 240.10 53 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; 6.87 54 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl) methanone; 12.75 55 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; 21.36 56 (1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 50.48 57 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl) methanone; 87.70 58 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; 272.58 59 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; 531.74 60 (1-benzyl-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 643.73 61 Benzo[d]isoxazol-3-yl((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 0.43 62 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-indazol-3-yl) methanone; 2.10 63 racemic ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; 0.54 64 ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinoxalin-6-yl) methanone; 3.77 65 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-(2-fluoroethoxy)quinolin-6-yl)methanone; 0.24 66 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(2-fluoroethoxy)phenyl)methanone; 2.24 68 racemic (2-(2H-1,2,3-Triazol-2-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 6.51 69 (2-(1H-1,2,4-triazol-5-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 10.00 70 (2-(5-chloro-1H-1,2,4-triazol-3-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3599.98 71 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone; 17.44 72 (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 23.90 73 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; 7.43 74 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) methanone; 26.10 75 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-fluoro-2-(oxazol-2-yl)phenyl)methanone; 18.97 76 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(2-(pyrimidin-2-yl)phenyl)methanone; 568.59 77 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-methoxy-1-methyl-1H-pyrazol-4-yl)methanone; 65.10 78 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; 178.61 79 racemic (5-cyclopropyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 76.00 80 racemic (5-cyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 74.71 81 racemic (3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 138.71 82 racemic (5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 264.61 83 Racemic (5-cyclopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 117.41 84 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 9.52 85 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)methanone; 81.10 86 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 2.82 87 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-fluoropyridin-4-yl)methanone; 101.25 88 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; 36.47 89 (5-aminopyridin-2-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 129.99 90 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxybenzofuran-2-yl) methanone; 63.69 91 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (2-methylbenzo[d]oxazol-6-yl) methanone; 0.64 92 (2-aminobenzo[d]oxazol-6-yl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl) methanone; 0.52 93 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (furo[3,2-b]pyridin-2-yl) methanone; 12.08 94 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-c]pyridin-4-yl)methanone; 14.13 95 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone; 3.59 96 racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone; 2.47 97 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; 0.56 98 ((5S,9R)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinolin-6-yl) methanone; 554.12 99 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (isoquinolin-3-yl) methanone; 7.73 100 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-7-yl)methanone; 1.19 101 (4-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 0.18 102 (3-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 7.62 103 (8-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 1.92 104 (2-chloroquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 38.00 105 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-5-yl)methanone; 3.60 106 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-6-yl)methanone; 1.64 107 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-(trifluoromethyl)quinolin-6-yl)methanone; 58.90 108 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-hydroxyquinolin-6-yl)methanone; 2.51 109 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxyquinolin-3-yl)methanone; 0.53 110 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-nitroquinolin-6-yl) methanone; 4.07 111 (8-aminoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; 11.58 112 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinazolin-7-yl) methanone; 20.00 113 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinoxalin-6-yl) methanone; 2.66 114 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinazolin-6-yl) methanone; 29.95 115 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylquinoxalin-6-yl)methanone; 13.79 116 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (7-fluoroquinoxalin-6-yl) methanone; 1.00 117 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,6-naphthyridin-5-yl) methanone; 1.91 118 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-3-yl)methanone; 19.50 119 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-4-yl)methanone; 42.90 120 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,7-naphthyridin-4-yl)methanone; 19.64 121 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,6-naphthyridin-4-yl)methanone; 10.26 122 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,5-naphthyridin-2-yl) methanone; 15.00 123 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-1-(2-fluoroethyl)quinoline-4(1H)-one; 11.51 124 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one; 8.01 125 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; 5.31 126 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7.44 127 racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone; 24.31 128 ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; 2.05 129 racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinoxalin-6-yl) methanone; 54.89 130 ((5R,9S)-3-(3-fluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 17.07 131 ((5R,9S)-3-(4-chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 55.92 132 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 262.00 133 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 55.89 134 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-methanone; 110.79 135 ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 27.15 136 ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylbenzo[d]oxazol-6-yl)methanone; 7.02 137 ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 1.00 138 ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 6.25 139 ((5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 188.50 140 ((5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; 147.71 141 (3-(4H-1,2,4Ttriazol-4-yl)phenyl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.67 142 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; 7.02 143 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxy-1-methyl-1H-pyrazol-4-yl) methanone; 10.96 144 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.31 145 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1-phenyl-1H-1,2,4-triazol-3-yl)methanone; 3.00 146 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; 6.90 147 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; 18.12 148 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 2.00 149 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-b]pyridin-2-yl)methanone; 19.71 150 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,5-a]pyridin-8-yl)methanone; 0.72 151 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,2-a]pyridin-3-yl)methanone; 3.55 152 (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.49 153 ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; 1.19 154 racemic ((5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinolin-6-yl) methanone; 38.43 155 racemic ((5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone; 120.34 156 ((5R,9S)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone; 57.28 157 (3-chloro-5-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.37 158 N-(3-methoxy-5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole-10-carbonyl)phenyl)acetamide; 2.56 159 (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 13.45 160 (2-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7476.53 161 (3-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.00 162 (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.41 163 (5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.14 164 (4-methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.66 165 (5-methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.93 166 (2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.22 167 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone; 39.13 168 (2-(1H-imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 20.77 169 (5-fluoro-2-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.77 170 (3-(1-methyl-1H-pyrazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 9.58 171 (3-(4-fluoro-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 12.35 172 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; 13.46 173 (3-(4-Methoxy-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 18.42 174 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; 54.97 175 (3-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.78 176 (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.24 177 (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 17.61 178 (3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 49.37 179 (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.87 180 (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.03 181 (2-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 88.53 182 (2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 37.07 183 (2-(1H-1,2,3-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 76.05 184 (3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 152.51 185 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4,5,6,7-tetrahydropyrazol[1,5-a]pyridin-3-yl)methanone; 5.05 186 (3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.70 187 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 9.40 188 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methanone; 26.91 189 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 86.42 190 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone; 3.03 191 (1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 14.22 192 (5-ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.88 193 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; 32.14 194 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)methanone; 18.49 195 (5-methoxy-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.53 196 (1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 13.69 197 (1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)- 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 19.03 198 (1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 18.07 199 (1-(3-methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 258.29 200 (4-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 26.04 201 (6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 26.76 202 (4-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 75.93 203 (5-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 245.58 204 (6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 102.00 205 (5-isopropoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 84.33 206 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-(trifluoromethoxy)pyridin-2-yl)methanone; 51.40 207 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(trifluoromethoxy)pyridin-2-yl)methanone; 1124.86 208 6-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-carbonyl) picolinonitrile; 294.10 209 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazin-2-yl)methanone; 665.12 210 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-4-yl)methanone; 1768.07 211 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyridazin-4-yl)methanone; 3199.63 212 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-5-yl)methanone; 3199.63 213 (5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 33.24 214 (6-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 45.44 215 (6-(1H-pyrrol-1-yl) pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 117.41 216 (6-(1H-imidazol-1-yl) pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 151.71 217 (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 27.03 218 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone; 10.04 219 1-(5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-3-yl)pyrrolidin-2-one; 139.09 220 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-morpholinopyridin-3-yl)methanone; 55.89 221 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylindolizin-6-yl)methanone; 142.10 222 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (2-methylbenzo[d]oxazol-6-yl) methanone; 5.06 223 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-3-yl)methanone; 1.49 224 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 1.11 225 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-5-yl)methanone; 8.95 226 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-6-yl)methanone; 12.20 227 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-2-yl)methanone; 28.00 228 Imidazo[1,2-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 13.20 229 Imidazo[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 15.73 230 Imidazo[1,5-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 15.30 231 Imidazo[1,2-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 20.31 232 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-3-yl)methanone; 17.77 233 (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.26 234 (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 14.63 235 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-b]pyridazin-5-yl)methanone; 1.14 236 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-a]pyrazin-8-yl)methanone; 1.26 237 (4-methoxy-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.89 238 (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 5.36 239 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-b]pyridazin-3-yl)methanone; 17.03 240 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-2-yl)methanone; 70.62 241 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; 23.31 242 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 10.26 243 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone; 73.60 244 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrazin-3-yl)methanone; 16.41 245 Imidazo[1,2-b]pyridazin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 23.81 246 Imidazo[1,2-b]pyridazin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.23 247 [1,2,4]triazol[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 418.99 248 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)methanone; 97.16 249 Imidazo[1,2-a]pyrimidin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 221.00 250 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-4-yl)methanone; 0.29 251 Isoquinolin-1-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 0.43 252 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; 1.28 253 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-7-yl)methanone; 3.09 254 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinazolin-4-yl)methanone; 0.43 255 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; 5.56 256 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylquinoxalin-6-yl)methanone; 15.78 257 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-2-yl)methanone; 16.00 258 Cinnolin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 20.34 259 Cinnolin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl) methanone; 28.46 260 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-2-yl)methanone; 12.41 261 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-3-yl)methanone; 53.24 262 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,6-naphthyridin-8-yl)methanone; 2.16 263 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 120.50 264 ((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; 168.62 265 ((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; 68.99 266 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 14.57 267 ((5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone; 20.84 268 ((5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; 5.32 269 ((5R,9S)-2-methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinolin-6-yl) methanone; 34.87 270 racemic-((5R,9S)-2-methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(quinolin-6-yl)methanone; 54.92

