Monoacylglycerol lipase regulators

Abstract

The fused and bridged compounds of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them, include methods of treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer, and ophthalmic conditions: [Formula 1] TIFF2023518511000311.tif30128 formula, R 1a , R 1b , R 2 , and R 3 is defined herein.

Description

[Technical Field]

[0001] The present invention relates to certain arylpiperidine chemical compounds having MGL modulating properties, pharmaceutical compositions containing these chemical compounds, chemical processes for preparing these chemical compounds, and their use in treating diseases, disorders or conditions associated with MGL receptor activity in subjects, particularly humans. [Background technology]

[0002] Asa and Δ 9 Analogs of -tetrahydrocannabinol have been used for therapeutic purposes since the days of folk medicine. The endocannabinoid system consists of two G protein-coupled receptors: cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346, 561-4) and 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 (Herkename et al., Proc. Nat. Acad. Sci., 1990, 87(5), 1932-1936). CB1 is also expressed peripherally 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) and under certain conditions in the brain (inflammation) (Benito et al., Brit J Pharmacol, 2008, 153, 277-285), as well as in skeletal muscle (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110), and cardiac muscle (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

[0003] In 1992, N-arachidonoylethanolamine (AEA, or anandamide) was identified as an endogenous ligand for cannabinoid receptors (Devane et al., Science, 1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) was also identified as an additional endogenous ligand for cannabinoid receptors (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97). It was reported that the concentration of 2-AG in rat brain was at least 100-fold higher than that of anandamide (Buczynski and Parsons, Brit J Pharmacol, 2010, 160(3), 423-42). Therefore, 2-AG may play a more important physiological role in the brain 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 agonist at CB1 and CB2 receptors, whereas anandamide is a partial agonist at both receptors (Suguira et al., Prog Lipid Res., 2006, 45(5):405-46). Unlike many classical neurotransmitters, endocannabinoids signal via 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 (also known as MGLL, MAG lipase, and MGL) is a serine hydrolase that degrades 2-AG 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). Anandamide is hydrolyzed by fatty acid amide hydrolase (FAAH) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). MGL exists in both soluble and membrane-bound forms (Dinh et al., Proc Natl Acad Sci U S A., 2002, Aug 6;99(16):10819-24). In the brain, MGL is located 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 high CB1 receptor density. Compared to wild-type controls, genetic disruption of MGL expression results in a 10-fold increase in brain 2-AG levels without affecting anandamide concentrations (Schlosburg et al., Nat Neurosci., 2010, Sep;13(9):1113-9).

[0004] Therefore, MGL modulation offers an interesting strategy for enhancing the cannabinoid system. A major advantage of this approach is that only brain regions where endocannabinoids are actively produced are modulated, potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL with covalent inhibitors in animals has been found to increase 2-AG content in brain and peripheral tissues, producing analgesic, anxiolytic, and anti-inflammatory effects that depend 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; Bedse et al., Transl Psychiatry., 2018, Apr 26, 8(1):92). In addition to MGL's role in terminating 2-AG signaling, MGL modulation, including MGL inhibition, also promotes CB1 / 2-independent effects on neuroinflammation (Nomura et al., Science., 2011, Nov 11;334(6057):809-13).MGL regulation, including MGL inhibition, has been shown to be beneficial in a variety of conditions, including 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):443-453), neurodegeneration 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), and 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 status epilepticus (Terrone et al. al.,Epilepsia.,2018,Jan,59(1),79-91; von Ruden et al.,Neurobiol Dis.,2015,May;77:238-45), resulting in a reduction in pro-inflammatory prostanoid signaling in animal models.

[0005] Therefore, by enhancing the cannabinoid system and attenuating the pro-inflammatory cascade, MGL modulation, including MGL inhibition, offers a compelling therapeutic approach for the treatment of a vast number of complex diseases. Importantly, MGL modulation, including MGL inhibition, in animals has been shown to improve Δ9 -Does not produce the full range of neurobehavioral effects observed with 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).

[0006] Decreased endocannabinoid activity is a risk factor for depression, anxiety, and post-traumatic stress disorder. Human cannabis use for thousands of years and short-term human treatment with the endocannabinoid antagonist rimonabant support this hypothesis. 2-AG levels are decreased in individuals with major depression (Hill et al., Pharmacopsychiatry., 2008, Mar;41(2):48-53; Hill et al., Psychoneuroendocrinology., 2009, Sep;34(8):1257-1262). Low circulating 2-AG concentrations can predict the susceptibility to depression (Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Decreased circulating concentrations of 2-AG have previously 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 progressive decrease in circulating 2-AG concentrations, which correlated with the onset of a decrease in positive affect (Yi et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97. Rimonabant, a CB1 receptor inverse agonist / antagonist, was withdrawn from the market due to a high incidence of severe depression and suicidal ideation (Christensen et al., The Lancet, 2007, 370, 1706-1713). Therefore, MGL modulators may be useful for the treatment of mood disorders, anxiety, PTSD, autism spectrum disorders, and Asperger's syndrome (Folkes et al., J Clin Invest. 2020;130(4):1728-1742; Jung et al., Nature Communications, 2012, 3, 1080; Wang et al., Mol Psychiatry, 2018, 8, 23(8):1798-1806).

[0007] Cannabinoid receptor agonists are used clinically to treat pain, spasticity, emesis, 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). Therefore, MGL modulators, including MGL inhibitors, are also potentially useful for these indications. MGL exerts CB1-dependent analgesic effects in animal models of noxious chemical, inflammatory, thermal, and neuropathic pain (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). MGL blockade reduces mechanical and acetone-induced cold allodynia in mice subjected to chronic sciatic nerve constriction injury (Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10). MGL inhibition results in an opiate-sparing event accompanied by decreased tolerance, constipation, and cannabis-like side effects (Wilkerson et al., J Pharmacol Exp Ther., 2016, Apr;357(1):145-56). MGL blockade is protective in models of inflammatory bowel disease (Alhouayek et al., FASEB J., 2011, Aug;25(8):2711-21). MGL inhibition also reverses paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy (Curry et al., J Pharmacol Exp Ther., 2018, Jul;366(1):169-18). MGL inhibitors are also potentially useful in treating chronic inflammatory conditions of the bladder, such as interstitial cystitis (Chinnadurai et al., Med Hypotheses 2019, Oct;131-109321).

[0008] Inhibition of 2-AG hydrolysis exerts antiproliferative activity and reduces prostate cancer cell invasiveness (Nithipatikom et al., Cancer Res., 2004, December 15, 64(24):8826-30; Nithipatikom et al., Biochem Biophys Res Commun., 2005, July 15, 332(4):1028-33; Nithipatikom et al., Prostaglandins Other Lipid Mediat., 2011, February 94(1-2):34-43). MGL is upregulated in invasive human cancer cells and primary tumors and has the unique role of providing a lipolytic source of free fatty acids for the synthesis of oncogenic signaling lipids that promote cancer invasiveness. Thus, beyond the physiological role of MGL in mediated endocannabinoid signaling, MGL in cancer plays a distinct role in regulating the fatty acid precursor pool for the synthesis of pro-tumorigenic signaling lipids in human malignant cancer cells.

[0009] MGL blockade exhibits antiemetic and antiemetic effects in the lithium chloride model of emesis in shrews (Sticht et al., Br J Pharmacol., 2012, Apr, 165(8):2425-35).

[0010] MGL modulators, including MGL inhibitors, may be useful in regulating opiate drug dependence. MGL blockade reduces the intensity of naloxone-induced morphine withdrawal symptoms in mice. MGL blockade also attenuated symptoms during spontaneous withdrawal in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther., 2011, Oct., 339(1):173-85).

[0011] MGL modulators are also potentially useful in treating ocular conditions, including but not limited to glaucoma and disease states resulting from elevated intraocular pressure (Miller et al., Pharmaceuticals, 2018, 11, 50). Summary of the Invention [Means for solving the problem]

[0012] Embodiments of the present invention relate to chemical entities, pharmaceutical compositions comprising them, methods for making and purifying them, and methods for their use in the treatment of pathologies, diseases, and conditions associated with MGL modulation. A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation using at least one chemical entity of the present invention.

[0013] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description as well as by practice of the invention.

[0014] Described herein are compounds of formula (I):

[0015] [ka] [In the formula, R 1a is C 1~4 is alkyl, R 1b is H, or R 1a and R 1b together to form -CH2CH2- or -CH2CH2CH2-, R 2 teeth, (a) Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 phenyl or pyridyl, each optionally substituted with one or two substituents selected from cycloalkyl, or with two adjacent ring substituents which, together with the carbons to which they are attached, form a monocyclic cycloalkyl or heterocycloalkyl ring; (b) Halo, C 1~4Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 bicyclic heteroaryl optionally substituted with one or two substituents selected from cycloalkyl; R 3 is 1H-C 1~4 Alkyl-pyrazolyl, 1H-C 1~4 Haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H-(C 3~6 cycloalkyl)-pyrazolyl, or 1H-(C 3~6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from the group consisting of halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 optionally substituted with haloalkyl; However, R 2 But, Halo, C 1~4 Alkyl or C 1~4 When R is phenyl or pyridyl, each optionally substituted with haloalkyl, 1a and R 1b together form -CH2CH2- or -CH2CH2CH2-, or (b) R 3 is 1H-C 1~4 Alkyl-pyrazol-5-yl(

[0016] [ka] ) or 1H-C 1~4 Haloalkyl-pyrazol-5-yl (

[0017] [ka] ) is not a compound and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0018] In some embodiments, a compound of formula (I):

[0019] [ka] [In the formula, R 1a is C 1~4 is alkyl, R 1b is H, or R 1a and R 1b together to form -CH2CH2- or -CH2CH2CH2-, R 2 teeth, (a)

[0020] [ka] (b)

[0021] [ka] 5,6-fused or 6,5-fused heteroaryl selected from (c)

[0022] [ka] a fused 6,6-heteroaryl selected from (d)

[0023] [ka] is selected from R 3 teeth,

[0024] [ka] is a 5-membered heteroaryl ring selected from During the ceremony, Ra H, halo, C 1~4 Alkyl, C 1~4 Haloalkyl and OC 1~4 alkyl, R b is C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl,

[0025] [ka] is selected from Each R c Ha, Halo, C 1~4 Alkyl and OC 1~4 independently selected from alkyl, R d is H or C 1~4 is alkyl, Each R e independently, halo, C 1~4 Alkyl or C 1~4 is haloalkyl, Each R f is C 1~4 Alkyl, C 1~4 Haloalkyl and OC 1~4 independently selected from alkyl, R g is C 1~4 Alkyl or C 1~4 is haloalkyl, R h is H, C 1~4 Alkyl, C 1~4 haloalkyl, and cycloalkyl; n is 0, 1, or 2; m is 0, 1, or 2; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof. DETAILED DESCRIPTION OF THE INVENTION

[0026] As used herein, the terms "comprise," "contain," and "include" are used in their open, non-limiting sense.

[0027] Unless specifically limited in a particular use, the term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that are deemed equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein. "C 1~6 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain. 1~4 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain.

[0028] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocycle having from 3 to 12 ring atoms per carbocycle. Illustrative cycloalkyl groups include the following entities in the form of appropriately bonded moieties:

[0029] [ka]

[0030] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0031] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, where a hydrogen is optionally replaced with a halogen. 1~4The term "haloalkyl," as used herein, refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), as well as groups deemed equivalent to any one of the foregoing examples given ordinary skill in the art and the teachings provided herein.

[0032] The term "aryl" refers to a monocyclic aromatic carbocycle (a ring structure having ring atoms that are all carbon) having six atoms per ring (the carbon atoms of an aryl group are sp2 hybridized).

[0033] The term "phenyl" refers to the following moiety:

[0034] [ka] Represents.

[0035] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms and at least one nitrogen ring atom. A heteroaryl group is bonded via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, fused to a benzene ring.

[0036] As used herein, the term "5-membered heteroaryl" refers to a heteroaryl group, as defined above, having 5 ring atoms. Non-limiting examples of exemplary 5-membered heteroaryls include:

[0037] [ka]

[0038] As used herein, the term "6-membered heteroaryl" refers to a heteroaryl group, as defined above, having 6 ring atoms. Non-limiting examples of exemplary 6-membered heteroaryls include:

[0039] [ka]

[0040] As used herein, the term "5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl" refers to a heteroaryl group as defined above having 9 ring atoms. Non-limiting examples of illustrative 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl include:

[0041] [ka]

[0042] As used herein, the term "6,6-fused bicyclic heteroaryl" refers to a heteroaryl group as defined above having 9 ring atoms. Non-limiting examples of illustrative 6,6-fused bicyclic heteroaryls include:

[0043] [ka]

[0044] The term "heterocycloalkyl," as used herein, refers to a ring system that is non-aromatic, in which 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms, and which may optionally be fused to another ring (aromatic or heteroaromatic). Non-limiting examples of illustrative heterocycloalkyls include:

[0045] [ka]

[0046] Those of ordinary skill in the art will understand that the species of heteroaryl, heterocycloalkyl, cycloalkyl, and aryl groups listed or exemplified above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0047] The term "substituted" means that the specified group or moiety 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 is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0048] The term "variable point of attachment" means that a group may be attached at two or more alternative positions within a structure. The bond always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bond, as shown in the diagram below, are represented by a single diagram.

[0049] [ka]

[0050] Those skilled in the art will recognize that when more than one such substituent is present on a given ring, the binding of each substituent is independent of all others. The groups listed or exemplified above are not exhaustive.

[0051] The term "substituted" means that the specified group or moiety 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 is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0052] Any formula given herein is intended to represent the compound having the structure depicted by that structural formula, as well as specific variations or forms. Specifically, compounds of any formula given herein may have asymmetric centers and, therefore, may exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, and mixtures thereof, are considered to be within the scope of such formula. Because compounds of the present invention may have one or more asymmetric centers, such compounds may be produced as individual (R)- or (S)-stereoisomers, or as mixtures thereof. Thus, any formula given herein is intended to represent the racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Furthermore, any formula given herein is intended to refer to any one of hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly enumerated.

[0053] The term "R" at a stereocenter indicates that the stereocenter is in the R-configuration only, as defined in the art. Similarly, the term "S" means that the stereocenter is in the S-configuration only. As used herein, the term "RS" refers to a stereocenter that exists as a mixture of R- and S-configurations.

[0054] A compound containing one stereocenter depicted without a stereochemical bond designation is a mixture of two enantiomers. A compound containing two stereocenters depicted without a stereochemical bond designation is a mixture of four diastereomers. A compound containing two stereocenters labeled "RS" and depicted with a stereochemical bond designation is a binary mixture with the relative stereochemistry as depicted. An unlabeled stereocenter depicted without a stereochemical bond designation is a mixture of R- and S-configurations. For an unlabeled stereocenter depicted with a stereochemical bond designation, the absolute stereochemistry is as depicted.

[0055] Reference to a compound described herein refers to either (a) the actual stated form of the compound, or (b) any one of the forms of the compound in the medium in which the compound is believed to exist when named. For example, a reference to a compound such as R-COOH herein includes a reference to any one of R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound, for example, as it may exist in a tablet or some other solid pharmaceutical composition or preparation, R-COOH(sol) refers to the undissociated form of the compound in the solvent, and R-COO-(sol) refers to the dissociated form of the compound in the solvent, for example, the dissociated form of the compound in an aqueous environment, regardless of whether such dissociated form is derived from R-COOH, its salt, or any other entity that generates R-COO- when believed to have dissociated in the medium. In another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to exposing such entity to the form of the compound R-COOH present in the medium in which such exposure occurs. In yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" refers to (a) a chemically related form of such entity present in the medium in which such reaction occurs, reacting with (b) a chemically related form of the compound R-COOH present in the medium in which such reaction occurs. In this context, when such an entity is present, for example, in an aqueous environment, it is understood that the entity is exposed to species such as R-COOH(aq) and / or R-COO-(aq) (the subscript "(aq)" denotes "aqueous solution" in accordance with its conventional meaning in chemistry and biochemistry), since the compound R-COOH is present in such same medium. In these nomenclature examples, a carboxylic acid functional group has been selected, but this selection is not intended to be limiting and is merely illustrative. It is understood that similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen members, such as nitrogen members in amines, and any other group that interacts or transforms in a known manner in a medium containing the compound.Such interactions and transformations include, but are not limited to, dissociation, association, tautomerization, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. Further examples in this regard are not provided herein, as these interactions and transformations that occur in a given medium are known to those skilled in the art.

[0056] Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced in enriched form with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention in excess of natural abundance include, respectively: 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 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or 11 C labeled compounds may be particularly preferred for PET or SPECT studies. Additionally, heavier isotopes, such as deuterium (i.e., 2Substitution with, for example, H, or D, may confer certain therapeutic advantages as a result of greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by practicing the schemes described below or the procedures disclosed in the Examples and Preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0057] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same selection of that species for the variable elsewhere. In other words, when a variable appears more than once, the selection of a species from a specified list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0058] Term C n-m Alkyl refers to an aliphatic chain, whether straight or branched, where the total number of carbon members in the chain, N, satisfies n≦N≦m (m>n).

[0059] When the same substituents are assigned to various groups, the assignment of each specific substituent to each such group is meant to be made independently of the assignment of each specific substituent to the remaining groups. By way of example, and not by way of limitation, when each of the Q and R groups can be H or F, the selection of H or F for the Q group is made independently of the selection of H or F for the R group, and therefore the selection of the assignment for the Q group does not determine or condition the selection of the assignment for the R group, unless expressly indicated otherwise, and vice versa. In this regard, the exemplary claim language will be interpreted as "each of the Q and R groups is independently H or F" or "each of the Q and R groups is independently selected from H and F."

[0060] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0061] In another example, zwitterionic compounds are encompassed herein by reference to compounds known to form zwitterions, even if not explicitly named in their zwitterionic form. Terms such as zwitterion and its synonyms, zwitterionic compound, are well-known and standard names recognized by IUPAC that are part of the standard set of defined scientific names. In this context, the name zwitterion has been assigned the identifier CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally known, zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salt." While other sources refer to these compounds as "zwitterions," this latter term is a misnomer in still other sources. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula HNCHCOOH and, in some media (in this case, neutral media), forms a zwitterionic form. + H3NCH2COO - Zwitterions, zwitterionic compounds, inner salts, and zwitterions, in the known and well-established meanings of these terms, are within the scope of the present invention in all cases, as recognized by those skilled in the art. Since it is not necessary to name every embodiment that will be recognized by those skilled in the art, structures of zwitterionic compounds related to the compounds of the present invention are not explicitly shown herein. However, these are also part of the embodiments of the present invention. Because interactions and transformations in a given medium that lead to various forms of a given compound are known to those skilled in the art, further examples related thereto are not provided herein.

[0062] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a named variable is not intended to define the same selection of that species for that variable appearing elsewhere. In other words, when a variable appears more than once, the selection of the species from a named list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0063] As a first example in the terminology of substituents, the substituent S 1 例 is one of S1 and S2, and the substituent S 2 例 If is one of S3 and S4, then these assignments are 1 例 is S1 and S 2 例 is S3;S 1 例 is S1 and S 2 例 is S4;S 1 例 is S1 and S 2 例 is S4;S 1 例 is S2 and S 2 例 is S3;S 1 例 is S2 and S 2 例 is S3;S 1 例 is S2 and S 2 例 is S4; and refers to embodiments of the invention provided according to the equivalents of each of such alternatives. Therefore, the shorter term "S 1 例 is one of S1 and S2, and S 2 例is one of S3 and S4" is used for purposes of brevity and not as a limitation. The first example above of substituent terminology written in generic terms is meant to illustrate the various substituent assignments described herein.

[0064] Furthermore, when more than one assignment is given for any member or substituent, embodiments of the invention include the various groupings that can be made from the listed assignments and their equivalents when taken independently. As a second example in substituent terminology, the substituent S 例 When is described herein as being one of S1, S2, and S3, this list is 例 is S1;S 例 is S2;S 例 is S3;S 例 is one of S1 and S2; S 例 is one of S1 and S3; S 例 is one of S2 and S3; S 例 is one of S1, S2, and S3; and any equivalents of each of these alternatives. Therefore, the shorter term "S" is used herein. 例 is one of S1, S2, and S3" is used for purposes of brevity and not as a limitation. The second example above of substituent terminology stated in generic terms is intended to illustrate the various substituent assignments described herein.

[0065] Nomenclature “C i ~C j " or "C i~j " (j>i) when applied herein to a class of substituents is meant to refer to embodiments of the invention in which each and every number of carbon members from i to j, inclusive, is independently realized. By way of example, the terms C1-C3 independently refer to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0066] "Pharmaceutically acceptable salt" is intended to mean an acid or base salt of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally S.M. 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 those that are pharmacologically effective and suitable for contact with a patient's tissues without undue toxicity, irritation, or allergic response.

[0067] The compounds of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and thus may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0068] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyl phosphate ... Examples of suitable benzoates include benzo-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0069] Since the compounds of formula (I) may contain at least one nitrogen with basic character, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by cleavage with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or an organic acid (e.g., 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, pyranolic acid, etc.). The free bases can be prepared by treating them with any compatible mixture of acids such as sidylic acids (e.g., glucuronic acid or galacturonic acid), alpha-hydroxy acids (e.g., mandelic acid, citric acid, or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those given as examples herein, and any other acids and mixtures thereof that are considered equivalents.

[0070] The compound of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salt may be prepared 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 provided herein as examples, and any other base and mixture thereof that is considered equivalent or acceptable substitute in light of the ordinary level of skill in the art. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methyl-glucamine, and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0071] The compounds of the present invention (collectively "active agent(s)"), including the pharmaceutically acceptable salts thereof, whether alone or in combination, are useful as MGL modulators in the methods of the present invention. Such methods of modulating MGL include the use of a therapeutically effective amount of at least one chemical entity of the present invention.

[0072] In some embodiments, the MGL modulator is an inhibitor and is used in subjects diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity, such as those described herein. Symptoms or disease states are intended to be included within the scope of "disease, disorder, or condition."

[0073] Thus, the present invention relates to a method of treating a subject diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity using the active agents described herein. As used herein, the term "treat" or "treatment" is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of providing a therapeutic or prophylactic benefit through modulation of MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, arresting the progression of, reducing the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such a disease, disorder, or condition associated with MGL modulation. The term "subject" refers to a mammalian patient, e.g., a human, in need of such treatment.

[0074] The term "composition" refers to a product containing therapeutically effective amounts of specified ingredients, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0075] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL and substantially reduce or eliminate the catalytic activity of MGL, thereby increasing the concentration of MGL substrates. The term "modulated by MGL" is used to refer to conditions affected by modulation of the MGL enzyme, including conditions affected by inhibition of the MGL enzyme. The present disclosure relates to methods for treating, ameliorating, and / or preventing pain-related diseases, conditions, or disorders (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions, by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0076] The term "modulator" includes both inhibitors and activators, where an "inhibitor" refers to a compound that decreases, blocks, inactivates, desensitizes, or downregulates the expression or activity of MGL, and an "activator" is a compound that increases, activates, promotes, sensitizes, or upregulates the expression or activity of MGL.

[0077] As used herein, unless otherwise noted, the terms "affect" or "affected" (when referring to a disease, condition, or disorder affected by inhibition of MGL) include reducing the frequency and / or severity of one or more symptoms or manifestations of the disease, condition, or disorder, and / or preventing the progression of one or more symptoms or manifestations of the disease, condition, or disorder, or the progression of the disease, condition, or disorder.

[0078] In the treatment methods of the present invention, a therapeutically effective amount of at least one active agent according to the present invention is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. A "therapeutically effective amount" refers to an amount or dose sufficient to generally provide the desired therapeutic or prophylactic benefit in a subject in need of such treatment for a specified disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention can be determined by routine methods, such as modeling, dose escalation studies, or clinical trials, and by taking into account routine factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease, disorder, or condition, previous or current treatments the subject has received, the subject's health status and response to the drug, and the judgment of the treating physician. For a 70 kg human, an exemplary range of suitable doses is about 1 to 1000 mg / day, in single or multiple dose units (e.g., BID, TID, QID, or as required by the modality).

[0079] Once the improvement of the target disease, disorder or condition occurs, the dosage can be adjusted for prevention or maintenance treatment.For example, dosage or administration frequency, or both, can be reduced according to the function of symptoms to the level that maintains the desired treatment or prevention effect.Of course, when the symptom is alleviated to an appropriate level, treatment can be stopped.However, if the symptom recurs, the target may need long-term intermittent treatment.

[0080] In addition, it is contemplated that the compounds of the present invention may be used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients in the treatment of the conditions described below. The additional active ingredients may be co-administered separately with at least one compound of the present invention, co-administered separately with an active agent of the present invention, or such agents may be included in a pharmaceutical composition according to the present invention. In exemplary embodiments, the additional active ingredient is one known or discovered to be effective in treating a condition, disorder, or disease associated with MGL modulation, such as another MGL inhibitor or a compound active against another target associated with a particular condition, disorder, or disease. Such combinations may serve to improve efficacy (e.g., by including a compound in the combination that enhances the efficacy or effectiveness of an agent according to the present invention), reduce one or more side effects, or reduce the required amount of an active agent according to the present invention.

[0081] When referring to inhibiting a target, "effective amount" means an amount sufficient to affect MGL regulation.

[0082] It is contemplated that the active agents of the present invention may be used alone or in combination with one or more additional active ingredients to formulate pharmaceutical compositions of the present invention, which comprise a therapeutically effective amount of at least one active agent according to the present invention.