No. approx. Connection name IR ₅₀ MGL (nM) 271 (4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 20.42 272 (2-fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 4.22 273 (2-fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 6.39 274 (3-fluoro-5-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7.30 275 (3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 18.07 276 (4-fluoro-3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 329.91 277 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 352.78 278 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-5-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 21.66 279 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; 43.04 280 (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.49 281 (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 55.87 282 (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 87.90 283 (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 10.30 284 (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 19.45 285 (2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 319.89 286 (2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 163.01 287 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)phenyl)methanone; 368.21 288 (5-methoxy-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 2.77 289 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanone; 206.92 290 (6-isopropylpyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 38.61 291 (6-methoxypyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; 296.89 292 (6-(dimethylamino)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 17.17 293 (5-methoxy-4-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 10.67 294 (6-methoxy-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 11.24 295 (5-fluoro-6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 67.92 296 (5-fluoro-2-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 46.16 297 (5,6-dimethoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 13.63 298 (5,6-dimethoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 31.07 299 (3-chloro-2-methoxypyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.73 300 (5-chloro-6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 35.46 301 (4-chloro-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 66.70 302 (4-chloro-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.26 303 (3-chloro-5-fluoropyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 23.74 304 (6-cyclopropyl-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 92.56 305 1-(5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-2-yl)cyclopropan-1-carbonitrile; 176.60 306 (2-(1H-pyrazol-1-yl)pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 62.85 307 (4-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 38.04 308 (4-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 11.86 309 (6-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 9.64 310 (6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 372.99 311 (4-methoxy-5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 618.44 312 (6-methyl-3-(1H-1,2,4-triazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 16.23 313 (5-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 183.40 314 (4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 48.55 315 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)methanone; 87.36 316 (5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 21.30 317 (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 12.08 318 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; 7.81 319 (1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 23.70 320 (5-ethyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 185.70 321 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone; 21.04 322 (5-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 97.01 323 (3-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 213.30 324 (3-fluoro-1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 33.92 325 (5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 22.41 326 (1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 89.21 327 (1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 31.28 328 (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 140.70 329 Indolizin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; 6.68 330 (4-fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.14 331 (6-fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.93 332 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 2.19 333 (4-methoxypyrazole[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 0.87 334 (6-methoxypyrazole[1,5-a] pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 18.93 335 Imidazo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 11.12 336 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,5-a]pyridin-6-yl)methanone; 8.76 337 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyridin-6-yl)methanone; 3.76 338 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-6-yl)methanone; 7.88 339 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-5-yl)methanone; 11.94 340 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-5-yl)methanone; 4.86 341 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-6-yl)methanone; 4.95 342 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-6-yl)methanone; 139.99 343 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-5-yl)methanone; 9.76 344 Imidazo[1,2-a]pyridin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7.79 345 (7-fluoroimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 88.72 346 (7-chloroimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 187.28 347 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl) methanone; 0.68 348 (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 11.76 349 ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 2.73 350 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone; 0.94 351 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone; 91.18 352 (2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 3.07 353 (2-methyl-2H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 14.24 354 (2,7-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 6.96 355 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone; 54.78 356 (5-isopropyl-3-methylpyrazolo[1,5-a]pyrimidin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1.76 357 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,3,5-trimethylpyrazolo[1,5-a]pyrimidin-7-yl)methanone; 39.62 358 (7-cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 9.15 359 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 10.11 360 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-b]pyridazin-3-yl)methanone; 5.91 361 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyrazin-8-yl)methanone; 60.26 362 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,5,8-trimethylimidazo[1,2-a]pyrazin-3-yl)methanone; 25.88 363 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone; 1.61 364 (2,7-dimethylimidazo[1,2-b]pyridazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 5.73 365 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methanone; 17.89 366 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone; 61.94 367 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone; 1.61 368 (1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 7.00 369 (1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 6.49 370 [1,2,4]triazol[4,3-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 737.90 371 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyrazin-1-yl)methanone; 32.14 372 ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl)methanone; 2.68 373 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methylquinolin-6-yl)methanone; 0.46 374 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-hydroxyquinolin-6-yl)methanone; 8.98 375 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl) quinoline 1-oxide; 23.03 376 ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl-4-t) methanone; n/a 377 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylquinazolin-4-yl)methanone; 9.17 378 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2-d) methanone; 2.08 379 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2,3-d2) methanone; 5.37 380 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 155.60 381 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 50.30 382 ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,6,6-trimethyl-6,7-dihydro-4H-pyrazol[5,1-c][1,4]oxazin-3-yl)methanone; 250.50 383 (3-chlorophenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 16.93 384 (3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 9.07 385 ((5R,8S)-3-(2,5-difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)( 3-methoxyphenyl) methanone; 41.39 386 (3-methoxyphenyl)((5R,8S)-2-methyl-3-(2,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; 141.09 387 ((5R,8S)-3-(2,3-difluorophenyl)-2-methyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)( 3-methoxyphenyl) methanone; 92.24 388 (2,3-dimethoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[ c]pyrazol-9-yl)metonone; 6.27 389 (2-fluoro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epiminecyclohepta[c]pyrazol-9-yl)metonone; 7.47 390 (2-chloro-3-methoxyphenyl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epiminecyclohepta[c]pyrazol-9-yl)metonone; 1.19 391 (6-methoxypyridin-2-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epiminecyclohepta[c]pyrazol-9-yl)metonone; 309.89 392 (1,5-dimethyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)metonone; 172.78 393 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3-fluoro-5-methylphenyl)-2-methyl-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 14.57 394 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 27.30 395 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,4-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 22.25 396 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(2,4-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 197.52 397 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-3-(3,5-difluorophenyl)-2-methyl-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 4.94 398 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(2,3,4-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 67.94 399 (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 25.85 400 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methyl-4-(trifluoromethyl)-1H-imidazol-5-yl)methanone; 576.90 401 (1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epimincyclohepta[c]pyrazol-9-yl)methanone; 68.44 402 (6-fluoro-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 44.21 403 (2,3-dimethyl-1H-indol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8- hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 442.08 404 (1H-indazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8- epiminecyclohepta[c]pyrazol-9-yl)metonone; 107.70 405 (1H-benzo[d]imidazol-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 323.00 406 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; 23.46 407 Furo[3,2-c]pyridin-4-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro -5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 590.20 408 (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 198.61 409 (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 116.90 410 Imidazo[1,2-a]pyridin-5-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 119.29 411 Imidazo[1,2-a]pyridin-3-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro- 5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 311.03 412 (2-chloroimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 5.91 413 (7-methoxyimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 721.61 414 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 40.84 415 (2,5-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6, 7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 52.78 416 (2,6-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6, 7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 512.27 417 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; 156.71 418 (5-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 320.33 419 (2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 21.68 420 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone; 16.27 421 (5-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4 ,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 33.13 422 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyridin-3-yl)methanone; 86.22 423 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; 15.19 424 (6-methoxypyrazole[1,5-a]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7, 8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 295.80 425 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl)methanone; 42.62 426 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyrazin-3-yl)methanone; 159.99 427 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; 229.09 428 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone; 15.38 429 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; 159.40 430 (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5, 6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone; 285.69 431 ((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)(quinolin-6-yl) methanone; 16.75 432 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-8-yl)methanone; 5.95 433 ((5S,8R)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-6-yl)methanone; > 10000 434 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinolin-6-yl)methanone; 18.52 435 (2,4-dimethylquinolin-7-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5, 8-epimincyclohepta[c]pyrazol-9-yl)methanone; 52.46 436 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(6-methylquinolin-8-yl)methanone; 5.44 437 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(quinoxalin-6-yl)methanone; 9.93 438 (2,3-dimethylquinolin-6-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5, 8-epimincyclohepta[c]pyrazol-9-yl)methanone; 73.30 439 ((5R,8S)-2-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)(quinoxalin-5-yl) methanone; 58.04 440 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(1,5-naphthyridin-3-yl)methanone; 478.08 441 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 183.11 442 ((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl )(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; 667.27 443 Isochroman-7-yl((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6,7,8-hexahydro-5,8-epimincyclohepta[c] pyrazol-9-yl) methanone; And 76.93 444 (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)((5R,8S)-2-methyl-3-(3,4,5-trifluorophenyl)-2,4,5,6 ,7,8-hexahydro-5,8-epimincyclohepta[c]pyrazol-9-yl)methanone. 26.71

Claims (541)

1. Compound having the structure of formula (I)

where R ² is selected from the group consisting of: (a)

; (b) a 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyrimidinyl substituted with C _1-4 alkyl or OC _1-4 alkyl; and pyridinyl, the pyridinyl being substituted with one or two substituents each independently selected from the group consisting of halo, C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, C _3-6 cycloalkyl, NH ₂ , CN, N(CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

And

; (c) a 5-membered heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

And

; (d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; (e) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; And (f)

,

,

,

,

,

,

And

; where R ^a is selected from the group consisting of H, halogen, C _1-4 alkyl, OC _1-4 alkyl, C _1-4 haloalkyl and OC _1-4 haloalkyl; R ^a1 is selected from the group consisting of C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, N(C=O)CH ₃ , oxazol-2-yl, pyrimidin-2-yl and 5-membered a heteroaryl ring containing two, three or four nitrogen atom members, the 5-membered heteroaryl ring being optionally substituted with one R ^a member; R ^b is H or C _1-4 alkyl; R ^c is H or C _1-4 haloalkyl; R ^d is H or halogen; R ^e is selected from the group consisting of H, halogen, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl and C _3-6 cycloalkyl; R ^f is selected from the group consisting of H, C _1-4 alkyl, CH ₂ CH ₂ OH, C _1-4 haloalkyl, cyclopropyl, phenyl and phenyl substituted with CF ₃ ; R ^g is selected from the group consisting of H, OC _1-4 alkyl and C _1-4 haloalkyl; R ⁱ is H, halogen, C _1-4 alkyl, C _1-4 haloalkyl, OH, OC _1-4 alkyl, OC _1-4 haloalkyl, C _3-6 cycloalkyl; R ^j is selected from the group consisting of H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ; R ³ is selected from the group consisting of: (g) phenyl, where phenyl is independently substituted with one, two or three substituents selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, and OC _1-4 alkyl; (h) 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; And (i) cyclopropyl; And R ⁴ is C _1-4 alkyl or C _3-4 cycloalkyl; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers. 2. The compound according to claim 1, wherein R ² is