[0083] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are non-toxic, biologically acceptable, and otherwise biologically suitable substances for administration to a subject, e.g., inert substances, that are compatible with pharmaceutical compositions and are added to or otherwise used in such compositions as vehicles, carriers, or diluents to facilitate administration of the drug. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0084] A pharmaceutical composition delivery form containing one or more dosage units of an active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art, and the composition may be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular, or by inhalation.

[0085] The preparations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The compositions may be formulated for any one of several routes of administration, such as intravenous infusion, topical administration, or oral administration. Preferably, the compositions may be formulated for oral administration.

[0086] For oral administration, the active agents of the present invention may be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare an oral composition, the active agent may be formulated to obtain a dosage for, for example, a 70 kg human, with an exemplary range of suitable dosages being about 1 to 1000 mg / day in single or multiple dosage units.

[0087] Oral tablets may contain the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary oral liquid excipients include ethanol, glycerol, water, and the like. Exemplary disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binders 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 may be coated with an enteric coating.

[0088] Oral capsules include hard and soft gelatin or (hydroxypropyl) methylcellulose capsules. For hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Oral liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous vehicles such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, if desired, flavorings or coloring agents.

[0089] The active agents of the present invention may also be administered parenterally. For example, the compositions may be formulated as suppositories, enemas, or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the present invention may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose forms such as ampoules or disposable injection devices, multi-dose forms such as vials from which the appropriate dose can be dispensed, or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion dosages are those in which the agent, mixed with a pharmaceutical carrier, is infused at a rate of about 1 to 1,000 μg / kg / min over a period ranging from several minutes to several days.

[0090] For topical administration, the drug may be mixed with a pharmaceutical carrier to provide a concentration of about 0.01% to about 20%, preferably 0.1% to 10%, of the drug relative to the vehicle. Another mode of administering the drug of the present invention may utilize a patch formulation for transdermal delivery.

[0091] In the methods of the present invention, the active agent may alternatively be administered by inhalation, nasal or oral routes, such as in a spray formulation (also containing a suitable carrier).

[0092] In a further embodiment, the present invention relates to a method for treating a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation, comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0093] The compounds of formula (I) are useful for the treatment, amelioration, and / or prevention of diseases, conditions, or disorders affected by the inhibition of MGL. Such methods comprise administering a therapeutically effective amount of a compound of formula (I), or an enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof, to a subject, including animals, mammals, and humans, in need of such treatment, amelioration, and / or prevention.

[0094] In particular, compounds of formula (I), or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, are useful for treating, ameliorating, and / or preventing pain, psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions. More specifically, compounds of formula (I), or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, as defined herein, are useful for treating, ameliorating, and / or preventing inflammatory pain, major depressive disorder, treatment-resistant depression, anxiety-related depression, or bipolar disorder by administering a therapeutically effective amount of a compound of formula (I), or its pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, to a subject in need thereof.

[0095] 1) Pain Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, disorder, or painful state including inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pains, musculoskeletal disorders, skin disorders, toothache, fever, burns, sunburn, snake bites, venomous snake bites, spider bites, insect stings, irritable bladder, interstitial cystitis, urinary tract infections, 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.

[0096] Inflammatory hyperalgesia / hypersensitivity is a type of inflammatory pain. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or painful conditions such as inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disorders, skin disorders, post-operative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / hypersensitivity and / or skin allergies, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, benign prostatic hyperplasia cough, and nasal hypersensitivity.

[0097] In one embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing inflammatory visceral hyperalgesia in which enhanced visceral irritability is present, the method comprising, consisting of, and / or consisting essentially of administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. In a further embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which hypersensitivity to thermal, mechanical, and / or chemical stimuli is present, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0098] Further embodiments of the present invention are directed to methods for treating, ameliorating, and / or preventing neuropathic pain. Examples of neuropathic pain include cancer, neuropathy, spinal and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, temporomandibular joint neuralgia, peripheral neuritis, polyneuropathy, stump pain, phantom limb pain, fractures, oral neuropathic pain, Charcot pain, complex regional pain syndromes I and II. The pain may be caused by a disease, condition, disorder, or painful state including: CRPSI / II, radiculopathy, Guillain-Barré syndrome, dysaesthetic femoral neuralgia, burning mouth syndrome, optic neuritis, post-febrile neuritis, migratory neuritis, segmental neuritis, Gombort neuritis, neuronal injury, cervicobachial neuralgia, cranial neuralgia, genu neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, post-herpetic neuralgia, burning mouth syndrome, erythropoietin, erythroderma, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.

[0099] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-related allodynic state in which there is hypersensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia due to diseases, conditions, disorders, or pain states, including neuropathic pain (neuralgia), pain caused by surgery or trauma to the spinal cord and peripheral nerves, traumatic brain injury (TBI), trigeminal neuralgia, post-herpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuropathy, complex regional pain syndrome I and II (CRPSI / II), and radiculopathy.

[0100] In a further embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing neuropathic cold allodynia in which hypersensitivity to cold stimuli is present, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0101] 2) Mental disorders Examples of mental disorders include, but are not limited to, anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, and depression such as major depression, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, and bipolar depression. Mood disorders and mood-affective disorders that can be treated according to the present invention include, but are not limited to, bipolar disorder type I depression, hypomania, mania, 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, anxious depression, bipolar disorder, depressive disorder with postpartum onset, depressive disorder with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, and euthymia; premenstrual dysphoric disorder; psychotic disorders; and developmental disorders such as autism spectrum disorder and Asperger's syndrome.

[0102] 3) Neurological disorders Examples of neurological disorders include, but are not limited to, tremors, dyskinesia, dystonia, spasticity, Tourette's syndrome; neurofasciitis, Parkinson's disease, Alzheimer's disease, senile dementia; Huntington's disease; epilepsy / seizure disorders, and sleep disorders.

[0103] 4) Cancer Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, embryonal tumor, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal adenoma, ependymoblastoma, malignant meningioma, sarcoma, malignant melanoma, schwannoma).

[0104] 5) Eye condition Examples of ocular conditions include, but are not limited to, ocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0105] Another embodiment of the present invention provides a method for modulating MGL receptor activity, including when the MGL receptor is in a subject, comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0106] In some embodiments of Formula (I), R 1a is CH3 and R 1b is H. In some embodiments, R 1a and R 1b together form -CHCH-. In some embodiments, R 1a and R 1b together to form -CH2CH2CH2-.

[0107] In some embodiments, R 2 teeth,

[0108] [ka] [In the formula, R a are H, Cl, F, and C 1~4 Alkyl or C 1~4 haloalkyl, and R b is C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 In some embodiments, R 2 teeth,

[0109] [ka] [In the formula, R a is Cl, F, or C 1~4 alkyl, and R b teeth,

[0110] [ka] In some embodiments, R 2 is as follows:

[0111] [ka]

[0112] In some embodiments, R 1a is CH3 and R 2 teeth,

[0113] [ka] [In the formula, R a is Cl or F, and R b OC 1~4 In some embodiments, R 2 teeth,

[0114] [ka] is.

[0115] In some embodiments, R 2 teeth,

[0116] [ka] is.

[0117] In some embodiments, R 2 teeth,

[0118] [ka] [In the formula, each R c are independently selected from F, CH3, and OCH3; n and m are each independently 0 or 1.

[0119] In some embodiments, R 2 is as follows:

[0120] [ka]

[0121] In some embodiments, R 1a is C 1~4 alkyl, and R 2 teeth,

[0122] [ka] In some embodiments, R 1a and R 1b together form -CH2CH2CH2-, and R 2 teeth,

[0123] [ka] is.

[0124] In some embodiments, R 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 In some embodiments, R is phenyl or pyridyl, each optionally substituted with one or two substituents selected from cycloalkyl, or two adjacent ring substituents which, together with the carbons to which they are attached, form a monocyclic cycloalkyl or heterocycloalkyl ring. 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 In some embodiments, R is a bicyclic heteroaryl optionally substituted with one or two substituents selected from cycloalkyl. 2 Ha, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl and OC 1~4 In some embodiments, R is a bicyclic heteroaryl optionally substituted with one or two substituents selected from haloalkyl. 2 Halo and C 1~4 and bicyclic heteroaryl optionally substituted with one or two substituents selected from alkyl.

[0125] In some embodiments, R 3 teeth,

[0126] [ka] is.

[0127] In some embodiments, R 3 teeth,

[0128] [ka] In some embodiments, R 3 teeth,

[0129] [ka] In some embodiments, R 3 teeth,

[0130] [ka] is.

[0131] In some embodiments, R 3 is 1H-C1~4 Haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H-(C 3~6 cycloalkyl)-pyrazolyl, or 1H-(C 3~6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from the group consisting of halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 In some embodiments, R 3 is 1H-C 1~4 Alkyl-pyrazolyl, 1H-C 1~4 Haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H-(C 3~6 cycloalkyl)-pyrazolyl, or 1H-(C 3~6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from the group consisting of halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 optionally substituted with haloalkyl, R 1a and R 1b taken together form -CHCH- or -CHCHCH-. In some embodiments, R 3 is 1H-C 1~4 Alkyl-pyrazolyl or 1H-C 1~4 haloalkyl-pyrazolyl, each pyrazolyl being halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 In some embodiments, R 3 is 1H-pyridyl-pyrazolyl, 1H-(C 3~6 cycloalkyl)-pyrazolyl, or 1H-(C 3~6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from the group consisting of halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 In some embodiments, R3 is 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl, each optionally substituted as described herein. In some embodiments, R 3 is 1H-pyrazol-3-yl or 1H-pyrazol-4-yl, each optionally substituted as described herein.

[0132] In some embodiments, n is 1 or 2. In some embodiments, m is 1 or 2. In some embodiments, m and n are each 1.

[0133] Further embodiments of the present invention are compounds as shown in Table 1 below.

[0134] [Table 1-1]

[0135] [Table 1-2]

[0136] [Table 1-3]

[0137] [Table 1-4]

[0138] [Table 1-5]

[0139] [Table 1-6] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0140] Further embodiments of the present invention are compounds as shown in Table 2 below.

[0141] [Table 2-1]

[0142] [Table 2-2] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0143] Further embodiments of the present invention are compounds as shown in Table 3 below.

[0144] [Table 3-1]

[0145] [Table 3-2]

[0146] [Table 3-3]

[0147] [Table 3-4]

[0148] [Table 3-5] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0149] Further embodiments of the present invention are compounds as shown in Table 4 below.

[0150] [Table 4] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0151] A further embodiment of the present invention comprises:

[0152] [ka] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0153] A further embodiment of the present invention is a compound of formula (IA):

[0154] [ka] [In the formula, R 2 teeth, (a)

[0155] [ka] (b)

[0156] [ka] 5,6-fused or 6,5-fused heteroaryl selected from (c)

[0157] [ka] a fused 6,6-heteroaryl selected from (d)

[0158] [ka] is selected from R 3 teeth,

[0159] [ka] is a 5-membered heteroaryl ring selected from During the ceremony, R a are H, Cl, F, and C 1~4 Alkyl, and C 1~4 haloalkyl; R b is C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl,

[0160] [ka] is selected from Each R c Ha, Halo, C 1~4 alkyl, and OCH3; R d is H or CH3, Each R e are independent of F, C 1~4 Alkyl or C 1~4 is haloalkyl, Each R f is C 1~4 Alkyl, C 1~4 haloalkyl, and OCH3; R g is C 1~4 Alkyl or C 1~4 is haloalkyl, n is 0, 1, or 2; m is 0, 1, or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0161] In some embodiments of Formula (IA), R 3 teeth,

[0162] [ka] is.

[0163] A further embodiment of the present invention is a compound of formula (IB):

[0164] [ka] [In the formula, n is 1 or 2, R 2 teeth, (a)

[0165] [ka] (b)

[0166] [ka] (c)

[0167] [ka] and, (d)

[0168] [ka] is selected from R 3 teeth,

[0169] [ka] and During the ceremony, R a is H, halo, or C 1~4 is alkyl, R b is C 1~4 Alkyl or OC 1~4 a compound of formula (I) having or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0170] In some embodiments of formula (IB), n is 2.

[0171] A further embodiment of the present invention is a compound selected from compounds of formula (I), formula (IA), and formula (IB), or combinations thereof.

[0172] A further embodiment of the present invention comprises: (A) a therapeutically effective amount of at least one compound selected from compounds of formula (I) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof; (B) at least one pharmaceutically acceptable excipient.

[0173] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from (a) the compounds of Table 1, (b) the compounds of Table 2, (c) the compounds of Table 3, and (d) the compounds of Table 4 (including pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof), pharmaceutically acceptable prodrugs of such compounds, and pharmaceutically active metabolites of such compounds, and at least one pharmaceutically acceptable excipient.

[0174] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IA), a pharmaceutically acceptable salt, N-oxide, or solvate of a compound of formula (IA), a pharmaceutically acceptable prodrug of a compound of formula (IA), and a pharmaceutically active metabolite of formula (IA), and at least one pharmaceutically acceptable excipient.

[0175] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IB), a pharmaceutically acceptable salt, N-oxide, or solvate of a compound of formula (IB), a pharmaceutically acceptable prodrug of a compound of formula (IB), and a pharmaceutically active metabolite of formula (IB), and at least one pharmaceutically acceptable excipient.

[0176] Also within the scope of the present invention are enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA) and (IB)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of the compounds of formula (I) (and formulas (IA) and (IB)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of the compounds of formula (I) (and formulas (IA) and (IB)), and pharmaceutically active metabolites of the compounds of formula (I) (and formulas (IA) and (IB)).

[0177] Also within the scope of the present invention are isotopic variants of the compounds of formula (I) (and formulas (IA) and (IB)), e.g., deuterated compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variants of the compounds of formula (I) (and formulas (IA) and (IB)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of isotopic variants of the compounds of formula (I) (and formulas (IA) and (IB)), and pharmaceutically active metabolites of isotopic variants of the compounds of formula (I) (and formulas (IA) and (IB)).

[0178] A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with 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 the compounds of formula (I) (and formulas (IA) and (IB)), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, such as enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA) and (IB)), isotopic variants of the compounds of formula (I) (formula (I) (and formulas (IA) and (IB))), and pharmaceutically acceptable salts of all of the foregoing.

[0179] Also described herein is the use of a compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, in the preparation of a medicament. In some embodiments, the medicament is for treating a disease, disorder, or condition mediated by MGL receptor activity. Also described herein is a compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, for use in a method for treating a disease, disorder, or condition mediated by MGL receptor activity.

[0180] Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation, followed by specific examples. To obtain the various compounds herein, those skilled in the art will understand that starting materials can be suitably selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be appropriately substituted with the desired substituent. Unless otherwise specified, variables are as defined above with reference to Formula (I). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be carried out under heating using conventional or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0181] Abbreviations and acronyms used herein are as follows in Table 5:

[0182] [Table 5-1]

[0183] [Table 5-2]

[0184] Preparation example Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples.

[0185] [ka]

[0186] According to Scheme 1, a compound of formula (IIIa) or (IIIb)e is F, m is 0 or 1, R d is H or C 1~4 alkyl, and X is CH or N] is alkylated with a suitable reagent such as iodomethane, 2,2,2-trifluoroethyl trifluoromethanesulfonate, a suitable base such as NaH, potassium carbonate, in a suitable solvent such as DMF at a suitable temperature such as 0° C. or room temperature to give a compound of formula (IVa) or (IVb) g is C 1~4 Alkyl or C 1~4 Hydrolysis of the methyl ester is carried out using conditions known to those skilled in the art with a suitable base such as NaOH, LiOH, (CH3)3SiOK, in a suitable solvent such as THF at a suitable temperature of 60°C for 24 hours to provide a compound of formula (Va) or (Vb), where M is potassium, Na, or Li, preferably potassium.

[0187] [ka]

[0188] According to Scheme 2, commercially available or synthetically available methyl 3-bromo-2-chlorobenzoate can be reacted with a palladium precatalyst such as Josiphos SL-J009-1 PD G3, a base such as cesium carbonate, and an amine such as 2-oxa-6-azaspiro[3.3]heptane in a suitable solvent such as DME at 70° C. for 1 hour to yield methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. Hydrolysis of the methyl ester of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate using the conditions previously described provides a compound of formula (VI), where M is potassium.

[0189] [ka]

[0190] According to Scheme 3, compounds of formula (VII) are prepared in two steps from L-alanine ethyl ester hydrochloride. In the first step, L-alanine ethyl ester hydrochloride is alkylated with 4-bromobutanoic acid ethyl ester using potassium iodide and a suitable base such as dibasic potassium phosphate. In the second step, BOC protection using established methodology provides compounds of formula (VII). Compounds of formula (VII) [where PG is BOC] are cyclized under Dieckmann condensation conditions using a suitable base such as LiHMDS or potassium tert-butoxide in a suitable solvent such as tetrahydrofuran at temperatures between -40°C and 20°C to provide ketoester compounds of formula (VIII).

[0191] [ka]

[0192] According to Scheme 4, (1S,8S)-(+)-trans-8-[(R)-phenylethylamino]cyclooct-4-enol and (1R,8R)-(-)-trans-8-[(R)-phenylethylamino]cyclooct-4-enol are prepared according to the method described in "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.

[0193] (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, (1S,8S,Z)-8-(((R)-1-phenylethyl)amino)cyclooct-4-en-1-ol is reacted with mercury(II) chloride in a suitable solvent such as diethyl ether, tetrahydrofuran, dioxane, water, or a mixture thereof at room temperature for 12-24 hours to give the mercury chloride complex with the alkenyl moiety. In the second step, reduction of the aforementioned mercuric chloride complex is carried out by reaction with 3 M sodium hydroxide and a reducing agent such as sodium borohydride at a temperature of about 0° C. to give the cyclized (1S,2S,5R)-9-((R)-1-phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol product.

[0194] The chiral (R)-methylbenzyl is deprotected using established methodology using hydrogenation conditions known to those skilled in the art, for example, using H2 in the presence of a catalyst such as Pd / C in a suitable solvent such as MeOH to give (1S,2S,5R)-9-azabicyclo[3.3.1]nonan-2-ol.

[0195] The amine moiety of (1S,2S,5R)-9-azabicyclo[3.3.1]nonan-2-ol is protected with a carbamate protecting group, such as tert-butyloxycarbonyl (BOC). For example, (1S,2S,5R)-9-azabicyclo[3.3.1]nonan-2-ol is reacted with BOC-anhydride at room temperature for about 4-7 hours to give a compound of formula (IX), where PG is BOC.

[0196] Compounds of formula (IX) are converted to compounds of formula (X) under oxidation conditions, such as Swern (Moffott-Swern) oxidation. For example, compounds of formula (IX) are treated with DMSO, oxalyl chloride, triethylamine, or the like in a suitable solvent, such as DCM, to give compounds of formula (X). In a preferred method, the reaction is initially carried out at -78°C, then allowed to warm to room temperature and stirred overnight.

[0197] Compounds of formula (X) are converted to compounds (XI) by treatment with a strong base such as lithium bis(trimethylsilyl)amide (LiHMDS / LHMDS) in a suitable solvent such as THF at a temperature of about −78° C. for about 30 minutes. The resulting lithium enolate is trapped with methyl or ethyl cyanoformate at a temperature of about −78° C. for 1 to 3 hours to provide β-ketoester compounds of formula (XI) where PG is BOC.

[0198] [ka]

[0199] According to Scheme 5, a compound of formula (XII) (including compounds of formula (VIII) and (XI)) 1a is CH3, or R 1a and R 1b together form -CHCHCH-, and PG is BOC (tert-butyloxycarbonyl), is reacted with methylhydrazine in AcOH at a temperature of about 80°C to give a compound of formula (XIII). Alternatively, a commercially available or synthetically available compound of formula (XII) [wherein PG is BOC (tert-butyloxycarbonyl)] is reacted with methylhydrazine in a suitable solvent such as toluene or ethanol and a suitable base such as DIEA at a temperature of 80-110°C to give a compound of formula (XIII).

[0200] Derivatization of compounds of formula (XIII) with a sulfonate-based leaving group such as trifluoromethanesulfonyl (triflate) is achieved by reaction with a triflating agent such as trifluoromethanesulfonic anhydride (TfO) and a base such as triethylamine (TEA), pyridine, or N-ethyldiisopropylamine (DIEA, DIPEA) in a suitable solvent such as DCM. Using a milder triflating agent such as N-phenylbis(trifluoromethanesulfonimide) (TfNPh) and a base such as TEA or DIEA in a suitable solvent such as DCM for better selectivity provides compounds of formula (XIV).

[0201] [ka]

[0202] According to Scheme 6, the compound of formula (XVI) (wherein PG is Boc) is prepared by the method described in J. Org. Chem. 2002, 67, 3479-3486. The ketoester compound of formula (XV) is reacted with commercially available or synthetically available methylhydrazine in an inert solvent such as toluene at a temperature of about 100° C. to give the compound of formula (XVI) (wherein PG is Boc).

[0203] Derivatization of compounds of formula (XVI) with a sulfonate-based leaving group such as trifluoromethanesulfonyl (triflate) is carried out by reaction with a triflating agent such as trifluoromethanesulfonic anhydride (TfO) and a base such as triethylamine (TEA) or pyridine in a suitable solvent such as DCM. Milder triflating agents such as N-phenylbis(trifluoromethanesulfonimide) (TfNPh) and a base such as TEA or DIEA in a suitable solvent such as DCM can be used for better selectivity to give compounds of formula (XIV) [wherein R 1a and R 1b The compounds shown in Figure 1 are obtained by chiral SFC purification to form -CH2CH2- and PG is BOC.

[0204] [ka]

[0205] According to Scheme 7, a compound of formula (XIV) [wherein R 1a is CH3, or R 1a and R 1b

[0033] Compounds of formula (XVII) [wherein PG is BOC] can be reacted with heteroarylboronic acids or boronic esters in a metal-mediated cross-coupling reaction to provide compounds of formula (XVII) [wherein PG is BOC]. For example, compounds of formula (XIV) can be reacted with appropriately substituted, commercially available or synthetically available five-membered heteroarylboronic acids or boronic esters, such as [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl(dtbpf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh)), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl(dppf)), or palladium(II) bis(triphenylphosphine)dichloride (Pd(PPh)Cl). In the presence of a palladium catalyst such as XPhos-Pd-G2 precatalyst (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), a base such as KPO solution, NaCO, NaCO, or CsCO, in a suitable solvent such as 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, or a mixture thereof, at a temperature between 60 and 180°C using microwave or conventional heating for about 30 minutes to 16 hours, compounds of formula (XVII) are obtained.

[0206] Cleavage of the BOC protecting group on compounds of formula (XVII) is carried out using established methodologies according to procedures known to those skilled in the art, for example under acidic conditions such as TFA / CH2Cl2, HCl / dioxane, etc. to give compounds of formula (XVIII).

[0207] [ka]

[0208] According to Scheme 8, compounds of formula (I) are prepared from compounds of formula (XVIII) using amide bond-forming techniques known to those skilled in the art, for example, by coupling with an appropriately substituted, commercially available or synthetically available aryl or heteroaryl carboxylic acid of formula (XIX) (as described above), or by reaction of an appropriately substituted aryl or heteroaryl acid chloride of formula (XX) with a base such as TEA (triethylamine) in a suitable solvent such as DCM, THF, or EtOAc (conversion to an acid chloride). For example, conventional amide bond-forming techniques, such as coupling reactions well known to those skilled in the art (e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), or conversion of an acid to an acid chloride), are used. For example, a compound of formula (XVIII) can be prepared by reacting a compound of formula (XIX) 3is an appropriately substituted 5-membered heteroaryl ring as defined in claim 1] with a commercially available or synthetically available (according to the scheme above) carboxylic acid of the formula [R,R-R], optionally with a suitable activating reagent, for example a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), in the presence of hydroxybenzotriazole (HOBt) and / or a catalyst, for example 4-dimethylaminopyridine (DMAP); (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®); a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another 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-trioxatriphosphorinane-2,4,6-trioxide (T3P®), or the like. The coupling reaction is carried out in a suitable solvent such as DCM, THF, DMF, and the like, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA), at a temperature range of about 0° C. to room temperature to provide a compound of formula (I).

[0209] [ka]

[0210] According to Scheme 9, cleavage of the BOC protecting group on a compound of formula (XIV) according to the methods previously described provides a compound of formula (XXI). 2is an appropriately substituted quinoline] is prepared by conventional amide bond formation techniques as described above to give a compound of formula (XXII). 2 is an appropriately substituted quinoline] is reacted in a metal-mediated cross-coupling reaction as described above to give a compound of formula (I). For example, a compound of formula (XXII) can be reacted with an appropriately substituted, commercially available or synthetically available heteroarylboronic acid, boronate ester, or the like, with [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl(dtbpf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh)), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl(dppf)), palladium(II) bis(triphenylphosphine) dichloride (Pd(PPh)Cl). ), a palladium catalyst such as XPhos-Pd-G2 precatalyst (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), a base such as K3PO4 solution, Na2CO3, Na2CO3, or Cs2CO3 in a suitable solvent such as 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, or a mixture thereof, at a temperature of 60-180°C using microwave or conventional heating for about 30 minutes to 16 hours to provide a compound of formula (I).

[0211] [ka]

[0212] According to Scheme 10, 7-bromothiazolo[4,5-c]pyridine can be prepared in three steps from commercially available or synthetically available 3-bromo-4-chloro-5-nitropyridine. For example, nucleophilic aromatic substitution of 3-bromo-4-chloro-5-nitropyridine with sodium hydrosulfite in a suitable solvent such as MeOH at 25°C for about 16 hours can give 3-bromo-5-nitropyridine-4-thiol. Reduction of 3-bromo-5-nitropyridine-4-thiol with stannous chloride and hydrochloric acid in a suitable solvent such as water at 25°C for about 3 hours can give 3-amino-5-bromopyridine-4-thiol. Condensation of 3-amino-5-bromopyridine-4-thiol with zinc and formic acid at 100°C for about 1 hour can give 7-bromothiazolo[4,5-c]pyridine.