, where R ^a represents H, halogen, C _1-4 alkyl or OC _1-4 alkyl; and R ^a1 is C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl or (C=O)NHCH ₃ . 3. The compound according to claim 1, in which R ² is:

4. The compound according to claim 1, in which R ² is:

, where R ^a represents H, halogen, C _1-4 alkyl, OC _1-4 alkyl or C _1-4 haloalkyl; and R ^a1 is:

5. The compound according to claim 4, where R ^a1 is:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

. 6. A compound according to claim 4 wherein R ^a is H, Cl, F, CH ₃ , CF ₃ or OCH ₃ . 7. A compound according to claim 4 wherein R ^b is H or CH ₃ . 8. A compound according to claim 4 wherein R ^c is H or CF ₃ . 9. A compound according to claim 4, wherein R ^d is H, Cl, or F. 10. The compound according to claim 1, in which R ² is:

11. The compound according to claim 1, in which R ² is:

12. The compound according to claim 1, in which R ² is:

13. The compound according to claim 1, in which R ² is:

14. The compound according to claim 1, in which R ² is:

,

or

. 15. The compound according to claim 1, in which R ² is

where R ^a is H, Cl, Br, F or OCH ₃ and R ^a1 is OCH ₃ or

16. The compound according to claim 1, in which R ² is:

17. The compound according to claim 1, in which R ² is:

18. The compound according to claim 1, in which R ² is:

19. The compound according to claim 1, in which R ² is:

20. The compound according to claim 1, in which R ² is:

21. The compound according to claim 1, in which R ² is:

22. The compound according to claim 1, in which R ² is

or

23. The compound of claim 22 wherein R ^e is independently selected from the group consisting of H, halo, C _1-4 alkyl _, C _1-4 haloalkyl, OC _1-4 alkyl, and cyclopropyl. 24. The compound of claim 22 wherein R ^f is selected from the group consisting of H, C _1-4 alkyl, CH ₂ CH ₂ OH, CH ₂ CF ₃ , cyclopropyl, phenyl, and phenyl substituted with CF ₃ . 25. A compound according to claim 22 wherein R ^g is H, OCH ₃ or CF ₃ . 26. The compound according to claim 1, in which R ² is:

27. The compound according to claim 1, in which R ² is

or

28. The compound according to claim 27, in which R ^a is independently selected from the group consisting of H, Cl, F, C _1-4 alkyl, OC _1-4 alkyl and C _1-4 haloalkyl; and R ^b is CH ₃ or CH(CH ₃ ) ₂ . 29. The compound according to claim 1, in which R ² is:

30. The compound according to claim 1, in which R ² is

. 31. The compound according to claim 1, in which R ² is:

32. The compound according to claim 1, in which R ² is:

33. The compound according to claim 1, in which R ² is:

34. The compound according to claim 1, in which R ² is:

35. The compound according to claim 1, in which R ² is:

36. The compound according to claim 1, in which R ² is:

37. The compound according to claim 1, in which R ² is:

38. The compound according to claim 1, in which R ² is:

39. The compound according to claim 1, in which R ² is:

40. The compound according to claim 1, in which R ² is:

. 41. The compound according to claim 1, in which R ² is:

42. The compound according to claim 1, where R ³ is:

43. A compound according to claim 1 wherein R ³ is cyclopropyl and R ⁴ is CH ₃ . 44. The compound according to p. 1, in which R ³ represents 5-(trifluoromethyl)-2-thienyl or 1-methylindol-2-yl; and R ⁴ is CH _3. 45. The compound according to claim 1, where R ³ is 3-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl and 4-chloro-3-fluorophenyl . 46. A compound according to claim 1 wherein R ⁴ is CH ₃ . 47. A compound according to claim 1 wherein R ⁴ is cyclopropyl. 48. The compound according to claim 1, where R ² is

where R ^a is F, Cl or OCH ₃ , R ^a1 is OCH ₃ , CH ₃ or 2H-1,2,3-triazol-2-yl and R ⁴ is CH ₃ . 49. The compound according to p. 1, having the structure of formula (1A)

where R ² is selected from the group consisting of: (a)

(b)

(c)

(d)

R ⁴ is CH ₃ or cyclopropyl; R ^q is halogen or CHF ₂ ; And n is 0, 1 or 2; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers. 50. The compound according to p. 1, having the structure of formula (1B)

where R ² is phenyl optionally independently substituted with one or two substituents selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, NH(C =O)(CH ₃ ),

where R ^a is selected from the group consisting of H, halogen, C _1-4 alkyl, OC _1-4 alkyl and C _1-4 haloalkyl; R ^b is C _1-4 alkyl; R ^c is H or CF ₃ ; R ^d is H or halogen; each R ^q is independently selected from the group consisting of Cl, F, CF ₃ and OCH ₃ ; And n is 0, 1, 2, or 3; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers. 51. The compound according to p. 1, having the structure of formula (1C)

where R ² is selected from the group consisting of: (a) a 5-membered heteroaryl selected from the group consisting of:

And (b) a 6-membered heteroaryl selected from the group consisting of: pyridazin-4-yl; pyrazin-2-yl; pyrimidinyl; pyrimidinyl substituted with C _1-4 alkyl or C _1-4 alkyl; and pyridinyl, the pyridinyl being substituted with one or two substituents each independently selected from the group consisting of halo, C _1-4 alkyl, OC _1-4 alkyl, OC _1-4 haloalkyl, cyclopropyl, NH ₂ , CN, N( CH ₃ ) ₂ ,

,

,

,

,

,

,

,

,

And

; where R ^a is selected from the group consisting of H, halo, OC _1-4 alkyl and C _1-4 haloalkyl; R ^b is C _1-4 alkyl; R ^e is selected from the group consisting of F, C _1-4 alkyl, CF ₂ H, CF ₃ , OCH ₃ and cyclopropyl; R ^f is selected from the group consisting of H, C _1-4 alkyl, cyclopropyl and phenyl; R ^g is H or CF ₃ ; And R ³ is phenyl substituted with one, two or three substituents each independently selected from the group consisting of Cl and F; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers. 52. The compound according to claim 51, in which R ² is:

53. The compound according to claim 51, in which R ² is:

54. The compound according to p. 1, having the structure of formula (1D)

where Ring A is selected from the group consisting of: (c) 6,6-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; And (d) 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

And

; where R ^a is selected from the group consisting of H, Cl, F, CH ₃ , OCH ₃ , CF ₃ and CF ₂ H; R ^b is H or CH ₃ ; R ^c is H or CF ₃ ; R ^d is selected from the group consisting of H, Cl and F; R ^e is selected from the group consisting of H, C _1-4 alkyl and cyclopropyl; R ⁱ is selected from the group consisting of H, Cl, Br, CH ₃ , CF ₃ , OH and OCH ₂ CH ₂ F; R ^j is selected from the group consisting of H, halogen, OCH ₃ , OH, NH ₂ and NO ₂ ; And R ³ is cyclopropyl, 1-methyl-1H-indol-2-yl or phenyl substituted with one, two or three substituents each independently selected from the group consisting of Cl, F, CH ₃ , OCH ₃ and CF ₃ ; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers. 55. The compound according to claim 54, in which R ³ is:

56. The compound according to claim 54, in which ring A is:

57. The compound according to claim 54, in which ring A is:

58. A compound selected from the group consisting of the following: racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6 -yl) methanone; ((5R,9S)-3-cyclopropyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6- yl) methanone; racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; (2-chloro-3-methoxyphenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; (2-chloro-3-methoxyphenyl) ((5S,9R)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole- 10-yl) methanone; racemic (2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (4-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (3-(1H-imidazol-1-yl)phenyl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl) methanone; racemic (1-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-chloro-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1-phenyl -1H-1,2,4-triazol-3-yl) methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (1-phenyl -1H-pyrazol-3-yl) methanone; racemic (5-methoxy-1-phenyl-1H-pyrazol-3-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl) methanone; racemic (1-methyl-1H-indol-4-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl)methanone; racemic (5-chloro-1H-indol-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) methanone; racemic (7-methyl-1H-indazol-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta [c]pyrazol-10-yl) methanone; racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic [1,2,4]triazol[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (4-chloroquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; racemic (4-hydroxyquinolin-6-yl) ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl) methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-5 -yl) methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinoxalin-6 -yl) methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinazolin-6 -yl) methanone; racemic ((5R,9S)-2-methyl-3-phenyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)(2-( trifluoromethyl)-1,8-naphthyridin-3-yl) methanone; racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(4-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (1,4-dimethyl-1H-pyrazol-3-yl)((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; racemic ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; racemic (2-chloro-3-methoxyphenyl) ((5R,9S)-3-(3-fluorophenyl-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; racemic-((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-phenyl-1H-1,2,4-triazol-3-yl) methanone; ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( furo[3,2-b]pyridin-6-yl) methanone; racemic ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; ((5S,9R)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; ((5R,9S)-3-(3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinolin-6-yl) methanone; racemic ((5R,9S)-2-cyclopropyl-3-(3-fluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; (3-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(1H-pyrazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(1H-pyrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(1H-tetrazol-1-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5 ,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-chloro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-isopropyl-1H-1,2,4-triazol-3-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(2-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl) methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)methanone; (1-(3-chlorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl) methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 5-methyl-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)methanone; (1-benzyl-1H-1,2,4-triazol-3-yl)((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; benzo[d]isoxazol-3-yl((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)( 1-methyl-1H-indazol-3-yl) methanone; racemic ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3-chlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) ( quinoxalin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-(2-fluoroethoxy)quinolin-6-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(2-fluoroethoxy)phenyl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(2-(fluoro-18F)ethoxy)phenyl)methanone; racemic (2-(2H-1,2,3-triazol-2-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(1H-1,2,4-triazol-5-yl)phenyl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl) methanone; (2-(5-chloro-1H-1,2,4-triazol-3-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone; (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(3-fluoro-2-(oxazol-2-yl)phenyl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(2-(pyrimidin-2-yl)phenyl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-methoxy-1-methyl-1H-pyrazol-4-yl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-ethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; racemic (5-cyclopropyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-cyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9 -hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic (5-cyclopropyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-methyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl)(5-ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-fluoropyridin-4-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; (5-aminopyridin-2-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxybenzofuran-2-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (2-methylbenzo[d]oxazol-6-yl) methanone; (2-aminobenzo[d]oxazol-6-yl) ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (furo[3,2-b]pyridin-2-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-c]pyridin-4-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl) methanone; racemic ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; ((5S,9 R)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (isoquinolin-3-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-7-yl)methanone; (4-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; (3-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; (8-bromoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; (2-chloroquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-5-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-fluoroquinolin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-(trifluoromethyl)quinolin-6-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-hydroxyquinolin-6-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxyquinolin-3-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(8-nitroquinolin-6-yl) methanone; (8-aminoquinolin-6-yl)((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9- epiminecycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinazolin-7-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (quinazolin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylquinoxalin-6-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (7-fluoroquinoxalin-6-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,6-naphthyridin-5-yl) methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-3-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,8-naphthyridin-4-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,7-naphthyridin-4-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1,6-naphthyridin-4-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl ) (1,5-naphthyridin-2-yl) methanone; 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-1-(2-fluoroethyl)quinoline-4(1H)-one; 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl)-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl)methanone; racemic ((5R,9S)-3-(3,4-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10- yl) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(3-fluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(4-chloro-3-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-methanone; ((5R,9S)-3-(3-chloro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylbenzo[d]oxazol-6-yl)methanone; ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; ((5R,9S)-3-(3-chloro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; ((5R,9S)-3-(3,5-dimethoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxy-1-methyl-1H-pyrazol-4-yl) methanone; (5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(1-phenyl-1H-1,2,4-triazol-3-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(5-methoxypyridin-3-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-methylbenzo[d]oxazol-6-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(furo[3,2-b]pyridin-2-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,5-a]pyridin-8-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(imidazo[1,2-a]pyridin-3-yl)methanone; (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-dichlorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinoxalin-6-yl)methanone; racemic ((5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinolin-6-yl) methanone; racemic ((5R,9S)-3-(3-(difluoromethyl)-4-fluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone; ((5R,9S)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c] pyrazol-10-yl) (quinoxalin-6-yl) methanone; (3-chloro-5-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; N-(3-methoxy-5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazole-10-carbonyl)phenyl)acetamide; (3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-methyl-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone; (2-(1H-imidazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro -2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-2-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(1-methyl-1H-pyrazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(4-fluoro-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; (3-(4-Methoxy-1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanone; (3-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)-4-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(1H-1,2,3-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4,5,6,7-tetrahydropyrazol[1,5-a]pyridin-3-yl)methanone; (3,4-dihydro-2H-pyrano[3,2-b]pyridin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)methanone; (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methanone; (1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-ethyl-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1-phenyl-5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl)methanone; (5-methoxy-1-phenyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-(4-fluorophenyl)-5-methyl-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)- 