[0213] [ka]

[0214] According to Scheme 11, a compound of formula (XXIII) (wherein Hal is Cl or Br, and X is CH or N, and only one X can be N) can be subjected to lithium-halogen exchange using a suitable base such as n-butyllithium, followed by reaction with a suitable carbon dioxide source such as dry ice in a suitable solvent such as tetrahydrofuran at a temperature range of −78 to 25° C. for about 2 to 24 hours to provide a compound of formula (XXV).

[0215] In an alternative method, metal-mediated cyanation of a compound of formula (XXIII) provides a compound of formula (XXIV), where X is CH or N, and only one X may be N. For example, the reaction of a compound of formula (XXIII) with zinc cyanide in the presence of zinc and a palladium catalyst such as tris(dibenzylidene)dipalladium(0) (Pd(dba)), palladium(II) trifluoroacetate (Pd(TFA)), or bis(tri-tert-butylphosphine)palladium(0) (Pd(t-BuP)), with or without the addition of a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (DPPF) or (binaphthyl)P(t-Bu) in a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide, at a temperature between 90 and 120°C using microwave or conventional heating for about 30 minutes to 16 hours, can provide a compound of formula (XXIV).

[0216] Hydrolysis of the nitrile group on compound of formula (XXIV) can be carried out using conditions known to one skilled in the art using a suitable base such as LiOH, NaOH, etc. in a suitable solvent such as tetrahydrofuran or a mixture of tetrahydrofuran / water at a temperature range of 25-100°C for about 16 hours to provide compound of formula (XXV).

[0217] [ka]

[0218] According to Scheme 12, compounds of formula (XXVIa) and (XXVIb) can be prepared under conditions known to those skilled in the art (McDonald, A, et al., U.S. Pat. No. 9,611,252), by the addition of a compound of formula (IIIc) [wherein R c is F or CH3, and R dis methyl, and n is 0 or 1] are prepared by condensation of commercially available or synthetically available substituted methyl 4-aminobenzoates with (E)-but-2-enal in the presence of a suitable oxidizing agent, such as 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione, in a suitable solvent, such as 6N HCl, at 100° C. for approximately 10 minutes. Hydrolysis of the methyl ester using conditions known to those skilled in the art with a suitable base, such as NaOH, LiOH, (CH)SiOK, in a suitable solvent, such as tetrahydrofuran, at 60° C. for 24 hours provides compounds of formula (XXVIIa) and (XXVIIb) where M is potassium, Na, or Li.

[0219] [ka]

[0220] According to Scheme 13, 6-bromo-2,4-dimethylquinoline is prepared under conditions known to those skilled in the art (Lindsley, CW, et al., International Application PCT2018112312) by reacting commercially available 6-bromo-2-methylquinoline with ethyl 2-mercaptopropanoate in the presence of an iridium catalyst such as Ir(ppy)2(dtbbpy)PF6 and a suitable acid such as p-toluenesulfonic acid in a suitable solvent mixture such as dimethyl sulfoxide and methanol. Compounds of formula (XXVIII) are prepared from 6-bromo-2,4-dimethylquinoline in two steps. For example, palladium-catalyzed carbonylation of 6-bromo-2,4-dimethylquinoline using a suitable combination of palladium catalysts such as palladium(II) acetate and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl(dppf)) in a suitable solvent such as methanol under an atmosphere of carbon monoxide, followed by hydrolysis of the resulting methyl ester using the conditions described above, provides compounds of formula (XXVIII) where M is K, Na, or Li.

[0221] [ka]

[0222] According to Scheme 14, methyl 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate can be prepared by reacting commercially available 4-aminobenzoic acid with ethyl 3-oxobutanoate and acetic acid in a suitable solvent such as toluene at a temperature of 120° C. for 16 hours, and the resulting solid can be further refluxed in a solvent such as diphenyl ether at 240° C. for 3 hours, followed by esterification with sulfuric acid in a suitable solvent such as methanol to give the corresponding methyl ester.

[0223] The compound of formula (XXIX) is prepared in two steps by heating methyl 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate with phosphorus oxychloride in the presence of a catalytic amount of DMF in a suitable solvent such as THF at 60° C. for 6 hours. Hydrolysis of the methyl ester is carried out using a suitable base such as sodium methanolate in a suitable solvent such as methanol at 60° C. for 16 hours using conditions known to those skilled in the art to provide the compound of formula (XXIX).

[0224] [ka]

[0225] According to Scheme 15, 7-methoxy-2-methylquinoline-5-carboxylic acid can be prepared by condensation of commercially available or synthetically available 3-amino-5-methoxybenzoic acid with an unsaturated aldehyde such as (E)-but-2-enal in a suitable solvent such as 6N HCl at a temperature of 100° C. for approximately 1 hour.

[0226] [ka]

[0227] According to Scheme 16, 3-fluoro-8-methoxyquinoline can be prepared by reacting commercially available or synthetically available 3-fluoroquinolin-8-ol with a suitable alkylating agent, such as iodomethane, in a suitable base, such as potassium carbonate, in a suitable solvent, such as N,N-dimethylformamide, at a suitable temperature range, such as 0 to 25° C. 3-Fluoro-8-methoxyquinoline-4-carboxylic acid can be prepared by metallation of 3-fluoro-8-methoxyquinoline with a suitable base, such as lithium diisopropylamide activated with potassium tert-butoxide, in a suitable solvent, such as tetrahydrofuran, at −75° C. for about 20 minutes, as described in Shi, G., et al., Tetrahedron Vol. 50, No. 4, 1129-1134, 1994, followed by quenching with a suitable carbon dioxide source, such as dry ice.

[0228] [ka]

[0229] According to Scheme 17, compounds of formula (XXXI) can be prepared by reacting a compound of formula (XXX) [wherein R a is F or CH3], with a suitable alkylating agent, such as iodomethane, and a suitable base, such as potassium carbonate, in a suitable solvent, such as N,N-dimethylformamide, at a suitable temperature range, such as 0-25°C, followed by hydrolysis of the methyl ester using conditions as set forth above to provide compounds of formula (XXXI), where M is K, Na, or Li.

[0230] [ka]

[0231] According to Scheme 18, commercially available 3-(trimethylsilyl)propionaldehyde can be treated with a halogenating agent such as N-iodosuccinimide in the presence of silver fluoride in a suitable solvent such as acetonitrile to give 3-iodopropionaldehyde. Condensation of commercially available 5-fluoro-2-hydrazinylpyrimidine with 3-iodopropionaldehyde (as described in Le Fouler, V., et al., J. Am. Chem. Soc. 2019, 141, 15901-15909) can give (E)-5-fluoro-2-(2-(3-iodoprop-2-yn-1-ylidene)hydrazinyl)pyrimidine. Subsequent intramolecular hetero-Diels-Alder cycloaddition of the imine intermediate can be carried out with an N-acetylating agent, such as trifluoroacetic anhydride, in the presence of 3-pentanone in a suitable solvent, such as tetrahydrofuran, at about 25° C. to afford 5-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine. Alkylation of 5-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine with a suitable reagent, such as iodomethane, a suitable base, such as potassium carbonate, in a suitable solvent, such as DMF, at a suitable temperature, such as 0° C. or room temperature, can afford 5-fluoro-4-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine. Palladium-catalyzed carbonylation of 5-fluoro-4-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine using a suitable combination of palladium catalysts such as palladium(II) acetate and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl(dppf)) in a suitable solvent such as methanol under an atmosphere of carbon monoxide, followed by hydrolysis of the resulting methyl ester using the conditions described above, can provide compounds of formula (XXXII) where M is K, Na, or Li.

[0232] [ka]

[0233] According to Scheme 19, 3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid is prepared via an Ullmann coupling reaction utilizing a base such as cesium carbonate by reacting 3-iodo-5-methylbenzoic acid with 1H-1,2,3-triazole using a copper catalyst such as CuI, a ligand such as trans-N,N'-dimethylcyclohexane-1,2-diamine, in a suitable solvent such as DMF at temperatures between 100-140 °C under microwave irradiation.

[0234] [ka]

[0235] According to Scheme 20, a compound of formula (XXXIII) [wherein R h Commercially available or synthetically available anilines of formula (XXXIV) [wherein R is CH3] can be treated with sodium thiocyanate and bromine in acetic acid at room temperature to give the corresponding 2-aminobenzo[d]thiazoles of formula (XXXIV) (Xu, Xiaodong, International Application PCT2018085148). Deamination of compounds of formula (XXXIV) can be carried out by treatment with phosphoric acid in the presence of sodium nitrite or isoamyl nitrite at a suitable temperature range, such as -4°C to 25°C, as described in Ismail, A., Sharp, E., and Chedeke, R., et al., J. Org. Chem., Vol. 45, No. 11, 1980, pp. 2243-2246. Subsequent hydrolysis of the methyl ester using the above conditions gives compounds of formula (XXXV) [wherein R is CH3]. b is CH3 and M is K, Na, or Li.

[0236] [ka]

[0237] According to Scheme 21, 4-bromo-2-(trifluoromethoxy)benzoic acid is reacted with trimethylboroxine to prepare 4-methyl-2-(trifluoromethoxy)benzoic acid using Suzuki cross-coupling conditions previously described.

[0238] The compound of formula (I) may be converted into its corresponding salt using methods known to those skilled in the art. For example, the amine of formula (I) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as EtO, CHCl, THF, MeOH, chloroform, or isopropanol to obtain the corresponding salt form. Alternatively, reverse-phase HPLC purification conditions may result in the trifluoroacetate or formate salt. Crystalline forms of pharmaceutically acceptable salts of the compound of formula (I) may be obtained in crystalline form by recrystallization from a polar solvent (including a mixture of polar solvents and an aqueous mixture of polar solvents) or a nonpolar solvent (including a mixture of nonpolar solvents).

[0239] When the compounds according to the present invention have at least one chiral center, they may consequently exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0240] The compounds prepared according to the above schemes can be obtained as a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above schemes can be obtained as a mixture of various forms, such as a racemic (1:1) mixture or a non-racemic (non-1:1) mixture. When racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers can be isolated using conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When regioisomeric or diastereomeric mixtures are obtained, single isomers can be separated, as appropriate, using conventional methods, such as chromatography or crystallization.

[0241] The following specific examples are provided to further illustrate the invention and various preferred embodiments. [Example]

[0242] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0243] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). Solutions were generally dried over a drying agent such as NaSO or MgSO. Mixtures, solutions, and extracts were typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions were performed in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.

[0244] For reactions conducted under continuous flow conditions, "flowing through an LTF-VS mixer" refers to the use of a Chemyx Fusion 100 touch syringe pump in series with an LTF-VS mixer (Little Things Factory GmbH (http: / / www.ltf-gmbH.com) via 1 / 16 inch PTFE tubing, unless otherwise specified.

[0245] Normal-phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked cartridges.

[0246] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by one of the following methods. Method A. Agilent HPLC using an Xterra Prep RP18 column (5 μM, 30×100 or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100, 50×100, or 50×150 mm) at a flow rate of 40 or 80 mL / min, with a mobile phase of 5% ACN in 20 mM NH4OH, held for 2 min, followed by a gradient of 5 to 99% ACN over 15 min, followed by a 5 min hold at 99% ACN. or Method B. Shimadzu LC-8A series HPLC using an Inertsil ODS-3 column (3 μm, 30 × 100 mm, T = 45 °C) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in HO (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5 to 99% ACN over 6 min, followed by a 3 min hold at 99% ACN. or Method C. Shimadzu LC-8A series HPLC using an XBridge C18 OBD column (5 μm, 50 × 100 mm) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5 to 99% ACN over 14 min, followed by a 10 min hold at 99% ACN. or Method D. Gilson HPLC using an XBridge C18 column (5 μm, 100 × 50 mm) at a flow rate of 80 mL / min with a mobile phase of 5 to 99% ACN in 20 mM NH4OH over 10 min, followed by a 2 min hold at 99 ACN. or Method E. ACCQ Prep HPLC using an XBridge C18 OBD column (5 μM, 30x100 or 50x100 mm) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in HO (both containing 0.05% TFA) with a 1 minute hold, followed by a 5-95% ACN gradient over 12 minutes, followed by a 2 minute hold at 95% ACN. or Method F. Agilent HPLC using an Xterra Prep RP18 column (5 μM, 30×100 or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100, 50×100, or 50×150 mm) at a flow rate of 40 or 80 mL / min, with a mobile phase of 5% ACN in HO (both containing 0.05% TFA) held for 2 min, followed by a gradient of 5 to 99% ACN over 15 min, followed by a 5 min hold at 99% ACN. or Method G. Boston Uni C18 150 x 40 mm x 5 μm column (eluent: 1% to 31% (v / v) ACN and 0.05% HCl in H2O)

[0247] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on either a Jasco preparative SFC system, a Berger Instruments APS 1010 system, or an SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100–150 bar with flow rates ranging from 40–60 mL / min. The column was heated to 35–40 °C.

[0248] Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated masses correspond to exact masses.

[0249] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. Multiplicity definitions are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadband, dd = doublet of doublet, dt = triplet of triplet, td = triplet of doublet. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0250] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0251] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0252] Intermediate 1: Potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate.

[0253] [ka]

[0254] Step A: Methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. To a solution of methyl 3-bromo-2-chlorobenzoate (150 mg, 0.6 mmol) in 1,2-dimethoxyethane (5.0 mL) was added 2-oxa-6-azaspiro[3.3]heptane (66 mg, 0.67 mmol), cesium carbonate (587 mg, 1.8 mmol), and Josiphos SL-J009-1 PD G3 (56 mg, 0.06 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 70 °C for 1 h and concentrated under reduced pressure. The residue was taken up in CHCl (10 mL) and washed with HO (2 × 5.0 mL), brine (1 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2; 0-50% hexane-EtOAc) to give the title compound as a yellow solid (88.1 mg, 55%). MS (ESI): Calculated mass, C 13 H 14 ClNO3, 267.1; m / z observed, 268.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.25(dd,J=8.2,7.6Hz,1H),7.03(dd,J=7.5,1.5Hz,1H),6.75(dd,J=8.2,1.5Hz,1H),4.71(s,4H),4.19(s,4H),3.82(s,3H).

[0255] Step B: Potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. To a solution of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate (85 mg, 0.32 mmol) in THF (4.0 mL) was added potassium trimethylsilanolate (41 mg, 0.32 mmol), and the resulting mixture was heated to 60° C. for 5 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, C 12 H 11 ClKNO3, 291.0; m / z observed, 254.1 [M-K+2+H] + .

[0256] Intermediate 2: Potassium 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate.

[0257] [ka]

[0258] Step A: Methyl 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate. To a cooled (0° C.) solution of methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (200 mg, 1.1 mmol) in DMF (4.0 mL) was added sodium hydride (60% in mineral oil, 68 mg, 1.7 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. After 1 h, the mixture was cooled to 0° C., and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.25 mL, 1.7 mmol) was added, and the reaction mixture was stirred for an additional 1 h. The reaction was then quenched with water and diluted with EtOAc (2×), and the combined organics were washed with brine (4×), dried over Na2SO4, filtered, and concentrated. The resulting residue was carried on to the next step without further purification. MS (ESI): Mass calculated, C 11 H9F3N2O2, 258.1; m / z measured, 259.1 [M+H] + .

[0259] Step B: Potassium 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate. The title compound was prepared in a manner similar to Intermediate 1, Step B, using methyl 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate instead of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. MS (ESI): Calculated mass, C 10 H7KF3N2O2, 282.0; m / z measured, 245.1 [M-K+2+H] + .

[0260] Intermediate 3: Potassium 4,6-difluoropyrazolo[1,5-a]pyridine-3-carboxylate.

[0261] [ka]

[0262] The title compound was prepared in a manner similar to Intermediate 1, Step B, using ethyl 4,6-difluoropyrazolo[1,5-a]pyridine-3-carboxylate instead of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate, and the reaction mixture was heated for 24 h. MS (ESI): mass calculated, CHFKN0, 235.9; m / z found, 199.1 [M-K+2+H] + .

[0263] Intermediate 4: Lithium 5,7-difluoroquinoline-3-carboxylate

[0264] [ka]

[0265] To a solution of ethyl 5,7-difluoroquinoline-3-carboxylate (75 mg, 0.32 mmol) in THF (2.5 mL) was added a solution of lithium hydroxide (15.0 mg, 0.63 mmol) in water (1.5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the title compound as a white solid, which was used in the next step without purification (quantitative yield). MS (ESI): Mass calculated, C 10 H4F2LiNO2, 215.0 m / z observed, 210.1 [M-Li+2+H] + .

[0266] Intermediate 5: Potassium 2-methyl-2H-indazole-4-carboxylate.

[0267] [ka]

[0268] The title compound was prepared in a manner similar to Intermediate 1, Step B, using methyl 2-methyl-2H-indazole-4-carboxylate instead of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. MS (ESI): mass calculated, CHKNO, 214.0; m / z found, 177.1 [M-K+H] + .

[0269] Intermediate 6: Lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate.

[0270] [ka]

[0271] Step A: Methyl 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate. The title compound was prepared in a manner similar to Intermediate 2, Step A, using 4,6-difluoro-1H-indazole-3-carboxylic acid instead of methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate and iodomethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. MS (ESI): Calculated mass, C 10 H8F2N2O2, 226.1; m / z measured, 226.9 [M+H] + .

[0272] Step B: Lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate. To a solution of methyl 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate (100 mg, 0.44 mmol) in THF (2.5 mL) was added a solution of lithium hydroxide (21.0 mg, 0.88 mmol) in water (1.5 mL). The mixture was stirred at room temperature for 1 hour, and then the solvent was concentrated to give the title compound as a white solid, which was used in the next step without purification (quantitative yield). MS (ESI): mass calculated, CHFLiNO, 218.05; m / z found, 213.0 [M-LiH] + .

[0273] Intermediate 7: Potassium 2-methyl-1,6-naphthyridine-5-carboxylate.

[0274] [ka]

[0275] The title compound was prepared in a manner similar to Intermediate 1, Step B, using ethyl 2-methyl-1,6-naphthyridine-5-carboxylate instead of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate. MS (ESI): Calculated mass, C 10 H7KN2O2, 226.0; m / z measured, 189.1 [M-K+2+H] + .

[0276] Intermediate 8: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid.

[0277] [ka]

[0278] Step A: Methyl 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate. Iodomethane (0.22 mL, 3.5 mmol) was added to a mixture of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (250 mg, 1.4 mmol) and potassium carbonate (575 mg, 4.2 mmol) in DMF (4.8 mL) at room temperature. After 16 hours, a saturated aqueous solution of sodium bicarbonate (20 mL) was added, and the mixture was extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (85 mg, 29%). MS (ESI): Mass calculated, C 10 H9FN2O2, 208.1; m / z measured, 209.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.40-8.38(m,1H),7.81(d,J=3.4Hz,1H),6.77(d,J=3.4Hz,1H),3.96(s,3H),3.86(s,3H).

[0279] Step B: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid. A mixture of methyl 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (85 mg, 0.4 mmol) and lithium hydroxide (4N in water, 0.51 mL, 2.0 mmol) in THF (3 mL) was stirred at room temperature. After 16 h, the reaction mixture was concentrated in vacuo. Purification (Method F) afforded the title compound (94 mg, 79%). MS (ESI): mass calculated, C9H7FN2O2, 194.1; m / z found, 195.1 [M+H] + .

[0280] Intermediate 9: 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole.

[0281] [ka]

[0282] The title compound was prepared in a manner similar to Intermediate 2, Step A, using 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole instead of methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate and iodomethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. MS (ESI): Calculated mass, C 12 H 18 BF3N2O2, 290.1; m / z measured, 291.1 [M+H] + .

[0283] Intermediate 10: (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate.

[0284] [ka]

[0285] Step A: Ethyl (S)-4-((1-ethoxy-1-oxopropan-2-yl)amino)butanoate. To a 50 L reactor were added DMF (21 L, 6 V), L-alanine ethyl hydrochloride (6.13 kg, 2.0 equiv, 90% w / w), KHPO (10.94 kg, 3.5 equiv), and KI (2.98 kg, 1.0 equiv) sequentially at 20–30 °C. The resulting mixture was warmed to 50–55 °C and maintained at this temperature for 30 min. Next, a solution of ethyl 4-bromobutanoate (3.50 kg, 1.0 equiv) in dimethylformamide (DMF) (7 L, 2 V) was added dropwise over 1 h, maintaining the temperature at 50–55 °C. The mixture was stirred at 50–55 °C for 3 h. After the reaction was complete, the reaction mixture was cooled to 20-30°C and transferred to another reactor, followed by the addition of water (87.5 L, 25V). The resulting mixture was extracted with tert-butyl methyl ether (MTBE) (17.5 L x 4). The organic phase was collected and washed with brine (17.5 L). The organic phase was combined with the organic phases from two other batches (1.00 kg batch and 2.50 kg batch). The solution was then concentrated under vacuum at 40-45°C to afford 6.8 kg of the title compound as a pale yellow oil (94% w / w as assayed by Q-NMR) in 82.2% yield. MS (ESI): Mass calculated, C 11 H 21 NO4, 231.1; m / z measured, 232.1 [M+H] + .

[0286] Step B: Ethyl (S)-4-((tert-butoxycarbonyl)(1-ethoxy-1-oxopropan-2-yl)amino)butanoate. Crude ethyl (S)-4-((1-ethoxy-1-oxopropan-2-yl)amino)butanoate (3.5 kg, 1.0 equiv.), tetrahydrofuran (THF) (10 L, 3 V), and di-tert-butyl dicarbonate (3.5 kg, 1.05 equiv.) were added to a 20 L reactor at 20-30°C. The resulting mixture was warmed to 55-60°C and maintained at this temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum at 40-45°C to afford 5624 g of the title compound as a yellow oil (purity 87.2% (GC) and 99.1% ee). The resulting residue was used in the next step without further purification.

[0287] Step C: 1-(tert-Butyl) 4-ethyl (2S)-2-methyl-3-oxopiperidine-1,4-dicarboxylate. To a 10 L four-neck flask was added crude ethyl (S)-4-((tert-butoxycarbonyl)(1-ethoxy-1-oxopropan-2-yl)amino)butanoate (450 g, 87% purity, 1.9 mol, 1.0 equiv.) and THF (2.25 L, 5 V) at 20-30°C. The mixture was cooled to -40-30°C and then lithium bis(trimethylsilyl)amide (LiHMDS) (1 M in THF, 2.9 L, 2.9 mol, 1.5 equiv.) was added dropwise, maintaining the temperature at -40-30°C. The resulting reaction mixture was warmed to 10-20°C and held at this temperature for 1 hour. After the reaction was complete, the reaction mixture was combined with the other two batches and then poured into aqueous citric acid (408.6 g, 2.9 mol, 1.5 equiv. in 2250 mL HO). After phase separation, the aqueous layer was re-extracted with MTBE (12 L, 10 V), and the combined organic layers were washed sequentially with brine (9 L × 2). The organic phase was dried over NaSO and concentrated in vacuo to give the crude product. The resulting residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the title compound (1100 g) in 70% yield and 99% purity over two steps. 1 H NMR(500MHz,CDCl3)δ 4.26-4.10(m,2H),2.79(s,1H),2.34-2.14(m,2H),1.47(d,J=27.0Hz,2H ),1.40(s,9H),1.36(s,1H),1.29(d,J=6.9Hz,3H),1.23(t,J=7.1Hz,3H).

[0288] Step D: tert-Butyl (7S)-2,7-dimethyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate. To a 10 L four-neck flask was added methylhydrazine sulfate (360 g, 2.5 mol, 1.5 equiv), EtOH (5 L, 10.6 V), and DIEA (399 mL, 2.4 mol, 1.45 equiv) at 20-30° C. The resulting mixture was warmed to 75-80° C. over 30 min. Next, a solution of 1-(tert-butyl) 4-ethyl (2S)-2-methyl-3-oxopiperidine-1,4-dicarboxylate (495 g crude, assay weight 470 g, 1.6 mol, 1.0 equiv.) in EtOH (500 mL) was added dropwise over 20 minutes while maintaining the temperature at 75-80°C. The resulting mixture was stirred at 75-80°C for 4 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum. The resulting residue was combined with the residue from another 470 g batch. The combined residue was diluted with DCM (8 L, 8.5 V), HO (2 L, 2.7 V), and brine (2.5 L, 2.7 V). After phase separation, the aqueous layer was re-extracted with DCM (2 L × 2). The combined organic layers were dried over NaSO and then concentrated under vacuum to give the title compound, which was used in the next step without further purification. MS (ESI): Mass calculated, C 13 H 21 N3O3, 267.2; m / z measured, 268.1 [M+H] + .

[0289] Step E: (S)-tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate. To a 10 L four-neck flask were added tert-butyl (7S)-2,7-dimethyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (940 g, 3.3 mol, 1.0 equiv.), DCM (6 L, 6.4 V), and DIEA (550 mL, 3.3 mol, 1.0 equiv.) at 20-30 °C. After cooling the mixture to 10-20 °C, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (902 g, 2.3 mol, 0.7 equiv.) was added batchwise while maintaining the temperature at 10-20 °C. Further N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (232 g, 0.6 mol, 0.18 equiv.) was added. After stirring overnight, HPLC indicated the reaction was complete. The reaction mixture was then concentrated under vacuum and purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 8 / 1) to give 1106 g of the title compound in 99% purity (84% yield over two steps). 1 H NMR(400MHz, CDCl3)δ 5.19(br,1H),4.30(br,1H),3.78(s,3H),2.99-2.85(m,1H),2.59-2.52(m,1H),1.48(s,10H),1.41(d,J=6.4Hz,3H).

[0290] Intermediate 11: tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole-10-carboxylate.

[0291] [ka]

[0292] 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 (mCPBA) (55%, 300 g, 956 mmol) in chloroform (1.75 L), and the reaction was stirred at room temperature for 42 h. The reaction mixture was washed with 20% sodium bisulfite (4 × 1 L), saturated sodium bicarbonate (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 (bp = 40 °C, 2 mmHg) to give the title compound (74.2 g, 51% yield) as a colorless liquid. MS (ESI): Mass calculated, CH 12 O, 124.1; m / z measured, 123.0 [MH] - .

[0293] Step B: (1S,8S,Z)-8-(((R)-1-phenylethyl)amino)cyclooct-4-en-1-ol. To a solution of ytterbium(III) trifluoromethanesulfonate hydrate (12.5 g, 20.2 mmol) in distilled tetrahydrofuran (200 mL) was added (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), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated to give the title compound (120 g, crude) as a yellow oil. The reaction was repeated on a 99 g scale (798 mmol). The products from both reactions were combined and converted to the hydrochloride salt in two batches. To 20 g of the resulting residue was added hydrogen chloride (3.88 M in diethyl ether, 82 mL, 318 mmol). The precipitate was collected, and the first crop (3.34 g, 11.8 mmol, 14%) was isolated as a white crystalline solid. To the remaining 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 minutes, and the precipitate was collected. The solid was suspended in water-saturated ethyl acetate (5.6 L) and stirred at 50 °C for 30 minutes. After cooling to room temperature, the precipitate was collected, and the second crop (78 g, 277 mmol, 24% yield) was isolated as a white crystalline solid. MS(ESI): Calculated mass, C 16 H 23 NO, 245.2; m / z measured, m / z = 246.2 [M+H] + . 1 H NMR(400MHz,CDCl3)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=6.8Hz,2H),1.38-1.27(m,2H).

[0294] 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-[[(1R)-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 was stirred at room temperature for 1 day. To the reaction mixture was added sodium hydroxide (3M, 280 mL, 840 mmol) and a solution of sodium borohydride (13.0 g, 344 mmol) in sodium hydroxide (3M, 70 mL, 210 mmol) at 0° C., and the reaction was 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,MS(ESI): Mass calculation value, C 16 H 23 NO, 245.2; m / z measured, 246.1 [M+H] + .

[0295] Step D: tert-Butyl (1S,2S,5R)-2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate. A mixture of (1R,2S,5R)-9-[(1R)-1-phenylethyl]-9-azabicyclo[3.3.1]nonan-4-ol (98.0 g, crude) and 10% palladium on carbon (42.5 g) in methanol (2.5 L) was stirred at room temperature under hydrogen for 2 hours. Di-tert-butyl dicarbonate (175 g, 802 mmol) and triethylamine (56 mL, 402 mmol) were added to the reaction mixture, and the reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered through a Celite® pad, and the Celite® was washed with methanol (2 × 500 mL). The combined filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with ethyl acetate. The residue was purified by gradient silica gel column chromatography eluting with heptane:ethyl acetate (100:0→3:1) to give a first crop of the title compound (43.4 g, 180 mmol, 44% yield) as a yellow oil. 1 H NMR (500MHz, DMSO-d6) 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).

[0296] 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 (1R,2S,5R)-2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (24.5 g, 102 mmol) in dichloromethane (140 mL), and the reaction was stirred at −78° C. for 30 minutes. Triethylamine (TEA) (85 mL, 61 mmol) was added, and the reaction 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.

[0297]

number

[0298] Step F: 9-(tert-butyl)3-ethyl (1S,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-3,9-dicarboxylate. To a solution of tert-butyl (1R,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (8.2 g, 34.3 mmol) in distilled tetrahydrofuran (180 mL) was added lithium bis(trimethylsilyl)amide (LiHMDS) (1 M in tetrahydrofuran, 41.2 mL, 41.2 mmol) at −78° C., and the reaction was stirred at −78° C. for 30 minutes. To the reaction mixture was added a solution of ethyl cyanoformate (4.4 mL, 44.5 mmol) in distilled tetrahydrofuran (20 mL), and the reaction was stirred at −78° C. for 1 hour. 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 heptane:ethyl acetate (4:1) to give the title compound (5.5 g, 18 mmol, 51% yield) as a pale yellow oil.

[0299]

number

[0300] Step G: tert-Butyl (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-epiminocycloocta[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 was stirred at 80 °C for 8 hours. The reaction mixture was evaporated, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate:methanol (10:1) to give the title compound (15.4 g, 52.5 mmol, 80% yield). MS(ESI): Calculated mass, C 15 H 23 N3O3, 293.2; m / z measured, 294.2 [M+H] + .

[0301] Step H: tert-Butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[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-epiminocycloocta[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-phenyl-bis(trifluoromethanesulfonimide) (26.8 g, 75.0 mmol), and the reaction was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated sodium bicarbonate (2 x 200 mL), 10% potassium bisulfate (2 x 200 mL), and brine (1 x 200 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by gradient silica column chromatography, eluting with heptane:ethyl acetate (6:1 to 4:1). The residue was dissolved 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 x 150 mL), dried over sodium sulfate, filtered, and evaporated. The combined products gave the title compound (16.4 g, 39 mmol, 56% yield) as a colorless oil. MS (ESI): Mass calculated, C 16 H 22 F3N3O5S, 425.1; m / z measured, 370.1 [M+2H-tbutyl] + . 1 H NMR(500MHz,DMSO-d6)δ 5.06(d,J=18.9Hz,1H),4.48(d,J=31.6Hz,1H),3.73(s,3H),2.84(dd,J=16.3,7.4Hz,1H),2 .44(d,J=16.3Hz,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:

[0302]

number

[0303] Intermediate 12: tert-Butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole-9-carboxylate.

[0304] [ka]

[0305] Step A: Ethyl 5-formyl-1H-pyrrole-2-carboxylate. To a cooled (0 °C) solution of dichloroethane (DCE) (250 mL) and POCl3 (18.7 mL, 201 mmol) was slowly charged N,N-dimethylformamide (DMF) (17.7 mL, 230 mmol), and the suspension was stirred at 0 °C for 15 min. Next, a solution of ethyl 1H-pyrrole-2-carboxylate (20 g, 144 mmol) in DCE (50 mL) was added to the reaction mixture, which was stirred at 0 °C for 30 min and allowed to warm to room temperature overnight. The completed reaction was cooled to 0 °C, and a 50 mL solution of NaOAc trihydrate (approximately 43 g) was added. The resulting mixture was heated to 75 °C for 30 min and then cooled to room temperature. The aqueous layer was extracted with methyl tert-butyl ether (MTBE, TBME), washed with aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated. Purification (FCC, eluting with 0-10% EtOAc / Hex) afforded the title compound (18.1 g, 75%). MS (ESI): mass calculated, C8H9NO3, 167.1; m / z found, 168.1 [M+H] + .

[0306] Step B: Ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate. To a cooled (0 °C) solution of NaH (8.7 g, 217 mmol) in THF (200 mL) was added triethylphosphonoacetate (61.7 g, 234 mmol). The reaction mixture was stirred at 0 °C for 3 h, and then ethyl 5-formyl-1H-pyrrole-2-carboxylate (27.9 g, 167 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with aqueous NH4Cl (200 mL), extracted into Et2O (x3), washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was recrystallized from 10% EtOAc / Hex to give the title compound (39.5 g, 99.8%). MS(ESI): Calculated mass, C 12 H 15 NO4, 237.1; m / z measured, 238.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 9.93(s,1H),7.56(d,J=16.0Hz,1H),6.98-6.81(m,1H),6.63-6.43(m,1H),6.32(d,J=16.0Hz, 1H),4.39(q,J=7.1Hz,2H),4.25(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H),1.32(t,J=7.2Hz,3H).

[0307] Step C: Ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate. A flask was charged with ethyl (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylate (39.5 g, 167 mmol) and rhodium-supported alumina (27.4 g, 13.3 mmol). The mixture was suspended in acetic acid (80 mL), evacuated, and refilled with N. The flask was then fitted with an H bladder and evacuated and refilled with H twice. The reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture was passed through Celite®, washed with DCM, and concentrated under reduced pressure. Water (400 mL) was added to the reaction mixture, and the reaction mixture was extracted with DCM (×3). The organic layers were combined, washed with aqueous NaHCO, brine, dried (NaSO), filtered, and concentrated under reduced pressure to give the title product as a colored oil (38.6 g, 95%). MS (ESI): Mass calculated, C 12 H 21 NO4, 243.1; m / z measured, 244.1 [M+H] + .

[0308] Step D: 1-(tert-butyl) 2-ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate. To a solution of ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate (38.6 g, 158 mmol) and Boc-anhydride (di-tert-butyl dicarbonate) (38 g, 175 mmol) in DCM (317 mL) was slowly added TEA (44.1 mL, 317 mmol). The resulting reaction mixture was stirred overnight at room temperature. 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 (ESI): Mass calculated, C 17 H 29 NO6, 343.2; m / z measured, 244.1 [M+2H-CO2tBu] + .

[0309] Step E: 8-(tert-Butyl) 3-ethyl 2-oxo-8-azabicyclo[3.2.1]octane-3,8-dicarboxylate. A 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 KOtBu (21.5 g, 191 mmol) was heated at 60 °C for 3 h. The reaction mixture was cooled and concentrated under reduced pressure. The resulting residue was resuspended in DCM (800 mL) and washed with saturated aqueous NH4Cl. The aqueous layer was re-extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, eluting with 0–10% EtOAc / hexanes) afforded the title compound (37.8 g, 79.7%). MS(ESI): Calculated mass, C 15 H 23 NO5, 297.2; m / z measured, 242.1 [M+2H-tBu] + .

[0310] Step F: Racemic tert-butyl 2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydro-5,8-epiminocyclohepta[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 °C for 2 h. The cooled reaction was concentrated under reduced pressure. Purification (FCC, SiO2, eluting with 0-10% MeOH / DCM) afforded the title compound as a clear oil. MS (ESI): Mass calculated, C 14 H 21 N3O3, 279.2; m / z measured, 280.2 [M+H] + .

[0311] Step G: tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole-9-carboxylate and tert-butyl (5S,8R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[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-epiminocyclohepta[c]pyrazole-9-carboxylate (9.48 g, 34 mmol) in DCM (152 mL) was added N-phenyl-bis(trifluoromethanesulfonimide) (13.5 g, 37 mmol), followed by DIEA (6.4 mL, 37 mmol). The resulting solution was stirred at room temperature for 18 h, and the completed reaction was concentrated under reduced pressure. Purification (FCC, SiO, eluting with 0-20% EtOAc / Hex) afforded the racemic mixture of the title compounds (11.2 g, 80%). MS (ESI): Mass calculated, C 15 H 20 F3N3O5S, 411.1; m / z measured, 356.0 [M+2H-tbutyl] + .

[0312] Chiral SFC purification of racemic tert-butyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole-9-carboxylate using Chiralpak IC 5 μm 250 * A single enantiomer was isolated using 30 mm, mobile phase: 93% CO2, 7% iPrOH to give tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole-9-carboxylate (single enantiomer; retention time 1.05 min). MS (ESI): mass calculated, C 15 H 20F3N3O5S, 411.1; m / z observed, 356.0 [M+2H-t-butyl] + .

[0313] Intermediate 13: (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.

[0314] [ka]

[0315] Step A: tert-Butyl (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate. To a solution of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Intermediate 10, 500 mg, 1.25 mmol) in 1,4-dioxane (4.0 mL), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (291 mg, 1.5 mmol), aqueous sodium carbonate (2 M, 1.0 mL, 2.74 mmol), and XPhos-Pd-G2 (49.3 mg, 0.06 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated to 90 °C for 2 h and concentrated under reduced pressure. The residue was taken up in ethyl acetate (EtOAc) (10 mL), washed with water (2 x 5.0 mL), brine (1 x 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO; 0-40% hexane-EtOAc) to afford the title compound as an oil (390 mg, 0.50 mmol, 77%). MS (ESI): Mass calculated, C 18 H 24 F3N5O2,399.2;m / z actual value,344.1[M+2H- t Bu] + . 1H NMR(400MHz,DMSO-d6)δ 7.08(d,J=0.8Hz,1H),5.11(s,1H),4.22-4.04(m,1H),3.78(s,3H),3.69(s,3H),3.05- 2.83(m,1H),2.50-2.41(m,1H),2.37-2.22(m,1H),1.44(s,9H),1.37(d,J=6.7Hz,3H).

[0316] Step B: (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine. To a mixture of tert-butyl (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (385 mg, 0.96 mmol) in dichloromethane (2 mL), trifluoroacetic acid (TFA) (2 mL, 26.1 mmol, 1.49 g / mL) was added at 0° C., and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with dichloromethane (25 mL), concentrated in vacuo, and the process repeated three times to give the title compound as a white solid, which was used in the next step without purification. MS (ESI): Mass calculated, C 13 H 16 F3N5, 299.2; m / z measured, 300.1 [M+H] + . 1 H NMR(500MHz, methanol-d4)δ 6.86(s,1H),4.61(q,J=6.7Hz,1H),3.81(s,3H),3.75(s,3H),3.67-3.60(m,1H),3.41-3.33(m,1H),2.88-2.67(m,2H),1.70(d,J=6.8Hz,3H).

[0317] Intermediate 14: (S)-2,7-Dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine trifluoroacetate.

[0318] [ka]

[0319] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), except that in Step A, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole was used instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid. The resulting mixture was used as the TFA salt without further purification. MS (ESI): Calculated mass, C 13 H 16 F3N5, 299.2; m / z measured, 300.2 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 6.71(s,1H),4.16(q,J=6.6Hz,1H),4.05(d,J=4.8Hz,6H),3.64-3.24(m,1H),3.07-2.97(m,2H),2.83-2.63(m,2H),1.55(d,J=6.6Hz,3H).

[0320] Intermediate 15: (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.

[0321] [ka]

[0322] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using (1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Calculated mass, C 13 H 16 F3N5, 299.2; m / z measured, 300.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.45(s,1H),4.08(d,J=1.0Hz,3H),4.04(q,J=6.6Hz,1H),3.65(s,3H),3.28-3.20(m ,1H),2.95-2.86(m,1H),2.51-2.41(m,1H),2.36-2.27(m,1H),1.49(d,J=6.6Hz,3H).

[0323] Intermediate 16: (S)-3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.

[0324] [ka]

[0325] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Calculated mass, C 13 H 19N5, 245.2; m / z measured, 246.1 [M+H] + .

[0326] Intermediate 17: (S)-3-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.

[0327] [ka]

[0328] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (Intermediate 9) instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Calculated mass, C 14 H 18 F3N5, 313.15; m / z measured, 314.1 [M+H] + .

[0329] Intermediate 18: (S)-3-(3-Methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine.

[0330] [ka]

[0331] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using 3-methoxy-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Calculated mass, C 13 H 19 NO, 261.2; m / z, 262.3 [M+H] + .

[0332] Intermediate 19: (S)-2,7-Dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine HCl salt.

[0333] [ka]

[0334] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A and HCl instead of TFA in Step B. EtOH was used instead of DCM in Step B. MS (ESI): Calculated mass, C 13 H 16 F3N5, 299.1; m / z measured, 300.1 [M+H] + .

[0335] Intermediate 20: (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole.

[0336] [ka]

[0337] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), except that tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole-10-carboxylate (Intermediate 11) was used in place of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate in Step A. MS (ESI): Calculated mass, C 15 H 18 F3N5, 325.2; m / z measured, 326.2 [M+H] + .

[0338] Intermediate 21: (5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole.

[0339] [ka]

[0340] Using tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole-10-carboxylate (Intermediate 11) instead of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, (1-methyl) The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole instead of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ylboronic acid. MS (ESI): Mass Calculated, C 15 H 18 F3N5, 325.2; m / z measured, 326.1 [M+H] + .

[0341] Intermediate 22: (5R,9S)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole.

[0342] [ka]

[0343] Instead of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole-10-carboxylate (Intermediate 11 The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Mass calculated, C 16 H 20 F3N5, 339.2; m / z measured, 340.3 [M+H] + .

[0344] Intermediate 23: (5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole.

[0345] [ka]

[0346] Instead of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate, tert-butyl (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole-10-carboxylate ( The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using Intermediate 11 and substituting (1,3-dimethyl-1H-pyrazol-5-yl)boronic acid for (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid in Step A. MS (ESI): Calculated mass, C 15 H 21 N5, 271.2; m / z measured, 272.1 [M+H] + .

[0347] Intermediate 24: (5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole.

[0348] [ka]

[0349] The title compound was prepared in a manner similar to that of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13), using tert-butyl (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Intermediate 12) instead of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate. MS (ESI): Calculated mass, C 14 H 16 F3N5, 311.1; m / z measured, 312.2 [M+H] + .

[0350] Intermediate 25: (S)-2,7-Dimethyl-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate.

[0351] [ka]

[0352] Step A: (S)-2,7-Dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate. To a solution of (S)-tert-butyl 2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Intermediate 10, 2.0 g, 5.0 mmol) in CHCl (15 mL) was added trifluoroacetic acid (7.4 mL, 19.4 mmol), and the reaction was stirred at room temperature for 30 minutes before being concentrated in vacuo. The residue was taken up in EtOAc, saturated aqueous NaHCO was carefully added, and the mixture was stirred for 1 minute. The layers were separated, and the aqueous layer was extracted with EtOAc followed by 20% iPrOH / CHCl. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

[0353] Step B: (S)-2,7-Dimethyl-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate. To a solution of (S)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate (1.5 g, 5.0 mmol) in CHCl (50 mL) was added quinoline-6-carboxylic acid (1.30 g, 7.51 mmol) and DIPEA (2.59 mL, 15.0 mmol), followed by propylphosphonic anhydride (50 wt% in EtOAc, 4.3 mL, 15.0 mmol). The reaction was stirred at room temperature for 30 minutes and then quenched with HO. After vigorously stirring the mixture for 1-2 minutes, the layers were separated and the organic layer was carefully washed with saturated aqueous NaHCO3 (CAUTION: gas formation). The combined aqueous layers were transferred to a round-bottom flask and vigorously stirred for 1-2 minutes until no further effervescence was observed, then extracted with CHCl2. The two organic solutions were combined, washed once with brine, dried over NaSO4, filtered, and concentrated in vacuo. The resulting residue was taken up in a mixture of CHCl2 / hexanes, and the resulting precipitate was collected by vacuum filtration and washed with hexanes to give the title compound as a brown solid (1.38 g). The filtrate was concentrated and purified by silica gel chromatography (0-20% MeOH in CHCl2) to give a second batch of the title compound (0.52 g). Combined yield: 83%. MS (ESI): Mass calculated, C 19 H 17 F3N4O4S, 454.1; m / z measured, 455.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.99(dd,J=4.2,1.7Hz,1H),8.19(dd,J=15.2,8.6Hz,2H),7.92(d,J=1.9Hz,1H),7.73(dd,J=8.6,1.9Hz,1H),7.48(dd,J=8.3,4.2Hz,1H),5.82(br s,0.51H),4.91(br s,0.70H),3.78(s,3.74H),3.27(br s,1H),2.94-2.44(m,2H),1.58(s,3H).

[0354] Intermediate 26: 3-Methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid.

[0355] [ka]

[0356] To a mixture of 3-iodo-5-methylbenzoic acid (200 mg, 0.76 mmol) in N,N-dimethylformamide (2.2 mL) was added 1H-1,2,3-triazole (199 μL, 3.44 mmol), cesium carbonate (423 mg, 1.30 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (20 μL, 0.13 mmol), and copper(I) iodide (15 mg, 78.8 μmol). The reaction mixture was stirred at 140° C. for 60 minutes under microwave irradiation. The reaction mixture was filtered through a pad of Celite®, and the Celite® was washed with ethyl acetate (2×5 mL). The combined filtrate was extracted with water (1×5 mL). The aqueous layer was acidified to pH 3 with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC to give the title compound (51 mg, 32% yield) as an off-white powder. MS (ESI): mass calculated, C9H6FN3O2, 203.1; m / z found, 204.1 [M+H] + .

[0357] Intermediate 27: 5-Fluoro-2-methylquinoline-6-carboxylic acid.

[0358] [ka]

[0359] A mixture of 4-amino-2-fluorobenzoic acid (2.0 g, 13.0 mmol) and concentrated HCl (6 M in water, 25.0 mL, 150 mmol) was stirred at 90° C. for 1 hour. (E)-But-2-enal (2.1 g, 30.0 mmol) was added to the reaction mixture at 90° C., and the reaction mixture was stirred for 45 minutes. The reaction mixture was cooled, poured into water (20 mL), and extracted with ethyl acetate (20 mL×3). The aqueous phase was concentrated to dryness under reduced pressure, and the resulting residue was purified by preparative HPLC (Method G) to give the title compound as a white solid (120 mg, 4.1% yield). MS (ESI): Mass calculated, C 11 H8FNO2, 205.1; m / z measured, 205.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.91(d,J=8.7Hz,1H),8.32-8.24(m,1H),8.13(d,J=8.9Hz,1H),7.88(d,J=8.7Hz,1H),2.91(s,3H).

[0360] Intermediate 28: 7-Fluoro-2-methylquinoline-6-carboxylic acid.

[0361] [ka]

[0362] The title compound was prepared in a similar manner to Intermediate 27. Purification was performed by SFC on a DAICEL CHIRALPAK AD-H (250 mm x 30 mm x 5 μm (isocratic elution: EtOH (containing 0.1% of 25% aqueous NH3): supercritical CO2, 25%:75% to 25%:75% (v / v)). MS (ESI): calculated mass, C 11 H8FNO2, 205.1; m / z measured, 205.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.36 (t, J = 7.7 Hz, 2H), 7.61 (d, J = 11.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 2.66 (s, 3H).

[0363] Intermediate 29: 2,5-dimethylquinoline-6-carboxylic acid.

[0364] [ka]

[0365] The title compound was prepared in a similar manner to Intermediate 27, using 4-amino-2-methylbenzoic acid instead of 4-amino-2-fluorobenzoic acid. The resulting isomeric mixture was purified by SFC on a DAICEL CHIRALPAK AD-H (250 mm x 30 mm x 5 um (isocratic elution) EtOH (containing 0.1% of 25% aqueous NH3):supercritical CO2, 25%:75% to 25%:75% (v / v)) to give the title compound as a white solid and 2,7-dimethylquinoline-6-carboxylic acid (Intermediate 30). MS (ESI): Calculated mass, C 12 H 11 NO2, 201.2; m / z measured, 202.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.53(d,J=8.5Hz,1H),7.94(d,J=8.8Hz,1H),7.78(d,J=8.8Hz,1H),7.50(d,J=8.8Hz,1H),2.84(s,3H),2.67(s,3H).

[0366] Intermediate 30: 2,7-dimethylquinoline-6-carboxylic acid.

[0367] [ka]

[0368] The title compound was isolated as a second crop from the mixture described in Intermediate 29. MS (ESI): Calculated mass, C 12 H 11 NO2, 201.2; m / z measured, 202.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.00(br.s,1H),8.46(s,1H),8.33(d,J=8.3Hz,1H),7.78(s,1H),7.41(d,J=8.5Hz,1H),2.68(s,3H),2.65(s,3H).

[0369] Intermediate 31: 2,4-dimethylquinoline-6-carboxylic acid.

[0370] [ka]

[0371] Step A: 6-Bromo-2,4-dimethylquinoline. To a mixture of 6-bromo-2-methylquinoline (555 mg, 2.5 mmol), ethyl 2-mercaptopropanoate (65 μL, 0.5 mmol), and 4-methylbenzenesulfonic acid (950 mg, 5.5 mmol) in DMSO (10 mL) and MeOH (20 mL) was added Ir(ppy)2(dtbbpy)PF6 catalyst (28 mg, 0.031 mmol) under a nitrogen atmosphere. The resulting mixture was degassed with nitrogen for an additional 5 minutes and then irradiated with a blue LED at room temperature. After 36 hours, 1 N NaOH (10.0 mL) and DCM (100.0 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2; 0-20% hexane-EtOAc) to give the title compound as a white solid (500 mg, 82%). MS (ESI): Calculated mass, C 11 H 10 BrN, 235.0; m / z measured, 236.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 8.07(d,J=2.0Hz,1H),7.87(d,J=9.0Hz,1H),7.72(dd,J=2.2,8.8Hz,1H),7.14(s,1H),2.67(s,3H),2.62(s,3H).

[0372] Step B: Methyl 2,4-dimethylquinoline-6-carboxylate. To a solution of 6-bromo-2,4-dimethylquinoline (250 mg, 1.06 mmol) in DMF (6.0 mL) and MeOH (6.0 mL) was added triethylamine (482 mg, 4.8 mmol), Pd(dppf)Cl (155 mg, 0.21 mmol), and Pd(OAc) (24 mg, 0.11 mmol) under a nitrogen atmosphere. The resulting mixture was saturated with CO and then heated to 80 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO; 0–20% hexane-EtOAc) to afford the title compound (200 mg, 84%) as a yellow solid. MS(ESI): Calculated mass, C 13 H 13 NO2, 215.1; m / z measured, 216.1 [M+H] + .

[0373] Step C: 2,4-Dimethylquinoline-6-carboxylic acid. To a solution of methyl 2,4-dimethylquinoline-6-carboxylate (200 mg, 0.93 mmol) in THF (4.0 mL) was added a solution of lithium hydroxide (110 mg, 4.6 mmol) in water (4.0 mL) dropwise, and the resulting mixture was stirred at room temperature for 8 hours. 2 M HCl solution was added to the resulting reaction mixture to adjust the pH to 3-4. The mixture was extracted with dichloromethane (3 x 50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound as a yellow solid. MS (ESI): Mass calculated, C 12 H 11 NO2, 201.1; m / z measured, 202.2 [M+H] + .

[0374] Intermediate 32: 4-Methoxy-2-methylquinoline-6-carboxylic acid.

[0375] [ka]

[0376] Step A: 2-Methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid. To a solution of 4-aminobenzoic acid (3.5 g, 25.5 mmol) and acetic acid (731 μL, 12.8 mmol) in toluene (50.0 mL) was added ethyl 3-oxobutanoate (5.0 g, 38.4 mmol), and the mixture was heated to 120° C. for 16 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered, washed with toluene (20 mL), and dried under reduced pressure. The resulting solid was then suspended in oxydibenzene (50.0 mL), and the mixture was stirred at 240° C. for 3 hours. The reaction mixture was cooled to room temperature, and the suspension was filtered and washed with toluene (20.0 mL) to give the title product as a yellow solid (1.8 g, 17.3%). MS (ESI): Mass calculated, C 11 H9NO3, 203.1; m / z measured, 203.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.78-12.63(m,1H),11.82(br s,1H),8.64(d,J=2.0Hz,1H),8.10(dd,J=2.0,8.8Hz,1H),7.54(d,J=8.5Hz,1H),5.98(s,1H),2.35(s,3H).

[0377] Step B: Methyl 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate. To a solution of 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.8 g, 8.8 mmol) in methanol (20 mL), concentrated sulfuric acid (2.0 mL) was added, and the resulting mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was poured into ice water (20 mL) and adjusted to pH 5 with 1 M NaOH. Methanol was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO2; 0-50% hexane-EtOAc) to afford the title compound as a yellow solid (650 mg, 33%). MS (ESI): Mass calculated, C 12 H 11NO3, 217.0; m / z measured, 217.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.13-11.64(m,1H),8.65(d,J=1.9Hz,1H),8.11(d,J=6.9Hz,1H),7.57(d,J=8.1Hz,1H),5.99(s,1H),3.87(s,3H),2.35(s,3H).

[0378] Step C: Methyl 4-chloro-2-methylquinoline-6-carboxylate. Phosphorus oxychloride (750 mg, 4.9 mmol) was added to a mixture of methyl 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (650 mg, 3.0 mmol) and THF (10.0 mL) in the presence of a catalytic amount of DMF (100 μL) at 0° C. The resulting mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the mixture was poured into water (10.0 mL), adjusted to pH 7-8 with 4 M aqueous NaOH, and concentrated under reduced pressure to remove THF. The resulting solid was filtered and washed with water (3 mL × 3) to give the title product as a yellow solid (600 mg, 82%). MS (ESI): Mass calculated, C 12 H 10 ClNO2, 235.0; m / z, 235.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.74(s,1H),8.26(d,J=8.6Hz,1H),8.09(d,J=8.8Hz,1H),7.83(s,1H),3.95(s,3H),2.69(s,3H).

[0379] Step D: 4-Methoxy-2-methylquinoline-6-carboxylic acid. To a solution of methyl 4-chloro-2-methylquinoline-6-carboxylate (200 mg, 0.85 mmol) in methanol (2.0 mL) was added sodium methoxide (92 mg, 1.7 mmol). The reaction mixture was heated at 60 °C for 16 h to give a mixture of 4-methoxy-2-methylquinoline-6-carboxylic acid and 4-chloro-2-methylquinoline-6-carboxylic acid. Purification by HPLC (Method: Boston Green ODS 150 × 30 mm × 5 um column (Eluent: 10% to 40% (v / v) CHCN and HO containing 0.225% HCOOH)) afforded the title compound, 4-methoxy-2-methylquinoline-6-carboxylic acid, as a yellow solid (20 mg, 10.3% yield). MS (ESI): Mass calculated, C 12 H 11 NO3, 217.1; m / z measured, 217.9 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.72(d,J=2.0Hz,1H),8.17(dd,J=2.3,9.0Hz,1H),7.84(d,J=9.0Hz,1H),6.13(s,1H),3.75(s,3H),2.49(s,3H).

[0380] Intermediate 33: 4-Methyl-2-(trifluoromethoxy)benzoic acid.

[0381] [ka]

[0382] To a solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.5 mmol) in dioxane:water (15:3 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (880 mg, 7.0 mmol), cesium carbonate (3.4 g, 10.53 mmol), and Pd(dppf)Cl (260 mg, 0.35 mmol) under a nitrogen atmosphere. The resulting mixture was purged with nitrogen for 5 minutes and heated to 100 °C for 16 hours. The resulting reaction mixture was filtered through a pad of Celite® and washed with ethyl acetate (5 mL x 4). The filtrate was concentrated under reduced pressure and purified by HPLC (Method: Boston Uni C18 150 × 40 mm × 5 μm column (Eluent: 33% to 63% (v / v) CH3CN and HO containing 0.225% FA)) to give the title compound as a yellow solid (100 mg, 13% yield). MS (ESI): mass calculated, C9H7F3O3, 220.1; m / z found, 220.9 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ 13.24(brs,1H),7.83(d,J=7.8Hz,1H),7.33(d,J=8.0Hz,1H),7.30(s,1H),2.40(s,3H).

[0383] Intermediate 34: 7-Methylbenzo[d]thiazole-6-carboxylic acid.

[0384] [ka]

[0385] Step A: Methyl 2-amino-7-methylbenzo[d]thiazole-6-carboxylate and methyl 2-amino-5-methylbenzo[d]thiazole-6-carboxylate. To an ice-cooled solution (0°C) of methyl 4-amino-2-methylbenzoate (1 g, 6.0 mmol), sodium thiocyanate (1.75 g, 21.6 mmol), and acetic acid (15.0 mL), bromine (0.3 mL, 6.0 mmol) in acetic acid (1.0 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 16 hours. The resulting suspension was filtered through a pad of Celite®, and the filtrate was diluted with water (20 mL). The mixture was quenched with 1 M NaOH to pH = 4, yielding a precipitate. The precipitate was filtered and washed with MeOH (5 mL x 2). The resulting product mixture was purified by SFC on a DAICEL CHIRALPAK AD-H (250 mm × 30 mm × 10 μm (isocratic elution: EtOH (containing 0.1% of 25% aqueous NH3): supercritical CO2, 30%:70% to 30%:70% (v / v)) to give the following two title products: Methyl 2-amino-7-methylbenzo[d]thiazole-6-carboxylate (220 mg, 16%); MS (ESI): mass calculated, C 10 H 10 N2O2S, 222.2; m / z measured, 222.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 7.87(s,2H),7.77(d,J=8.5Hz,1H),7.22(d,J=8.5Hz,1H),3.80(s,3H),2.61(s,3H). Methyl 2-amino-5-methylbenzo[d]thiazole-6-carboxylate (220 mg, 16%); MS (ESI): mass calculated, C 10 H 10 N2O2S, 222.2; m / z measured, 222.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.18 (s, 1H), 7.84 (s, 2H), 7.22 (s, 1H), 3.79 (s, 3H), 2.54-2.54 (m, 3H).

[0386] Step B: Methyl 7-methylbenzo[d]thiazole-6-carboxylate. To a solution of methyl 2-amino-7-methylbenzo[d]thiazole-6-carboxylate (200 mg, 0.9 mmol) in THF (5 mL) was added isopentyl nitrite (232 mg, 2.0 mmol), and the mixture was stirred at 65° C. for 14 hours. The resulting mixture was concentrated to dryness under reduced pressure to give the title product as a brown solid, which was used in the next step without purification. MS (ESI): Mass calculated, C 10 H9NO2S, 207.1; m / z measured, 207.8 [M+H] + .

[0387] Step C: 7-Methylbenzo[d]thiazole-6-carboxylic acid. To a solution of methyl 7-methylbenzo[d]thiazole-6-carboxylate (180 mg, 0.87 mmol) in dioxane:water (1:1, 5 mL) was added lithium hydroxide monohydrate (180 mg, 4.3 mmol). The resulting mixture was stirred at room temperature for 14 hours. The resulting reaction was diluted with water and extracted with ethyl acetate (10 mL x 3). The aqueous phase was quenched with 3 M HCl to pH = 4.0 and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid (170 mg). MS (ESI): mass calculated, CHNOS, 193.0; m / z found, 193.8 [M+H] + .

[0388] Intermediate 35: 5-Methylbenzo[d]thiazole-6-carboxylic acid.

[0389] [ka]

[0390] The title compound was prepared in a manner similar to Intermediate 34, Steps B and C, using methyl 2-amino-5-methylbenzo[d]thiazole-6-carboxylate (Intermediate 34, Step A) instead of methyl 2-amino-7-methylbenzo[d]thiazole-6-carboxylate. MS (ESI): mass calculated, CHNOS, 193.0; m / z found, 193.8 [M+H] + .

[0391] Intermediate 36: 5-Methylbenzo[d]thiazole-6-carboxylic acid.

[0392] [ka]

[0393] The title compound was prepared in a manner similar to Intermediate 34, using methyl 4-amino-3-methylbenzoate from Step A instead of methyl 4-amino-2-methylbenzoate. MS (ESI): mass calculated, CHNOS, 193.0; m / z found, 193.8 [M+H] + .

[0394] Example 1: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-5-yl)methanone.

[0395] [ka]

[0396] To a solution of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 13, 25 mg, 83.5 μmol) in CHCl (2.0 mL) was added 2-methylquinoline-5-carboxylic acid (17.2 mg, 0.092 mmol), HATU (41.3 mg, 0.11 mmol), and N,N-diisopropylethylamine (43.2 μL, 0.25 mmol). After stirring at room temperature for 30 minutes, the mixture was concentrated in vacuo and purified by preparative HPLC (Method A) to give the title compound as a white powder (13 mg, 33% yield). MS (ESI): Mass calculated, C 24 H 23 FNO, 468.2; m / z measured, 469.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.12-7.71(m,3H),7.66-7.29(m,2H),7.10(d,J=16.6Hz,1H),5.96-5.68(m,1H),4.92-4 .27(m,1H),3.89-3.59(m,6H),2.74-2.58(m,4H),2.31-2.13(m,2H),1.67-1.30(m,3H).

[0397] Example 2: (S)-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone.

[0398] [ka]

[0399] The title compound was prepared in a manner similar to that of Example 1, using (S)-3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 16) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 27 NO, 393.2; m / z measured, 394.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 7.49-7.36(m,1H),7.36-7.18(m,1H),7.10-6.95(m,1H),6.91-6.70(m,1H),5.77-5.52(m,1H),4.76-4.32(m,1H), 3.86-3.78(m,3H),3.65-3.49(m,6H),3.28-3.12(m,1H),2.42-1.96(m,4H),1.92-1.75(m,4H),1.54-1.31(m,3H).

[0400] Example 3: (S)-(3-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone.

[0401] [ka]

[0402] The title compound was prepared in a manner similar to that of Example 1, using (S)-3-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 17) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 26 F3N5O2, 461.2; m / z measured, 462.0 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 7.25-7.13(m,1H),6.90-6.63(m,2H),6.09-5.78(m,1H),5.06-4.81(m,1 H),4.72-4.64(m,1H),3.91(d,J=13.1Hz,3H),3.88-3.78(m,3H),3.63-3. 45(m,4H),3.29-2.96(m,1H),2.75-2.37(m,1H),2.29-2.20(m,1H),2.06- 1.97(m,1H),1.92(s,1H),1.62(dd,J=8.5,6.7Hz,3H),1.46-0.99(m,2H).

[0403] Example 4: (S)-(2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0404] [ka]

[0405] The title compound was prepared in a manner similar to that of Example 1, using potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)benzoate (Intermediate 1) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 26 ClF3N6O2, 534.2; m / z measured, 535.0 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 7.36-7.04(m,2H),6.86-6.48(m,2H),5.63(td,J=7.1,3.3Hz,1H),4.80-4.64(m,4H),4.30 -4.10(m,4H),3.85-3.62(m,6H),3.29-2.95(m,2H),2.47-2.16(m,2H),1.52-1.22(m,3H).

[0406] Example 5: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-1H-indol-3-yl)methanone.

[0407] [ka]

[0408] The title compound was prepared in a manner similar to that of Example 1, using 4-fluoro-1H-indole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 20 F4NO, 460.2; m / z measured, 461.1 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 11.75(s,1H),7.63(s,1H),7.30(d,J=8.2Hz,1H),7.21-7.04(m,2H),6.83(dd,J=11.0,7.8Hz,1H),5.92-5.26(m ,1H),3.79(s,3H),3.71(s,3H),3.20-3.15(m,1H),2.63-2.54(m,2H),2.44-2.18(m,1H),1.46(d,J=6.8Hz,3H).

[0409] Example 6: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-3-yl)methanone.

[0410] [ka]

[0411] The title compound was prepared in a manner similar to that of Example 1, using 1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.96(d,J=8.2Hz,1H),7.73(d,J=8.5Hz,1H),7.47(t,J=7.7Hz,1H),7.25(t,J=7.6Hz,1H),5.92-5.47(m,1H),4. 85-4.61(m,1H),4.18-4.09(m,3H),3.76-3.62(m,4H),2.78-2.56(m,4H),1.74-1.66(m,2H),1.51-1.43(m,3H).

[0412] Example 7: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylpyrazolo[1,5-a]pyridin-3-yl)methanone.

[0413] [ka]

[0414] The title compound was prepared in a manner similar to that of Example 1, using 4-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 7.87(s,1H),7.57(d,J=9.0Hz,1H),7.42(dd,J=9.0,6.9Hz,1H),6.96-6.84(m,2H),5.83-5.59(m,1H),4.30-4.10(m, 1H),3.82(s,3H),3.77-3.66(m,3H),3.60-3.48(m,1H),2.90-2.74(m,1H),2.68-2.41(m,4H),1.64(d,J=6.8Hz,3H).

[0415] Example 8: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone.

[0416] [ka]

[0417] The title compound was prepared in a manner similar to that of Example 1, using lithium 5-methylimidazo[1,2-a]pyridine-3-carboxylate instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.65-8.53(m,1H),8.36-8.04(m,1H),7.17-7.03(m,2H),7.00-6.82(m,1H),5.81-5.54(m,1H),5.08-4.40(m, 1H),3.80(s,3H),3.75-3.63(m,3H),3.29-3.09(m,1H),2.84-2.56(m,2H),2.36(s,3H),1.49(d,J=6.8Hz,3H).

[0418] Example 9: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-4-yl)methanone.

[0419] [ka]

[0420] The title compound was prepared in a manner similar to that of Example 1, using 2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 FNO, 468.2; m / z measured, 469.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.08-7.92(m,1H),7.82-7.38(m,4H),7.19-7.01(m,1H),5.93-5.60(m,1H),4.97-4.44(m,1H),3.87-3.5 5(m,6H),3.24-3.14(m,1H),2.75-2.66(m,3H),2.66-2.54(m,1H),2.36-2.13(m,1H),1.66-1.39(m,3H).

[0421] Example 10: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone.

[0422] [ka]

[0423] The title compound was prepared in a manner similar to that of Example 1, using 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 FNO, 486.2; m / z measured, 487.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.13-7.95(m,1H),7.77-7.55(m,1H),7.55-7.26(m,2H),7.22-7.02(m,1H),5.93-5.69(m,1H),4.96-4.2 7(m,1H),3.86-3.57(m,6H),3.25-3.08(m,1H),2.96-2.56(m,4H),2.29-2.17(m,1H),1.69-1.39(m,3H).

[0424] Example 11: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone.

[0425] [ka]

[0426] The title compound was prepared in a manner similar to that of Example 1, using 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 19 F4NO, 461.2; m / z measured, 462.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.69(d,J=6.8Hz,1H),8.27(s,1H),7.26(dd,J=10.7,7.7Hz,1H),7.10(s,1H),7.05-6.92(m,1H),5.86-5.44(m ,1H),3.79(s,3H),3.71(s,3H),3.17(s,2H),2.71-2.55(m,1H),2.32(d,J=15.0Hz,1H),1.48(d,J=6.7Hz,3H).

[0427] Example 12: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone.

[0428] [ka]

[0429] The title compound was prepared in a manner similar to that of Example 1, using potassium 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (Intermediate 2) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 21 FNO, 525.2; m / z measured, 526.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.41(d,J=4.8Hz,1H),7.76-7.61(m,1H),7.21(d,J=4.8Hz,1H),7.17-7.04(m,1H),6.58-6.36(m,1H),5.81-5.69(m,1H),5.36- 5.15(m,2H),4.86-4.51(m,1H),3.86-3.58(m,6H),3.52-3.38(m,1H),2.87-2.55(m,1H),2.45-2.17(m,1H),1.64-1.29(m,3H).

[0430] Example 13: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-3-yl)methanone.

[0431] [ka]

[0432] The title compound was prepared in a manner similar to that of Example 1, using 2-methylquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 FNO, 468.2; m / z measured, 469.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.29(s,1H),7.97(d,J=8.7Hz,2H),7.87-7.73(m,1H),7.68-7.53(m,1H),7.11(d,J=17.8Hz,1H),5.81-5.60(m,1H),4.85-4.47(m,1H) ),3.09-3.02(m,1H),3.85-3.77(m,3H),3.75-3.64(m,3H),3.44-3.36(m,1H),2.60(s,3H),2.34-2.19(m,1H),1.56(d,J=6.7Hz,3H).

[0433] Example 14: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-methoxyquinolin-5-yl)methanone.

[0434] [ka]

[0435] The title compound was prepared in a manner similar to that of Example 1, using 8-methoxyquinoline-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 F3N6O2, 484.2; m / z measured, 485.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.91(s,1H),8.12(d,J=8.5Hz,1H),7.72-7.45(m,2H),7.34-7.01(m,2H),5.89-5.60(m,1H),4.99-4.69(m,1H), 4.02(s,3H),3.87-3.61(m,6H),3.51-3.36(m,1H),2.76-2.60(m,1H),2.24(d,J=16.7Hz,1H),1.73-1.38(m,3H).

[0436] Example 15: (S)-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0437] [ka]

[0438] The title compound was prepared in a manner similar to that of Example 1, using 1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 23 FNO, 472.2; m / z measured, 473.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.11-7.78(m,1H),7.23-7.01(m,2H),5.85-5.53(m,1H),4.89-4.52(m,1H),4.11-3.95(m,3H),3.90- 3.59(m,6H),3.56-3.43(m,1H),3.18-3.09(m,1H),2.52(s,3H),2.36-2.18(m,1H),1.68-1.33(m,3H).

[0439] Example 16: (S)-(3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0440] [ka]

[0441] The title compound was prepared in a manner similar to that of Example 1, except that (S)-3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 18) was used instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and quinoline-6-carboxylic acid was used instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 24 NO, 416.2; m / z measured, 417.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.97(dd,J=4.2,1.7Hz,1H),8.53-8.40(m,1H),8.15-8.03(m,2H),7.84-7.72(m,2H),7.61(dd,J=8.3,4.2Hz,1H),5.68-5.43(m ,1H),4.78-4.55(m,1H),3.84(s,3H),3.76-3.67(m,6H),3.22-3.10(m,1H),2.69-2.57(m,1H),2.41-2.26(m,1H),1.48(s,3H).

[0442] Example 17: (S)-(4,6-difluoropyrazolo[1,5-a]pyridin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0443] [ka]

[0444] The title compound was prepared in a manner similar to that of Example 1, using potassium 4,6-difluoropyrazolo[1,5-a]pyridine-3-carboxylate (Intermediate 3) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C21 H 18 F5NO, 479.2; m / z measured, 480.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 9.22-9.06(m,1H),8.43-8.24(m,1H),7.74-7.58(m,1H),7.20-6.95(m,1H),5.74-5.42(m,1H),4.38-4.10(m,1H), 3.82-3.76(m,3H),3.74-3.60(m,3H),3.23-2.73(m,1H),2.74-2.58(m,1H),2.42-2.25(m,1H),1.60-1.40(m,3H).

[0445] Example 18: (S)-(5,7-Difluoroquinolin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0446] [ka]

[0447] The title compound was prepared in a manner similar to that of Example 1, using lithium 5,7-difluoroquinoline-3-carboxylate (Intermediate 4) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 19 F5N6O, 490.15; m / z measured, 491.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 9.14-9.00(m,1H),8.66-8.48(m,1H),7.90-7.60(m,2H),7.16-7.05(m,1H),5.77-5.57(m,1H),4.75(d,J=75. 1Hz,1H),3.90-3.78(m,3H),3.77-3.64(m,3H),2.82-2.58(m,2H),2.32(d,J=14.6Hz,1H),1.66-1.31(m,3H).

[0448] Example 19: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone.

[0449] [ka]

[0450] The title compound was prepared in a manner similar to that of Example 1, except that (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) was used instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid was used instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 19 F4NO, 461.2; m / z measured, 462.2 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.70(dd,J=6.9,1.4Hz,1H),8.27(d,J=1.5Hz,1H),7.33-7.14(m,2H),7.09-6.96(m,1H),5.77-5.46(m,1H),4.95- 4.51(m,1H),4.05(s,3H),3.98(s,3H),3.24-3.11(m,1H),2.82-2.72(m,1H),2.68-2.55(m,1H),1.51-1.39(m,3H).

[0451] Example 20: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-4-yl)methanone.

[0452] [ka]

[0453] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 2-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 F3N6O2, 484.2; m / z measured, 485.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 7.92-7.79(m,1H),7.79-7.32(m,3H),7.32-6.95(m,2H),5.83-5.65(m,1H),5.05-4.27(m,1H), 4.12-3.84(m,9H),3.48-3.37(m,1H),3.30-3.10(m,1H),3.03-2.63(m,1H),1.71-1.32(m,3H).

[0454] Example 21: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-1-methyl-1H-indazol-4-yl)methanone.

[0455] [ka]

[0456] The title compound was prepared in a manner similar to that of Example 1, using 7-fluoro-1-methyl-1H-indazole-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F4NO, 475.2; m / z measured, 476.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.01(s,1H),7.29(dd,J=12.0,7.8Hz,1H),7.22-7.06(m,2H),5.84-5.54(m,1H),4.92-4.44(m,1H),4.28-4.13( m,3H),3.80(s,3H),3.71(s,3H),3.18(d,J=4.8Hz,1H),2.61(d,J=54.6Hz,1H),2.41-2.18(m,1H),1.53(s,3H).

[0457] Example 22: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-indazol-3-yl)methanone.

[0458] [ka]

[0459] The title compound was prepared in a manner similar to that of Example 1, using 5-fluoro-1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F4NO, 475.2; m / z measured, 476.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.86-7.62(m,2H),7.47-7.33(m,1H),7.11(s,1H),6.26-5.62(m,1H),5.12-4.63(m,1H),4.13(d,J=15.4Hz,3H),3. 85-3.77(m,3H),3.74-3.63(m,3H),3.20-3.11(m,1H),2.78-2.64(m,1H),2.46-2.35(m,1H),1.57(d,J=27.2Hz,3H).

[0460] Example 23: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-2H-indazol-4-yl)methanone.

[0461] [ka]

[0462] The title compound was prepared in a manner similar to that of Example 1, using potassium 2-methyl-2H-indazole-4-carboxylate (Intermediate 5) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.1 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ 8.33(s,1H),7.75-7.64(m,1H),7.30(dd,J=8.7,6.7Hz,1H),7.17-7.04(m,2H),5.86-5.50(m,1H),4.96-4.47(m,1H) ,4.18(s,3H),3.81(s,3H),3.77-3.65(m,3H),2.69-2.53(m,1H),2.64-2.55(m,1H),2.42-2.24(m,1H),1.53(s,3H).

[0463] Example 24: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-3-yl)methanone.

[0464] [ka]

[0465] The title compound was prepared in a manner similar to that of Example 1, using 7-fluoro-2-methylquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O, 486.2; m / z measured, 487.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.35(s,1H),8.18-8.00(m,1H),7.73(dd,J=10.5,2.6Hz,1H),7.64-7.47(m,1H),7.18-6.98(m,1H),5.90-5.56(m,1H),4 .85-4.38(m,1H),3.80(s,3H),3.74(s,3H),3.67(s,1H),3.29(s,1H),2.60(s,3H),2.34-2.19(m,1H),1.66-1.47(m,3H).

[0466] Example 25: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,6-dimethylquinolin-4-yl)methanone.

[0467] [ka]

[0468] The title compound was prepared in a manner similar to that of Example 1, using 2,6-dimethylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 FNO, 482.2; m / z measured, 483.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.90(dd,J=8.7,4.1Hz,1H),7.69-7.20(m,3H),7.17-7.02(m,1H),5.93-5.74(m,1H),4.88-4.28(m,1H),3.87-3.60 (m,6H),3.27-3.14(m,1H),3.04-2.72(m,1H),2.73-2.63(m,4H),2.42(s,1H),2.35-2.14(m,2H),1.69-1.39(m,3H).

[0469] Example 26: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-methoxy-2-methylquinolin-4-yl)methanone.

[0470] [ka]

[0471] The title compound was prepared in a manner similar to that of Example 1, using 6-methoxy-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 F3N6O2, 498.2; m / z measured, 499.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.92(d,J=9.1Hz,1H),7.54-7.26(m,2H),7.13-6.87(m,2H),5.98-5.68(m,1H),4.97-4.30(m,1H),3.85-3.73(m,6H), 3.72-3.43(m,3H),3.21-3.14(m,1H),2.71-2.59(m,3H),2.60-2.55(m,1H),2.24(d,J=14.5Hz,1H),1.72-1.35(m,3H).

[0472] Example 27: (S)-(4,6-Difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0473] [ka]

[0474] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate (Intermediate 6) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 20 F5NO, 494.2; m / z measured, 495.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.90-7.79(m,1H),7.55(t,J=9.3,2.7Hz,1H),7.15-6.97(m,1H),5.65(q,J=6.7Hz,1H),5.10-4.61(m,1H),4.13-4.01 (m,6H),3.92-3.83(m,1H),3.61(d,J=28.2Hz,3H),3.18-3.02(m,1H),2.33-2.13(m,1H),1.47(dd,J=24.0,6.7Hz,3H).

[0475] Example 28: (S)-(4,6-Difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0476] [ka]

[0477] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 4,6-difluoro-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 18 F5NO, 479.2; m / z measured, 480.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.85(d,J=5.4Hz,1H),7.30(dd,J=9.1,2.1Hz,1H),7.11-6.91(m,1H),5.65(q,J=6.6Hz,1H),4.87(dd,J=127.6,9.1Hz,1H), 4.11-4.02(m,3H),3.95-3.80(m,1H),3.67-3.52(m,3H),3.20-2.96(m,2H),2.45-2.16(m,1H),1.48(dd,J=19.5,6.7Hz,3H).

[0478] Example 29: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-(trifluoromethyl)phenyl)methanone.

[0479] [ka]

[0480] The title compound was prepared in a manner similar to that of Example 1, using 2-(trifluoromethyl)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 19 FNO, 471.2; m / z measured, 472.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.87-7.46(m,4H),7.18-6.94(m,1H),5.76-5.42(m,1H),4.66-4.30(m,1H),3.84-3.6 0(m,6H),3.27-3.17(m,1H),2.65-2.52(m,1H),2.37-2.16(m,1H),1.56-1.34(m,3H).

[0481] Example 30: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone.

[0482] [ka]

[0483] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2-fluoro-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 F4NO, 435.2; m / z measured, 436.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=10.7Hz,1H),7.36-7.02(m,3H),5.58(q,J=6.7Hz,1H),4.74-4.50(m,1H),4.10-4.02(m,3H),3.68-3 .53(m,3H),3.49(dd,J=13.9,5.0Hz,1H),3.25-2.97(m,1H),2.36(s,3H),2.26-2.18(m,1H),1.54-1.30(m,3H).

[0484] Example 31: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-7-yl)methanone.

[0485] [ka]

[0486] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-indazole-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.21-8.09(m,1H),7.99-7.76(m,2H),7.44-7.15(m,2H),5.92-5.50(m,1H),4.86-4.38(m,1H),4. 12-3.78(m,6H),3.65(s,3H),3.54-3.43(m,1H),2.43-2.03(m,2H),1.49(dd,J=47.5,6.7Hz,3H).

[0487] Example 32: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone.

[0488] [ka]

[0489] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 FNO, 458.2; m / z measured, 459.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.66(d,J=4.7Hz,1H),8.07(s,1H),7.88-7.77(m,1H),7.25(d,J=4.6Hz,1H),5.73-5.59(m,1H),4.82-4.45(m,1H) ,4.15-3.98(m,6H),3.68-3.51(m,3H),3.50-3.38(m,1H),2.44-2.28(m,1H),2.23-2.08(m,1H),1.60-1.30(m,3H).

[0490] Example 33: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone.

[0491] [ka]

[0492] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2,8-dimethylquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 FNO, 482.2; m / z measured, 483.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.31(d,J=8.4Hz,1H),7.93-7.76(m,2H),7.64-7.38(m,2H),5.74-5.44(m,1H),4.85-4.53(m,1H),4.10-3.99(m,3H),3.7 5-3.54(m,3H),3.18(d,J=5.1Hz,1H),2.76-2.68(m,6H),2.55(d,J=6.9Hz,1H),2.37-2.17(m,1H),1.50(d,J=6.7Hz,3H).

[0493] Example 34: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone.

[0494] [ka]

[0495] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 FNO, 486.2; m / z measured, 487.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.08(s,1H),7.84(d,J=24.8Hz,1H),7.65(d,J=61.9Hz,1H),7.48(s,1H),7.37-7.14(m,1H),5.88-5.58(m,1H),4 .87-4.27(m,1H),4.11-3.98(m,3H),3.71-3.54(m,4H),2.71-2.62(m,3H),2.47-2.04(m,2H),1.69-1.34(m,3H).

[0496] Example 35: (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0497] [ka]

[0498] The title compound was prepared in a manner similar to that of Example 1, using 2-chloro-3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21ClF3N5O2, 467.1; m / z observed, 468.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.37-7.21(m,0.9H),7.00-6.86(m,2H),6.77(dd,J=7.6,1.3Hz,0.1H),6.63-6.56(m,1H ),5.99-5.89(m,0.60H),5.03-4.65(m,0.73H),3.97-3.88(m,3H),3.84-3.67(m,6H),3.6 0-3.50(m,0.70H),3.41-3.20(m,0.69H),3.15-2.98(m,0.43H),2.87-2.68(m,0.66H),2 .48-2.36(m,0.80H),2.26-2.16(m,0.62H),1.66-1.60(m,1.83H),1.51-1.39(m,1.38H).

[0499] Example 36: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone.

[0500] [ka]

[0501] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 24 F3N5O2, 447.2; m / z measured, 448.2 [M+H] + . 1H NMR (600 MHz, CDCl3) δ 7.26-7.13(m,1H),6.88-6.75(m,2H),6.67-6.57(m,1H),6.01-5.93(m,0 .57H),5.04-4.91(m,0.52H),4.70(q,J=6.8Hz,0.26H),3.89-3.54(m,10H ),3.27-3.01(m,1H),2.79-2.69(m,0.41H),2.50-2.39(m,1H),2.27-2.13 (m, 2.85H), 1.97 (s, 0.84H), 1.66-1.60 (m, 1.70H), 1.46-1.35 (m, 1.30H).

[0502] Example 37: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)methanone.

[0503] [ka]

[0504] The title compound was prepared in a manner similar to that of Example 1, using 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 21 F4NO, 487.2; m / z measured, 488.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.85-7.46(m,3H),7.26-7.08(m,2H),6.62-6.17(m,2H),5.79-5.72(m,0.81H),4.86-4.64(m,0.59H),3.82-3.64(m,7H),3.56 -3.42(m,0.83H),3.16-2.90(m,1H),2.53-2.35(m,0.79H),2.29-2.17(m,0.71H),1.96-1.90(m,0.33H),1.52-1.34(m,2.34H).

[0505] Example 38: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxyphenyl)methanone.

[0506] [ka]

[0507] The title compound was prepared in a manner similar to that of Example 1, using 3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 22 F3N5O2, 433.2; m / z measured, 434.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.33(t,J=7.7Hz,1H),7.00-6.94(m,3H),6.59(d,J=0.6Hz,1H),5.86(br s,0.37H),5.09-4.76(m,0.58H),3.84-3.80(m,7H),3.72(br s,3H),3.34-3.00(m,1H),2.81-2.47(m,1H),2.34(br s,1H),1.59(br s,3H).

[0508] Example 39: (S)-(3-chloro-5-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0509] [ka]

[0510] The title compound was prepared in a manner similar to that of Example 1, using 3-chloro-5-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 ClF3N5O2, 467.1; m / z measured, 468.0 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 6.99-6.94(m,2H),6.83(s,1H),6.60(s,1H),5.83(s,0.40H),5.03-4.73(m,0.63H), 3.86-3.65(m,10H),3.38-3.01(m,1H),2.81-2.47(m,1H),2.35(s,1H),1.56(s,3H).

[0511] Example 40: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylphenyl)methanone.

[0512] [ka]

[0513] The title compound was prepared in a manner similar to that of Example 1, using 4-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 24 F3N5O2, 447.2; m / z measured, 448.2 [M+H] + . 1H NMR(600MHz,CDCl3)δ 7.22-7.06(m,1H),6.80-6.69(m,2H),6.63-6.56(m,1H),5.94(br s,0.54H),5.01-4.66(m,0.60H),3.85-3.56(m,10H),3.28-2.98(m,1H),2.7 9-2.66(m,0.36H),2.50-2.06(m,4.77H),1.61(d,J=6.8Hz,1.53H),1.41(br s,1.41H).

[0514] Example 41: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-4-methylphenyl)methanone.

[0515] [ka]

[0516] The title compound was prepared in a manner similar to that of Example 1, using 2-methoxy-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 24 F3N5O2, 447.2; m / z measured, 448.2 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.19-6.96(m,1H),6.88-6.66(m,2H),6.62-6.53(m,1H),5.93(q,J=6.7Hz,0.60H),5.03-4.73(m,0.67H),3.90-3.54(m,10H),3. 31-2.95(m,0.90H),2.79-2.60(m,0.65H),2.44-2.33(m,4H),2.25-2.15(m,0.62H),1.63-1.58(m,1.68H),1.50-1.36(m,1.29H).

[0517] Example 42: (S)-(2-chloro-4-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0518] [ka]

[0519] The title compound was prepared in a manner similar to that of Example 1, using 2-chloro-4-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 ClF3N5O2, 467.1; m / z observed, 468.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.30-7.18(m,1H),7.09-6.78(m,2H),6.62-6.57(m,1H),5.97-5.90(m ,0.61H),5.00-4.70(m,0.71H),3.87-3.68(m,9.86H),3.63-3.54(m,0. 63H),3.42-2.97(m,0.90H),2.80-2.68(m,0.60H),2.46-2.35(m,0.77 H), 2.27-2.20(m, 0.62H), 1.65-1.59(m, 1.83H), 1.43-1.39(m, 0.81H).

[0520] Example 43: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3,4-dimethylphenyl)methanone.

[0521] [ka]

[0522] The title compound was prepared in a manner similar to that of Example 1, using 3,4-dimethylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 24 FNO, 431.2; m / z measured, 432.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.20(s,1H),7.18-7.12(m,2H),6.61-6.58(m,1H),5.85(br s,0.23H),5.15-4.70(m,0.24H),4.01-3.61(m,7H),3.37-2.99(m,0.58H),2.83-2.51(m,0.65H),2.39-2.22(m,7.79H),1.57(br s,3H).

[0523] Example 44: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(isoquinolin-1-yl)methanone.

[0524] [ka]

[0525] The title compound was prepared in a manner similar to that of Example 1, using isoquinoline-1-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 21 FNO, 454.2; m / z measured, 455.2 [M+H] + . 1H NMR(500MHz,CDCl3)δ 8.56-8.50(m,1H),8.07-7.98(m,1H),7.91-7.86(m,1H),7.77-7.68(m,2H),7.66-7.56(m,1H), 6.63-6.55(m,1H),6.09(q,J=6.8Hz,0.62H),5.18-5.11(m,0.36H),4.81(q,J=6.7Hz,0.35H),3. 85-3.73(m,4.87H),3.65(s,1H),3.53-3.45(m,0.63H),3.33-3.15(m,1H),2.92-2.64(m,1H),2 .55-2.47(m,0.34H),2.21-2.14(m,0.64H),1.75(d,J=6.8Hz,1.88H),1.46(d,J=6.8Hz,1.04H).

[0526] Example 45: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indol-4-yl)methanone.

[0527] [ka]

[0528] The title compound was prepared in a manner similar to that of Example 1, using 1-methyl-1H-indole-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 23 FNO, 456.2; m / z measured, 457.3 [M+H] + . 1H NMR(500MHz,CDCl3)δ 7.38(dd,J=8.3,1.0Hz,1H),7.28-7.22(m,1H),7.15-7.06(m,2H),6.59(s,1H),6.43(br s,1H),6.04(br s,0.51H),5.07(br s,J=44.6Hz,0.60H),3.91-3.61(m,10H),3.22(br s,1H),2.90-2.07(m,2H),1.76-1.38(m,3H).

[0529] Example 46: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone.

[0530] [ka]

[0531] The title compound was prepared in a manner similar to that of Example 1, using 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 23 FNO, 457.2; m / z measured, 458.3 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.40(d,J=4.8Hz,1H),7.29-7.20(m,1H),7.05(d,J=4.8Hz,1H),6.66-6.57(m,1H),6.48-6.32(m,1H),6.05-5.96(m,0.54H) ,5.07-4.86(m,0.75H),3.92(s,3H),3.87-3.62(m,7H),3.34-3.06(m,1H),2.88-2.16(m,2H),1.68(d,J=6.7Hz,2H),1.43(br s,1H).

[0532] Example 47: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone.

[0533] [ka]

[0534] The title compound was prepared in a manner similar to that of Example 1, using 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (Intermediate 8) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F4NO, 475.2; m / z measured, 476.2 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.26(s,1H),7.31(s,1H),6.60(d,J=19.2Hz,1H),6.46-5.98(m,1H),5.10-4.78(m,0.74H),3.96-3.60(m,10 H),3.47-3.09(m,1H),2.86-2.65(m,0.71H),2.54-2.15(m,1.27H),1.69(d,J=6.7Hz,2H),1.52-1.33(m,1H).

[0535] Example 48: (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0536] [ka]

[0537] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2-chloro-3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 ClF3N5O2, 467.1; m / z observed, 468.2 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 7.35-7.17(m,1.20H),7.00-6.87(m,1.80H),6.78-6.64(m,1H),5.96-5.85(m,0.55H),5.06-4. 96(m,0.39H),4.86-4.78(m,0.11H),4.69-4.62(m,0.24H),4.10-4.00(m,6H),3.96-3.88(m,3H ),3.61-3.50(m,0.56H),3.42-3.22(m,0.54H),3.18-3.02(m,0.37H),2.97-2.85(m,0.61H),2. 74-2.46(m,1.35H),1.67-1.58(m,1.80H),1.48(d,J=6.8Hz,0.45H),1.39(d,J=6.7Hz,0.81H).

[0538] Example 49: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone.

[0539] [ka]

[0540] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 8.39(s,1H),7.29-7.14(m,1H),7.05(s,1H),6.71(d,J=55.2Hz,1H),6.39(d,J=81.9Hz,1H),5.98(d,J=7.0Hz,0.52H),5.10-4.81(m,0.68H) ,4.14-3.87(m,9.56H),3.67(d,J=13.5Hz,0.56H),3.36-3.11(m,1H), 3.03-2.44(m,2H),1.66(d,J=6.8Hz,1.75H),1.40(d,J=6.7Hz,1.22H).

[0541] Example 50: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0542] [ka]

[0543] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 26) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 23 FNO, 484.2; m / z measured, 485.3 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 8.00-7.95(m,2H),7.81(s,2H),7.22(s,1H),6.72(s,1H),5.86(br s,0.4H),5.06-4.83(m,0.69H),4.13-3.97(m,6.56H),3.91-3.83(m,0.39 H),3.41-3.08(m,0.83H),3.00-2.55(m,2H),2.47(s,3.32H),1.60(s,3H).

[0544] Example 51: (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0545] [ka]

[0546] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2-chloro-3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 ClF3N5O2, 467.1; m / z observed, 468.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 7.50-7.44(m,1H),7.33-7.20(m,1H),6.97-6.86(m,1H),5.95-5.86(m,0.58H),4.99-4.90(m,0.46H),4.81(q, J=6.7Hz,0.15H),4.65(q,J=6.8Hz,0.30H),4.11-4.06(m,3H),3.96-3.88(m,3H),3.70-3.61(m,3H),3.56-3.44 (m,0.59H),3.38-3.30(m,0.37H),3.27-3.18(m,0.18H),3.14-2.97(m,0.41H),2.78-2.63(m,0.61H),2.42-2. 31(m,0.84H),2.21-2.15(m,0.57H),1.67-1.58(m,2.27H),1.48(d,J=6.8Hz,0.45H),1.40(d,J=6.8Hz,0.87H).

[0547] Example 52: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone.

[0548] [ka]

[0549] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.39(d,J=4.8Hz,1H),7.52-7.43(m,1H),7.25-7.18(m,1H),7.04(d,J=4.8Hz,1H),6.47- 6.24(m,1H),6.03-5.92(m,0.69H),5.04-4.81(m,1.16H),4.13-4.05(m,2.36),3.91(s,3H) ),3.73-3.57(m,3.45H),3.33-3.06(m,1.29),2.83-2.67(m,0.49),2.50-2.38(m,1.13H), 2.23-2.12(m,0.62H),1.67(d,J=6.8Hz,1.8H),1.57(s,3.80H),1.40(d,J=6.8Hz,1.15H).

[0550] Example 53: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone.

[0551] [ka]

[0552] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 26) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 23 FNO, 484.2; m / z measured, 485.3 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 8.00-7.93(m,2H),7.81(s,2H),7.48(s,1H),7.22(s,1H),5.84(br s,0.50H),5.05-4.76(m,1H),4.09(s,3.H),3.88-3.56(m,4H),3.39-3 .03(m,1H),2.78-2.52(m,1H),2.47(s,3H),2.42-2.21(m,1H),1.60(br s,3H).

[0553] Example 54: (S)-Chroman-8-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0554] [ka]

[0555] The title compound was prepared in a manner similar to Example 1, using chroman-8-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 23 H 24 F3N5O2, 459.2; m / z measured, 460.3 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 7.12-6.99(m,1.78H),6.95-6.77(m,1.21H),6.62-6.55(m,0.96H),5.93 (p,J=7.0Hz,0.59H),5.02-4.78(m,0.87H),4.30-3.61(m,8.88H),3.35-3 .15(m,0.65H),3.11-2.94(m,0.47H),2.88-2.62(m,2.78H),2.47-2.31(m ,0.73H),2.28-2.15(m,0.62H),2.12-1.85(m,2.09H),1.69-1.34(m,3H).

[0556] Example 55: (S)-Chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0557] [ka]

[0558] The title compound was prepared in a manner similar to Example 1, using chroman-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 23 H 24 F3N5O2, 459.2; m / z measured, 460.2 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ 7.13(d,J=7.7Hz,1H),7.09(s,1H),6.84(d,J=7.7Hz,1H),6.74(s,1H),5.54(s,0.65H),4.92-4.42(m,0.34H),4.20-4.10(m,2H),3.8 3-3.59(m,7H),3.26-2.98(m,1H),2.77(t,J=6.4Hz,2H),2.64-2.56(m,1H),2.38-2.22(m,1H),1.98-1.88(m,2H),1.53-1.36(m,3H).

[0559] Example 56: (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0560] [ka]

[0561] The title compound was prepared in a manner similar to Example 1, using benzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 19 F3N6OS, 460.1; m / z measured, 461.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 9.10(s,1H),8.19(d,J=8.3Hz,1H),8.08(s,1H),7.58(d,J=8.1Hz,1H),6.60(s,1H),5.90(br s,0.43H),5.18-4.69(m,0.74H),4.00-3.55(m,6.75H),3.44-3.04(m,1H),2.89-2.23(m,2H),1.80-1.41(m,3H).

[0562] Example 57: (S)-Benzo[d]thiazol-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0563] [ka]

[0564] The title compound was prepared in a manner similar to Example 1, using benzo[d]thiazole-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 19 F3N6OS, 460.1; m / z measured, 461.2 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 9.07(s,1H),8.25-8.19(m,1H),7.61-7.48(m,2H),6.60(s,1H),5.99-5.21(m,0.69H),4.73 -3.59(m,7.2H),3.37-3.20(m,1H),2.81-2.60(m,1H),2.45-2.31(m,1H),1.74-1.59(m,3H).

[0565] Example 58: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylbenzo[d]thiazol-6-yl)methanone.

[0566] [ka]

[0567] The title compound was prepared in a manner similar to Example 1, using 2-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 22 H 21 F3N6OS, 474.1; m / z measured, 475.2 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 7.98(d,J=8.3Hz,1H),7.95-7.92(m,1H),7.52-7.47(m,1H),6.60(s,1H),6.05-5.68(m,0.48H),5.25-4.63( m,0.83H),4.05-3.59(m,6.82H),3.44-3.05(m,1H),2.93-2.52(m,4H),2.47-2.26(m,1H),1.71-1.50(m,3H).

[0568] Example 59: (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0569] [ka]

[0570] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and benzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 19F3N6OS, 460.1; m / z measured, 461.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 9.08(s,1H),8.17(d,J=8.3Hz,1H),8.08-8.05(m,1H),7.57(dd,J=8.4,1.6Hz,1H),7.48(s,1H),5.86(br s,0.46H),5.16-4.65(m,0.86H),4.10(s,3H),3.90-3.51(m,3.44H),3.4 1-3.02(m,1H),2.82-2.47(m,1H),2.44-2.19(m,1H),1.69-1.52(m,3H).

[0571] Example 60: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone.

[0572] [ka]

[0573] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 15) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2-methoxy-3-methylisonicotinic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 23 F3N6O2, 448.2; m / z measured, 449.2 [M+H] + . 1H NMR(500MHz,CDCl3)δ 8.11-7.96(m,1H),7.51-7.42(m,1H),6.81-6.55(m,1H),5.94-5.85(m,1H),4.95-4.87(m,0.4 5H),4.84-4.77(m,0.12H),4.62(q,J=6.7Hz,0.30H),4.12-4.04(m,3H),4.01-3.91(m,3H),3.7 2-3.59(m,3H),3.56-3.44(m,0.59H),3.30-3.20(m,0.55H),3.04(td,J=12.7,4.0Hz,0.44H),2 .71-2.59(m,0.44H),2.46-2.32(m,1H),2.25-2.09(m,2.65H),1.93(s,1H),1.65-1.35(m,3H).

[0574] Example 61: (S)-Chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0575] [ka]

[0576] The title compound was prepared in a manner similar to that of Example 1, except that (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine·HCl salt (Intermediate 19) was used instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and chroman-7-carboxylic acid was used instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 23 H 24 F3N5O2, 459.2; m / z measured, 460.2 [M+H] + . 1H NMR (500 MHz, CDCl3) δ 7.44-7.42(m,1H),7.07-7.02(m,1H),6.89-6.84(m,1H),6.82-6.80(m,1H ),5.79(s,0.48H),5.11-4.65(m,1H),4.23-4.14(m,2H),4.03(s,3H),3.92 -3.74(m,0.52H),3.63(s,3H),3.30-2.95(m,1H),2.79(t,J=6.4Hz,2H),2 .71-2.43(m,1H),2.38-2.17(m,1H),2.04-1.97(m,2H),1.64-1.44(m,3H).

[0577] Example 62: (S)-(2,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0578] [ka]

[0579] A microwave vial was charged with (S)-2,7-dimethyl-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate (Intermediate 25, 15 mg, 33 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.2 mg, 39.6 μmol), XPhos-Pd-G2 precatalyst (1.3 mg, 1.65 μmol), saturated aqueous Na2CO3 (0.11 mL), and 1,4-dioxane (0.45 mL). After evacuating the headspace under vacuum and backfilling with N2 (×3), the reaction was stirred at 110 °C for 30 min in a microwave reactor. After cooling to room temperature, the mixture was diluted with DCM and H2O, the layers were separated, and the aqueous layer was extracted with DCM (x2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to give a white foam (7.3 mg, 57% yield). MS (ESI): Mass calculated, C 22 H 22 NO, 386.2; m / z, 387.2 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 8.98(dd,J=4.2,1.8Hz,1H),8.23-8.13(m,2H),7.93(s,1H),7.75(dd,J=8.6,1.9Hz,1H),7.60(s,1H),7.49-7.44(m,2H),5.89(br s,0.35H),5.06-4.83(m,0.74H),4.04-3.72(m,7H),3.43-3.10(m,1H),2.97-2.66(m,1H),2.62-2.39(m,1H),1.61(br s,J=20.6Hz,3H).

[0580] Example 63: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0581] [ka]

[0582] The title compound was prepared in a manner similar to Example 62, using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 23 H 21 FNO, 454.2; m / z measured, 455.1 [M+H] + . 1 H NMR(600MHz,CDCl3)δ 8.98(dd,J=4.2,1.7Hz,1H),8.25-8.12(m,2H),7.93(s,1H),7.75(d,J=8.6Hz,1H),7.46(dd,J=8.3,4.2Hz,1H),6.73(s,1H),5.89(br s,0.42H),4.95(br s,0.66H),4.12-3.78(m,7H),3.45-3.10(m,1H),3.05-2.53(m,2H),1.58(br s,3H).

[0583] Example 64: (S)-(2,7-dimethyl-3-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0584] [ka]

[0585] The title compound was prepared in a manner similar to that of Example 62, using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C22 H 19 FNO, 440.2; m / z measured, 441.2 [M+H] + . 1 H NMR(CDCl3,500MHz):δ 9.00(d,J =4.0Hz,1H),8.21(d,J =8.1Hz,1H),8.17(d,1H),7.93(d,J =7.2Hz,2H),7.90(s,1H),7.76(d,J =8.6Hz,1H),7.49(dd,J =8.2,4.1Hz,1H),6.01-5.79(m,1H),5.05-4.85(m,1H),3.97-3.73(m,3H) ),3.37-3.17(m,1H),3.01-2.80(m,1H),2.58-2.38(m,1H),1.64(s,3H).

[0586] Example 65: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0587] [ka]

[0588] The title compound was prepared in a manner similar to that of Example 62, using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 23 H 21 FNO, 454.2; m / z measured, 455.2 [M+H] + . 1H NMR (DMSO-d6,500MHz): δ 8.91(d,J =3.3Hz,1H),8.36(d,J =8.1Hz,1H),8.07(d,J =8.6Hz,1H),8.01(s,1H),7.74(d,J =8.5Hz,1H),7.52(dd,J =8.2,4.2Hz,1H),6.79(s,1H),5.73-5.58(m,1H),4.90-4.62(m,1H),3.85(s,3H) ,3.73(s,3H),3.36-3.24(m,1H),2.81-2.72(m,1H),2.40-2.27(m,1H),1.56(d,J =5.9Hz,3H).

[0589] Example 66: (S)-(3-(1-ethyl-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0590] [ka]

[0591] The title compound was prepared in a manner similar to Example 62, using 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 23 H 24 NO, 400.2; m / z measured, 401.2 [M+H] + . 1H NMR(DMSO-d6,500MHz):δ 8.91(d,J=3.8Hz,1H),8.36(d,J=8.1Hz,1H),8.07(d,J=8.6Hz,1H),8.00(s,1H) ,7.76-7.66(m,2H),7.52(dd,J=8.2,4.1Hz,1H),6.38(s,1H),5.68-5.49(m,1H) ,4.22(q,J=7.3,7.3,7.2Hz,2H),4.09-3.73(m,4H),3.38-3.16(m,1H),2.90-2. 81(m,1H),2.68-2.54(m,1H),1.53(d,J=5.8Hz,3H),1.49(t,J=7.3,7.3Hz,3H).

[0592] Example 67: (S)-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0593] [ka]

[0594] The title compound was prepared in a manner similar to Example 62, using 1-(difluoromethyl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 22 H 20 F2NO, 422.2; m / z measured, 423.2 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.98-8.92(m,1H),8.20-8.10(m,2H),7.92-7.84(m,2H),7.76-7.69(m,1H),7.48-7.42(m,1H),7.23(t,J=60.6,60.6Hz,1H),6.58(s,1H) ),5.90-4.88(m,1H),4.14-3.98(m,3H),3.98-3.67(m,1H),3.41-3.11(m,1H),3.06-2.79(m,1H),2.77-2.58(m,1H),1.63-1.42(m,3H).

[0595] Example 68: (S)-(3-(1-cyclopropyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0596] [ka]

[0597] The title compound was prepared in a manner similar to that of Example 62, using 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 24 H 24 NO, 412.2; m / z measured, 413.2 [M+H] + . 1H NMR(500MHz,MeOD)δ 8.96-8.92(m,1H),8.48(d,J=8.3Hz,1H),8.15(d,J=8.7Hz,1H),8.09(s,1H),7.87-7 .79(m,1H),7.66-7.60(m,1H),7.57(s,1H),6.47(d,J=2.0Hz,1H),5.91-5.73(m,1H), 3.97-3.78(m,1H),3.78-3.59(m,3H),3.55-3.49(m,1H),3.49-3.36(m,1H),2.84-2.7 1(m,1H),2.59-2.37(m,1H),1.70-1.55(m,3H),1.09-1.01(m,1H),1.01-0.91(m,3H).

[0598] Example 69: (S)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0599] [ka]

[0600] The title compound was prepared in a manner similar to Example 62, using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 22 H 20 F2NO, 422.2; m / z measured, 423.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.01-8.95(m,1H),8.63(s,1H),8.51-8.44(m,1H),8.14(s,1H),8.13-8.08(m,2H),8.05-7.74(m,2H),7.65-7.57(m,1H),5.68- 4.66(m,1H),3.98-3.79(m,3H),3.79-3.61(m,1H),3.32-3.04(m,1H),2.92-2.80(m,1H),2.49-2.36(m,1H),1.57-1.41(m,3H).

[0601] Example 70: (S)-(2,7-dimethyl-3-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0602] [ka]

[0603] The title compound was prepared in a manner similar to that of Example 62, using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 26 H 23 NO, 449.2; m / z measured, 450.2 [M+H] + . 1H NMR (500 MHz, CD3OD) δ 8.97-8.93(m,1H),8.87(s,1H),8.52-8.46(m,2H),8.17(d,J=8.6Hz,1H), 8.13-8.07(m,1H),8.04(s,1H),8.04-7.96(m,2H),7.90-7.82(m,1H),7.64 (dd,1H),7.36(t,1H),5.91-5.68(m,1H),3.99(s,3H),3.89-3.83(m,1H),3 .53-3.38(m,1H),3.00-2.89(m,1H),2.66-2.53(m,1H),1.67-1.56(m,3H).

[0604] Example 71: (S)-(3-(1-(cyclopropylmethyl)-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone.

[0605] [ka]

[0606] The title compound was prepared in a manner similar to Example 62, using 1-(cyclopropylmethyl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ESI): Calculated mass, C 25 H 26 NO, 426.2; m / z, 427.2 [M+H] + . 1H NMR(500MHz,CD3OD)δ 8.97-8.92(m,1H),8.48(d,J=8.3Hz,1H),8.16(d,J=8.7Hz,1H),8.09(s,1H),7.91-7.80( m,1H),7.67-7.60(m,2H),6.50(s,1H),6.01-5.63(m,1H),4.00-3.92(m,1H),3.92-3.77( m,2H),3.77-3.57(m,3H),3.50-3.34(m,1H),2.82-2.64(m,1H),2.56-2.27(m,1H),1.70- 1.54(m,3H),1.11-1.03(m,1H),0.56-0.45(m,2H),0.29-0.10(m,1H),0.10-0.02(m,1H).

[0607] Example 72: ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(2-fluoro-4-methylphenyl)methanone.

[0608] [ka]

[0609] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 23) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 2-fluoro-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 26 FNO, 407.2; m / z measured, 408.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.36-6.99(m,3H),6.36-5.62(m,2H),5.11-4.50(m,1H),4.13-3.81(m,1H),3.76-3.48(m ,6H),2.94-2.58(m,1H),2.35(d,J=9.6Hz,3H),2.20(d,J=5.8Hz,3H),1.90-1.28(m,6H).

[0610] Example 73: ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(3-methoxy-2-methylphenyl)methanone.

[0611] [ka]

[0612] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 23) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 29 NO, 419.2; m / z measured, 420.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.35-7.15(m,1H),7.07-6.40(m,2H),6.33-6.19(m,1H),5.80(s,1H),4.54-4.39(m,1H),3.86-3.77(m,3H),3. 74-3.51(m,6H),2.98-2.83(m,1H),2.72-2.53(m,1H),2.44-2.26(m,1H),2.23-2.10(m,5H),1.80-1.34(m,6H).

[0613] Example 74: (3-Methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0614] [ka]

[0615] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 26 F3N5O2, 473.2; m / z measured, 474.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.32-7.14(m,1H),7.14-7.05(m,1H),7.06-6.94(m,1H),6.90-6.41(m,1H),5.96-5.74(m,1H),5.22-4.92(m,1H),4.60-4.36(m,1H),3 .89-3.78(m,4H),3.76-3.67(m,3H),3.63(d,J=7.3Hz,1H),3.08-2.79(m,1H),2.48-2.26(m,1H),2.23-2.06(m,2H),1.95-1.31(m,7H).

[0616] Example 75: chroman-7-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0617] [ka]

[0618] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and chroman-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 26 F3N5O2, 485.2; m / z measured, 486.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.19-7.03(m,2H),6.85-6.61(m,2H),4.91(d,J=34.2Hz,1H),4.22-3.99(m,3H),3.79(s,3H),3.66(d, J=23.5Hz,3H),2.96-2.69(m,3H),2.39(dd,J=33.7,16.4Hz,1H),2.00-1.88(m,2H),1.87-1.30(m,6H).

[0619] Example 76: ((5R,9S)-2-Methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone.

[0620] [ka]

[0621] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 24 FNO, 443.2; m / z measured, 444.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.43-7.02(m,5H),5.80-5.56(m,1H),5.04-4.73(m,1H),3.80(s,3H),3. 72-3.49(m,3H),3.00-2.69(m,1H),2.39-2.30(m,4H),1.98-1.30(m,6H).

[0622] Example 77: (3-Methoxy-5-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0623] [ka]

[0624] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-5-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 26 F3N5O2, 473.2; m / z measured, 474.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.16-7.06(m,1H),6.94-6.63(m,3H),5.78-5.62(m,1H),5.08-4.78(m,1H),3.83-3.7 2(m,6H),3.72-3.56(m,3H),2.99-2.67(m,1H),2.39-2.25(m,4H),1.96-1.34(m,6H).

[0625] Example 78: ((5R,9S)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone.

[0626] [ka]

[0627] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 22) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 26 FNO, 457.2; m / z measured, 458.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.45-6.98(m,5H),5.83-5.59(m,1H),5.08-4.76(m,1H),4.07-3.99(m,2H),3.72-3.5 6(m,3H),2.97-2.67(m,1H),2.45-2.26(m,4H),2.02-1.38(m,6H),1.35-1.26(m,3H).

[0628] Example 79: (3-Methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0629] [ka]

[0630] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 21) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 26 F3N5O2, 473.2; m / z measured, 474.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.33-7.09(m,2H),7.04-6.33(m,2H),5.84-5.58(m,1H),5.26-5.00(m,1H),4.53-4.37(m,1H),4.10-3.99(m,4H), 3.95-3.74(m,4H),3.23-3.07(m,1H),2.97-2.79(m,1H),2.77-2.52(m,1H),2.21-2.08(m,1H),1.90-1.29(m,7H).

[0631] Example 80: ((5R,9S)-2-Methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone.

[0632] [ka]

[0633] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and quinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 23 FNO, 480.2; m / z measured, 481.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 9.04-8.86(m,1H),8.48(t,J=8.0Hz,1H),8.19-8.01(m,2H),7.84-7.67(m,1H),7.70-7.48(m,1H),7.20-7.05(m,1H),5.91-5.5 9(m,1H),4.21-4.00(m,1H),3.82(s,3H),3.67(d,J=51.1Hz,3H),3.02-2.80(m,1H),2.37(d,J=16.4Hz,1H),2.10-1.33(m,6H).

[0634] Example 81: (5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0635] [ka]

[0636] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 20 F4NO, 488.2; m / z measured, 489.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.60(s,1H),8.25-8.05(m,1H),7.10(s,1H),6.66-5.83(m,1H),5.72-5.08(m,1 H),3.84-3.76(m,3H),3.72-3.59(m,3H),3.09-2.79(m,2H),2.12-1.41(m,7H).

[0637] Example 82: (2-methyl-1,6-naphthyridin-5-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0638] [ka]

[0639] The title compound was prepared in a manner similar to that of Example 1, except that (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) was used instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and potassium 2-methyl-1,6-naphthyridine-5-carboxylate (Intermediate 7) was used instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 24 FNO, 495.2; m / z measured, 496.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.76-8.61(m,1H),8.18(dd,J=18.9,8.6Hz,1H),7.90(dd,J=12.6,5.9Hz,1H),7.62-7.52(m,1H),7.13(d,J=11.4Hz,1H),6.04-5.83(m,1H),5. 30-5.15(m,0.5H),4.52-4.40(m,0.5H),3.80(d,J=15.9Hz,3H),3.72(d ,J=1.2Hz,3H),3.63-3.52(m,1H),2.78-2.63(m,4H),2.06-1.39(m,6H).

[0640] Example 83: (5-Fluoroquinolin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0641] [ka]

[0642] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 5-fluoroquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 22 F4N6O, 498.2; m / z measured, 499.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.06-8.87(m,1H),8.57-8.34(m,1H),8.00-7.80(m,2H),7.55(q,J=8.6Hz,1H),7.13(d,J=8.1Hz,1H),5.86-5.73(m,1H) ,4.31-4.08(m,1H),3.85-3.76(m,3H),3.74-3.59(m,3H),3.05-2.81(m,1H),2.36(d,J=16.4Hz,1H),2.10-1.35(m,6H).

[0643] Example 84: benzo[d]isoxazol-3-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0644] [ka]

[0645] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using benzo[d]isoxazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 21 F3N6O2, 470.2; m / z measured, 471.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 7.99-7.70(m,2H),7.61-7.35(m,1H),7.27-7.00(m,1H),5.97-5.41(m,1H),5. 24-4.58(m,1H),3.88-3.61(m,7H),2.95(d,J=64.1Hz,2H),2.11-1.09(m,6H).

[0646] Example 85: (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0647] [ka]

[0648] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 23 FNO, 484.2; m / z measured, 485.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.73-8.57(m,1H),8.48-8.29(m,1H),7.35(dd,J=7.8,4.8Hz,1H),7.11(s,1H),6.53-5.63(m,1H),5.52-5.04(m,1H),4.15( dd,J=23.0,1.9Hz,3H),3.80(s,3H),3.68(dd,J=19.9,1.9Hz,3H),3.50-3.42(m,1H),3.05-2.88(m,1H),2.13-1.42(m,6H).

[0649] Example 86: (5-Fluoro-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0650] [ka]

[0651] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 20) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 5-fluoro-1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 F4NO, 501.2; m / z measured, 502.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.90-7.75(m,1H),7.68(dd,J=9.1,2.5Hz,1H),7.47-7.31(m,1H),7.19-6.99(m,1H),6.46-5.80(m,1H),5.56-5.07(m,1 H),4.15(dd,J=23.4,2.0Hz,3H),3.85-3.75(m,3H),3.67(dd,J=21.6,2.0Hz,3H),3.06-2.84(m,1H),2.06-1.39(m,7H).

[0652] Example 87: ((5R,9S)-2-Methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone.

[0653] [ka]

[0654] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 21) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and quinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 23 FNO, 480.2; m / z measured, 481.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.05-8.91(m,1H),8.48(d,J=8.3Hz,1H),8.16-8.01(m,2H),7.82-7.53(m,2H),7.25(d,J=13.9Hz,1H),5.76(s, 1H),5.13-4.74(m,1H),4.09-3.89(m,6H),3.20-2.99(m,1H),2.68(dd,J=49.5,16.6Hz,1H),2.04-1.35(m,6H).

[0655] Example 88: (6-Fluoro-2-methylquinolin-4-yl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone.

[0656] [ka]

[0657] The title compound was prepared in a manner similar to that of Example 1, using (5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazole (Intermediate 21) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 26 H 24 F4N6O, 512.2; m / z measured, 513.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.07(d,J=5.7Hz,1H),7.83-7.47(m,2H),7.41-6.77(m,2H),5.96-5.75(m,1H),4.46-4 .33(m,1H),4.10-3.74(m,7H),3.14-2.96(m,1H),2.73-2.61(m,3H),2.09-1.35(m,6H).

[0658] Example 89: (3-Methoxy-2-methylphenyl)((5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazol-9-yl)methanone.

[0659] [ka]

[0660] The title compound was prepared in a manner similar to that of Example 1, using (5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazole (Intermediate 24) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 24 F3N5O2, 459.2; m / z measured, 460.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 7.37-7.13(m,1H),7.17-6.92(m,2H),6.92-6.63(m,1H),5.59-5.45(m,1H),5.01-4.86(m,1H),4.47-4.2 8(m,1H),3.99-3.85(m,1H),3.85-3.56(m,8H),3.29-2.94(m,1H),2.67-2.53(m,1H),2.36-1.57(m,6H).

[0661] Examples 96-109, 111, 114-116, 119, 124-131, 136-138 are prophetic compounds that can be made according to the methods described.

[0662] Example 90: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-methylquinolin-6-yl)methanone.

[0663] [ka]

[0664] The title compound was prepared in a manner similar to that of Example 1, using 5-fluoro-2-methylquinoline-6-carboxylic acid (Intermediate 27) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O, 486.2; m / z measured, 487.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.36(d,J=8.5Hz,1H),7.95-7.86(m,1H),7.68-7.57(m,1H),7.42(d,J=8.5Hz,1H),6. 64-6.59(m,1H),6.02-5.94(m,0.66H),5.01(dd,J=5.0,13.1Hz,0.41H),4.91(q,J=6.6 Hz,0.41H),3.85-3.81(m,3H),3.77(s,2H),3.75-3.72(m,0.54H),3.70(s,1H),3.47-3.33(m,0.70 H),3.21-3.10(m,0.42H),2.85-2.82(m,0.24H),2.81-2.79(m,3H),2.78-2.7 5(m,0.43H),2.46(dd,J=3.1,15.7Hz,0.49H),2.35-2.26(m,0.73H),1.67(d,J =6.5Hz,2H),1.51(d,J=6.3Hz,1H).

[0665] Example 91: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-6-yl)methanone.

[0666] [ka]

[0667] The title compound was prepared in a manner similar to that of Example 1, using 7-fluoro-2-methylquinoline-6-carboxylic acid (Intermediate 28) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H22 FNO, 486.2; m / z measured, 487.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.10-8.02(m,1H),7.90-7.78(m,1H),7.72(d,J=10.7Hz,1H),7.32(d,J=8.5Hz,1H),6.64-6.58(m,1H),6. 02-5.91(m,0.64H),5.00(dd,J=5.1,13.1Hz,0.35H),4.87(q,J=6.8Hz,0.35H),3.85-3.80(m,3H),3.78-3. 69(m,3H),3.69-3.65(m,0.63H),3.47-3.31(m,0.64H),3.20-3.09(m,0.37H),2.84-2.78(m,1H),2.78-2.7 5(m,3H),2.46(dd,J=2.8,15.4Hz,0.48H),2.35-2.24(m,0.62H),1.67(d,J=6.7Hz,2H),1.55-1.44(m,1H).

[0668] Example 92: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,5-dimethylquinolin-6-yl)methanone.

[0669] [ka]

[0670] The title compound was prepared in a manner similar to that of Example 1, using 2,5-dimethylquinoline-6-carboxylic acid (Intermediate 29) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 FNO, 482.2; m / z measured, 483.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.39-8.13(m,1H),8.02-7.86(m,1H),7.62-7.43(m,1H),7.42-7.33(m,1H),6.67-6.55(m,1H),6.09-5.9 8(m,0.5H),5.08-5.04(m,0.2H),4.93-4.65(m,0.3H),3.88-3.76(m,3H),3.76-3.67(m,3H),3.59-3.54( m,0.2H),3.33-3.23(m,0.5H),3.14-3.08(m,0.3H),2.86-2.74(m,3H),2.72-2.60(m,2H),2.55-2.48(m, 0.4H), 2.47-2.36 (m, 1H), 2.32-2.12 (m, 0.6H), 1.70-1.52 (m, 2H), 1.45-1.35 (m, 1H), 1.33-1.19 (m, 2H).

[0671] Example 93: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,7-dimethylquinolin-6-yl)methanone.

[0672] [ka]

[0673] The title compound was prepared in a manner similar to that of Example 1, using 2,7-dimethylquinoline-6-carboxylic acid (Intermediate 30) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 FNO, 482.2; m / z measured, 483.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.08-7.95(m,1H),7.95-7.79(m,1H),7.76-7.41(m,1H),7.33-7.27(m,1H),6.61(d,J= 14.9Hz,1H),6.08-5.98(m,0.5H),5.10-4.97(m,0.5H),4.71-4.63(m,0.3H),3.81(s,3H) ),3.76-3.68(m,3H),3.68-3.48(m,0.7H),3.36-3.04(m,1H),2.78-2.70(m,3H),2.62-2 .42(m,3H),2.35-2.19(m,1H),1.68-1.66(m,1H),1.48-1.43(m,1H),1.28-1.20(m,2H).

[0674] Example 94: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,4-dimethylquinolin-6-yl)methanone. #78625872

[0675] [ka]

[0676] The title compound was prepared in a manner similar to that of Example 1, using 2,4-dimethylquinoline-6-carboxylic acid (Intermediate 31) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 FNO, 482.2; m / z measured, 483.2 [M+H] + . 1H NMR(400MHz,CDCl3)δ 8.13-8.02(m,2H),7.85-7.57(m,1H),7.21(s,1H),6.61(s,1H),6.15-5.7 2(m,0.5H),5.26-4.68(m,1H),3.98-3.84(m,0.5H),3.83(s,3H),3.74(br .s.,3H),3.47-3.05(m,1H),2.94-2.73(m,1H),2.73(s,3H),2.69(s,3H),2.50-2.25(m,1H),1.86-1.65(m,3H).

[0677] Example 95: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylquinolin-6-yl)methanone.

[0678] [ka]

[0679] The title compound was prepared in a manner similar to that of Example 1, using 4-methoxy-2-methylquinoline-6-carboxylic acid (Intermediate 32) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 F3N6O2, 498.2; m / z measured, 499.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.50(s,1H),7.80(s,1H),7.58(d,J =8.7Hz,1H),6.61(s,1H),6.27(s,1H),6.04-5.75(m,0.5H),5.03-4.84(m,0.5H),3.85(s,3H),3.78(s,3H), 3.76-3.59(m,4H),3.49-3.17(m,1H),2.81-2.69(m,1H),2.52(s,3H),2.40-2.29(m,1H),1.62-1.56(m,3H).

[0680] Example 96: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-2-methylquinolin-6-yl)methanone.

[0681] [ka]

[0682] The title compound can be prepared in a manner similar to that of Example 1, using 4-fluoro-2-methylquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O,486.2.

[0683] Example 97: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-6-yl)methanone.

[0684] [ka]

[0685] The title compound can be prepared in a manner similar to that of Example 1, using 2-methoxyquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 23 F3N6O2,484.2.

[0686] Example 98: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methoxy-2-methylquinolin-5-yl)methanone.

[0687] [ka]

[0688] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 7-methoxy-2-methylquinoline-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 F3N6O2,498.2.

[0689] Example 99: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methoxyquinolin-4-yl)methanone.

[0690] [ka]

[0691] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 3-fluoro-8-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O2,502.2.

[0692] Example 100: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methylquinolin-4-yl)methanone.

[0693] [ka]

[0694] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 3-fluoro-8-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O,486.2.

[0695] Example 101: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-fluoroisoquinolin-4-yl)methanone.

[0696] [ka]

[0697] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 8-fluoroisoquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 23 H 20 F4N6O,472.2.

[0698] Example 102: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methoxyquinolin-4-yl)methanone.

[0699] [ka]

[0700] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 6-fluoro-2-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 F4N6O,502.2.

[0701] Example 103: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone.

[0702] [ka]

[0703] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 20 F4N8O,502.2.

[0704] Example 104: (S)-(6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0705] [ka]

[0706] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F5N8O,508.2.

[0707] Example 105: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanone.

[0708] [ka]

[0709] The title compound can be prepared in a manner similar to that of Example 1, using 1-methyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 F3N8O,458.2.

[0710] Example 106: (S)-(1,6-Dimethyl-1H-pyrazolo[4,3-c]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0711] [ka]

[0712] The title compound can be prepared in a manner similar to that of Example 1, using 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 23 F3N8O,472.2.

[0713] Example 107: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanone.

[0714] [ka]

[0715] The title compound can be prepared in a manner similar to that of Example 1, using 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 F3N8O,458.2.

[0716] Example 108: (S)-(1,6-Dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0717] [ka]

[0718] The title compound can be prepared in a manner similar to that of Example 1, using 1,6-dimethyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 23 F3N8O,472.2.

[0719] Example 109: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-(trifluoromethoxy)phenyl)methanone.

[0720] [ka]

[0721] The title compound can be prepared in a manner similar to that of Example 1, using 4-methoxy-2-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C22 H 21 F6N5O,517.2.

[0722] Example 110: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methyl-2-(trifluoromethoxy)phenyl)methanone.

[0723] [ka]

[0724] The title compound was prepared in a manner similar to that of Example 1, using 4-methyl-2-(trifluoromethoxy)benzoic acid (Intermediate 33) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F6N5O2, 501.2; m / z measured, 502.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.38-7.28(m,1H),7.22-7.07(m,2H),6.62-6.58(m,1H),5.98-5.86(m,0.64H),4.99-4.90(m,0.4 2H),4.82-4.71(m,0.41H),3.82-3.77(m,3H),3.75(s,2H),3.70(s,1H),3.63-3.55(m,0.66H),3. 38-3.23(m,0.67H),3.13-3.00(m,0.39H),2.78-2.65(m,0.64H),2.49-2.44(m,0.32H),2.42(s,3 H),2.40-2.36(m,0.30H),2.25(dd,J=2.5,15.6Hz,0.67H),1.61-1.59(m,2H),1.51-1.42(m,1H).

[0725] Example 111: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-3-(trifluoromethoxy)phenyl)methanone.

[0726] [ka]

[0727] The title compound can be prepared in a manner similar to that of Example 1, using 2-methyl-3-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F6N5O2,501.2.

[0728] Example 112: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone.

[0729] [ka]

[0730] The title compound was prepared in a manner similar to that of Example 1, using 2-fluoro-3-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 18 F7N5O2, 505.1; m / z measured, 506.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ7.43-7.29(m,2H),7.27-7.21(m,1H),6.63-6.59(m,1H),5.97-5.84( m,0.65H),5.00-4.87(m,0.40H),4.83-4.73(m,0.40H),3.84-3.79(m,3H),3.78-3.70(m,3 H),3.66-3.57(m,0.65H),3.47-3.31(m,0.61H),3.18-3.06(m,0.40H),2.80-2.69(m,0.59 H),2.48-2.40(m,0.51H),2.36-2.24(m,0.82H),2.04-1.98(m,0.22H),1.66-1.48(m,3H).

[0731] Example 113: (S)-(2-chloro-4-(trifluoromethoxy)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0732] [ka]

[0733] The title compound was prepared in a manner similar to that of Example 1, using 2-chloro-4-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 18 ClF6N5O2, 521.1; m / z observed, 522.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.44-7.28(m,2H),7.24-7.15(m,1H),6.64-6.58(m,1H),5.98-5.89(m,0.63H),5.02-4.9 3(m,0.43H),4.83-4.64(m,0.43H),3.84-3.79(m,3H),3.77-3.71(m,3H),3.58-3.46(m,0. 68H),3.46-3.37(m,0.41H),3.34-3.24(m,0.24H),3.18-3.00(m,0.48H),2.82-2.69(m,0 .72H), 2.49-2.37(m, 0.87H), 2.33-2.23(m, 0.72H), 1.67-1.62(m, 2H), 1.47-1.41(m, 1H).

[0734] Example 114: (S)-(4,6-Difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0735] [ka]

[0736] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate (Intermediate 6) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 20 F5N7O,494.2.

[0737] Example 115: (S)-(4,6-Difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0738] [ka]

[0739] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 4,6-difluoro-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 18 F5N7O,479.15.

[0740] Example 116: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone.

[0741] [ka]

[0742] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 2-fluoro-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 F4N5O,435.2.

[0743] Example 117: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-7-yl)methanone.

[0744] [ka]

[0745] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-indazole-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 22 FNO, 457.2; m / z measured, 458.2 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 8.20-8.09(m,1H),7.94-7.83(m,1H),7.50-7.13(m,3H),5.84-5.57(m,1H),4.95-4.70(m,1H),4.06(d,J=9. 4Hz, 3H), 4.02-3.81 (m, 6H), 3.72-3.65 (m, 1H), 3.56-3.45 (m, 1H), 2.79 (d, J=15.7Hz, 1H), 1.63-1.39 (m, 3H).

[0746] Example 118: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone.

[0747] [ka]

[0748] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and 1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 21 H 21 FNO, 458.2; m / z measured, 459.2 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ 8.73-8.60(m,1H),8.20-7.90(m,1H),7.22(d,J=41.2Hz,2H),5.83-5.52(m,1H),4.87-4.48(m,1H ),4.13-4.08(m,3H),4.08-3.86(m,6H),3.53-3.43(m,1H),2.93-2.61(m,2H),1.62-1.32(m,3H).

[0749] Example 119: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone.

[0750] [ka]

[0751] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 2,8-dimethylquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 25 H 25 F3N6O,482.2.

[0752] Example 120: (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone.

[0753] [ka]

[0754] The title compound was prepared in a manner similar to that of Example 1, except that (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) was used instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and benzo[d]thiazole-6-carboxylic acid was used instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 19 F3N6OS, 460.1; m / z measured, 461.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ 9.08(s,1H),8.18(d,J=8.4Hz,1H),8.07(s,1H),7.61-7.55(m,1H),6.72(s,1H),5.86(br s,0.46H),5.15-5.74(m,0.88H),4.19-3.73(m,6.73H),3.43-3.08(m,1H),3.01-2.52(m,2H),1.74-1.43(m,3H).

[0755] Example 121: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone.

[0756] [ka]

[0757] The title compound was prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 2-methoxy-3-methylisonicotinic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): Calculated mass, C 21 H 23 F3N6O2, 448.2; m / z measured, 449.2 [M+H] + . 1 H NMR (500 MHz, CDCl3) δ 8.11-7.95(m,1H),6.81-6.54(m,2H),5.94-5.86(m,0.56H),4.98(dd,J=13. 1,5.4Hz,0.46H),4.84-4.77(m,0.14H),4.62(q,J=6.7Hz,0.32H),4.09-3.93 (m,9H),3.62-3.49(m,0.56H),3.34-3.24(m,0.57H),3.13-3.03(m,0.45H), 2.93-2.81(m,0.47H),2.76-2.49(m,1.63H),2.24-1.91(m,3H),1.57(s,3H).

[0758] Example 122: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone.

[0759] [ka]

[0760] The title compound was prepared in a manner similar to that of Example 1, using thiazolo[4,5-c]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS, 461.1; m / z measured, 462.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.42-9.35(m,1H),9.15(s,1H),8.42-8.35(m,1H),6.61-6.56(m,1H),5.91-5.83(m,0.5 9H),5.46-5.39(m,0.43H),4.94-4.86(m,0.41H),4.22-4.14(m,0.63H),3.84-3.78(m,3 H),3.76-3.65(m,3H),3.36-3.27(m,0.62H),3.22-3.11(m,0.44H),3.01-2.91(m,0.67H ),2.84-2.73(m,0.50H),2.46-2.39(m,0.50H),2.35-2.26(m,0.72H),1.38-1.21(m,3H).

[0761] Example 123: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone.

[0762] [ka]

[0763] The title compound was prepared in a manner similar to that of Example 1, using thiazolo[4,5-b]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS, 461.1; m / z measured, 462.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),8.84-8.82(m,1H),8.82-8.79(m,1H),7.10(s,1H),5.62(br s,1H),5.06-4.38(m,1H),3.82(s,3H),3.73(s,3H),3.70-3.65(m,1H),2.84-2.69(m,1H),2.41-2.27(m,1H),1.53(d,J=6.4Hz,3H).

[0764] Example 124: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone.

[0765] [ka]

[0766] The title compound can be prepared in a manner similar to that of Example 1, using thiazolo[4,5-b]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0767] Example 125: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone.

[0768] [ka]

[0769] The title compound can be prepared in a manner similar to that of Example 1, using thiazolo[4,5-c]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0770] Example 126: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone.

[0771] [ka]

[0772] The title compound can be prepared in a manner similar to that of Example 1, using thiazolo[5,4-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0773] Example 127: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone.

[0774] [ka]

[0775] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using thiazolo[4,5-c]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0776] Example 128: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone.

[0777] [ka]

[0778] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using thiazolo[4,5-b]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0779] Example 129: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone.

[0780] [ka]

[0781] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using thiazolo[4,5-b]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0782] Example 130: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone.

[0783] [ka]

[0784] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using thiazolo[4,5-c]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0785] Example 131: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone.

[0786] [ka]

[0787] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using thiazolo[5,4-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 20 H 18 F3N7OS,461.1.

[0788] Example 132: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone.

[0789] [ka]

[0790] The title compound is prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 24 H 22 FNO, 486.2; m / z measured, 487.2 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 8.08(s,1H),7.78-7.43(m,2H),7.39-7.02(m,2H),5.87-5.55(m,1H),4.76(d,J=93.2Hz,2H),4. 17-3.76(m,6H),3.18(d,J=4.5Hz,1H),2.88-2.62(m,3H),2.50-2.47(m,1H),1.80-1.16(m,3H).

[0791] Example 133: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone.

[0792] [ka]

[0793] The title compound was prepared in a manner similar to that of Example 1, using 7-methylbenzo[d]thiazole-6-carboxylic acid (Intermediate 34) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F3N6OS, 474.1; m / z measured, 475.3 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 9.07(s,1H),7.88(s,1H),7.38(s,1H),6.61(s,1H),6.05-5.75(m,0.52H),5.14-4.97(m,0.41H),4.95-4.77(m,0.41H),3.98- 3.86(m,0.47H),3.83(s,3H),3.73(s,3H),3.40-3.07(m,1H),2.83(s,3H),2.78-2.54(m,1H),2.44-2.29(m,1H),1.62(s,3H).

[0794] Example 134: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone.

[0795] [ka]

[0796] The title compound was prepared in a manner similar to that of Example 1, using 5-methylbenzo[d]thiazole-6-carboxylic acid (Intermediate 35) instead of 2-methylquinoline-5-carboxylic acid, and HOBt and EDCI instead of HATU. MS (ESI): Calculated mass, C 22 H 21 F3N6OS, 474.1; m / z measured, 475.2 [M+H]+ . 1 H NMR(400MHz,CDCl3)δ 9.05(s,1H),8.09-7.96(m,1H),7.90-7.67(m,1H),6.64-6.58(m,1H),6.06-5.96(m,0.65H),5.09- 4.92(m,0.57H),4.71-4.62(m,0.28H),3.81(s,3H),3.77(s,2H),3.70(s,1H),3.55(dd,J=4.5,13.4 Hz,0.52H),3.36-3.25(m,0.68H),3.15-3.05(m,0.43H),2.82-2.70(m,0.47H),2.57(s,0.32H),2.5 1-2.43(m,3H),2.29(s,0.79H),2.27-2.20(m,0.69H),1.67(d,J=6.7Hz,2H),1.45(d,J=5.8Hz,1H).

[0797] Example 135: (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone.

[0798] [ka]

[0799] The title compound was prepared in a manner similar to that of Example 1, using 4-methylbenzo[d]thiazole-6-carboxylic acid (Intermediate 36) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F3N6OS, 474.1; m / z measured, 475.3 [M+H] + . 1H NMR(400MHz,CDCl3)δ 9.07(s,1H),8.11-7.97(m,1H),7.48(d,J=8.3Hz,0.23H),7.37(d,J=8.3Hz,0.61H),6.65-6.58(m,1H),6.07-5.96(m,0. 62H),5.10-4.89(m,0.60H),4.75-4.65(m,0.28H),3.86-3.79(m,3H),3.77(s,2H),3.69(s,1H),3.58(dd,J=4.5,13.6Hz, 0.37H),3.34-3.25(m,0.63H),3.12(dt,J=3.9,12.7Hz,0.44H),2.83-2.72(m,0.43H),2.70-2.64(m,0.33H),2.63-2.55( m,2H),2.54-2.47(m,0.66H),2.42(s,1H),2.24(dd,J=2.4,15.4Hz,0.65H),1.68(d,J=6.8Hz,2H),1.47(d,J=6.3Hz,1H).

[0800] Example 136: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone.

[0801] [ka]

[0802] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 7-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F3N6OS,474.1.

[0803] Example 137: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone.

[0804] [ka]

[0805] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 5-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F3N6OS,474.1.

[0806] Example 138: (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone.

[0807] [ka]

[0808] The title compound can be prepared in a manner similar to that of Example 1, using (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine (Intermediate 14) instead of (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine, and using 4-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): Calculated mass, C 22 H 21 F3N6OS,474.1.

[0809] Biological data The assay used to measure the in vitro activity of MGL was adapted from that used for other serine hydrolases (FAAHs) described by Wilson et al., 2003 (A high-throughput-compatible assay for determining the activity of fatty acid amide hydrolase. Wilson SJ, Lovenberg TW, Barbier AJ. Anal Biochem. 2003 Jul 15;318(2):270-5). This assay combines endogenously expressed MGL from HeLa cells with test compounds and [glycerol-1,3- 3After addition of [H]-oleylglycerol and incubation for 1 hour, the cleaved [1,3- 3 The amount of cleaved tritiated glycerol that passes through the carbon filter is proportional to the activity of the MGL enzyme in that particular well / test condition.

[0810] The standard conditions for this assay were: 300 nM [glycerol-1,3- 3 [H]-oleylglycerol was mixed with human MGL derived from HeLa cells and test compounds for 1 hour, after which the reaction mixture was filtered through activated charcoal and tritium was measured in the flow-through fraction. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest concentration of compound in the assay is determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0811] [Table 6-1]

[0812] [Table 6-2]

[0813] [Table 6-3]

[0814] [Table 6-4]

[0815] [Table 6-5]

[0816] [Table 6-6]

[0817] [Table 6-7] NT means not tested. The present invention includes the following embodiments. [1] Formula (I): [ka] [In the formula, R 1a is C 1~4 is alkyl, R 1b is H, or R 1a and R 1b together, -CH 2 CH 2 -or -CH 2 CH 2 CH 2 - Forms R 2 teeth, (a) Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 phenyl or pyridyl, each optionally substituted with one or two substituents selected from cycloalkyl, or with two adjacent ring substituents which, together with the carbons to which they are attached, form a monocyclic cycloalkyl or heterocycloalkyl ring; (b) Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl, OC 1~4 haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C 3~6 bicyclic heteroaryl optionally substituted with one or two substituents selected from cycloalkyl; R 3 is 1H-C 1~4 Alkyl-pyrazolyl, 1H-C 1~4 Haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H-(C3~6 cycloalkyl)-pyrazolyl, or 1H-(C 3~6 cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from the group consisting of halo, C 1~4 Alkyl, C 1~4 Haloalkyl, OC 1~4 Alkyl or OC 1~4 optionally substituted with haloalkyl; However, R 2 But, Halo, C 1~4 Alkyl or C 1~4 When R is phenyl or pyridyl, each optionally substituted with haloalkyl, 1a and R 1b together, -CH 2 CH 2 -or -CH 2 CH 2 CH 2 or (b) R 3 is 1H-C 1~4 Alkyl-pyrazol-5-yl(

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[10] R 2 but,

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[11] R 2 but,

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[12] R 2 but,

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[13] R 2 but,

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[14] R 1a C 1~4 alkyl, and R 2 but,

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[15] R1a and R 1b together, -CH 2 CH 2 CH 2 -forms R 2 but,

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[16] R 3 but,

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[17] R 3 but,

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[18] R 3 but,

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[19] R 3 but,

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[20] The compound according to [2] above, wherein m is 1 or 2.

[21] The compound according to [2] above, wherein n is 1 or 2.

[22] The compound according to [2] above, wherein m and n are each 1.

[23] (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-5-yl)methanone; (S)-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(3-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-1H-indol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-methoxyquinolin-5-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(4,6-difluoropyrazolo[1,5-a]pyridin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(5,7-difluoroquinolin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-1-methyl-1H-indazol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-indazol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-2H-indazol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,6-dimethylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-methoxy-2-methylquinolin-4-yl)methanone; (S)-(4,6-difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(4,6-difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-(trifluoromethyl)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxyphenyl)methanone; (S)-(3-chloro-5-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-4-methylphenyl)methanone; (S)-(2-chloro-4-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3,4-dimethylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(isoquinolin-1-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-chroman-8-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-Benzo[d]thiazol-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylbenzo[d]thiazol-6-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone; (S)-chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-ethyl-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-cyclopropyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(cyclopropylmethyl)-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(2-fluoro-4-methylphenyl)methanone; ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(3-methoxy-2-methylphenyl)methanone; (3-Methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; chroman-7-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone; (3-Methoxy-5-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone; (3-Methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone; (5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (2-methyl-1,6-naphthyridin-5-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (5-Fluoroquinolin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; Benzo[d]isoxazol-3-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (5-Fluoro-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone; (6-Fluoro-2-methylquinolin-4-yl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (3-Methoxy-2-methylphenyl)((5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazol-9-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,5-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,7-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,4-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methyl-2-(trifluoromethoxy)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone; (S)-(2-chloro-4-(trifluoromethoxy)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone; and (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone; and (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[24] (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methoxy-2-methylquinolin-5-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-fluoroisoquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-(6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-(trifluoromethoxy)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-3-(trifluoromethoxy)phenyl)methanone; (S)-(4,6-difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(4,6-difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone; and (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[25]

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[26] Formula (IA):

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Claims

1. Formula (I): 【Chemical 1】 [In the formula, R １ａ is C １～４ is alkyl, R １ｂ is H, or R １ａ and R １ｂ together, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ - forms, R ２ teeth, (a) Halo, C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, OC １～４ haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C ３～６ phenyl or pyridyl, each optionally substituted with one or two substituents selected from cycloalkyl, or with two adjacent ring substituents which, together with the carbons to which they are attached, form a monocyclic cycloalkyl or heterocycloalkyl ring; (b) Halo, C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, OC １～４ haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl, and C ３～６ bicyclic heteroaryl optionally substituted with one or two substituents selected from cycloalkyl; R ３ is 1H-C １～４ Alkyl-pyrazolyl, 1H-C １～４ Haloalkyl-pyrazolyl, 1H-pyridyl-pyrazolyl, 1H-(C ３～６ cycloalkyl)-pyrazolyl, or 1H—(C ３～６ cycloalkyl-methyl)-pyrazolyl, each pyrazolyl being selected from halo, C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, or OC １～４ optionally substituted with haloalkyl; However, R ２ But, Halo, C １～４ Alkyl, or C １～４ When R is phenyl or pyridyl, each optionally substituted with haloalkyl, １ａ and R １ｂ together, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ or (b) forming R ３ is 1H-C １～４ Alkyl-pyrazol-5-yl ( 【Chemistry 2】 ) or 1H-C １～４ Haloalkyl-pyrazol-5-yl （ 【Chemistry 3】 )isn't it] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

2. Formula (I): 【Chemistry 4】 [In the formula, R １ａ is C １～４ is alkyl, R １ｂ is H, or R １ａ and R １ｂ together, -CH ２ CH ２ - or -CH ２ CH ２ CH ２ - forms, R ２ teeth, (a) 【Chemistry 5】 (b) 【Chemistry 6】 5,6-fused or 6,5-fused heteroaryl selected from (c) 【Chemistry 7】 a fused 6,6 heteroaryl selected from (d) 【Chemistry 8】 is selected from R ３ teeth, 【Chemistry 9】 is a 5-membered heteroaryl ring selected from During the ceremony, R ａ is H, halo, C １～４ Alkyl, C １～４ Haloalkyl, and OC １～４ alkyl, R ｂ is C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, OC １～４ haloalkyl, 【Chemistry 10】 is selected from Each R ｃ Ha, Halo, C １～４ Alkyl, and OC １～４ independently selected from alkyl, R ｄ is H or C １～４ is alkyl, Each R ｅ are independent, halo, C １～４ Alkyl, or C １～４ is haloalkyl, Each R ｆ is C １～４ Alkyl, C １～４ Haloalkyl, and OC １～４ independently selected from alkyl, R ｇ is C １～４ Alkyl, or C １～４ is haloalkyl, R ｈ is H, C １～４ Alkyl, C １～４ haloalkyl, and cycloalkyl; n is 0, 1, or 2; m is 0, 1, or 2. or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

3. R １ａ is CH ３ and R １ｂ is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

4. R １ａ and R １ｂ Together -CH ２ CH ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, which forms:

5. R １ａ and R １ｂ Together -CH ２ CH ２ CH ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, which forms:

6. R ２ but, 【Chemistry 11】 [In the formula, R ａ are H, Cl, F, C １～４ Alkyl or C １～４ haloalkyl, and R ｂ is C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, or OC １～４ haloalkyl] 3. The compound of claim 1 or 2, wherein:

7. R ２ but, 【Chemistry 12】 [In the formula, R ａ is Cl, F, or C １～４ alkyl, and R ｂ teeth, 【Chemistry 13】 is] 3. The compound of claim 1 or 2, wherein:

8. R ２ but, 【Chemistry 14】 3. The compound of claim 1 or 2, wherein:

9. R １ａ is CH ３ and R ２ but, 【Chemistry 15】 [In the formula, R ａ is Cl or F, and R ｂ is OC １～４ alkyl] 3. The compound of claim 1 or 2, wherein:

10. R ２ but, 【Chemistry 16】 3. The compound of claim 1 or 2, wherein:

11. R ２ but, 【Chemistry 17】 3. The compound of claim 1 or 2, wherein:

12. R ２ but, 【Chemistry 18】 [In the formula, each R ｃ is F, CH ３ , and OCH ３ are independently selected from m and n are each independently 0 or 1.

3. The compound of claim 1 or 2, wherein:

13. R ２ but, 【Chemistry 19】 3. The compound of claim 1 or 2, wherein:

14. R １ａ is C １～４ alkyl, and R ２ but, 【Chemistry 20】 3. The compound of claim 1 or 2, wherein:

15. R １ａ and R １ｂ together, -CH ２ CH ２ CH ２ -, and R ２ but, 【Chemical 21】 3. The compound of claim 1 or 2, wherein:

16. R ３ but, 【Chemical 22】 3. The compound of claim 1 or 2, wherein:

17. R ３ but, 【Chemical 23】 3. The compound of claim 1 or 2, wherein:

18. R ３ but, 【Chemistry 24】 3. The compound of claim 1 or 2, wherein:

19. R ３ but, 【Chemistry 25】 3. The compound of claim 1 or 2, wherein:

20. 3. The compound of claim 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein m is 1 or 2.

21. 3. The compound of claim 2, wherein n is 1 or 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

22. 3. The compound of claim 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein m and n are each 1.

23. (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-5-yl)methanone; (S)-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(3-(1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-1H-indol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylpyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylimidazo[1,2-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylquinolin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-methoxyquinolin-5-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(4,6-difluoropyrazolo[1,5-a]pyridin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(5,7-difluoroquinolin-3-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoropyrazolo[1,5-a]pyridin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-1-methyl-1H-indazol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-indazol-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-2H-indazol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-3-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,6-dimethylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-methoxy-2-methylquinolin-4-yl)methanone; (S)-(4,6-difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(4,6-difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-(trifluoromethyl)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxy-2-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-(1H-pyrazol-1-yl)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methoxyphenyl)methanone; (S)-(3-chloro-5-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-4-methylphenyl)methanone; (S)-(2-chloro-4-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3,4-dimethylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(isoquinolin-1-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indol-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-(2-chloro-3-methoxyphenyl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-methyl-5-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-chroman-8-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-Benzo[d]thiazol-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methylbenzo[d]thiazol-6-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone; (S)-chroman-7-yl(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-ethyl-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(difluoromethyl)-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-cyclopropyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-(pyridin-2-yl)-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; (S)-(3-(1-(cyclopropylmethyl)-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone; ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(2-fluoro-4-methylphenyl)methanone; ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(3-methoxy-2-methylphenyl)methanone; (3-methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; chroman-7-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone; (3-methoxy-5-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-3-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(m-tolyl)methanone; (3-methoxy-2-methylphenyl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone; (5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (2-methyl-1,6-naphthyridin-5-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (5-fluoroquinolin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; Benzo[d]isoxazol-3-yl((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (5-fluoro-1-methyl-1H-indazol-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; ((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)(quinolin-6-yl)methanone; (6-fluoro-2-methylquinolin-4-yl)((5R,9S)-2-methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-epiminocycloocta[c]pyrazol-10-yl)methanone; (3-methoxy-2-methylphenyl)((5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6,7,8-hexahydro-5,8-epiminocyclohepta[c]pyrazol-9-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,5-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,7-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,4-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methyl-2-(trifluoromethoxy)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-3-(trifluoromethoxy)phenyl)methanone; (S)-(2-chloro-4-(trifluoromethoxy)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-indazol-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-Benzo[d]thiazol-6-yl(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxy-3-methylpyridin-4-yl)methanone; and, (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone; and, (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

24. (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-fluoro-2-methylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methoxyquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methoxy-2-methylquinolin-5-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(3-fluoro-8-methylquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-fluoroisoquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(6-fluoro-2-methoxyquinolin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)methanone; (S)-(6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanone; (S)-(1,6-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methoxy-2-(trifluoromethoxy)phenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-methyl-3-(trifluoromethoxy)phenyl)methanone; (S)-(4,6-difluoro-1-methyl-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(4,6-difluoro-1H-indazol-3-yl)(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-fluoro-4-methylphenyl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-b]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[4,5-c]pyridin-7-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(thiazolo[5,4-c]pyridin-4-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methylbenzo[d]thiazol-6-yl)methanone; (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(5-methylbenzo[d]thiazol-6-yl)methanone; and, (S)-(2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(4-methylbenzo[d]thiazol-6-yl)methanone; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

25.

26. or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

26. Formula (IA): 【Chemical 27】 [In the formula, R ２ teeth, (a) 【Chemical formula 28】 (b) 【Chemical Formula 29】 5,6-fused or 6,5-fused heteroaryl selected from (c) 【Chemistry 30】 a fused 6,6-heteroaryl selected from (d) 【Chemical 31】 is selected from R ３ teeth, 【Chemical 32】 is a 5-membered heteroaryl ring selected from During the ceremony, R ａ are H, Cl, F, C １～４ Alkyl, and C １～４ haloalkyl; R ｂ is C １～４ Alkyl, C １～４ Haloalkyl, OC １～４ Alkyl, 【Chemical 33】 is selected from Each R ｃ Ha, Halo, C １～４ Alkyl, and OCH ３ are independently selected from R ｄ is H or CH ３ and Each R ｅ are independent of F, C １～４ Alkyl, or C １～４ is haloalkyl, Each R ｆ is C １～４ Alkyl, C １～４ Haloalkyl, and OCH ３ are independently selected from R ｇ is C １～４ Alkyl, or C １～４ is haloalkyl, n is 0, 1, or 2; m is 0, 1, or 2.

2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

27. R ３ but, 【Chemical 34】 27. The compound of claim 26, wherein:

28. Formula (IB): 【Chemistry 35】 [In the formula, n is 1 or 2; R ２ teeth, (b) 【Chemical 36】 (e) 【Chemical 37】 (f) 【Chemical 38】 and, (g) 【Chemical Formula 39】 is selected from R ３ teeth, 【Chemistry 40】 and During the ceremony, R ａ is H, halo, or C １～４ is alkyl, R ｂ is C １～４ Alkyl or OC １～４ alkyl] 2. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

29. 29. The compound of claim 28, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein n is 2.

30. (A) a therapeutically effective amount of at least one compound of any one of claims 1, 2, or 23-29, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; (B) at least one pharmaceutically acceptable excipient; and A pharmaceutical composition comprising:

31. 31. The pharmaceutical composition of claim 30, wherein the compound is a compound of claim 23.

32. 32. The pharmaceutical composition of claim 30 or 31 for treating a subject suffering from or diagnosed with a disease or disorder mediated by the MGL receptor.

33. 33. The pharmaceutical composition of claim 32, wherein the disease or disorder mediated by the MGL receptor is selected from pain, a psychiatric disease or disorder, a neurological disease or disorder, cancer, and an eye disease or disorder.

34. 33. The pharmaceutical composition of claim 32, wherein the disease or disorder mediated by the MGL receptor is selected from major depressive disorder, treatment-resistant depression, anxious depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder.

35. 33. The pharmaceutical composition of claim 32, wherein the disease or disorder mediated by the MGL receptor is inflammatory pain.

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