4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-(2-methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-(3-methoxyphenyl)-1H-1,2,4-triazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5, 6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-isopropoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-(trifluoromethoxy)pyridin-2-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(trifluoromethoxy)pyridin-2-yl)methanone; 6-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-carbonyl) picolinonitrile; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazin-2-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-4-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyridazin-4-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrimidin-5-yl)methanone; (5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-(1H-pyrrol-1-yl) pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-(1H-imidazol-1-yl) pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-(pyrrolidin-1-yl)pyridin-3-yl)methanone; 1-(5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-3-yl)pyrrolidin-2-one; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-morpholinopyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylindolizin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (2-methylbenzo[d]oxazol-6-yl) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-5-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyridin-2-yl)methanone; imidazo[1,2-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; imidazo[1,5-a]pyridin-5-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; imidazo[1,5-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; imidazo[1,2-a]pyridin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-3-yl)methanone; (1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-b]pyridazin-5-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrrolo[1,2-a]pyrazin-8-yl)methanone; (4-methoxy-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-b]pyridazin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-2-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrimidin-5-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(pyrazolo[1,5-a]pyrazin-3-yl)methanone; imidazo[1,2-b]pyridazin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; imidazo[1,2-b]pyridazin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; [1,2,4]triazol[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)methanone; imidazo[1,2-a]pyrimidin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-4-yl)methanone; isoquinolin-1-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinolin-6-yl) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-7-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinazolin-4-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl) (quinoxalin-6-yl) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylquinoxalin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-2-yl)methanone; cinnolin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; cinnolin-6-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-2-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,5-naphthyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,6-naphthyridin-8-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; ((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-3-(3,5-difluoro-4-methoxyphenyl)-2-methyl-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanone; ((5R,9S)-3-(3,4-difluoro-5-methoxyphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole -10-yl)(quinolin-6-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-1H-indol-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c ]pyrazol-10-yl) (quinolin-6-yl) methanone; racemic-((5R,9S)-2-methyl-3-(5-(trifluoromethyl)thiophen-2-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)(quinolin-6-yl)methanone; (4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; (2-fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-fluoro-4-methoxyphenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-fluoro-5-(1H-pyrazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-fluoro-3-(4H-1,2,4-triazol-4-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-5-(4H-1,2,4-triazol-4-yl)phenyl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methyl-3-(4H-1,2,4-triazol-4-yl)phenyl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)-3-(trifluoromethyl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4 ,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl)phenyl)methanone; (5-methoxy-2-(1H-1,2,4-triazol-1-yl)phenyl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)methanone; (6-isopropylpyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methoxypyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5, 9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-(dimethylamino)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H -5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-methoxy-4-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methoxy-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-6-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-2-methoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5,6-dimethoxypyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5,6-dimethoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H- 5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-chloro-2-methoxypyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-chloro-6-methoxypyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-chloro-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-chloro-5-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-chloro-5-fluoropyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-cyclopropyl-2-methylpyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; 1-(5-((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazole-10-carbonyl)pyridin-2-yl)cyclopropan-1-carbonitrile; (2-(1H-pyrazol-1-yl)pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8 ,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-methoxy-5-(1H-pyrazol-1-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6 ,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methyl-3-(1H-1,2,4-triazol-1-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl) -4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-(4H-1,2,4-triazol-4-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(4H-1,2,4-triazol-4-yl)pyridin-2-yl)methanone; (5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4.5 ,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methyl-4-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone; (1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9- hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-ethyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(1,3,5-trimethyl-1H-pyrazol-4-yl)methanone; (5-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-methoxy-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-fluoro-1,5-dimethyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (5-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-cyclopropyl-5-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-cyclopropyl-3-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; indolizin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[ c]pyrazol-10-yl)methanone; (4-fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-fluoropyrazolo[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; (4-methoxypyrazole[1,5-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (6-methoxypyrazole[1,5-a] pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; imidazo[1,5-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,5-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylimidazo[1,2-a]pyridin-5-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-5-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,2-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-5-yl)methanone; imidazo[1,2-a]pyridin-3-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (7-fluoroimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (7-chloroimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8, 9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl) methanone; (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone; (2-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2-methyl-2H-indazol-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro- 2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (2,7-dimethylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanone; (5-isopropyl-3-methylpyrazolo[1,5-a]pyrimidin-7-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,3,5-trimethylpyrazolo[1,5-a]pyrimidin-7-yl)methanone; (7-cyclopropyl-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylpyrazolo[1,5-b]pyridazin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-a]pyrazin-8-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,5,8-trimethylimidazo[1,2-a]pyrazin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2-methylimidazo[1,2-b]pyridazin-3-yl)methanone; (2,7-dimethylimidazo[1,2-b]pyridazin-3-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7, 8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-7-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone; (1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; (1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6, 7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; [1,2,4]triazol[4,3-a]pyridin-7-yl((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7 ,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(3-methylimidazo[1,5-a]pyrazin-1-yl)methanone; ((5R,9S)-3-(3-fluoro-5-methylphenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinolin-6-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(4-methylquinolin-6-yl)methanone; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(2-hydroxyquinolin-6-yl)methanone; 6-((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -carbonyl) quinoline 1-oxide; ((5R,9S)-3-(3,5-difluorophenyl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazol-10-yl )(quinolin-6-yl-4-t) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(6-methylquinazolin-4-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2-d) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(quinoxalin-6-yl-2,3-d2) methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methanone; And ((5R,9S)-2-methyl-3-(3,4,5-trifluorophenyl)-4,5,6,7,8,9-hexahydro-2H-5,9-epimincycloocta[c]pyrazole-10 -yl)(2,6,6-trimethyl-6,7-dihydro-4H-pyrazol[5,1-c][1,4]oxazin-3-yl)methanone; and its pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers.