Monoacylglycerol lipase modulators

Abstract

The present invention provides fused and bridged compounds of formula (I) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, pharmaceutical compositions containing them, methods of preparing them and methods of using them, including methods for 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, refractory depression, anxious depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer and ocular disorders: wherein R 1a , R 1b , R 2 and R 3 Defined in this article.

Description

Technical Field

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

[0002] Cannabis Sativa and Δ 9 - an analogue of tetrahydrocannabinol. The endocannabinoid system consists of two G-protein coupled receptors, the cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346, 561-4) and the cannabinoid receptor type 2 (CB2) (Munro et al., Nature, 1993, 365, 61-5). The CB1 receptor is one of the most abundant G protein coupled receptors expressed in the brain (Herkenam et al., Proc. Nat. Acad. Sci., 1990, 87 (5), 1932-1936). 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 (inflammation) in the brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285) and in bones (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110) and myocardium (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

[0003] In 1992, N-arachidonoylethanolamine (AEA or anandamide) was found to be an endogenous ligand for cannabinoid receptors (Devane et al., Science, 1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) 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 is reported that the concentration of 2-AG is at least 100 times that of anandamide in rat brain (Buczynski and Parsons, Brit J Pharmacol, 2010, 160 (3), 423-42). Therefore, compared with anandamide, 2-AG may play a more important physiological role in the brain endocannabinoid system (Sugiura et al., Prostaglandins Leukot Essent Fatty Acids., February-March 2002, 66 (2-3): 173-92). The endocannabinoid 2-AG is a full agonist of CB1 and CB2 receptors, while anandamide is a partial agonist of these two receptors (Suguira et al., Prog Lipid Res, 2006, 45 (5): 405-46). Unlike many classical neurotransmitters, endocannabinoids signal through a retrograde mechanism. They are synthesized in postsynaptic neurons as needed and then rapidly degraded after binding to presynaptic cannabinoid receptors (Ahn et al., Chem Rev. 2008, 108 (5): 1687-707). Monoacylglycerol lipase (MGLL, also known as MAG lipase and MGL) is a serine hydrolase responsible for the degradation of 2-AG into 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 localized 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 regions associated with high CB1 receptor density. Genetic ablation of MGL expression caused a 10-fold increase in brain 2-AG levels compared to wild-type controls without affecting anandamide concentrations (Schlosburg et al., Nat Neurosci., 2010 Sep;13(9):1113-9).

[0004] Therefore, MGL modulation provides an interesting strategy for enhancing the endocannabinoid system. A major advantage of this approach is that only brain regions that efficiently produce endocannabinoids will be modulated, thereby potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL by covalent inhibitors in animals increases 2-AG levels in brain and peripheral tissues and has been found to produce analgesic, anxiolytic, and anti-inflammatory effects that are dependent on CB1 and / or CB2 receptors (Long et al., Nat Chem Biol., 2009 Jan, 5(1):37-44; Ghosh et al., Life Sci., 2013, Mar 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry., 2017, Oct 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015 Jan, 63(1):163-76; Patel et al., Neurosci Biobehav Rev., 2017 May, 76(Pt A):56-66; Betse et al., Transl Psychiatry., 2018 Apr 26, 8(1):92). In addition to the role of MGL in 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 modulation (including MGL inhibition) results in reduced proinflammatory prostaglandin signaling in animal models of 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), neurodegenerative diseases 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., Nov. 29, 2012, 2(5): 1329-39), Parkinson's disease (Nomura et al., Science, Nov. 11, 2011, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., Nov. 2017, 110: 14-24), amyotrophic lateral sclerosis (Pasquarelli et al., Neuropharmacology, Sept. 15, 2017, 124: 157-169), multiple sclerosis (Hernadez-Torres et al., Angew Chem Int Ed., Nov. 2014, 134: 157-169), Engl., Dec 8, 2014, 53(50):13765-70; Bemal-Chico et al., Glia., Jan 2015, 63(1):163-76), Huntington's disease (Covey et al., Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome and status epilepticus (Terrone et al., Epilepsia., Jan 2018, 59(1), 79-91; von Ruden et al., Neurobiol Dis., May 2015, 77:238-45).

[0005] Thus, by enhancing the cannabinoid system and attenuating the pro-inflammatory cascade, MGL modulation (including MGL inhibition) offers an attractive therapeutic approach for the treatment of a wide range of complex diseases. Importantly, MGL modulation (including MGL inhibition) in animals does not produce the same effects as Δ 9 - The full range of neurobehavioral effects observed with THC 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] Low endocannabinoid activity is a risk factor for the treatment of depression, anxiety, and post-traumatic stress disorder. Thousands of years of human use of cannabis and a brief period of human treatment with the endocannabinoid antagonist rimonabant provide support for this hypothesis. 2-AG levels are reduced in individuals with major depressive disorder (Hill et al., Pharmacopsychiatry., March 2008, 41 (2): 48-53; Hill et al., Psychoneuroendocrinology., September 2009, 34 (8): 1257-1262). Low circulating 2-AG levels predict the incidence of depression (Hauer et al., Rev Neurosci., 2012, 23 (5-6): 681-90). Circulating 2-AG has been found to be reduced in patients with post-traumatic stress disorder (PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38 (12), 2952-2961). Healthy volunteers exposed to chronic stressors showed a gradual decrease in circulating 2-AG levels, which was associated with the onset of a decrease in measures of positive emotion (Yi et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97). The CB1 receptor inverse agonist / antagonist rimonabant has been withdrawn from the market due to high incidences of severe depression and suicidal ideation (Christensen et al., The Lancet, 2007, 370, 1706-1713). Therefore, MGL modulators are potentially useful for treating mood disorders, anxiety, PTSD, autism spectrum disorders, and Asperger 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, Aug 2018, 23(8): 1798-1806).

[0007] Cannabinoid receptor agonists are clinically used to treat pain, spasticity, vomiting and anorexia (Di Marzo et al., Annu Rev Med., 2006, 57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009 Jul, 13(3):321-31). Therefore, MGL modulators (including MGL inhibitors) may also be potentially useful for these indications. MGL exerts CB1-dependent analgesic effects in animal models of noxious chemical pain, inflammatory pain, thermal pain, 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 touch-evoked allodynia in mice subjected to chronic compressive sciatic nerve injury (Kinsey et al., J Pharmacol Exp Ther., 2009 Sep, 330(3):902-10). MGL inhibition produces tolerance, constipation, and opioid sparing events with reduced cannabinoid side effects (Wilkerson et al., J Pharmacol Exp Ther., 2016 Apr, 357(1):145-56). MGL blockade is protective in an inflammatory bowel disease model (Alhouayek et al., FASEB J., 2011 Aug, 25(8):2711-21). MGL inhibition also reverses nociceptive behaviors and proinflammatory markers induced by paclitaxel 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 for 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 produces antiproliferative activity and reduces prostate cancer cell invasiveness (Nithipatikom et al., Cancer Res., Dec 15, 2004, 64(24):8826-30; Nithipatikom et al., Biochem Biophys Res Commun., Jul 15, 2005, 332(4):1028-33; Nithipatikom et al., Prostaglandins Other Lipid Mediat., Feb 2011, 94(1-2):34-43). MGL is upregulated in aggressive human cancer cells and primary tumors, where MGL has a unique role in providing a lipolytic source of free fatty acids for the synthesis of oncogenic signaling lipids that promote cancer aggressiveness. Thus, in addition to the physiological role of MGL in mediated endocannabinoid signaling, MGL in cancer plays a unique role in regulating the fatty acid precursor pool for the synthesis of proto-oncogene signaling lipids in malignant human cancer cells.

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

[0010] MGL modulators, including MGL inhibitors, may have utility in modulating drug dependence on opioids. MGL blockade reduces the intensity of naloxone-prompted morphine withdrawal symptoms in mice. MGL blockade also attenuates natural withdrawal signs in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther., Oct 2011, 339(1): 173-85).

[0011] MGL modulators are also potentially useful for treating ocular disorders, including but not limited to glaucoma and disease states due to elevated intraocular pressure (Miller et al., Pharmaceuticals, 2018, 11, 50). Summary of the invention

[0012] Embodiments of the invention relate to chemical entities, pharmaceutical compositions containing the chemical entities, methods of making and purifying the chemical entities, and methods of using the chemical entities to treat diseases, disorders, and conditions associated with MGL modulation. Additional embodiments of the invention are methods of using at least one chemical entity of the invention to treat a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation.

[0013] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

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

[0015]

[0016] in

[0017] R 1a C 1-4 alkyl;

[0018] R 1b is H;

[0019] or R 1a and R 1b Together they form -CH2CH2- or -CH2CH2CH2-;

[0020] R 2 Selected from:

[0021] (a) phenyl or pyridyl, each optionally selected from halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl and C 3-6 One or two substituents of a cycloalkyl group are substituted, or two adjacent ring substituents are taken together with the carbon to which they are attached to form a monocyclic cycloalkyl or heterocycloalkyl ring;

[0022] (b) bicyclic heteroaryl, the bicyclic heteroaryl is optionally selected from halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl and C 3-6 One or two substituents of the cycloalkyl group are substituted; and

[0023] R 3 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 optionally substituted with halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 Haloalkyl substitution;

[0024] The prerequisite is that when R2 are each optionally substituted with a halogenated group, a C 1-4 Alkyl or C 1-4 When phenyl or pyridyl is substituted with a haloalkyl group, then (a) R 1a and R 1b together to form -CH2CH2- or -CH2CH2CH2-; or (b) R 3 Not 1H-C 1-4 Alkyl-pyrazol-5-yl or 1H-C 1-4 Haloalkyl-pyrazol-5-yl

[0025] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0026] In some embodiments of compounds of Formula (I):

[0027]

[0028] in

[0029] R 1a C 1-4 alkyl;

[0030] R 1b is H;

[0031] or R 1a and R 1b Together they form -CH2CH2- or -CH2CH2CH2-;

[0032] R 2 Selected from:

[0033] (a)

[0034] (b) a 5,6-fused or 6,5-fused heteroaryl group selected from the group consisting of:

[0035]

[0036] (c) a fused 6,6-heteroaryl selected from:

[0037]

[0038] as well as

[0039] (d)

[0040] R 3 is a 5-membered heteroaryl ring selected from:

[0041] in

[0042] R a Selected from: H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl and OC 1-4 alkyl;

[0043] R b Selected from: C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Halogenated alkyl,

[0044] Each R c Independently selected from: halo, C 1-4 Alkyl and OC 1-4 alkyl;

[0045] R d H or C 1-4 alkyl;

[0046] Each R e are independently halo, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0047] Each R f Independently selected from: C 1-4 Alkyl, C 1-4 Haloalkyl and OC 1-4 alkyl;

[0048] R g C 1-4 Alkyl or C 1-4 haloalkyl; and

[0049] R h Selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl and cycloalkyl groups;

[0050] n is 0, 1 or 2; and

[0051] m is 0, 1 or 2;

[0052] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof. DETAILED DESCRIPTION

[0053] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0054] Unless otherwise specified in a specific example of 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 would be considered equivalent to any of the foregoing examples based on common skills 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 from 1 to 4 carbon atoms in the chain.

[0055] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic or spiropolycyclic carbocyclic ring having 3 to 12 ring atoms per carbocyclic ring. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:

[0056]

[0057] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine.

[0058] The term "haloalkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain, which is optionally substituted with a halogen for hydrogen. 1-4 "Haloalkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms in the chain, optionally replacing hydrogen with a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that would be considered equivalent to any of the foregoing examples based on one of ordinary skill in the art and the teachings provided herein.

[0059] The term "aryl" refers to a monocyclic aromatic carbocyclic ring (a ring structure in which the ring atoms are all carbon) having 6 atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0060] The term "phenyl" represents the following moiety:

[0061] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms in the ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms. In one embodiment, the heteroaryl group has 5 to 10 ring atoms. In another embodiment, the heteroaryl group is a monocyclic ring and has 5 or 6 ring atoms. In another embodiment, the heteroaryl group is a monocyclic ring and has 5 or 6 ring atoms and at least one nitrogen ring atom. The heteroaryl group is engaged via a ring carbon atom, and any nitrogen atom of the heteroaryl group may be optionally oxidized to a corresponding N-oxide. The term "heteroaryl" also encompasses heteroaryl groups fused to a benzene ring as defined above.

[0062] 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 heteroaryl groups include:

[0063]

[0064] 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 heteroaryl groups include:

[0065]

[0066] 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 exemplary 5,6-fused bicyclic heteroaryl or 6,5-fused bicyclic heteroaryl groups include:

[0067]

[0068] 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 exemplary 6,6-fused bicyclic heteroaryl groups include:

[0069]

[0070] As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring system, from 1 to 4 of the ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms, which may be optionally fused to another ring (aromatic or heteroaromatic). Non-limiting examples of exemplary heterocycloalkyls include:

[0071]

[0072] One skilled in the art will recognize that the heteroaryl, heterocycloalkyl, cycloalkyl, and aryl groups listed or exemplified above are not exhaustive and that other species within the scope of these defined terms may also be selected.

[0073] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that substitution occurs at any valency-permitted position on the system.

[0074] The term "variable point of attachment" means that a group is allowed to be attached at more than one alternative position in the structure. Attachment is always to replace a hydrogen atom on one of the ring atoms. In other words, all arrangements of bonding are represented by a single schematic, as shown in the following illustration.

[0075]

[0076] One skilled in the art will recognize that if more than one such substituent is present for a given ring, then the bonding of each substituent is independent of all the other substituents.The groups listed or exemplified above are not exhaustive.

[0077] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that substitution occurs at any valency-permitted position on the system.

[0078] Any formula given herein is intended to represent compounds having the structure shown in the structural formula and certain variations or forms. Specifically, the compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds with general formula and their mixtures are considered to be within the scope of such formulas. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Therefore, any formula given herein is intended to represent racemates, one or more forms of their enantiomeric forms, one or more forms of their diastereomeric forms, and mixtures thereof. In addition, any formula given herein is intended to also refer to any one of the hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly listed.

[0079] The term "R" at a stereocenter indicates that the stereocenter has only the R-configuration, as defined in the art; similarly, the term "S" means that the stereocenter has only the S-configuration. As used herein, the term "RS" refers to a stereocenter that exists in a mixture of the R-configuration and the S-configuration.

[0080] A compound containing one stereocenter without a stereobond label is a mixture of 2 enantiomers. A compound containing 2 stereocenters, neither of which has a stereobond label, is a mixture of 4 diastereomers. A compound having 2 stereocenters, both labeled "RS", with stereobond labels, is a 2-component mixture with relative stereochemistry as drawn. An unlabeled stereocenter without a stereobond label is a mixture of R- and S-configurations. For unlabeled stereocenters with stereobond labels, the absolute stereochemistry is as stated.

[0081] Reference to a compound herein represents a reference to any of: (a) the form of such compound actually mentioned, and (b) any form of such compound in the medium in which the compound is considered when referring to the compound. For example, reference to a compound such as R-COOH herein encompasses reference to any of: for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to a solid compound, which may be in the form of a tablet or some other solid pharmaceutical composition or formulation, for example; R-COOH(sol) refers to an undissociated form of the compound in a solvent; and R-COO-(sol) refers to a dissociated form of the compound in a solvent, such as a dissociated form of the compound in an aqueous environment, whether such dissociated form is derived from R-COOH, a salt thereof, or from any other entity that, upon dissociation in the medium in question, produces R-COO-. In another example, a statement such as "exposing an entity to a compound of formula R-COOH" refers to exposing the entity to one or more forms of the compound R-COOH present in the medium in which the exposure occurs. In yet another example, a statement such as "reacting an entity with a compound of formula R-COOH" refers to reacting (a) such entity (in one or more chemically related forms of such entity as it exists in the medium in which such reaction occurs) with (b) compound R-COOH as it exists in one or more chemically related forms in the medium in which such reaction occurs. In this regard, if the entity is, for example, in an aqueous environment, it is understood that compound R-COOH is in the same medium and that the entity is therefore being exposed to substances such as R-COOH(aq) and / or R-COO-(aq), wherein the subscript "(aq)" represents "aqueous" according to its conventional meaning in chemistry and biochemistry. In these naming examples, the carboxylic acid functional group is selected; however, this selection is not intended to be limiting, but is merely illustrative. It should be understood that similar examples can be provided with other functional groups, including but not limited to hydroxyl groups, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a known manner in a medium containing the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation and deprotonation. No further examples are provided herein in this regard, as these interactions and transformations in a given medium are known to any ordinary technician in the art.

[0082] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number in enriched form. Examples of isotopes that may be incorporated into the compounds of the invention in excess of natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 36 Cl and 12 5I. Such isotope-labeled compounds can be used for metabolic studies (preferably with 14 C labeling), reaction kinetic studies (e.g. 2 H or 3 H labeling), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including tissue distribution assays of drugs or substrates, or can be used for radiation therapy of patients. Specifically, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies. In addition, compounds labeled with heavier isotopes such as deuterium (i.e. 2 H or D) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents to carry out the procedures disclosed in the "Schemes" or in the "Examples and Preparations" described below.

[0083] When referring to any formula given herein, for a specified variable, the selection of a specific part from a list of possible species is not intended to limit the selection of the same species when such variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0084] Terminology C n-m Alkyl refers to an aliphatic chain, whether straight or branched, in which the total number of carbon members N in the chain satisfies n≤N≤m, and m>n.

[0085] When the same multiple substituents are assigned to multiple groups, the specific individual substituent assignments assigned to each of such groups are intended to be independently selected relative to the specific individual substituents assigned to the remaining groups. By way of example, but not limitation, if each of the groups Q and R can be H or F, the selection of H or F for Q is made independently of the selection of H or F for R, so that unless otherwise expressly stated, the selection of the assignment to Q does not determine or determine the selection of the assignment to R, or vice versa, the selection of the assignment to R does not determine or determine the selection of the assignment to Q. In this regard, the exemplary claim expressions will be understood to mean "each of Q and R is independently H or F", or "each of Q and R is independently selected from H and F".

[0086] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise.Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0087] In another example, zwitterionic compounds are covered herein by referring to compounds known to form zwitterions, even if it is not explicitly mentioned in its zwitterionic form. Terms such as one or more zwitterions and their synonyms zwitterionic compounds are standard names recognized by IUPAC, which are well known and part of the standard set of defined scientific names. In this regard, the name zwitterion is assigned the name identifier CHEBI: 27369 by the molecular entity dictionary of the Chemical Entities of Biological Inerest (ChEBI). It is well known that zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. Sometimes, these compounds are referred to by the term "inner salts". Other sources call these compounds "dipole ions", but this term is considered a misnomer by other other sources. As a specific example, aminoacetic acid (amino acid glycine) has the formula H2NCH2COOH, and it is a zwitterion + H3NCH2COO -The forms exist in some medium (in this case in a neutral medium). The terms zwitterion, zwitterionic compound, inner salt and dipole ion fall within the scope of the present invention in their known and established meanings, as understood in any case by those skilled in the art. Since it is not necessary to name every embodiment that one of ordinary skill in the art would recognize, the structures of zwitterionic compounds associated with the compounds of the present invention are not explicitly given herein. However, they are part of the embodiments of the present invention. In this regard, no further examples are provided herein, because the interactions and transformations that lead to the production of various forms of a given compound in a given medium are known to anyone of ordinary skill in the art.

[0088] When referring to any formula given herein, for a specified variable, the selection of a particular part from a list of possible species is not intended to limit the selection of the same species when the variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0089] Using the first example of substituent terminology, if the substituent S 1 实施例 is one of S1 and S2, and the substituent S 2 实施例 is one of S3 and S4, then these designations refer to the embodiments of the present invention given by the following selections: S 1 实施例 is S1 and S 2 实施例 It is S3; S 1 实施例 YesS 1 And S 2 实施例 It is S4; S 1 实施例 is S2 and S 2 实施例 It is S3; S 1 实施例 is S2 and S 2 实施例 is S4; and equivalents of each of such options. The shorter term "S 1 实施例 is one of S1 and S2, and S 2 实施例 "is one of S3 and S4" is therefore used herein for brevity, but not in a limiting manner. The first example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0090] Furthermore, when more than one designation is given for any member or substituent, embodiments of the invention include various groupings that can be made independently from the listed designations, and equivalents thereof. By way of a second example of substituent terminology, if a substituent S is described herein 实施例 is one of S1, S2 and S3, then the list refers to an embodiment of the present invention, in which S 实施例 It is S1; S 实施例 It is S2; S 实施例 It is S3; S 实施例 is one of S1 and S2; S 实施例 is one of S1 and S3; S 实施例 is one of S2 and S3; S 实施例 is one of S1, S2 and S3; and S 实施例 are any equivalents of each of these options. The shorter term "S 实施例 "One of S1, S2 and S3" is therefore used herein for brevity, but not in a limiting manner. The second example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0091] Where j>i is named ″C i -C j ″ or ″C i-j ”, when applied herein to a class of substituents, is intended to refer to embodiments of the invention in which each and every one of the numbers of carbon members from i to j (inclusive) is independently realized. By way of example, the terms C1-C3 independently refer to an embodiment having one carbon member (C1), an embodiment having two carbon members (C2), and an embodiment having three carbon members (C3).

[0092] "Pharmaceutically acceptable salts" are intended to mean acid or base salts of compounds represented by formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response.

[0093] The compounds of formula (I) may possess sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0094] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-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.

[0095] The compound of formula (I) may contain at least one nitrogen with basic properties, and thus the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid , salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosiduronic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those given as examples herein, and any other acids and mixtures thereof deemed equivalent.

[0096] The compounds of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salts 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), an alkali metal hydroxide, an alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other bases and mixtures thereof deemed by one of ordinary skill in the art to be equivalent or acceptable substitutes. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, tertiary amines and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methylglucamine and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0097] Compounds of the invention, including pharmaceutically acceptable salts thereof, either alone or in combination (collectively "active agents"), are useful as MGL modulators in the methods of the invention. Such methods for modulating MGL comprise administering a therapeutically effective amount of at least one chemical entity of the invention.

[0098] In some embodiments, MGL modulators are inhibitors and are used to diagnose a subject having 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".

[0099] Therefore, the present invention relates to methods of treating subjects diagnosed with or suffering from a disease, disorder or condition associated with MGL receptor activity using the active agents described herein. The term "treatment" as used herein is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of achieving a therapeutic or preventive benefit by modulating MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, inhibiting progression, reducing severity, or preventing a disease, disorder or condition associated with MGL modulation or one or more symptoms of such a disease, disorder or condition. The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.

[0100] The term "composition" refers to a product comprising the specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0101] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL to significantly reduce or eliminate its catalytic activity, thereby increasing the concentration of its substrate. The term "MGL-modulated" is used to refer to conditions affected by MGL enzyme modulation, including conditions affected by MGL enzyme inhibition. The present disclosure relates to methods for treating, ameliorating and / or preventing diseases, conditions or disorders associated with pain (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancers and ocular disorders by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0102] The term "modulator" includes both inhibitors and activators, wherein "inhibitors" refers to compounds that reduce, prevent, inactivate, desensitize or downregulate MGL expression or activity, while "activators" refers to compounds that increase, activate, promote, sensitize or upregulate MGL expression or activity.

[0103] Unless otherwise indicated, as used herein, the terms "affect" or "affected" (when referring to a disease, condition or disorder, that is affected by MGL inhibition) include a reduction in the frequency and / or severity of one or more symptoms or clinical manifestations of the disease, condition or disorder; and / or include preventing the development of the disease, condition or disorder or the development of one or more symptoms or clinical manifestations of the disease, condition or disorder.

[0104] In the method of treatment according to the present invention, a therapeutically effective amount of at least one activating agent according to the present invention is administered to a subject suffering from or diagnosed with such a disease, disorder or condition. "Therapeutically effective amount" refers to an amount or dosage sufficient to produce a desired therapeutic or preventive beneficial effect in a subject who needs to carry out such treatment for a specified disease, disorder or condition as a whole. The effective amount or dosage of the activating agent of the present invention can be explored by conventional methods such as modeling, dose escalation studies or clinical trials, and explored by considering conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder or condition, the therapy previously performed or currently performed by the subject, the health status of the subject and the response to the drug, and the judgment of the attending physician. For a 70kg person, the exemplary range of a suitable dosage is in single dose units or multiple dose units (e.g., BID, TID, QID or as needed for therapy), about 1 mg / day to 1000 mg / day.

[0105] Once the subject's disease, disorder or condition improves, the dosage can be adjusted to preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventive effect, depending on the symptoms. Of course, if the symptoms have been alleviated to an appropriate level, treatment can be stopped. However, the subject may require long-term intermittent treatment due to any recurrence of symptoms.

[0106] In addition, it is also envisioned that the compounds of the present invention are used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients for the treatment of the conditions described below. Additional active ingredients may be co-administered alone with at least one compound of the present invention, co-administered with an active agent of the present invention, or included in a pharmaceutical composition according to the present invention together with such agents. In an exemplary embodiment, the additional active ingredients are those active ingredients known or found to be effective in treating conditions, disorders or diseases associated with MGL regulation, such as another MGL inhibitor or a compound active against another target associated with the particular condition, disorder or disease. The combination may help to improve efficacy (e.g., by including in the combination a compound that enhances the potency or effectiveness of an active agent according to the present invention), reduce one or more side effects, or reduce the required dose of an active agent according to the present invention.

[0107] When referring to an inhibitory target, "effective amount" means an amount sufficient to affect the regulation of MGL.

[0108] It is contemplated that the active agents of the invention are used alone or in combination with one or more additional active ingredients to formulate the pharmaceutical compositions of the invention.The pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one active agent according to the invention.

[0109] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are non-toxic, biologically tolerable and otherwise biologically suitable substances for administration to a subject, such as inert substances, which are added to the pharmaceutical composition or otherwise used as vehicles, carriers or diluents to facilitate administration of the agent and are compatible therewith. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0110] The delivery form of the pharmaceutical composition containing one or more dosage units of the active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art. The composition can be administered in the method of the present invention by a suitable delivery route, such as oral, parenteral, rectal, topical or ocular administration, or by inhalation.

[0111] The preparation may be in the form of a tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation or suppository. The composition may be formulated for any of a variety of routes of administration, such as intravenous infusion, topical administration or oral administration. Preferably, the composition may be formulated for oral administration.

[0112] For oral administration, the active agent of the present invention can be provided in the form of tablets or capsules, or as a solution, emulsion or suspension. In order to prepare an oral composition, the active agent can be formulated to produce, for example, a dosage of about 1 mg / day to 1000 mg / day in a single dose unit or multiple dose units as an exemplary range of suitable dosages for a 70 kg person.

[0113] Oral tablets may include one or more active ingredients mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, colorants and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinyl pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are exemplary disintegrants. Binders may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid or talcum powder. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with enteric coatings.

[0114] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules or (hydroxypropyl) methylcellulose capsules. To prepare hard gelatin capsules, one or more active ingredients can be mixed with solid, semisolid or liquid diluents. Liquids for oral administration can be in the form of suspensions, solutions, emulsions or syrups, or can be lyophilized or presented as dry products for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally include: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and (if necessary) flavoring agents or coloring agents.

[0115] The activating agent of the present invention can also be administered by non-oral routes. For example, the composition can be formulated into suppositories, enemas or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the activating agent of the present invention can be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or provided in an oil acceptable to parenterals. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be presented in unit dosage forms (such as ampoules or disposable injection devices), in multiple dose forms (such as vials) from which appropriate doses can be extracted, or in solid forms or pre-concentrates that can be used to prepare injectable preparations. Exemplary infusion doses range from about 1 to 1000 μg / kg / minute of the activating agent mixed with a pharmaceutically acceptable carrier, for a few minutes to a few days.

[0116] For topical administration, the active agent may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20%, preferably 0.1% to 10% drug to vehicle. Another way to administer the active agents of the present invention may utilize a patch formulation to achieve transdermal delivery.

[0117] Alternatively, in the methods of the present invention the active agent may be administered via the intranasal or oral route by inhalation, for example in the form of a spray formulation also containing a suitable carrier.

[0118] In another embodiment, the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder or condition associated with MGL modulation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0119] The compounds of formula (I) are useful in methods for treating, ameliorating and / or preventing diseases, conditions or disorders affected by MGL inhibition. Such methods include 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, improvement and / or prevention.

[0120] Specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent diseases, disorders or disorders that cause pain, mental disorders, neurological disorders, cancer and eye disorders. More specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent inflammatory pain, major depressive disorder, refractory depression, anxious depression or bipolar disorder, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined herein or its pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer.

[0121] 1) Pain

[0122] Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, disorder, or pain state, including inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, fatigue, musculoskeletal disorders, skin disorders, toothache, febrile illnesses, burns, sunburn, snake bites, venomous snake bites, spider bites, insect bites, neurogenic 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.

[0123] One type of inflammatory pain is inflammatory hyperalgesia / hypersensitivity. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or pain states, including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, postoperative 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 disease (including Crohn's disease), ulcerative colitis, benign prostatic hypertrophy, and nasal hypersensitivity.

[0124] In one embodiment, the present invention relates to a method for treating, ameliorating and / or preventing inflammatory visceral hyperalgesia in which there is enhanced visceral irritability, the method comprising, consisting of and / or consisting essentially of the following steps: 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 another embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which there is hypersensitivity to thermal, mechanical and / or chemical stimulation, 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.

[0125] Another embodiment of the present invention relates to a method for treating, ameliorating and / or preventing neuropathic pain. Examples of neuropathic pain include pain due to diseases, conditions, disorders or pain states, including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, 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, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, prosthetic pain, fractures, oral neuropathic pain, Charcot pain, complex regional pain syndrome type I and II (CRPS I / II), radiculopathy, Guillain-Barre syndrome, meralgia paresthesia, burning mouth syndrome, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gomberg's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglion neuralgia, glossopharyngeal neuralgia, neuralgic migraine, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, sphenopalatine ganglion neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvar pain, vidian neuralgia, or chemotherapy-induced neuropathy.

[0126] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of an abnormal pain state associated with a neuropathy in which there is a hypersensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, disorder, or pain state, including neuropathic pain (neuralgia), pain caused by spinal and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome type I and II (CRPS I / II), and radiculopathy.

[0127] In another embodiment, the present invention relates to a method for treating, ameliorating and / or preventing neuropathic cold touch-induced allodynia in which hypersensitivity to cold stimulation 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.

[0128] 2) Mental disorders

[0129] Examples of psychiatric 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, as well as depression disorders such as major depressive disorder, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, and bipolar depression. Mood disorders and mood disorders that can be treated according to the present invention include, but are not limited to, depression, hypomania, mania, and mixed forms of bipolar I disorder; bipolar II disorder; depressive disorders such as single depression or recurrent major depression, minor depression, refractory depression, anxious depression, bipolar disorder, postpartum onset depression, depression with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, euthymia; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorders and Asperger's syndrome.

[0130] 3) Neurological disorders

[0131] Examples of neurological disorders include, but are not limited to, tremor, dyskinesia, dystonia, spasticity, Tourette syndrome; neuromyelitis optica, Parkinson's disease; Alzheimer's disease; senile dementia; Huntington's chorea; epilepsy / epileptic disorders, and sleep disorders.

[0132] 4) Cancer

[0133] Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, and brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, tumors of embryonal origin, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal tumors, ependymoblastoma, malignant meningioma, sarcoidosis, malignant melanoma, schwannoma).

[0134] 5) Eye diseases

[0135] Examples of ocular disorders include, but are not limited to, intraocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0136] Other embodiments of the present invention provide a method for modulating the activity of an MGL receptor, comprising modulating such receptor while present in a subject, the method comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0137] In some embodiments of Formula (I), R 1a is CH3 and R 1b is H. In some embodiments, R 1a and R 1bTaken together to form -CH2CH2-. In some embodiments, R 1a and R 1b Together they form -CH2CH2CH2-.

[0138] In some embodiments, R 2 for Where R a H, Cl, F, C 1-4 Alkyl or C 1-4 haloalkyl; and R b C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 In some embodiments, R 2 for Where R a Cl, F or C 1-4 alkyl; and R b for In some embodiments, R 2 for

[0139] or

[0140] In some embodiments, R 1a is CH3 and R 2 for Where R a is Cl or F, and R b For OC 1-4 In some embodiments, R 2 for

[0141] or

[0142] In some embodiments, R 2 for

[0143] or

[0144] In some embodiments, R 2 for

[0145] Each R c are independently selected from: F, CH3 and OCH3; and

[0146] n and m are each independently 0 or 1.

[0147] In some embodiments, R 2 for

[0148] or

[0149] In some embodiments, R 1a C 1-4 Alkyl and R 2 for

[0150] In some embodiments, R 1a and R 1b together to form -CH2CH2CH2-; and R 2 for

[0151]

[0152] In some embodiments, R 2 is phenyl or pyridyl, each optionally selected from halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl and C 3-6 One or two substituents of the cycloalkyl group may be substituted, or two adjacent ring substituents may be taken together with the carbon atoms to which they are attached to form a monocyclic cycloalkyl or heterocycloalkyl ring. 2 is optionally selected from halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Haloalkyl, N-linked monocyclic or bicyclic heterocycloalkyl, monocyclic heteroaryl and C 3-6 In some embodiments, R 2 is optionally selected from halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl and OC 1-4 In some embodiments, R 2 is optionally selected from halo and C 1-4 A bicyclic heteroaryl group substituted with one or two substituents of an alkyl group.

[0153] In some embodiments, R 3 for

[0154]

[0155] In some embodiments, R 3 for or In some embodiments, R 3 for In some embodiments, R3 is or

[0156] In some embodiments, R 3 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 optionally substituted with halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 In some embodiments, R 3 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 optionally substituted with halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 is substituted with a haloalkyl group; and R 1a and R 1b Taken together to form -CH2CH2- or -CH2CH2CH2-. In some embodiments, R 3 1H-C 1-4 Alkyl-pyrazolyl or 1H-C 1-4 haloalkyl-pyrazolyl, each pyrazolyl being replaced by a halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 In some embodiments, R 3 1H-pyridyl-pyrazolyl, 1H-(C 3-6 Cycloalkyl)-pyrazolyl or 1H-(C 3-6 Cycloalkyl-methyl)-pyrazolyl, each pyrazolyl optionally substituted with halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC1-4 Alkyl or OC 1-4 In some embodiments, R 3 is 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl, each optionally substituted as described herein. 3 is 1H-pyrazol-3-yl or 1H-pyrazol-4-yl, each optionally substituted as described herein.

[0157] 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.

[0158] Another embodiment of the present invention is a compound as shown in Table 1 below.

[0159] Table 1 .

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0169] Another embodiment of the present invention is a compound as shown in Table 2 below.

[0170] Table 2 .

[0171]

[0172]

[0173]

[0174] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0175] Another embodiment of the present invention is a compound as shown in Table 3 below.

[0176] Table 3 .

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0185] Another embodiment of the present invention is a compound as shown in Table 4 below.

[0186] Table 4 .

[0187]

[0188]

[0189] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0190] Another embodiment of the present invention is a compound selected from the group consisting of:

[0191]

[0192] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0193] An additional embodiment of the present invention is a compound of formula (I) having formula (IA):

[0194]

[0195] in

[0196] R 2 Selected from:

[0197] (a)

[0198] (b) a 5,6-fused or 6,5-fused heteroaryl group selected from the group consisting of:

[0199]

[0200] (c) a fused 6,6-heteroaryl selected from:

[0201] as well as

[0202] (d)

[0203] R 3 is a 5-membered heteroaryl ring selected from:

[0204] in

[0205] Ra is selected from: H, Cl, F, C 1-4 Alkyl and C 1-4 Haloalkyl;

[0206] R b Selected from: C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 alkyl,

[0207] Each R c Independently selected from: halo, C 1-4 Alkyl and OCH3;

[0208] R d is H or CH3;

[0209] Each R e Independently for F, C 1-4 Alkyl or C 1-4 Haloalkyl;

[0210] Each R f Independently selected from: C 1-4 Alkyl, C 1-4 haloalkyl and OCH3; and

[0211] R g C 1-4 Alkyl or C 1-4 Haloalkyl;

[0212] n is 0, 1 or 2; and

[0213] m is 0, 1 or 2;

[0214] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0215] In some embodiments of Formula (IA), R 3 for

[0216] An additional embodiment of the present invention is a compound of formula (I) having formula (IB):

[0217]

[0218] in

[0219] n is 1 or 2;

[0220] R 2 Selected from:

[0221] (a)

[0222] (b)

[0223] (c) as well as

[0224] (d) and

[0225] R 3 for

[0226] in

[0227] R a is H, halo or C 1-4 Alkyl; and

[0228] R b C 1-4 Alkyl or OC 1-4 alkyl;

[0229] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0230] In some embodiments of Formula (IB), n is 2.

[0231] Additional embodiments of the present invention are compounds selected from the group consisting of compounds of Formula (I), Formula (IA) and Formula (IB) or combinations thereof.

[0232] An additional embodiment of the present invention is a pharmaceutical composition comprising:

[0233] (A) a therapeutically effective amount of at least one compound selected from the group consisting of a compound of formula (I) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof; and

[0234] (B) at least one pharmaceutically acceptable excipient.

[0235] An additional embodiment of the present invention is a pharmaceutical composition comprising: a therapeutically effective amount of at least one compound selected from the group consisting of: (a) a compound in Table 1, (b) a compound in Table 2, (c) a compound in Table 3, and (d) a compound in 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.

[0236] An additional embodiment of the present invention is a pharmaceutical composition comprising: a therapeutically effective amount of at least one compound selected from the group consisting of: a compound of Formula (IA), and 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.

[0237] An additional embodiment of the present invention is a pharmaceutical composition comprising: a therapeutically effective amount of at least one compound selected from the group consisting of: a compound of formula (IB), and 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.

[0238] The present invention also encompasses enantiomers and diastereomers of compounds of formula (I) (and formulas (IA) and (IB)). The present invention also encompasses pharmaceutically acceptable salts, N-oxides or solvates of compounds of formula (I) (and formulas (IA) and (IB)). The present invention also encompasses pharmaceutically acceptable prodrugs of compounds of formula (I) (and formulas (IA) and (IB)) and pharmaceutically active metabolites of compounds of formula (I) (and formulas (IA) and (IB)).

[0239] The invention also encompasses isotopic variants of formula (I) (and formulas (IA) and (IB)), such as deuterated compounds of formula (I). The invention also encompasses pharmaceutically acceptable salts, N-oxides or solvates of isotopic variants of compounds of formula (I) (and formulas (IA) and (IB)). The invention also encompasses pharmaceutically acceptable prodrugs of isotopic variants of compounds of formula (I) (and formulas (IA) and (IB)) and pharmaceutically active metabolites of isotopic variants of compounds of formula (I) (and formulas (IA) and (IB)).

[0240] An additional embodiment of the invention is a method for 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 group consisting of a compound of Formula (I) (and Formulas (IA) and (IB)) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, including enantiomers and diastereomers of compounds of Formula (I) (and Formulas (IA) and (IB)), isotopic variants of compounds of Formula (I) (and Formulas (IA) and (IB)), and pharmaceutically acceptable salts of all of the foregoing.

[0241] Also described herein are the use of compounds of formula (I), (IA) or (IB) or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates or stereoisomers in the preparation of medicaments. In some embodiments, the medicament is used to treat a disease, disorder or condition mediated by MGL receptor activity. Also described herein are compounds of formula (I), (IA) or (IB) or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates or stereoisomers for use in methods of treating a disease, disorder or condition mediated by MGL receptor activity.

[0242] Exemplary compounds that can be used in the methods of the present invention will now be described with reference to exemplary synthesis schemes for their general preparation and subsequent specific examples below. Those skilled in the art will recognize that, in order to obtain a variety of compounds herein, the starting materials can be appropriately selected so that, with or without protection as required, the final desired substituent will be carried throughout the reaction scheme to obtain the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be subjected to the entire reaction scheme and replaced with the desired substituent where appropriate. Unless otherwise indicated, the variables are as defined above for formula (I). The reaction can be carried out between the melting point and reflux temperature of the solvent, and preferably between 0°C and the reflux temperature of the solvent. Conventional heating or microwave heating can be used to heat the reaction. The reaction can also be carried out in a closed pressure vessel at a normal reflux temperature higher than the solvent.

[0243] Abbreviations and acronyms used herein include those listed in Table 5 below.

[0244] Table 5 .

[0245]

[0246]

[0247]

[0248]

[0249] Preparation Example

[0250] Exemplary compounds useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation below and for the specific examples that follow.

[0251] Solution 1

[0252]

[0253] According to Scheme 1, a compound of formula (IIIa) or (IIIb) (wherein R e is F, m is 0 or 1, R d H or C 1-4 alkyl, and X is CH or N) alkylation: using a suitable reagent (such as iodomethane, 2,2,2-trifluoroethyl trifluoromethanesulfonate, etc.), a suitable base (such as NaH, potassium carbonate, etc.), in a suitable solvent (such as DMF, etc.), at a suitable temperature (such as 0°C or room temperature), to obtain a compound of formula (IVa) or (IVb), wherein Rg is C1-4 alkyl or C 1-4 The hydrolysis of the methyl ester is achieved by using a suitable base (such as NaOH, LiOH, (CH3)3SiOK, etc.) in a suitable solvent (such as THF) at a suitable temperature of 60°C for a period of 24 h, using conditions known to those skilled in the art to obtain a compound of formula (Va) or (Vb), wherein M is potassium, Na or Li, preferably potassium.

[0254] Solution 2

[0255]

[0256] According to Scheme 2, commercially available or synthetically available methyl 3-bromo-2-chlorobenzoate is reacted with a palladium precatalyst (such as Josiphos SL-J009-1PD G3, etc.), a base (such as cesium carbonate, etc.), an amine (such as 2-oxa-6-azaspiro[3.3]heptane, etc.) in a suitable solvent (such as DME) at a temperature of 70° C. for a period of 1 h to give methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate. Methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate is hydrolyzed using the aforementioned conditions to give a compound of formula (VI), wherein M is potassium.

[0257] Solution 3

[0258]

[0259] According to Scheme 3, the compound of formula (VII) is prepared from L-alanine ethyl ester hydrochloride in two steps. In the first step, L-alanine ethyl ester hydrochloride is alkylated with ethyl 4-bromobutyrate using potassium iodide and a suitable base such as dipotassium hydrogen phosphate. In the second step, BOC protection is performed using established methods to obtain the compound of formula (VII). Cyclization of the compound of formula (VII) (wherein PG is BOC) under Dieckmann condensation conditions is performed as follows: using a suitable base such as LiHMDS or potassium tert-butoxide; in a suitable solvent such as tetrahydrofuran; at a temperature of -40°C to 20°C; to obtain the ketoester compound of formula (VIII).

[0260] Solution 4

[0261]

[0262] According to Scheme 4, (1S,8S)-(+)-trans-8-[(R)-phenylethylamino)cyclooct-4-enol and (1R,8R)-(-)-trans-8-[(R)-phenylethylamino]cyclooct-4-enol were 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.

[0263] (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 mercuric(II) chloride in a suitable solvent such as diethyl ether, tetrahydrofuran, dihydrogen ether, The reaction is carried out in alkane, water or a mixture thereof for a period of 12-24 hours at room temperature to obtain a mercuric chloride complex at the alkenyl moiety. In the second step, the reduction of the mercuric chloride complex is completed by reacting with 3M sodium hydroxide and a reducing agent (such as sodium borohydride) at a temperature of about 0°C to obtain a cyclized (1S, 2S, 5R)-9-((R)-1-phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol product.

[0264] The chiral (R)-methylbenzyl group is deprotected using established methods using hydrogenation conditions known to those skilled in the art, for example, using H in the presence of a catalyst such as Pd / C in a suitable solvent such as MeOH to afford (1S, 2S, 5R)-9-azabicyclo[3.3.1]nonan-2-ol.

[0265] The amine portion 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 a period of about 4-7 hours to give a compound of formula (IX) wherein PG is BOC.

[0266] The compound of formula (IX) is converted to the compound of formula (X) under oxidation conditions (such as Swem (Moffott-Swern) oxidation). For example, the compound of formula (IX) is treated with DMSO, oxalyl chloride, triethylamine in a suitable solvent (such as DCM, etc.) to obtain the compound of formula (X). In a preferred method, the reaction is initially carried out at -78°C, then warmed to room temperature and stirred overnight.

[0267] The compound of formula (X) is converted to compound (XI) by treatment with a strong base such as lithium bis(trimethylsilyl)amide (LiHMDS / LHMDS) in a suitable solvent such as THF for a period of about 30 minutes at a temperature of about -78°C. The resulting lithium enolate is trapped with methyl cyanoformate or ethyl cyanoformate at a temperature of about -78°C for a period of 1-3h to give a β-ketoester compound of formula (XI), wherein PG is BOC.

[0268] Solution 5

[0269]

[0270] According to Scheme 5, a commercially available or synthetically obtainable compound of formula (XII) (which includes compounds of formula (VIII) and (XI)) (wherein R 1a is CH3, or R 1aand R 1b The 2-hydroxy-2-oxo-1-oxo ...

[0271] Derivatization of the compound of formula (XIII) with a sulfonate-based leaving group such as trifluoromethanesulfonyl (trifluoromethanesulfonate) is achieved by reacting with a trifluoromethanesulfonylating agent such as trifluoromethanesulfonic anhydride (Tf2O)), a base such as triethylamine (TEA), pyridine, N-ethyldiisopropylamine (DIEA, DIPEA), etc. in a suitable solvent such as DCM, etc. In order to achieve better selectivity, a milder trifluoromethanesulfonylating agent such as N-phenylbis(trifluoromethanesulfonimide) (Tf2NPh)), a base such as TEA, DIEA, etc. is used in a suitable solvent such as DCM, etc. to obtain a compound of formula (XIV).

[0272] Solution 6

[0273]

[0274] According to Scheme 6, the compound of formula (XVI) is prepared in a manner as described in J. Org. Chem. 2002, 67, 3479-3486, wherein PG is BOC. In an inert solvent (such as toluene, etc.), at a temperature of about 100° C., the ketoester compound of formula (XV) is reacted with commercially available or synthetically available methylhydrazine to obtain a compound of formula (XVI), wherein PG is Boc.

[0275] The compound of formula (XVI) is derivatized with a sulfonate-based leaving group (such as trifluoromethanesulfonyl (trifluoromethanesulfonate)) by reacting with a trifluoromethanesulfonylating agent (such as trifluoromethanesulfonic anhydride (Tf2O)), a base (such as triethylamine (TEA), pyridine, etc.) in a suitable solvent (such as DCM, etc.). In order to achieve better selectivity, a milder trifluoromethanesulfonylating agent (such as N-phenylbis(trifluoromethanesulfonimide) (Tf2NPh)), a base (such as TEA, DIEA, etc.) is used in a suitable solvent (such as DCM, etc.) to obtain a compound of formula (XIV), wherein R 1a and R 1b Together they form -CH2CH2-, and PG is BOC. Single enantiomers are isolated by chiral SFC purification.

[0276] Solution 7

[0277]

[0278] According to Scheme 7, a compound of formula (XIV) wherein R 1a is CH3, or R 1a and R 1b Combined to form -CH2CH2- or -CH2CH2CH2-, and PG is BOC; reacted with a heteroaryl boronic acid or boronic ester in a metal-mediated cross-coupling reaction to obtain a compound of formula (XVII), wherein PG is BOC. For example, the compound of formula (XIV) is reacted with a suitably substituted commercially available or synthetically available 5-membered heteroaryl boronic acid, boronic ester, etc. in the presence of a palladium catalyst (such as [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)), tetrakis(triphenylphosphino)palladium(0) (Pd(PPh3)4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), bis(triphenylphosphine) Palladium(II) chloride (Pd(PPh3)2Cl2)), XPhos-Pd-G2 precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) etc.), a base (such as K3PO4, Na2CO3 aqueous solution, Na2CO3, Cs2CO3 etc.) in the presence of a suitable solvent (such as 1,2-dimethoxyethane, 1,4-dimethoxyethane, The reaction is carried out in oxane, DMF, water or a mixture thereof at a temperature ranging from 60°C to 180°C, using microwave or conventional heating, for a period of about 30 min to 16 h to obtain a compound of formula (XVII).

[0279] The cleavage of the BOC protecting group on the compound of formula (XVII) is achieved according to procedures known to those skilled in the art and using established methods. For example, under acidic conditions (such as TFA / CH2Cl2, HCl / dihydrochloric acid) alkane, etc.), to obtain a compound of formula (XVIII).

[0280] Solution 8

[0281]

[0282] 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, such as coupling reactions with appropriately substituted commercially available or synthetically available aryl or heteroaryl carboxylic acids of formula (XIX) as described previously, or by reaction of appropriately substituted aryl or heteroaryl acid chlorides of formula (XX) (converting the acid into the acid chloride), using a base such as TEA (triethylamine) or the like, in an appropriate solvent such as DCM, THF, EtOAc, or the like. For example, conventional amide bond forming techniques, such as coupling reactions well known to those skilled in the art such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino) hexafluorophosphate), or converting the acid into an acid chloride). For example, reacting a compound of formula (XVIII) with a commercially available or synthetically obtainable (according to the above scheme) carboxylic acid of formula (XIX), wherein R 3 is a suitably substituted 5-membered heteroaryl ring as defined above, wherein the acid is optionally activated 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 such as 4-dimethylaminopyridine (DMAP); a halogenated triamino Salts (such as (benzotriazol-1-yloxy)tris(dimethylamino) Hexafluorophosphate (BOP) or brominated tripyrrolidinyl Hexafluorophosphate Suitable pyridine Salts (such as 2-chloro-1-methylpyridine 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]pyridine 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide Etc. The coupling reaction is carried out at a temperature ranging from about 0°C to room temperature, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA) or triethylamine (TEA), in a suitable solvent such as DCM, THF, DMF, etc. to provide compounds of formula (I).

[0283] Solution 9

[0284]

[0285] According to Scheme 9, the BOC protecting group on the compound of formula (XIV) is cleaved according to the aforementioned method to obtain the compound of formula (XXI). The compound of formula (XXII), wherein R 2 is a suitably substituted quinoline; prepared by conventional amide bond forming techniques as described above to give a compound of formula (XXII). 2 is a suitably substituted quinoline; 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) is reacted with a suitably substituted commercially available or synthetically available heteroarylboronic acid, boric acid ester, or the like in the presence of a palladium catalyst (such as [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)), tetrakis(triphenylphosphino)palladium(0) (Pd(PPh3)4), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), bis(triphenylphosphine) Palladium(II) chloride (Pd(PPh3)2Cl2), XPhos-Pd-G2 precatalyst (chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) etc.), a base (such as K3PO4, Na2CO3 aqueous solution, Na2CO3, Cs2CO3 etc.) in the presence of a suitable solvent (such as 1,2-dimethoxyethane, 1,4-dimethoxyethane, The reaction is carried out in oxane, DMF, water or a mixture thereof at a temperature ranging from 60°C to 180°C, using microwave or conventional heating, for a period of about 30 min to 16 h to obtain a compound of formula (I).

[0286] Solution 10

[0287]

[0288] 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 hydrosulfide at a temperature of 25°C in a suitable solvent such as MeOH for a period of about 16 hours can provide 3-bromo-5-nitropyridine-4-thiol. Reduction of 3-bromo-5-nitropyridine-4-thiol can be achieved using stannous chloride and hydrochloric acid in a suitable solvent such as water for a period of about 3 hours at a temperature of 25°C to provide 3-amino-5-bromopyridine-4-thiol. Condensation of 3-amino-5-bromopyridine-4-thiol using zinc and formic acid at a temperature of 100°C for a period of about 1 hour can provide 7-bromothiazolo[4,5-c]pyridine.

[0289] Solution 11

[0290]

[0291] According to Scheme 11, a compound of formula (XXIII), wherein Hal is Cl or Br; and X is CH or N, wherein only one X can be N; can be subjected to lithium-halogen exchange using a suitable base such as n-butyllithium; and reacted with a suitable source of carbon dioxide such as dry ice in a suitable solvent such as tetrahydrofuran at a temperature in the range of -78°C to 25°C for a period of about 2h to 24h to give a compound of (XXV).

[0292] In an alternative approach, compounds of formula (XXIII) may undergo metal-mediated cyanation to give compounds of formula (XXIV), wherein X is CH or N, wherein only one X may be N. For example, compounds of formula (XXIII) may be reacted with zinc cyanide in the presence of zinc and a palladium catalyst such as tris(dibenzylidene)dipalladium(0) (Pd2(dba)3), palladium(II) trifluoroacetate (Pd(TFA)2), bis(tri-tert-butylphosphine)palladium(0) (Pd(t-Bu3P)2), etc.; with or without the addition of a ligand such as 1,1'-bis(diphenylphosphino)ferrocene (DPPF), (binaphthyl)P(t-Bu)2, etc.; in a suitable solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; at a temperature in the range of 90°C to 120°C; using microwave or conventional heating; for a period of about 30 min to 16 h to give compounds of formula (XXIV).

[0293] The hydrolysis of the nitrile group on the compound of formula (XXIV) can be achieved by 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 in the range of 25°C to 100°C for a period of about 16 h, using conditions known to those skilled in the art to provide a compound of formula (XXV).

[0294] Solution 12

[0295]

[0296] According to Scheme 12, compounds of formula (XXVIa) and (XXVIb) are prepared by reacting a substituted 4-aminobenzoic acid methyl ester of formula (IIIc) (wherein R c F or CH3, R d is methyl, and n is 0 or 1) is condensed with (E)-but-2-enal in the presence of a suitable oxidant such as 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione in a suitable solvent such as 6N HCl at a temperature of 100° C. for a period of about 10 minutes. The hydrolysis of the methyl ester is achieved by using a suitable base such as NaOH, LiOH, (CH 3 ) 3 SiOK, etc., in a suitable solvent such as tetrahydrofuran, at a temperature of 60° C. for a period of 24 h using conditions known to those skilled in the art to give compounds of formula (XXVIIa) and (XXVIIb), wherein M is potassium, Na or Li.

[0297] Solution 13

[0298]

[0299] According to Scheme 13, 6-bromo-2,4-dimethylquinoline is prepared as follows: by reacting commercially available 6-bromo-2-methylquinoline with ethyl 2-mercaptopropionate in the presence of an iridium catalyst (such as Ir(ppy)2(dtbbpy)PF6, etc.) and a suitable acid (such as p-toluenesulfonic acid, etc.) in a suitable solvent mixture (such as dimethyl sulfoxide and methanol) under conditions known to those skilled in the art (Lindsley, CW et al., PCT Patent Publication No. WO 2018112312). The compound of formula (XXVIII) is prepared in two steps from 6-bromo-2,4-dimethylquinoline. For example, palladium-catalyzed carbonylation of 6-bromo-2,4-dimethylquinoline is carried out using a suitable combination of palladium catalysts such as palladium(II) acetate and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) in a suitable solvent such as methanol under a carbon monoxide atmosphere, followed by hydrolysis of the resulting methyl ester under the conditions shown above to give a compound of formula (XXVIII), wherein M is K, Na or Li.

[0300] Solution 14

[0301]

[0302] According to Scheme 14, methyl 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate is prepared by reacting commercially available 4-aminobenzoic acid with ethyl 3-oxobutanoate and acetic acid in a suitable solvent (such as toluene, etc.) at a temperature of 120°C for a period of 16 h and further reflux the resulting solid in a solvent (such as diphenyl ether) at 240°C for a period of 3 h, followed by esterification with sulfuric acid in a suitable solvent (such as methanol, etc.) to give the corresponding methyl ester.

[0303] 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 at 60° C. for a period of 6 h in the presence of a catalytic amount of DMF in a suitable solvent such as THF. The hydrolysis of the methyl ester is performed by using a suitable base such as sodium methoxide in a suitable solvent such as methanol at a temperature of 60° C. for a period of 16 h using conditions known to those skilled in the art to give the compound of formula (XXIX).

[0304] Solution 15

[0305]

[0306] According to Scheme 15, 7-methoxy-2-methylquinoline-5-carboxylic acid can be prepared by condensing commercially available or synthetically available 3-amino-5-methoxybenzoic acid with an unsaturated aldehyde such as (E)-but-2-enal using a suitable solvent such as 6N HCl at a temperature of 100°C for a period of about 1 h.

[0307] Scheme 16

[0308]

[0309] 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, etc.), a suitable base (such as potassium carbonate, etc.) in a suitable solvent (such as N,N-dimethylformamide, etc.) at a suitable temperature range (such as 0 to 25° C.). 3-Fluoro-8-methoxyquinoline-4-carboxylic acid can be prepared by metallating 3-fluoro-8-methoxyquinoline using a suitable base (such as lithium diisopropylamide) activated by potassium tert-butoxide in a suitable solvent (such as tetrahydrofuran, etc.) at a temperature of -75° C. for a period of about 20 minutes in a manner 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).

[0310] Solution 17

[0311]

[0312] According to Scheme 17, the compound of formula (XXXI) can be prepared by reacting a commercially available or synthetically obtainable benzyl alcohol of formula (XXX) (wherein R a F or CH3) is reacted with a suitable alkylating agent (such as iodomethane, etc.) using a suitable base (such as potassium carbonate, etc.) in a suitable solvent (such as N,N-dimethylformamide, etc.) at a suitable temperature range (such as 0°C to 25°C), and then the methyl ester is hydrolyzed under the conditions shown above to obtain a compound of formula (XXXI), wherein M is K, Na or Li.

[0313] Scheme 18

[0314]

[0315] According to Scheme 18, commercially available 3-(trimethylsilyl)propanal can be treated with a halogenating agent (such as N-iodosuccinimide, etc.) in the presence of silver fluoride in a suitable solvent (such as acetonitrile, etc.) to give 3-iodopropynal. Condensation with commercially available 5-fluoro-2-hydrazinopyrimidine and 3-iodopropynal 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)hydrazino)pyrimidine. The imine intermediate can then undergo an intramolecular hetero-Diels-Alder cycloaddition using an N-acetylating agent (such as trifluoroacetic anhydride, etc.) in the presence of 3-pentanone in a suitable solvent (such as tetrahydrofuran, etc.) at a temperature of about 25° C. to give 5-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine. 5-Fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine can be alkylated using a suitable reagent (such as iodomethane, etc.), a suitable base (such as potassium carbonate, etc.) in a suitable solvent (such as DMF, etc.) at a suitable temperature (such as 0° C. or room temperature) to give 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 is carried out using a suitable combination of palladium catalysts such as palladium(II) acetate and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) in a suitable solvent such as methanol under a carbon monoxide atmosphere, followed by hydrolysis of the resulting methyl ester under the conditions shown above to obtain a compound of formula (XXXII) wherein M is K, Na or Li.

[0316] Solution 19

[0317]

[0318] According to Scheme 19, 3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid is prepared by reacting 3-iodo-5-methylbenzoic acid with 1H-1,2,3-triazole via an Ullman coupling reaction in a suitable solvent such as DMF at a temperature of 100°C-140°C under microwave irradiation using a base such as cesium carbonate, a copper catalyst such as CuI, a ligand such as trans-N,N′-dimethylcyclohexane-1,2-diamine.

[0319] Solution 20

[0320]

[0321] According to Scheme 20, a commercially available or synthetically obtainable aniline of formula (XXXIII) (wherein Rh =CH3) is treated with sodium thiocyanate and bromine in acetic acid at room temperature to obtain the corresponding 2-aminobenzo[d]thiazole of formula (XXXIV) (Xu, Xiaodong, PCT Patent Publication No. WO 2018085148). The deamination of the compound of formula (XXXIV) is achieved by treating with phosphoric acid in the presence of sodium nitrite or isopentyl nitrite in 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, 2243-2246. The methyl ester is then hydrolyzed using the conditions shown above to obtain a compound of formula (XXXV), wherein Rb is CH3, and M is K, Na or Li.

[0322] Solution 21

[0323]

[0324] According to Scheme 21, 4-methyl-2-(trifluoromethoxy)benzoic acid was prepared by reacting 4-bromo-2-(trifluoromethoxy)benzoic acid with trimethylboroxine using Suzuki cross-coupling conditions as described previously.

[0325] The compound of formula (I) can be converted into their corresponding salt using methods known to those of ordinary skill in the art. For example, the amine of formula (I) is treated with trifluoroacetic acid, HCl or citric acid in a solvent (such as Et2O, CH2Cl2, THF, MeOH, chloroform or isopropanol) to obtain the corresponding salt form. Alternatively, trifluoroacetic acid or formate is obtained by reversed-phase HPLC purification conditions. With a polar solvent (comprising a mixture of polar solvents and an aqueous mixture of polar solvents) or with a non-polar solvent (comprising a mixture of non-polar solvents), the crystalline form of a pharmaceutically acceptable salt of the compound of formula (I) can be obtained by recrystallization.

[0326] If the compounds according to the invention have at least one chiral center, they may exist in enantiomeric form accordingly. If the compounds have two or more chiral centers, they may exist in diastereomeric form in addition. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0327] 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 mixture (1:1) or a non-racemic mixture (non-1:1). In the case of obtaining a racemic mixture and a non-racemic mixture of enantiomers, the single enantiomers can be separated using conventional separation methods known to those of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation or enzymatic transformation. In the case of obtaining a mixture of regioisomers or a mixture of diastereomers, the single isomers can be separated using conventional methods such as chromatography or crystallization, as applicable.

[0328] The following specific examples are provided to further illustrate the present invention and various preferred embodiments.

[0329] Example

[0330] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0331] Unless otherwise indicated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were "dried", they were typically dried over a desiccant such as Na2SO4 or MgSO4. Where mixtures, solutions and extracts were "concentrated", they were typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation were performed in a Biotage Initiator or CEM (microwave reactor) Discover instrument.

[0332] For reactions performed under continuous flow conditions, unless otherwise stated, "flow through the LTF-VS mixer" refers to the use of a Chemyx Fusion 100 Touch syringe pump (LittleThings Factory GmbH (http: / / www.ltf-gmbh.com) connected to the LTF-VS mixer via 1 / 16" PTFE tubing.

[0333] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked columns.

[0334] Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed on either of the following equipment:

[0335] Method AAn Agilent HPLC with 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) and a mobile phase of 5% ACN in 20 mM NH 4 OH was held for 2 min, followed by a gradient of 5%-99% ACN over 15 min, and then held at 99% ACN for 5 min, with a flow rate of 40 or 80 mL / min.

[0336] or

[0337] Method B A Shimadzu LC-8A series HPLC (mobile phase 5% ACN in H2O (each containing 0.05% TFA)) with an Inertsil ODS-3 column (3 μm, 30×100 mm, T=45°C) was maintained for 1 min, followed by a gradient of 5%-99% ACN over 6 min, and then maintained at 99% ACN for 3 min, with a flow rate of 80 mL / min.

[0338] or

[0339] Method C A Shimadzu LC-8A series HPLC with an XBridge C18 OBD column (5 μm, 50×100 mm) (mobile phase 5% ACN in H2O (each containing 0.05% TFA)) was maintained for 1 min, followed by a gradient of 5%-99% ACN over 14 min, and then maintained at 99% ACN for 10 min, with a flow rate of 80 mL / min.

[0340] or

[0341] Method D A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm) (mobile phase 5%-99% ACN in 20 mM NH 4 OH) was used for 10 min, then maintained at 99% ACN for 2 min, with a flow rate of 80 mL / min.

[0342] or

[0343] Method E An ACCQ Prep HPLC with an XBridge C18 OBD column (5 μM, 30×100 or 50×100 mm) (mobile phase 5% ACN in H2O (both containing 0.05% TFA)) was maintained for 1 min, followed by a gradient of 5%-95% ACN over 12 min, followed by a hold at 95% ACN for 2 min, with a flow rate of 80 mL / min.

[0344] or

[0345] Method F An Agilent HPLC with 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) and a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) was maintained for 2 min, followed by a gradient of 5%-99% ACN over 15 min, and then maintained at 99% ACN for 5 min, with a flow rate of 40 or 80 mL / min.

[0346] or

[0347] method G. Boston Uni C18 150×40mm×5μm column (eluent: 1% to 31% (v / v) ACN and H2O, containing 0.05% HCl)

[0348] Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Jasco preparative SFC system, an APS 1010 system from Bergerinstruments or a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100 to 150 bar with a flow rate in the range of 40 to 60 mL / min. The column was heated to 35 to 40°C.

[0349] Unless otherwise indicated, mass spectra (MS) were obtained on an Agilent series 1100MSD using electrospray ionization (ESI) in positive ion mode. The calculated masses (calcd.) correspond to the exact masses.

[0350] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. The multiplicity is defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = double of doublets, dt = double of triplets, td = triple of doublets. It should 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.

[0351] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0352] Compounds designated *R or *S are enantiomerically pure compounds where the absolute configuration is undetermined.

[0353] Intermediate 1: Potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate.

[0354]

[0355] Step A: Methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-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-J009-1PD 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 CH2Cl2 (10 mL), washed with H2O (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 (88.1 mg, 55%) as a yellow solid. MS (ESI): C 13 H 14 The calculated mass value of ClNO3 is 267.1; the measured m / z value is 268.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.25 (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).

[0356] Step B: Potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate. To a solution of methyl 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate (85 mg, 0.32 mmol) in THF (4.0 mL) was added potassium trimethylsilanol (41 mg, 0.32 mmol) and the resulting mixture was heated to 60 °C for 5 h. The reaction mixture was then filtered and washed with THF to give the title compound as a white solid, which was carried to the next step without purification. MS (ESI): C 12 H 11 The calculated mass value of ClKNO3 is 291.0; the measured m / z value is 254.1 [M-K+2+H] + .

[0357] Intermediate 2: Potassium 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate .

[0358]

[0359] Step A: 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester . To a cooled (0°C) solution of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester (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, then 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.25 mL, 1.7 mmol) was added, and the reaction mixture was stirred for another hour. The reaction was then quenched with water, diluted with EtOAc (2 times) and the combined organics were washed with brine (4 times), dried over Na2SO4, filtered and concentrated. The resulting residue was taken to the next step without further purification. MS (ESI): C 11 The calculated mass value of H9F3N2O2 is 258.1; the measured m / z value is 259.1 [M+H] + .

[0360] 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]hept-6-yl)benzoate. MS (ESI): C 10 The calculated mass value of H7KF3N2O2 is 282.0; the measured m / z value is 245.1 [M-K+2+H] + .

[0361] Intermediate 3: Potassium 4,6-difluoropyrazolo[1,5-a]pyridine-3-carboxylate .

[0362]

[0363] 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]hept-6-yl)benzoate and heating the reaction mixture for 24 hours. MS (ESI): mass calculated for C8H3F2KN2O2 235.9; m / z found 199.1 [M-K+2+H] + .

[0364] Intermediate 4: Lithium 5,7-difluoroquinoline-3-carboxylate

[0365]

[0366] 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 h and then concentrated under reduced pressure to give the title compound as a white solid, which was further carried to the next step without purification (quantitative yield). MS (ESI): C 10 The calculated mass value of H4F2LiNO2 is 215.0, and the measured m / z value is 210.1 [M-Li+2+H] + .

[0367] Intermediate 5: Potassium 2-methyl-2H-indazole-4-carboxylate .

[0368]

[0369] 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]hept-6-yl)benzoate. MS (ESI): mass calculated for C9H7KN2O2 214.0; m / z found 177.1 [M-K+2+H] + .

[0370] Intermediate 6: Lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate .

[0371]

[0372] Step A: 4,6-difluoro-1-methyl-1H-indazole-3-carboxylic acid methyl ester 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 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester and iodomethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. MS (ESI): C10 The calculated mass value of H8F2N2O2 is 226.1; the measured m / z value is 226.9 [M+H] + .

[0373] 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 h, and then the solvent was concentrated to give the title compound as a white solid, which was further carried to the next step without purification (quantitative yield). MS (ESI): mass calculated for C9H5F2LiN2O2 is 218.05; m / z found is 213.0 [M-Li+2+H] + .

[0374] Intermediate 7: Potassium 2-methyl-1,6-naphthyridine-5-carboxylate

[0375]

[0376] The title compound was prepared in a manner analogous 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]hept-6-yl)benzoate. MS (ESI): C 10 The calculated mass value of H7KN2O2 is 226.0; the measured m / z value is 189.1 [M-K+2+H] + .

[0377] Intermediate 8: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid .

[0378]

[0379] Step A: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester . Methyl iodide (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 h, saturated aqueous sodium bicarbonate solution (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): C 10 The calculated mass value of H9FN2O2 is 208.1; the measured m / z value is 209.1 [M+H] + . 1H 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).

[0380] Step B: 5-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid . A mixture of 5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester (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 hours, the reaction mixture was concentrated under vacuum. Purification (Method F) gave the title compound (94 mg, 79%). MS (ESI): mass calculated for C9H7FN2O2 is 194.1; m / z found is 195.1 [M+H] + .

[0381] Intermediate 9: 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl 1H-pyrazole .

[0382]

[0383] The title compound was prepared in a manner analogous 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 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid methyl ester and iodomethane instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate. MS (ESI): C 12 H 18 The calculated mass value of BF3N2O2 is 290.1; the measured m / z value is 291.1 [M+H] + .

[0384] Intermediate 10: (S)-2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrrolidone Tert-butyl oxazolo[3,4-c]pyridine-6-carboxylate .

[0385]

[0386] Step A: (S)-ethyl 4-((1-ethoxy-1-oxopropan-2-yl)amino)butanoate. DMF (21 L, 6 V), L-alanine ethyl ester hydrochloride (6.13 kg, 2.0 equivalents, 90% w / w), K2HPO4 (10.94 kg, 3.5 equivalents) and KI (2.98 kg, 1.0 equivalents) were added to a 50 L reactor in sequence at 20°C-30°C. The resulting mixture was warmed to 50°C-55°C and maintained at this temperature for 30 min. A solution of ethyl 4-bromobutyrate (3.50 kg, 1.0 equivalents) in dimethylformamide (DMF) (7 L, 2 V) was then added dropwise over 1 h while maintaining the temperature at 50°C-55°C. The mixture was stirred at 50°C-55°C for 3 h. After the reaction was completed, the reaction mixture was cooled to 20°C-30°C and transferred to another reactor, followed by the addition of water (87.5 L, 25 V). The resulting mixture was extracted with tert-butyl methyl ether (MTBE) (17.5 L×4). The organic phase was collected and washed with brine (17.5 L). The organic phase was combined with the organic phases from the other two batches (1.00 kg batch and 2.50 kg batch). The solution was then concentrated under vacuum at 40°C-45°C to give 6.8 kg of the title compound as a light yellow oil (94% w / w by Q-NMR) in a yield of 82.2%. MS (ESI): C 11 H 21 The calculated mass value of NO4 is 231.1; the measured m / z value is 232.1 [M+H] + .

[0387] Step B: (S)-4-((tert-Butoxycarbonyl)(1-ethoxy-1-oxopropan-2-yl)amino)butanoic acid ethyl Ester. Crude (S)-4-((1-ethoxy-1-oxopropyl-2-yl)amino)butyric acid ethyl ester (3.5kg, 1.0 equivalent), tetrahydrofuran (THF) (10L, 3V) and di-tert-butyl dicarbonate (3.5kg, 1.05 equivalent) were added to a 20L reactor at 20°C-30°C. The resulting mixture was warmed to 55°C-60°C and maintained at this temperature for 3h. After the reaction was completed, the reaction mixture was concentrated under vacuum at 40°C-45°C to obtain 5624g of the yellow oily title compound with a purity of 87.2% (GC) and 99.1%ee. The resulting residue was used in the next step without further purification.

[0388] Step C: (2S)-1-(tert-butyl)4-ethyl 2-methyl-3-oxopiperidine-1,4-dicarboxylate. Crude (S)-4-((tert-butoxycarbonyl)(1-ethoxy-1-oxopropyl-2-yl)amino)butanoic acid ethyl ester (450 g, 87% pure, 1.9 mol, 1.0 equiv) and THF (2.25 L, 5 V) were added to a 10 L four-necked flask at 20°C-30°C. After the mixture was cooled to -40°C to -30°C, lithium bis(trimethylsilyl)amide (LiHMDS) (1 M in THF, 2.9 L, 2.9 mol, 1.5 equiv) was added dropwise while maintaining the temperature at -40°C to -30°C. The resulting reaction mixture was warmed to 10°C-20°C and maintained at this temperature for 1 h. After the reaction was complete, the reaction mixture was combined with the other two batches and then poured into an aqueous citric acid solution (408.6 g in 2250 mL H2O, 2.9 mol, 1.5 equiv). After phase separation, the aqueous layer was extracted again with MTBE (12 L, 10 V), and the combined organic layer was washed with brine (9 L x 2). The organic phase was dried over Na2SO4 and then concentrated under vacuum to give a 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 two steps with a purity of 99% and a yield of 70%. 1 H NMR (500MHz, CDCl3) δ4.26-4.10 (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).

[0389] Step D: (7S)-2,7-dimethyl-3-oxo-2,3,3a,4,5,7-hexahydro-6H-pyrazolo[3,4-c]pyridine- tert-Butyl 6-formate. Methyl hydrazine sulfate (360g, 2.5mol, 1.5 equivalents), EtOH (5L, 10.6V) and DIEA (399mL, 2.4mol, 1.45 equivalents) were added to a 10L four-necked flask at 20°C-30°C. The resulting mixture was warmed to 75°C-80°C in 30min. Then a solution of (2S)-2-methyl-3-oxopiperidin-1,4-dicarboxylic acid 1-(tert-butyl) 4-ethyl ester (495g crude, measured weight 470g, 1.6mol, 1.0 equivalents) in EtOH (500mL) was added dropwise in 20min while maintaining the temperature at 75°C-80°C. The resulting mixture was stirred at 75°C-80°C for 4h. After the reaction was complete, the reaction mixture was concentrated under vacuum. The resulting residue was combined with the residue from another 470g batch. The combined residues were diluted with DCM (8 L, 8.5 V), H2O (2 L, 2.7 V) and brine (2.5 L, 2.7 V). After phase separation, the aqueous layer was extracted again with DCM (2 L x 2). The combined organic layers were dried over Na2SO4 and then concentrated under vacuum to give the title compound, which was used in the next step without further purification. MS (ESI): C 13 H 21 The calculated mass value of N3O3 is 267.2; the measured m / z value is 268.1 [M+H] + .

[0390] Step E: (S)-2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-4,5-dihydro-2H-pyrazolo[3,4-c] Pyridine-6(7H)-carboxylic acid tert-butyl ester To a 10 L four-necked flask was 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°C-30°C. After the mixture was cooled to 10°C-20°C, N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (902 g, 2.3 mol, 0.7 equiv) was added in portions while maintaining the temperature at 10°C-20°C. Additional N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonimide) (232 g, 0.6 mol, 0.18 equiv) was added. After stirring overnight, HPLC showed that the reaction was complete. The reaction mixture was then concentrated under vacuum and subsequently purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 0 to 8 / 1) to give 1106 g of the title compound with a purity of 99% (84% in two steps). 1HNMR (400MHz, CDCl3) δ5.19 (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).

[0391] Intermediate 11: (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro- 2H-5,9-Cycloiminocyclooctane[c]pyrazole-10-carboxylic acid tert-butyl ester .

[0392]

[0393] 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 at 2 mm Hg) to give the title compound (74.2 g, 51% yield) as a colorless liquid. MS (ESI): CH 12 The calculated mass value of O is 124.1; the measured m / z value is 123.0 [MH] - .

[0394] 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 at 100 ° C for 48 h in a sealed tube, 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 as a yellow oil (120 g, crude). The reaction was repeated on a 99 g scale (798 mmol). The resulting products from the two reactions were combined in 2 batches and converted into hydrochloride. To 20g of the obtained residue, hydrogen chloride (3.88M in ether, 82mL, 318mmol) was added. The precipitate was collected and the first batch of white crystalline solids (3.34g, 11.8mmol, 14%) was isolated. To the remaining crude product (280g, 114mmol) in ethyl acetate (560mL) was added hydrogen chloride (3.88M in ether, 560mL, 2173mmol). The suspension was stirred at room temperature for 30min and the precipitate was collected. The solid was suspended in ethyl acetate saturated with water (5.6L) and stirred at 50°C for 30min. After cooling to room temperature, the precipitate was collected and the second batch of white crystalline solids (78g, 277mmol, 24% yield) was isolated. MS (ESI): C 16 H 23 The calculated mass value of NO is 245.2; the measured m / z value is m / z=246.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ7.46-7.18 (m, 6H), 4.33-4.09 (m, 2H), 3.88 (br.s., 4H), 3.42 (s, 1H), 3.0 2-2.82 (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).

[0395] Step C: (1S,2S,5R)-9-((R)-1-phenylethyl)-9-azabicyclo[3.3.1]nonan-2-ol. To a solution of mercuric (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 (3M, 116 mL, 348 mmol) and the reaction was stirred at room temperature for 1 day. To the reaction mixture was added a solution of sodium hydroxide (3M, 280 mL, 840 mmol) and 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 =2.019min, MS (ESI): C 16 H 23 The calculated mass value of NO is 245.2; the measured m / z value is 246.1 [M+H] + .

[0396] Step D: (1S,2S,5R)-2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 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 h. 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 h. The reaction mixture was stirred by pad filter; and The product 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 the first batch of yellow oily title compound (43.4 g, 180 mmol, 44% yield). 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).

[0397] Step E: (1R,5R)-tert-butyl 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. A solution of (1R, 2S, 5R)-tert-butyl 2-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate (24.5 g, 102 mmol) in dichloromethane (140 mL) was added to the reaction mixture and the reaction was stirred at -78 °C for 30 min. Triethylamine (TEA) (85 mL, 61 mmol) was added and the reaction was allowed to warm to room temperature and stirred for 2 h. 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. (c 0.110, MeOH). MS (ESI): C 13 H 21 The calculated mass value of NO3 is 239.2; the measured m / z value is 262.1 [M+Na] + .

[0398] Step F: 9-(tert-butyl)3-ethyl(1S,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-3,9-dicarboxylate ester To a solution of (1R,5R)-2-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (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 min. A solution of ethyl cyanoformate (4.4 mL, 44.5 mmol) in distilled tetrahydrofuran (20 mL) was added to the reaction mixture and the reaction was stirred at -78 °C for 1 h. The reaction was quenched with saturated ammonium chloride (200 mL). The aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (2×150 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with heptane:ethyl acetate (4:1) to give the title compound (5.5 g, 18 mmol, 51% yield) as a pale yellow oil. (c 0.185, MeOH). MS(ESI):C 16 H 25 The calculated mass value of NO5 is 311.2; the measured m / z value is 256.1 [M+2H-tBu] + . 1H NMR (300MHz, DMSO-d6) δ11.83 (s, 1H), 4.52-4.37 (m, 1H), 4.36-4.25 (m, 1H), 4.20 (q, J=7.1Hz, 2H) , 2.66-2.49 (m, 1H), 2.09 (d, J=16.5Hz, 1H), 1.76-1.45 (m, 6H), 1.39 (s, 9H), 1.24 (t, J=7.1Hz, 3H).

[0399] Step G: (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-cycloiminocyclooctane [c] tert-Butyl 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 h. 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): C 15 H 23 The calculated mass value of N3O3 is 293.2; the measured m / z value is 294.2 [M+H] + .

[0400] b Step H: (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro- 2H-5， 9-Cycloiminocyclooctane[c]pyrazole-10-carboxylic acid tert-butyl esterTo a solution of (5R,9S)-2-methyl-3-oxo-2,3,4,5,6,7,8,9-octahydro-1H-5,9-cycloiminocyclooctane[c]pyrazole-10-carboxylic acid tert-butyl ester (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 h. The reaction mixture was washed with saturated sodium bicarbonate (2×200 mL), 10% potassium bisulfate (2×200 mL) and brine (1×200 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with heptane:ethyl acetate (6:1→4:1). The residue was dissolved in ethyl acetate (100 mL) and evaporated. The less pure fractions were combined and evaporated. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate (3×150 mL), dried over sodium sulfate, filtered and evaporated. The products were combined to give the title compound (16.4 g, 39 mmol, 56% yield) as a colorless oil. MS (ESI): C 16 H 22 The calculated mass value of F3N3O5S is 425.1; the measured m / z value is 370.1 [M+2H-tert-butyl] + . 1 H NMR (500 MHz, DMSO-d6) δ 5.06 (d, J = 18.9 Hz, 1H), 4.48 (d, J = 31.6 Hz, 1H), 3.73 (s, 3H), 2.84 (dd, J = 16.3, 7.4 Hz, 1H), 2.44 (d, J = 16.3 Hz, 1H), 1.78-1.61 (m, 3H), 1.59-1.41 (m, 2H), 1.38 (s, 9H), 1.27-1.16 (m, 1H). Optical rotation: (c 0.15, MeOH).

[0401] Intermediate 12: (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro- 5,8-Cycloiminocycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester .

[0402]

[0403] Step A: 5-Formyl-1H-pyrrole-2-carboxylic acid ethyl ester. Into a cooling (0 ℃) solution of dichloroethane (DCE) (250mL) and POCl3 (18.7mL, 201mmol), N, N-dimethylformamide (DMF) (17.7mL, 230mmol) was slowly loaded, and the suspension was stirred at 0 ℃ for 15min. Then, a solution of 1H-pyrrole-2-carboxylic acid ethyl ester (20g, 144mmol) dissolved in DCE (50mL) was loaded into the reaction mixture and stirred at 0 ℃ for 30min, warming to room temperature overnight. The completed reaction was cooled to 0 ℃ and 50mL of trihydrate NaOAc solution (about 43g) was added. The resulting mixture was heated to 75 ℃ for 30min and then cooled to room temperature. The water layer was extracted with methyl tert-butyl ether (MTBE, TBME), washed with NaHCO3 aqueous solution, brine, dried over Na2SO4, filtered and concentrated. Purification (FCC, eluting with 0&-10% EtOAc / hexane) gave the title compound (18.1 g, 75%). MS (ESI): mass calculated for C8H9NO3: 167.1; m / z found: 168.1 [M+H] + .

[0404] Step B: (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylic acid ethyl ester . Triethylphosphonoacetate (61.7 g, 234 mmol) was charged into a cooled (0 ° C) solution of NaH (8.7 g, 217 mmol) in THF (200 mL). The reaction mixture was stirred at 0 ° C for 3 hours, and then 5-formyl-1H-pyrrole-2-carboxylic acid ethyl ester (27.9 g, 167 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH4Cl aqueous solution (200 mL) and extracted into Et2O (× 3), washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting material was recrystallized from 10% EtOAc / hexane to give the title compound (39.5 g, 99.8%). MS (ESI): C 12 H 15 The calculated mass value of NO4 is 237.1; the measured m / z value is 238.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.93 (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).

[0405] Step C: Ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-2-carboxylate. To the flask was added (E)-5-(3-ethoxy-3-oxoprop-1-en-1-yl)-1H-pyrrole-2-carboxylic acid ethyl ester (39.5 g, 167 mmolmmol), rhodium alumina (27.4 g, 13.3 mmol) and suspended in acetic acid (80 mL), and evacuated and backfilled with N2. The flask was then equipped with a H2 balloon and evacuated and backfilled with H2 twice. The reaction mixture was stirred at room temperature for 48 hours. The resulting reaction mixture was passed through The mixture was washed with DCM and then concentrated under reduced pressure. Water (400 mL) was added to the reaction mixture and the reaction mixture was extracted into DCM (×3). The organic layers were combined, washed with NaHCO3, brine, dried (Na25O4), filtered and concentrated under reduced pressure to give the title compound (38.6 g, 95%) as a colored oil. MS (ESI): C 12 H 21 The calculated mass value of NO4 is 243.1; the measured m / z value is 244.1 [M+H] + .

[0406] Step D: 1-(tert-Butyl)2-ethyl 5-(3-ethoxy-3-oxopropyl)pyrrolidine-1,2-dicarboxylate . TEA (44.1 mL, 317 mmol) was slowly charged into 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). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (200 mL) and washed with water, brine, dried over Na2SO4, filtered and concentrated to give the title compound (54.8 g, 100.6%). MS (ESI): C 17 H 29 The calculated mass value of NO6 is 343.2; the measured m / z value is 244.1 [M+2H-CO2tBu] + .

[0407] 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 NH4Cl. The aqueous layer was extracted again with EtOAc (×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification (FCC, SiO2, eluted with 0%-10% EtOAc / hexane) gave the title compound (37.8 g, 79.7%). MS (ESI): C 15 H 23 The calculated mass value of NO5 is 297.2; the measured m / z value is 242.1 [M+2H-tBu] + .

[0408] Step F: rac-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydro-5,8-cycloiminocyclohepta[c]pyrrolidone Tert-Butyl oxadiazole-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 charged methylhydrazine (467 mL). The resulting mixture was heated at 110°C for 2 hours. The cooled reaction was concentrated under reduced pressure. Purification (FCC, SiO2, eluted with 0%-10% MeOH / DCM) gave the title compound as a clear oil. MS (ESI): C 14 H 21 The calculated mass value of N3O3 is 279.2; the measured m / z value is 280.2 [M+H] + .

[0409] Step G: (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8- Cycloiminocycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester and (5S,8R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)- 2,4,5,6,7,8-Hexahydro-5,8-cycloiminocyclohepta[c]pyrazole-9-carboxylic acid tert-butyl ester . To a solution of racemic-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydro-5,8-cycloiminocycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester (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. The completed reaction was concentrated under reduced pressure. Purification (FCC, SiO2, eluted with 0%-20% EtOAc / hexane) gave a racemic mixture of the title compound (11.2 g, 80%). MS (ESI): C 15 H 20The calculated mass value of F3N3O5S is 411.1; the measured m / z value is 356.0 [M+2H-tert-butyl] + .

[0410] The single isomer was separated by chiral SFC purification of racemic 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-cycloiminocycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester using stationary phase: Chiralpak IC5μm250*30mm, mobile phase: 93% CO2, 7% iPrOH to give (5R,8S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-cycloiminocycloheptyl[c]pyrazole-9-carboxylic acid tert-butyl ester (single isomer; 1.05min retention time). MS (ESI): C 15 H 20 The calculated mass value of F3N3O5S is 411.1; the measured m / z value is 356.0 [M+2H-tert-butyl] + .

[0411] 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 .

[0412]

[0413] Step A: (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,7-tetramethyl Hydrogen-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester Under nitrogen atmosphere, (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) was added to 1,4-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate. To a solution of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid (291 mg, 1.5 mmol), aqueous sodium carbonate solution (2 M, 1.0 mL, 2.74 mmol) and XPhos-Pd-G2 (49.3 mg, 0.06 mmol) in 2M 2-oxane (4.0 mL) was added. 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 (2×5.0 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%-40% hexanes-EtOAc) to give the title compound (390 mg, 0.50 mmol, 77%) as an oil. MS (ESI): C 18 H 24 The calculated mass value of F3N5O2 is 399.2; the measured m / z value is 344.1 [M+2H-t Bu] + . 1 H NMR (400MHz, DMSO-d6) δ7.08 (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).

[0414] Step B: (S)-2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7-tetramethyl Hydrogen-2H-pyrazolo[3,4-c]pyridine To a mixture of (S)-tert-butyl 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) at 0°C was added trifluoroacetic acid (TFA) (2 mL, 26.1 mmol, 1.49 g / mL) and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated with dichloromethane (25 mL), concentrated in vacuo, and the process was repeated an additional 3 times to give the title compound as a white solid, which was taken to the next step without purification. MS (ESI): C 13 H 16 The calculated mass of F3N5 is 299.2; the measured m / z is 300.1 [M+H] + . 1 H NMR (500 MHz, methanol-d4) δ 6.86 (s, 1H), 4.61 (q, J = 6.7 Hz, 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 = 6.8 Hz, 3H).

[0415] 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 .

[0416]

[0417] The title compound was prepared in analogy to (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-pyrazol-5-yl)boronic acid in step A. The resulting mixture was carried forward as the TFA salt without further purification. MS (ESI): C 13 H 16 The calculated mass value of F3N5 is 299.2; the measured m / z value is 300.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ6.71 (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).

[0418] 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 .

[0419]

[0420] The title compound was prepared in a manner analogous to (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): C 13 H 16 The calculated mass of F3N5 is 299.2; the measured m / z is 300.1 [M+H] + . 1 H NMR (600MHz, CDCl3) δ7.45 (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).

[0421] 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 .

[0422]

[0423] The title compound was prepared in a manner analogous to (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): C 13 H 19 The calculated mass value of N5 is 245.2; the measured m / z value is 246.1 [M+H] + .

[0424] 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 .

[0425]

[0426] The title compound was prepared in a manner analogous to (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): C 14 H 18 The calculated mass value of F3N5 is 313.15; the measured m / z value is 314.1 [M+H] + .

[0427] Intermediate 18: (S)-3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-4,5,6,7-tetra Hydrogen-2H-pyrazolo[3,4-c]pyridine .

[0428]

[0429] The title compound was prepared in a manner analogous to (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): C 13 H 19 The calculated mass value of N5O is 261.2; the measured m / z value is 262.3 [M+H] + .

[0430] 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 .

[0431]

[0432] The title compound was prepared in a manner analogous to (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 and EtOH instead of DCM in step B. MS (ESI): C 13 H 16 The calculated mass of F3N5 is 299.1; the measured m / z is 300.1 [M+H] + .

[0433] 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-cycloiminocyclooctyl[c]pyrazole .

[0434]

[0435] The title compound was prepared in a manner analogous to (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 (5R,9S)-tert-butyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctane[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 in step A. MS (ESI): C 15 H 18 The calculated mass value of F3N5 is 325.2; the measured m / z value is 326.2 [M+H] + .

[0436] 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-cycloiminocyclooctane[c]pyrazole .

[0437]

[0438] In a manner analogous to (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), (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctane[c]pyrazole-10-carboxylic acid tert-butyl ester (Intermediate 14) was used in step A. Intermediate 11) was used instead of (S)-2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylic acid tert-butyl ester and 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-pyrazol-5-yl)boronic acid to prepare the title compound. MS (ESI): C 15 H 18 The calculated mass value of F3N5 is 325.2; the measured m / z value is 326.1 [M+H] + .

[0439] 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-cycloiminocyclooctane[c]pyrazole .

[0440]

[0441] In a manner analogous to (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), (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[c]pyridine was used in step A. The title compound was prepared by using tert-butyl oxadiazole-10-carboxylate (Intermediate 11) instead of (S)-2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate and (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid. MS (ESI): C 16 H 20 The calculated mass value of F3N5 is 339.2; the measured m / z value is 340.3 [M+H] + .

[0442] Intermediate 23: (5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexahydro- 2H-5,9-Cycloiminocyclooctane[c]pyrazole .

[0443]

[0444] In a manner analogous to (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), (5R,9S)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctane[ c] tert-butyl pyrazole-10-carboxylate (Intermediate 11) was used instead of (S)-2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate and (1,3-dimethyl-1H-pyrazol-5-yl)boronic acid was used instead of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid to prepare the title compound. MS (ESI): C 15 H 21 The calculated mass value of N5 is 271.2; the measured m / z value is 272.1 [M+H] + .

[0445] Intermediate 24: (5R,8S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2,4,5,6, 7,8-Hexahydro-5,8-cycloiminocyclohepta[c]pyrazole .

[0446]

[0447] The title compound was prepared in a manner analogous to (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 (5R,8S)-tert-butyl 2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,4,5,6,7,8-hexahydro-5,8-cycloiminocyclohepta[c]pyrazole-9-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): C 14 H 16 The calculated mass value of F3N5 is 311.1; the measured m / z value is 312.2 [M+H] + .

[0448] Intermediate 25: (S)-2,7-dimethyl-6-(quinoline-6-carbonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c] Pyridin-3-yl trifluoromethanesulfonate .

[0449]

[0450] 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 min and then concentrated in vacuo. The residue was taken up in EtOAc, saturated aqueous NaHCO3 was carefully added, and the mixture was stirred for 1 min. The layers were separated and the aqueous layer was extracted with EtOAc followed by 20% iPrOH / CHCl3. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.

[0451] 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 CH2Cl2 (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 min and then quenched with H2O. After the mixture was stirred vigorously for 1-2 min, the layers were separated and the organic layer was carefully washed with saturated NaHCO aqueous solution (note: gas is formed). The combined aqueous layer was transferred to a round-bottomed flask and stirred vigorously for 1-2 min until no more bubbling was observed, and then extracted with CH2Cl2. The two organic solutions were combined and washed once with brine, dried over Na2SO4, filtered and concentrated in vacuo. The gained residue was absorbed in CH2Cl2 / hexane mixture, and the gained precipitate was collected via vacuum filtration, washed with hexane to obtain the title compound (1.38 g) as a brown solid. The filtrate was concentrated and purified by silica gel chromatography (0%-20% MeOH in CH2Cl2) to obtain the second batch of title compound (0.52 g). The combined yield was 83%. MS (ESI): C 19 H 17 The calculated mass value of F3N4O4S is 454.1; the measured m / z value is 455.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.99 (dd, J=4.2, 1.7Hz, 1H), 8.19 (dd, J=15.2, 8.6Hz, 2H), 7.9 2 (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).

[0452] Intermediate 26: 3-Methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid .

[0453]

[0454] 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 min under microwave irradiation. The reaction mixture was stirred at 140 ° C for 60 min under microwave irradiation. The reaction mixture was stirred at 140 ° C for 2 ... Filter the pad and The reaction mixture 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 as an off-white powder (51 mg, 32% yield). MS (ESI): The mass calculated value for C9H6FN3O2 is 203.1; the m / z found value is 204.1 [M+H] + .

[0455] Intermediate 27: 5-Fluoro-2-methylquinoline-6-carboxylic acid .

[0456]

[0457] 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 and 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): C 11 The calculated mass value of H8FNO2 is 205.1; the measured m / z value is 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).

[0458] Intermediate 28: 7-Fluoro-2-methylquinoline-6-carboxylic acid .

[0459]

[0460] The title compound was prepared in a similar manner to Intermediate 27. Purification by SFC on DAICEL CHIRALPAK AD-H (250 mm×30 mm×5 um (isocratic elution: EtOH (containing 0.1% of 25% NH3 in water): supercritical CO2, 25%:75% to 25%:75% (v / v)). MS (ESI): C 11 The calculated mass value of H8FNO2 is 205.1; the measured m / z value is 205.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.36 (t, J=7.7Hz, 2H), 7.61 (d, J=11.9Hz, 1H), 7.42 (d, J=8.5Hz, 1H), 2.66 (s, 3H).

[0461] Intermediate 29: 2,5-Dimethylquinoline-6-carboxylic acid .

[0462]

[0463] 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 mixture of isomers was purified by SFC on DAICEL CHIRALPAK AD-H (250 mm×30 mm×5 um (isocratic elution: EtOH (containing 0.1% of 25% NH3 aqueous solution): supercritical CO2, 25%:75% to 25%:75% (v / v)) to give the title compound and 2,7-dimethylquinoline-6-carboxylic acid (Intermediate 30) as a white solid. MS (ESI): C 12 H 11 The calculated mass value of NO2 is 201.2; the measured m / z value is 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).

[0464] Intermediate 30: 2,7-Dimethylquinoline-6-carboxylic acid .

[0465]

[0466] The title compound was isolated as the second product from the mixture described in Intermediate 29. MS (ESI): C 12 H 11 The calculated mass value of NO2 is 201.2; the measured m / z value is 202.2 [M+H] + . 1 H 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).

[0467] Intermediate 31: 2,4-Dimethylquinoline-6-carboxylic acid .

[0468]

[0469] Step A: 6-Bromo-2,4-dimethylquinoline . To a mixture of 6-bromo-2-methylquinoline (555 mg, 2.5 mmol), ethyl 2-mercaptopropionate (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 another 5 minutes and then irradiated with a blue LED at room temperature. After 36 hours, 1N 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 (500 mg, 82%) as a white solid. MS (ESI): C 11 H 10 The calculated mass of BrN is 235.0; the measured m / z is 236.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.07 (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).

[0470] 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)Cl2 (155 mg, 0.21 mmol) and Pd(OAc)2 (24 mg, 0.11 mmol) under a nitrogen atmosphere. The resulting mixture was saturated with CO and then heated to 80°C for 12 hours. 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 (SiO2; 0%-20% hexane-EtOAc) to give the title compound (200 mg, 84%) as a yellow solid. MS (ESI): C 13 H 13 The calculated mass value of NO2 is 215.1; the measured m / z value is 216.1 [M+H] + .

[0471] 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. 2M HCl solution was added to the resulting reaction to adjust to pH = 3-4. The mixture was extracted with dichloromethane (3×50 mL) and 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. MS (ESI): C 12 H 11 The calculated mass value of NO2 is 201.1; the measured m / z value is 202.2 [M+H] + .

[0472] Intermediate 32: 4-Methoxy-2-methylquinoline-6-carboxylic acid .

[0473]

[0474] 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 diphenyl ether (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 compound (1.8 g, 17.3%) as a yellow solid. MS (ESI): C 11 The calculated mass value of H9NO3 is 203.1; the measured m / z value is 203.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.78-12.63(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).

[0475] Step B: 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid methyl ester . To a solution of 2-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.8 g, 8.8 mmol) in methanol (20.0 mL) was added concentrated sulfuric acid (2.0 mL) and the resulting mixture was stirred at room temperature for 16 hours. The resulting reaction mixture was then poured into ice water (20.0 mL) and then 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 give the title compound (650 mg, 33%) as a yellow solid. MS (ESI): C 12 H 11 The calculated mass value of NO3 is 217.0; the measured m / z value is 217.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.13-11.64 (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).

[0476] 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) at 0°C in the presence of a catalytic amount of DMF (100 μL). 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 4M NaOH aqueous solution and concentrated under reduced pressure to remove THF. The resulting solid was filtered and washed with water (3 mL×3) to give the title compound (600 mg, 82%) as a yellow solid. MS (ESI): C 12 H 10 The calculated mass value of ClNO2 is 235.0; the measured m / z value is 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).

[0477] Step D: 4-Methoxy-2-methylquinoline-6-carboxylic acid . Sodium methoxide (92 mg, 1.7 mmol) was added to a solution of methyl 4-chloro-2-methylquinoline-6-carboxylate (200 mg, 0.85 mmol) in methanol (2.0 mL). The reaction mixture was heated to 60 ° C for 16 hours to give a mixture of 4-methoxy-2-methylquinoline-6-carboxylic acid and 4-chloro-2-methylquinoline-6-carboxylic acid. The title compound, i.e. 4-methoxy-2-methylquinoline-6-carboxylic acid (20 mg, 10.3% yield) was purified by HPLC (method: Boston Green ODS 150*30mm*5um column (eluent: 10% to 40% (v / v) CH3CN and H2O, containing 0.225% HCOOH)) to give a yellow solid. 12 H 11 The calculated mass value of NO3 is 217.1; the measured m / z value is 217.9 [M+H] + . 1 HNMR (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).

[0478] Intermediate 33: 4-Methyl-2-(trifluoromethoxy)benzoic acid .

[0479]

[0480] Under nitrogen atmosphere, 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.5 mmol) was added to dichloromethane. 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)Cl2 (260 mg, 0.35 mmol) were added to a solution of 1,3,5,2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (880 mg, 7.0 mmol), cesium carbonate (3.4 g, 10.53 mmol) and Pd(dppf)Cl2 (260 mg, 0.35 mmol) in oxane:water (15:3 mL). The resulting mixture was purged with nitrogen for 5 minutes and heated to 100°C for 16 hours. The resulting reaction mixture was purified by The pad was filtered and washed with ethyl acetate (5 mL×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 H2O, containing 0.225% FA)) to obtain the title compound as a yellow solid (100 mg, 13% yield). MS (ESI): The mass calculated value of C9H7F3O3 is 220.1; the m / z found value is 220.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.24 (br s, 1H), 7.83 (d, J=7.8Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.30 (s, 1H), 2.40 (s, 3H).

[0481] Intermediate 34: 7-Methylbenzo[d]thiazole-6-carboxylic acid .

[0482]

[0483] Step A: 2-amino-7-methylbenzo[d]thiazole-6-carboxylic acid methyl ester and 2-amino-5-methylbenzo[d]thiazole- 6-Methyl formate To an ice-cold 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) was added dropwise bromine (0.3 mL, 6.0 mmol) in acetic acid (1.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, warmed to room temperature and stirred for 16 hours. The resulting suspension was filtered through The mixture was filtered and the filtrate was diluted with water (20 mL). The mixture was quenched with 1 M NaOH until pH = 4 to obtain a precipitate. The precipitate was filtered and washed with MeOH (5 mL × 2). The resulting product mixture was purified by SFC on DAICEL CHIRALPAKAD-H (250 mm × 30 mm × 10 um (isocratic elution: EtOH (containing 0.1% of 25% NH3 aqueous solution): supercritical CO2, 30%: 70% to 30%: 70% (v / v)) to obtain two title products:

[0484] 2-Amino-7-methylbenzo[d]thiazole-6-carboxylic acid methyl ester (220 mg, 16%); MS (ESI): C 10 H 10 The calculated mass value of N2O2S is 222.2; the measured m / z value is 222.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.87 (s, 2H), 7.77 (d, J=8.5Hz, 1H), 7.22 (d, J=8.5Hz, 1H), 3.80 (s, 3H), 2.61 (s, 3H).

[0485] 2-Amino-5-methylbenzo[d]thiazole-6-carboxylic acid methyl ester (220 mg, 16%); MS (ESI): C 10 H 10 The calculated mass value of N2O2S is 222.2; the measured m / z value is 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).

[0486] 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 isoamyl nitrite (232 mg, 2.0 mmol) and the mixture was stirred at 65 °C for 14 h. The resulting mixture was concentrated to dryness under reduced pressure to give the title compound as a brown solid, which was used in the next step without purification. MS (ESI): C 10 The calculated mass value of H9NO2S is 207.1; the measured m / z value is 207.8 [M+H] + .

[0487] Step C: 7-Methylbenzo[d]thiazole-6-carboxylic acid7-Methylbenzo[d]thiazole-6-carboxylic acid methyl ester (180 mg, 0.87 mmol) was added to distilled water. To the solution in oxane: water (1: 1, 5 mL), lithium hydroxide monohydrate (180 mg, 4.3 mmol) was added. 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×3). The aqueous phase was quenched with 3M HCl until pH=4.0 and then extracted with ethyl acetate (10 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (170 mg) as a yellow solid. MS (ESI): The mass calculated value of C9H7NO2S is 193.0; the m / z found value is 193.8 [M+H] + .

[0488] Intermediate 35: 5-Methylbenzo[d]thiazole-6-carboxylic acid .

[0489]

[0490] The title compound was prepared in a manner analogous 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 for C9H7NO2S 193.0; m / z found 193.8 [M+H] + .

[0491] Intermediate 36: 5-Methylbenzo[d]thiazole-6-carboxylic acid .

[0492]

[0493] The title compound was prepared in a manner analogous to Intermediate 34 using methyl 4-amino-3-methylbenzoate instead of methyl 4-amino-2-methylbenzoate in step A. MS (ESI): mass calculated for C9H7NO2S: 193.0; m / z found: 193.8 [M+H] + .

[0494] 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 .

[0495]

[0496] 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 CH2Cl2 (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 min, 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): C 24 H 23 The calculated mass value of F3N6O is 468.2; the measured m / z value is 469.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.12-7.71(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).

[0497] 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 .

[0498]

[0499] The title compound was prepared in a manner similar to 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): C 22 The calculated mass value of H27N5O2 is 393.2; the measured m / z value is 394.1 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ7.49-7.36 (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).

[0500] 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 .

[0501]

[0502] The title compound was prepared in a manner analogous to Example 1 using (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 (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): C 23 H 26 The calculated mass value of F3N5O2 is 461.2; the measured m / z value is 462.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.25-7.13(m, 1H), 6.90-6.63(m, 2H), 6.09-5.78(m, 1H), 5.06-4.81(m, 1H), 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).

[0503] Example 4: (S)-(2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-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)methyl ketone .

[0504]

[0505] The title compound was prepared in a manner similar to Example 1 using potassium 2-chloro-3-(2-oxa-6-azaspiro[3.3]hept-6-yl)benzoate (Intermediate 1) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 26 The calculated mass value of ClF3N6O2 is 534.2; the measured m / z value is 535.0 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.36-7.04(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).

[0506] 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 .

[0507]

[0508] The title compound was prepared in a manner similar to Example 1 using 4-fluoro-1H-indole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 20 The calculated mass value of F4N6O is 460.2; the measured m / z value is 461.1 [M+H] + . 1 HNMR (500MHz, DMSO-d6) δ11.75 (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).

[0509] 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 .

[0510]

[0511] The title compound was prepared in a manner similar to Example 1 using 1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.96 (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), 5.92-5.4 7 (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).

[0512] 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 .

[0513]

[0514] The title compound was prepared in a manner similar to Example 1 using 4-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.2 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.87 (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), 4.3 0-4.10 (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).

[0515] 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 .

[0516]

[0517] The title compound was prepared in a manner similar to Example 1 using lithium 5-methylimidazo[1,2-a]pyridine-3-carboxylate instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 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).

[0518] 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 .

[0519]

[0520] The title compound was prepared in a manner similar to Example 1 using 2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 23 The calculated mass value of F3N6O is 468.2; the measured m / z value is 469.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.08-7.92 (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, 1 H), 3.87-3.55(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).

[0521] 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 .

[0522]

[0523] The title compound was prepared in a manner similar to Example 1 using 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 487.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.13-7.95(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) ), 4.96-4.27(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).

[0524] 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 .

[0525]

[0526] The title compound was prepared in a manner similar to Example 1 using 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 19 The calculated mass value of F4N7O is 461.2; the measured m / z value is 462.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.69 (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).

[0527] 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]pyridine-4- methyl ketone .

[0528]

[0529] The title compound was prepared in a manner similar to 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): C 23 H21 The calculated mass value of F6N7O is 525.2; the measured m / z value is 526.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41 (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).

[0530] 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 .

[0531]

[0532] The title compound was prepared in a manner similar to Example 1 using 2-methylquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 23 The calculated mass value of F3N6O is 468.2; the measured m / z value is 469.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.29 (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), 4.8 5-4.47(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).

[0533] 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 .

[0534]

[0535] The title compound was prepared in a manner similar to Example 1 using 8-methoxyquinoline-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C24 H 23 The calculated mass value of F3N6O2 is 484.2; the measured m / z value is 485.2 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.91 (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).

[0536] 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 .

[0537]

[0538] The title compound was prepared in a manner similar to Example 1 using 1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 23 The calculated mass value of F3N8O is 472.2; the measured m / z value is 473.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.11-7.78(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).

[0539] Example 16: (S)-(3-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-2,7-dimethyl-2,4,5,7-tetramethyl Hydrogen-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone .

[0540]

[0541] The title compound was prepared in a manner analogous to Example 1 using (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) 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): C 23 H 24 The calculated mass value of N6O2 is 416.2; the measured m / z value is 417.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.97 (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).

[0542] 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 .

[0543]

[0544] The title compound was prepared in a manner similar to Example 1 using potassium 4,6-difluoropyrazolo[1,5-a]pyridine-3-carboxylate (Intermediate 3) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 18 The calculated mass value of F5N7O is 479.2; the measured m / z value is 480.1 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ9.22-9.06 (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).

[0545] 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 .

[0546]

[0547] The title compound was prepared in a manner similar to Example 1 using lithium 5,7-difluoroquinoline-3-carboxylate (Intermediate 4) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 19 The calculated mass value of F5N6O is 490.15; the measured m / z value is 491.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.14-9.00 (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).

[0548] 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 .

[0549]

[0550] The title compound was prepared in a manner analogous to 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 4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 19 The calculated mass value of F4N7O is 461.2; the measured m / z value is 462.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.70 (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).

[0551] 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 .

[0552]

[0553] The title compound was prepared in a manner analogous to 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-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 23 The calculated mass value of F3N6O2 is 484.2; the measured m / z value is 485.1 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ7.92-7.79 (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).

[0554] 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 .

[0555]

[0556] The title compound was prepared in a manner similar to Example 1 using 7-fluoro-1-methyl-1H-indazole-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F4N7O is 475.2; the measured m / z value is 476.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.01 (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).

[0557] 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 .

[0558]

[0559] The title compound was prepared in a manner similar to Example 1 using 5-fluoro-1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F4N7O is 475.2; the measured m / z value is 476.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.86-7.62 (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).

[0560] 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 .

[0561]

[0562] The title compound was prepared in a manner similar to Example 1 using potassium 2-methyl-2H-indazole-4-carboxylate (Intermediate 5) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.1 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.33 (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).

[0563] 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 .

[0564]

[0565] The title compound was prepared in a manner similar to Example 1 using 7-fluoro-2-methylquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 487.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.35 (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).

[0566] 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 .

[0567]

[0568] The title compound was prepared in a manner similar to Example 1 using 2,6-dimethylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O is 482.2; the measured m / z value is 483.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90 (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).

[0569] 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 .

[0570]

[0571] The title compound was prepared in a manner similar to Example 1 using 6-methoxy-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O2 is 498.2; the measured m / z value is 499.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.92 (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).

[0572] 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 .

[0573]

[0574] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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 lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate (Intermediate 6) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 20 The calculated mass value of F5N7O is 494.2; the measured m / z value is 495.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.90-7.79 (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).

[0575] 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 .

[0576]

[0577] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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): C 21 H 18 The calculated mass value of F5N7O is 479.2; the measured m / z value is 480.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.85 (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).

[0578] 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 .

[0579]

[0580] The title compound was prepared in a manner similar to Example 1 using 2-(trifluoromethyl)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 19 The calculated mass value of F6N5O is 471.2; the measured m / z value is 472.1 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ7.87-7.46 (m, 4H), 7.18-6.94 (m, 1H), 5.76-5.42 (m, 1H), 4.66-4.30 (m, 1 H), 3.84-3.60(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).

[0581] 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 .

[0582]

[0583] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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-fluoro-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of F4N5O is 435.2; the measured m / z value is 436.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.84 (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).

[0584] 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 .

[0585]

[0586] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.21-8.09 (m, 1H), 7.99-7.76 (m, 2H), 7.44-7.15 (m, 2H), 5.92-5.50 (m, 1H), 4.86-4.3 8 (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).

[0587] 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 .

[0588]

[0589] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of F3N8O is 458.2; the measured m / z value is 459.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.66 (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).

[0590] 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 .

[0591]

[0592] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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): C 25 H 25 The calculated mass value of F3N6O is 482.2; the measured m / z value is 483.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.31 (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), 3.75-3.54 (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).

[0593] 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 .

[0594]

[0595] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 487.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ8.08 (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).

[0596] 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 .

[0597]

[0598] The title compound was prepared in a manner similar to Example 1 using 2-chloro-3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of ClF3N5O2 is 467.1; the measured m / z value is 468.1 [M+H] + . 1 HNMR (600MHz, CDCl3) δ7.37-7.21 (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), 3.60-3.50 (m, 0.70H), 3.41-3.20 (m, 0.69H), 3.15-2.98 (m, 0.43H), 2.87-2.68 (m, 0.6 6H), 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).

[0599] 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 .

[0600]

[0601] The title compound was prepared in a manner similar to Example 1 using 3-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 24The calculated mass value of F3N5O2 is 447.2; the measured m / z value is 448.2 [M+H] + . 1 HNMR (600MHz, CDCl3) δ7.26-7.13(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).

[0602] 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 .

[0603]

[0604] The title compound was prepared in a manner similar to Example 1 using 5-fluoro-2-(1H-pyrazol-1-yl)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 21 The calculated mass value of F4N7O is 487.2; the measured m / z value is 488.1 [M+H] + . 1 H NMR (600MHz, CDCl3) δ7.85-7.46(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).

[0605] 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 .

[0606]

[0607] The title compound was prepared in a manner similar to Example 1 using 3-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 22 The calculated mass value of F3N5O2 is 433.2; the measured m / z value is 434.1 [M+H] + . 1 H NMR (600MHz, CDCl3) δ7.33 (t, J=7.7Hz, 1H), 7.00-6.94 (m, 3H), 6.59 (d, J=0.6 Hz, 1H), 5.86 (brs, 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).

[0608] 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 .

[0609]

[0610] The title compound was prepared in a manner similar to Example 1 using 3-chloro-5-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of C1F3N5O2 is 467.1; the measured m / z value is 468.0 [M+H] + . 1 HNMR (600MHz, CDCl3) δ6.99-6.94 (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).

[0611] 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 .

[0612]

[0613] The title compound was prepared in a manner similar to Example 1 using 4-methoxy-2-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 24The calculated mass value of F3N5O2 is 447.2; the measured m / z value is 448.2 [M+H] + . 1 HNMR (600MHz, CDCl3) δ7.22-7.06(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).

[0614] 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 .

[0615]

[0616] The title compound was prepared in a manner similar to Example 1 using 2-methoxy-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 24 The calculated mass value of F3N5O2 is 447.2; the measured m / z value is 448.2 [M+H] + . 1 HNMR (600MHz, CDCl3) δ7.19-6.96 (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).

[0617] 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 .

[0618]

[0619] The title compound was prepared in a manner similar to Example 1 using 2-chloro-4-methoxybenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21The calculated mass value of ClF3N5O2 is 467.1; the measured m / z value is 468.1 [M+H] + . 1 HNMR (600MHz, CDCl3) δ7.30-7.18(m, 1H), 7.09-6.78(m, 2H), 6.62-6.57(m, 1 H), 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 , 0.77H), 2.27-2.20 (m, 0.62H), 1.65-1.59 (m, 1.83H), 1.43-1.39 (m, 0.81H).

[0620] 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 .

[0621]

[0622] The title compound was prepared in a manner similar to Example 1 using 3,4-dimethylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 24 The calculated mass value of F3N5O is 431.2; the measured m / z value is 432.1 [M+H] + . 1 H NMR (600MHz, CDCl3) δ7.20 (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).

[0623] 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 .

[0624]

[0625] The title compound was prepared in a manner similar to Example 1 using isoquinoline-1-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 21The calculated mass value of F3N6O is 454.2; the measured m / z value is 455.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.56-8.50 (m, 1H), 8.07-7.98 (m, 1H), 7.91-7.86 (m, 1H), 7.77-7.68 (m, 2H), 7.6 6-7.56 (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, 1 H), 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).

[0626] 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 .

[0627]

[0628] The title compound was prepared in a manner similar to Example 1 using 1-methyl-1H-indole-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 23 The calculated mass value of F3N6O is 456.2; the measured m / z value is 457.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.38 (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).

[0629] 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 .

[0630]

[0631] The title compound was prepared in a manner similar to Example 1 using 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 23 The calculated mass value of F3N6O is 457.2; the measured m / z value is 458.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.40 (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).

[0632] 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]pyridine - 4-Methyl) ketone .

[0633]

[0634] The title compound was prepared in a manner similar to 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): C 22 H 21 The calculated mass value of F4N7O is 475.2; the measured m / z value is 476.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.26 (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, 10H), 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).

[0635] 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 .

[0636]

[0637] The title compound was prepared in a manner analogous to 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): C 21 H 21 ClF3N s The calculated mass value of O2 is 467.1; the measured m / z value is 468.2 [M+H] + . 1 H NMR (600MHz, CDCl3) δ7.35-7.17(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, 0.61 H), 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).

[0638] 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 .

[0639]

[0640] The title compound was prepared in a manner analogous to 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): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.2 [M+H] + . 1 H NMR (600MHz, CDCl3) δ8.39 (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).

[0641] 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 .

[0642]

[0643] The title compound was prepared in a manner analogous to 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): C 23 H 23 The calculated mass value of F3N8O is 484.2; the measured m / z value is 485.3 [M+H] + . 1H NMR (600MHz, CDCl3) δ8.00-7.95 (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).

[0644] 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 .

[0645]

[0646] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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): C 21 H 21 ClF3N s The calculated mass value of O2 is 467.1; the measured m / z value is 468.1 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.50-7.44 (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),2.4 2-2.31 (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).

[0647] 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 .

[0648]

[0649] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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-pyrrolo[2,3-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ8.39 (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).

[0650] 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 .

[0651]

[0652] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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 using 3-methyl-5-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 26) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 23 The calculated mass value of F3N8O is 484.2; the measured m / z value is 485.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.00-7.93 (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).

[0653] Example 54: (S)-Chrom-8-yl (2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl) 2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0654]

[0655] 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): C 23 H 24 The calculated mass value of F3N5O2 is 459.2; the measured m / z value is 460.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.12-6.99(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, 8.88 H), 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).

[0656] Example 55: (S)-Chrom-7-yl (2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl) 2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0657]

[0658] 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): C 23 H 24 The calculated mass value of F3N5O2 is 459.2; the measured m / z value is 460.2 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ7.13 (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), 3.83-3.59 (m, 7H), 3.26-2.98 (m, 1H), 2.77 (t, J=6.4Hz, 2H), 2.6 4-2.56 (m, 1H), 2.38-2.22 (m, 1H), 1.98-1.88 (m, 2H), 1.53-1.36 (m, 3H).

[0659] Example 56: (S)-Benzo[d]thiazol-6-yl (2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrrolidone) oxazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0660]

[0661] 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): C 21 H 19 The calculated mass value of F3N6OS is 460.1; the measured m / z value is 461.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.10 (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).

[0662] Example 57: (S)-Benzo[d]thiazol-7-yl (2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrrolidone) oxazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0663]

[0664] 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): C 21 H 19 The calculated mass value of F3N6OS is 460.1; the measured m / z value is 461.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ9.07 (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).

[0665] 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 .

[0666]

[0667] 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): C 22 H 21 The calculated mass value of F3N6OS is 474.1; the measured m / z value is 475.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.98 (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).

[0668] Example 59: (S)-Benzo[d]thiazol-6-yl (2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrrolidone) oxazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0669]

[0670] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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): C 21H 19 The calculated mass value of F3N6OS is 460.1; the measured m / z value is 461.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.08 (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).

[0671] 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 .

[0672]

[0673] The title compound was prepared in a manner analogous to Example 1 using (S)-2,7-dimethyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-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-methoxy-3-methylisonicotinic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): C 21 H 23 The calculated mass value of F3N6O2 is 448.2; the measured m / z value is 449.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ8.11-7.96 (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, 0.45H), 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), 3.72-3.59 (m, 3H), 3.56-3.44 (m, 0.59H), 3.30-3.20 (m, 0.55H), 3.04 (td, J=12.7, 4.0Hz, 0.4 4H), 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).

[0674] Example 61: (S)-Chroman-7-yl (2,7-dimethyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl) 2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0675]

[0676] The title compound was prepared in a manner analogous to Example 1 using (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 (Intermediate 19) 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. DMF was used instead of DCM. MS (ESI): C 23 H 24 The calculated mass value of F3N5O2 is 459.2; the measured m / z value is 460.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.44-7.42(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, 2 H), 2.71-2.43(m, 1H), 2.38-2.17(m, 1H), 2.04-1.97(m, 2H), 1.64-1.44(m, 3H).

[0677] Example 62: (S)-(2,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4,5,7-tetrahydro-6H-pyrazole 6-(3,4-c)pyridin-6-yl)(quinolin-6-yl)methanone .

[0678]

[0679] 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-difluoromethanesulfonate. alkane (0.45mL). The headspace was evacuated under vacuum and refilled with N2 (×3), and the reaction was then stirred in a microwave reactor at 110°C for 30min. 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 (×2). 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 (7.3mg, 57% yield). MS (ESI): C 22 H 22 The calculated mass value of N6O is 386.2; the measured m / z value is 387.2 [M+H] + . 1HNMR (600MHz, CDCl3) δ8.98 (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).

[0680] Example 63: (S)-(2,7-dimethyl-3-(1-methyl-5-(trioxymethyl)-1H-pyrazol-3-yl)-2,4,5, 7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone .

[0681]

[0682] 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): C 23 H 21 The calculated mass value of F3N6O is 454.2; the measured m / z value is 455.1 [M+H] + . 1 H NMR (600MHz, CDCl3) δ8.98 (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).

[0683] 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 .

[0684]

[0685] The title compound was prepared in a manner similar to 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): C 22 H 19 The calculated mass value of F3N6O is 440.2; the measured m / z value is 441.2 [M+H] + . 1 H NMR (CDCl3, 500MHz): δ9.00 (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, 3 H), 3.37-3.17(m, 1H), 3.01-2.80(m, 1H), 2.58-2.38(m, 1H), 1.64(s, 3H).

[0686] 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 .

[0687]

[0688] The title compound was prepared in a manner similar to 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): C 23 H 21 The calculated mass value of F3N6O is 454.2; the measured m / z value is 455.2 [M+H] + . 1H NMR (DMSO-d6, 500MHz): δ8.91 (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).

[0689] Example 66: (S)-(3-(1-ethyl-1H-pyrazol-3-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazole 6-(3,4-c)pyridin-6-yl)(quinolin-6-yl)methanone .

[0690]

[0691] 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): C 23 H 24 The calculated mass value of N6O is 400.2; the measured m / z value is 401.2 [M+H] + . 1 H NMR (DMSO-d6, 500MHz): δ8.91 (d, J=3.8Hz, 1H), 8.36 (d, J=8.1Hz, 1H), 8.07 (d, J=8.6H z, 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).

[0692] 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 .

[0693]

[0694] 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): C 22 H 20 The calculated mass value of F2N6O is 422.2; the measured m / z value is 423.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.98-8.92(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).

[0695] Example 68: (S)-(3-(1-cyclopropyl-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetrahydro-6H-pyrazol-5-yl)- Oxazo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone .

[0696]

[0697] The title compound was prepared in a manner similar to 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): C 24 H 24 The calculated mass value of N6O is 412.2; the measured m / z value is 413.2 [M+H] + . 1HNMR (500MHz, MeOD) δ8.96-8.92 (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), 2.8 4-2.71 (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).

[0698] 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 .

[0699]

[0700] 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): C 22 H 20 F2N6 O The calculated mass value is 422.2; the measured m / z value is 423.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.01-8.95 (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).

[0701] 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 .

[0702]

[0703] The title compound was prepared in a manner similar to 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): C 26 H 23 The calculated mass value of N7O is 449.2; the measured m / z value is 450.2 [M+H] + . 1 HNMR (500MHz, CD3OD) δ8.97-8.93(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).

[0704] Example 71: (S)-(3-(1-(Cyclopropylmethyl)-1H-pyrazol-5-yl)-2,7-dimethyl-2,4,5,7-tetramethyl Hydrogen-6H-pyrazolo[3,4-c]pyridin-6-yl)(quinolin-6-yl)methanone .

[0705]

[0706] 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): C 25 H 26 The calculated mass value of N6O is 426.2; the measured m / z value is 427.2 [M+H] + . 1H NMR (500MHz, CD3OD) δ8.97-8.92 (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).

[0707] Example 72: ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexa Hydrogen-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)(2-fluoro-4-methylphenyl)methanone .

[0708]

[0709] The title compound was prepared in a manner similar to 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-cycloiminocyclooctane[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): C 23 H 26 The calculated mass value of FN5O is 407.2; the measured m / z value is 408.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.36-6.99 (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).

[0710] Example 73: ((5R,9S)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-2-methyl-4,5,6,7,8,9-hexa Hydrogen-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)(3-methoxy-2-methylphenyl)methanone .

[0711]

[0712] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 24 H 29 The calculated mass value of N5O2 is 419.2; the measured m / z value is 420.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.35-7.15 (m, 1H), 7.07-6.40 (m, 2H), 6.33-6.19 (m, 1H), 5.80 (s, 1H), 4.54-4.39 (m, 1H), 3.86-3.7 7(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).

[0713] Example 74: (3-methoxy-2-methylphenyl) ((5R,9S)-2-methyl-3-(1-methyl-3-(trimethyl)- 1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0714]

[0715] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 24 H 26 The calculated mass value of F3N5O2 is 473.2; the measured m / z value is 474.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.32-7.14 (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).

[0716] Example 75: Chroman-7-yl ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-yl)- 4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0717]

[0718] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 25 H 26 The calculated mass value of F3N5O2 is 485.2; the measured m / z value is 486.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.19-7.03 (m, 2H), 6.85-6.61 (m, 2H), 4.91 (d, J=34.2Hz, 1H), 4.22-3.99 (m, 3H), 3.79 (s, 3 H), 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).

[0719] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)(m-tolyl)methanone .

[0720]

[0721] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 23 H 24 The calculated mass of F3N5O is 443.2; the measured m / z is 444.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.43-7.02 (m, 5H), 5.80-5.56 (m, 1H), 5.04-4.73 (m, 1H), 3.8 0(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).

[0722] Example 77: (3-methoxy-5-methylphenyl) ((5R,9S)-2-methyl-3-(1-methyl-3-(trioxymethyl)- 1H-pyrazol-5-yl)-4,5,6,7,8,9-hexaoxo-2H-5,9-cycloiminocyclooctane[c]pyrazol-10-yl)methanone .

[0723]

[0724] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 24 H 26 The calculated mass value of F3N5O2 is 473.2; the measured m / z value is 474.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.16-7.06(m, 1H), 6.94-6.63(m, 3H), 5.78-5.62(m, 1H), 5.08-4.78(m, 1H ), 3.83-3.72(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).

[0725] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)(m-tolyl)methanone .

[0726]

[0727] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 24 H 26 The calculated mass value of F3N5O is 457.2; the measured m / z value is 458.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.45-6.98(m, 5H), 5.83-5.59(m, 1H), 5.08-4.76(m, 1H), 4.07-3.99(m, 2H ), 3.72-3.56(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).

[0728] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0729]

[0730] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 24 H 26 The calculated mass value of F3N5O2 is 473.2; the measured m / z value is 474.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.33-7.09 (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).

[0731] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)(quinolin-6-yl)methanone .

[0732]

[0733] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 25 H 23 The calculated mass value of F3N6O is 480.2; the measured m / z value is 481.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ9.04-8.86 (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) ), 5.91-5.59 (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).

[0734] Example 81: (5-Fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3- (trioxymethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexaoxo-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)methyl ketone .

[0735]

[0736] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 20 The calculated mass value of F4N8O is 488.2; the measured m / z value is 489.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.25-8.05 (m, 1H), 7.10 (s, 1H), 6.66-5.83 (m, 1H), 5.7 2-5.08 (m, 1H), 3.84-3.76 (m, 3H), 3.72-3.59 (m, 3H), 3.09-2.79 (m, 2H), 2.12-1.41 (m, 7H).

[0737] Example R2: (2-methyl-1,6-naphthyridin-5-yl) ((5R,9S)-2-methyl-3-(1-methyl-3-(=fluoromethyl) 1H-pyrazol-5-yl)-4,5,6,7,8,9-hexaoxo-2H-5,9-cycloiminocyclooctane[c]pyrazol-10-yl)methanone .

[0738]

[0739] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 potassium 2-methyl-1,6-naphthyridine-5-carboxylate (Intermediate 7) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 24 The calculated mass value of F3N7O is 495.2; the measured m / z value is 496.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.76-8.61 (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), 6.04-5.8 3(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).

[0740] Example 83: (5-Fluoroquinolin-3-yl)((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrrolidone) oxazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0741]

[0742] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 5-fluoroquinoline-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 22 The calculated mass value of F4N6O is 498.2; the measured m / z value is 499.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.06-8.87 (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).

[0743] Example 84: Benzo[d]iso Oxazol-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-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0744]

[0745] In a manner similar to Example 1, (5R,9S)-2-methyl-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[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 benzo[d]iso[3,4-d]pyridine was used. The title compound was prepared by replacing 2-methylquinoline-5-carboxylic acid with oxadiazole-3-carboxylic acid. MS (ESI): C 23 H 21 The calculated mass value of F3N6O2 is 470.2; the measured m / z value is 471.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.99-7.70 (m, 2H), 7.61-7.35 (m, 1H), 7.27-7.00 (m, 1H), 5.97-5.4 1 (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).

[0746] 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-cycloiminocyclooctyl[c]pyrazol-10-yl) Ketone .

[0747]

[0748] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 1-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 23 The calculated mass value of F3N8O is 484.2; the measured m / z value is 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).

[0749] Example 86: (5-Fluoro-1-methyl-1H-indazol-3-yl) ((5R,9S)-2-methyl-3-(1-methyl-3-(trifluoro methyl)-1H-pyrazol-5-yl)-4,5,6,7,8,9-hexahydro-2H-5,9-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0750]

[0751] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 5-fluoro-1-methyl-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 23 The calculated mass value of F4N7O is 501.2; the measured m / z value is 502.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.90-7.75 (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), 5.5 6-5.07 (m, 1H), 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).

[0752] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)(quinolin-6-yl)methanone .

[0753]

[0754] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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): C 25 H 23 The calculated mass value of F3N6O is 480.2; the measured m / z value is 481.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.05-8.91 (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, 1 H), 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).

[0755] 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-cycloiminocyclooctyl[c]pyrazol-10-yl)methanone .

[0756]

[0757] The title compound was prepared in a manner analogous to 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-cycloiminocyclooctane[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 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 26 H 24 The calculated mass value of F4N6O is 512.2; the measured m / z value is 513.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.07 (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).

[0758] 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-cycloiminocyclohepta[c]pyrazol-9-yl)methanone .

[0759]

[0760] The title compound was prepared in a manner analogous to 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-cycloiminocyclohepta[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): C 23 H 24 The calculated mass value of F3N5O2 is 459.2; the measured m / z value is 460.1 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ7.37-7.13(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 ), 4.47-4.28(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).

[0761] Examples 96-109, 111, 114-116, 119, 124-131, 136-138 are prophetic compounds that can be prepared according to the method:

[0762] 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 .

[0763]

[0764] The title compound was prepared in a manner similar to Example 1 using 5-fluoro-2-methylquinoline-6-carboxylic acid (Intermediate 27) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 487.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.36 (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, 1 H), 6.02-5.94 (m, 0.66H), 5.01 (dd, J=5.0, 13.1Hz, 0.41H), 4.91 (q, J=6.6Hz, 0.41H), 3.85-3.81 (m, 3H), 3.77 (s, 2H), 3.7 5-3.72(m, 0.54H), 3.70(s, 1H), 3.47-3.33(m, 0.70H), 3.21-3.10(m, 0.42H), 2.85-2.82(m, 0.24H), 2.81-2.79(m, 3H), 2. 78-2.75 (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).

[0765] 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 .

[0766]

[0767] The title compound was prepared in a manner similar to Example 1 using 7-fluoro-2-methylquinoline-6-carboxylic acid (Intermediate 28) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 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), 2.7 8-2.75 (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).

[0768] 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 .

[0769]

[0770] The title compound was prepared in a manner similar to Example 1 using 2,5-dimethylquinoline-6-carboxylic acid (Intermediate 29) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O is 482.2; the measured m / z value is 483.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.39-8.13(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), 6.09-5.98 (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).

[0771] 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 .

[0772]

[0773] The title compound was prepared in a manner similar to Example 1 using 2,7-dimethylquinoline-6-carboxylic acid (Intermediate 30) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O is 482.2; the measured m / z value is 483.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.08-7.95(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).

[0774] 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

[0775]

[0776] The title compound was prepared in a manner similar to Example 1 using 2,4-dimethylquinoline-6-carboxylic acid (Intermediate 31) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O is 482.2; the measured m / z value is 483.2 [M+H] + .

[0777] 1 H NMR (400MHz, CDCl3) δ8.13-8.02(m, 2H), 7.85-7.57(m, 1H), 7.21(s, 1H), 6.61(s, 1H), 6.15-5.72(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).

[0778] 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 .

[0779]

[0780] The title compound was prepared in a manner similar to Example 1 using 4-methoxy-2-methylquinoline-6-carboxylic acid (Intermediate 32) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O2 is 498.2; the measured m / z value is 499.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.50 (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).

[0781] 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 .

[0782]

[0783] The title compound can be prepared in a similar manner to Example 1 using 4-fluoro-2-methylquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2.

[0784] 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 .

[0785]

[0786] The title compound can be prepared in a similar manner to Example 1 using 2-methoxyquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 23 The calculated mass value of F3N6O2 is 484.2.

[0787] Example 98: (S)-(2,7-dimethyl-3-(1-methyl-3-(trimethyl)-1H-pyrazol-5-yl)-2,4,5- 7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(7-methoxy-2-methylquinolin-5-yl)methanone .

[0788]

[0789] The title compound can be prepared in a manner similar to 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 7-methoxy-2-methylquinoline-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O2 is 498.2.

[0790] 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 .

[0791]

[0792] The title compound can be prepared in a manner similar to 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 3-fluoro-8-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O2 is 502.2.

[0793] 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 .

[0794]

[0795] The title compound can be prepared in a manner similar to 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 3-fluoro-8-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2.

[0796] Example 101: (S)-(2,7-dimethyl-3-(1-methyl-3-(tricrylmethyl)-1H-pyrazol-5-yl)-2,4,5- 7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(8-fluoroisoquinolin-4-yl)methanone .

[0797]

[0798] The title compound can be prepared in a manner similar to 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 8-fluoroisoquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 23 H 20 The calculated mass value of F4N6O is 472.2.

[0799] 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 .

[0800]

[0801] The title compound can be prepared in a manner similar to 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 6-fluoro-2-methoxyquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 502.2.

[0802] 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 .

[0803]

[0804] The title compound can be prepared in a manner similar to 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 5-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 20 The calculated mass value of F4N8O is 502.2.

[0805] Example 104: (S)-(6-(Difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)(2,7-difluoromethyl Methyl-3-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine- 6-Methyl) ketone .

[0806]

[0807] The title compound can be prepared in a manner similar to 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 6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F5N8O is 508.2.

[0808] 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 .

[0809]

[0810] The title compound can be prepared in a similar manner to Example 1 using 1-methyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of F3N8O is 458.2.

[0811] 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 .

[0812]

[0813] The title compound can be prepared in a similar manner to Example 1 using 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 23 The calculated mass value of F3N8O is 472.2.

[0814] 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 .

[0815]

[0816] The title compound can be prepared in a similar manner to Example 1 using 1-methyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 21 The calculated mass value of F3N8O is 458.2.

[0817] 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 .

[0818]

[0819] The title compound can be prepared in a similar manner to Example 1 using 1,6-dimethyl-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 23 The calculated mass value of F3N8O is 472.2.

[0820] 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 .

[0821]

[0822] The title compound can be prepared in a similar manner to Example 1 using 4-methoxy-2-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F6N5O is 517.2.

[0823] 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 .

[0824]

[0825] The title compound was prepared in a manner similar to Example 1 using 4-methyl-2-(trifluoromethoxy)benzoic acid (Intermediate 33) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F6N5O2 is 501.2; the measured m / z value is 502.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.38-7.28(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, 0.42H), 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), 2.4 2 (s, 3H), 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).

[0826] 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 .

[0827]

[0828] The title compound can be prepared in a similar manner to Example 1 using 2-methyl-3-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F6N5O2 is 501.2.

[0829] 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 .

[0830]

[0831] The title compound was prepared in a manner similar to Example 1 using 2-fluoro-3-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 18 The calculated mass value of F7N5O2 is 505.1; the measured m / z value is 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).

[0832] Example 113: (S)-(2-chloro-4-(trifluoromethoxy)phenyl)(2,7-dimethyl-3-(1-methyl-3-(trifluoromethoxy)phenyl) methyl)-1H-pyrazol-5-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methanone .

[0833]

[0834] The title compound was prepared in a manner similar to Example 1 using 2-chloro-4-(trifluoromethoxy)benzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 18 The calculated mass value of ClF6N5O2 is 521.1; the measured m / z value is 522.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.44-7.28(m, 2H), 7.24-7.15(m, 1H), 6.64-6.58(m, 1H), 5.98-5.89(m, 0. 63H), 5.02-4.93(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).

[0835] 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 .

[0836]

[0837] The title compound can be prepared in a manner similar to 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 lithium 4,6-difluoro-1-methyl-1H-indazole-3-carboxylate (Intermediate 6) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 20 The calculated mass value of F5N7O is 494.2.

[0838] 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 .

[0839]

[0840] The title compound can be prepared in a manner similar to 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 4,6-difluoro-1H-indazole-3-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H 18 The calculated mass of F5N7O is 479.15

[0841] Example 116: (S)-(2,7-dimethyl-3-(1-methyl-5-(tricrylmethyl)-1H-pyrazol-3-yl)-2,4,5, 7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2-krypton-4-methylphenyl)methanone .

[0842]

[0843] The title compound can be prepared in a manner similar to 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-fluoro-4-methylbenzoic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 21 H21 The calculated mass value of F4N5O is 435.2.

[0844] 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 .

[0845]

[0846] The title compound was prepared in a manner analogous to 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): C 22 H 22 The calculated mass value of F3N7O is 457.2; the measured m / z value is 458.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.20-8.09 (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).

[0847] 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 .

[0848]

[0849] The title compound was prepared in a manner analogous to 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): C 21 H21 The calculated mass value of F3N8O is 458.2; the measured m / z value is 459.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.73-8.60 (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).

[0850] Example 119: (S)-(2,7-dimethyl-3-(1-methyl-5-(tricrylmethyl)-1H-pyrazol-3-yl)-2,4,5, 7-Tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)(2,8-dimethylquinolin-6-yl)methanone .

[0851]

[0852] The title compound can be prepared in a manner similar to 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 2,8-dimethylquinoline-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 25 H 25 The calculated mass value of F3N6O is 482.2.

[0853] 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 .

[0854]

[0855] The title compound was prepared in a manner analogous to 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 benzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): C 21 H 19The calculated mass value of F3N6OS is 460.1; the measured m / z value is 461.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ9.08 (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).

[0856] 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 .

[0857]

[0858] The title compound was prepared in a manner analogous to 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-methoxy-3-methylisonicotinic acid instead of 2-methylquinoline-5-carboxylic acid. DMF was used instead of DCM. MS (ESI): C 21 H 23 The calculated mass value of F3N6O2 is 448.2; the measured m / z value is 449.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ8.11-7.95 (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, 0.4 5H), 2.93-2.81(m, 0.47H), 2.76-2.49(m, 1.63H), 2.24-1.91(m, 3H), 1.57(s, 3H).

[0859] 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 .

[0860]

[0861] The title compound was prepared in a manner similar to Example 1 using thiazolo[4,5-c]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 The calculated mass value of H18F3N7OS is 461.1; the measured m / z value is 462.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.42-9.35 (m, 1H), 9.15 (s, 1H), 8.42-8.35 (m, 1H), 6.61-6.56 (m, 1H), 5 .91-5.83(m, 0.59H), 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, 3H), 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).

[0862] 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 .

[0863]

[0864] The title compound was prepared in a manner similar to Example 1 using thiazolo[4,5-b]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass value of F3N7OS is 461.1; the measured m / z value is 462.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.81 (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).

[0865] 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 .

[0866]

[0867] The title compound can be prepared in a manner similar to Example 1 using thiazolo[4,5-b]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0868] 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 .

[0869]

[0870] The title compound can be prepared in a manner similar to Example 1 using thiazolo[4,5-c]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0871] 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 .

[0872]

[0873] The title compound can be prepared in a manner similar to Example 1 using thiazolo[5,4-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0874] 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 .

[0875]

[0876] The title compound can be prepared in a manner similar to 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 thiazolo[4,5-c]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0877] 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 .

[0878]

[0879] The title compound can be prepared in a manner similar to 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 thiazolo[4,5-b]pyridine-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0880] 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 .

[0881]

[0882] The title compound can be prepared in a manner similar to 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 thiazolo[4,5-b]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0883] 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 .

[0884]

[0885] The title compound can be prepared in a manner similar to 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 thiazolo[4,5-c]pyridine-7-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0886] 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 .

[0887]

[0888] The title compound can be prepared in a manner similar to 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 thiazolo[5,4-c]pyridine-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 20 H 18 The calculated mass of F3N7OS is 461.1.

[0889] 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 .

[0890]

[0891] The title compound was prepared in a manner analogous to 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 6-fluoro-2-methylquinoline-4-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 24 H 22 The calculated mass value of F4N6O is 486.2; the measured m / z value is 487.2 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.08 (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).

[0892] 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 .

[0893]

[0894] The title compound was prepared in a manner similar to Example 1 using 7-methylbenzo[d]thiazole-6-carboxylic acid (Intermediate 34) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F3N6OS is 474.1; the measured m / z value is 475.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.07 (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, 0.4 1H), 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).

[0895] 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 .

[0896]

[0897] The title compound was prepared in a manner similar to 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): C 22 H 21 The calculated mass value of F3N6OS is 474.1; the measured m / z value is 475.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.05 (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, 13.4Hz, 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 ), 2.51-2.43 (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).

[0898] 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]oxazol-6-yl)methanone .

[0899]

[0900] The title compound was prepared in a manner similar to Example 1 using 4-methylbenzo[d]thiazole-6-carboxylic acid (Intermediate 36) instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass value of F3N6OS is 474.1; the measured m / z value is 475.3 [M+H] + . 1H NMR (400MHz, CDCl3) δ9.07 (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).

[0901] 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 .

[0902]

[0903] The title compound can be prepared in a manner analogous to 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 7-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass of F3N6OS is 474.1.

[0904] 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 .

[0905]

[0906] The title compound can be prepared in a manner analogous to 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 5-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass of F3N6OS is 474.1.

[0907] 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 .

[0908]

[0909] The title compound can be prepared in a manner analogous to 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 4-methylbenzo[d]thiazole-6-carboxylic acid instead of 2-methylquinoline-5-carboxylic acid. MS (ESI): C 22 H 21 The calculated mass of F3N6OS is 474.1.

[0910] Biological data

[0911] The assay used to measure the in vitro activity of MGL was adapted from an assay for another serine hydrolase (FAAH) described in 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). The assay involves combining endogenously expressed MGL from HeLa cells with the test compound, adding [glycerol-1,3- 3H]-oleoylglycerol, incubated for one hour, and then the cleavage of [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 the specific well / assay conditions.

[0912] The standard conditions for this assay are 300 nM [glycerol-1,3- 3 H]-oleoylglycerol was combined with human MGL from HeLa cells and the test compound for one hour, and then the reaction was filtered through activated charcoal and tritium in the flow-through was measured. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest compound concentration in the assay was determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0913] Table 6 .

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923] NT means not tested.

Claims

1. A compound of formula (I): in R 1a C 1-4 alkyl; R 1b is H; or R 1a and R 1b Combined to form -CH2CH2- or -CH2CH2CH2-; R 2 Selected from: (a) (b) a 5,6-fused or 6,5-fused heteroaryl group selected from the following: (c) a fused 6,6-heteroaryl selected from the group consisting of: as well as (d) and R 3 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 optionally substituted with halo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 Haloalkyl substitution; The prerequisite is that when R 2 are each optionally substituted with a halogenated group, a C 1-4 Alkyl or C 1-4 When phenyl or pyridyl is substituted with a haloalkyl group, then (a) R 1a and R 1b together to form -CH2CH2- or -CH2CH2CH2-; or (b) R 3 Not 1H-C 1-4 Alkyl-pyrazol-5-yl or 1H-C 1-4 Haloalkyl-pyrazol-5-yl in R a Selected from: H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl and OC 1-4 alkyl; R b Selected from: C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl, OC 1-4 Halogenated alkyl, Each R c Independently selected from: halo, C 1-4 Alkyl and OC 1-4 alkyl; R d H or C 1-4 alkyl; Each R e are independently halo, C 1-4 Alkyl or C 1-4 haloalkyl; and R h Selected from: H, C 1-4 Alkyl and C 1-4 Haloalkyl; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R 3 is a 5-membered heteroaryl ring selected from: Each R f Independently selected from: C 1-4 Alkyl, C 1-4 Haloalkyl and OC 1-4 alkyl; R g C 1-4 Alkyl or C 1-4 Halogenated alkyl.

3. The compound according to claim 1, wherein R 1a is CH3 and R 1b For H.

4. The compound according to claim 1, wherein R 1a and R 1b Together they form -CH2CH2- or -CH2CH2CH2-.

5. The compound according to claim 1, wherein R 2 for (a) Where R a H, Cl, F, C 1-4 Alkyl or C 1-4 haloalkyl; and R b C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 Alkyl or OC 1-4 haloalkyl; or (b) Where R a Cl, F or C 1-4 alkyl; and R b for 6. The compound according to claim 1, wherein R 2 for 7. The compound according to claim 5 or 6, wherein R 1a is CH3 and R 2 for Where R a is Cl or F, and R b For OC 1-4 alkyl.

8. The compound according to claim 1, wherein R 2 for: (a) (b) or (c) 9. The compound according to claim 1, wherein R 2 for Each R c are independently selected from: F, CH3 and OCH3; and m and n are each independently 0 or 1.

10. The compound according to claim 1, wherein (a) R 1a C 1-4 Alkyl or R 1a and R 1b together to form -CH2CH2CH2-; and (b) R 2 for 11. The compound according to claim 1 or claim 2, wherein R 3 for 12. The compound according to claim 2, wherein (a) m is 1 or 2; (b) n is 1 or 2; Or (c) m and n are each 1.

13. The compound according to claim 1, wherein the compound is selected from: (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]hept-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-cycloiminocyclooctane[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-cycloiminocyclooctyl[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctyl[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[c]pyrazol-10-yl)methanone; Benzo[d]iso Oxazol-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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclooctane[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-cycloiminocyclohepta[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 thereof.

14. The compound according to claim 1, wherein the compound is selected from: (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 thereof.

15. The compound according to claim 1, wherein the compound is selected from: and pharmaceutically acceptable salts thereof.

16. The compound according to claim 1, which has the structure of formula (IA): in R 2 Selected from: (a) (b) a 5,6-fused or 6,5-fused heteroaryl group selected from the following: (c) a fused 6,6-heteroaryl selected from the group consisting of: and (d) R 3 is a 5-membered heteroaryl ring selected from: in R a Selected from: H, Cl, F, C 1-4 Alkyl and C 1-4 Haloalkyl; R b Selected from: C 1-4 Alkyl, C 1-4 Halogenated alkyl, OC 1-4 alkyl, Each R c Independently selected from: halo, C 1-4 Alkyl and OCH3; R d is H or CH3; Each R e Independently for F, C 1-4 Alkyl or C 1-4 Haloalkyl; Each R f Independently selected from: C 1-4 Alkyl, C 1-4 haloalkyl and OCH3; and R g C 1-4 Alkyl or C 1-4 Haloalkyl; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein R 3 for 18. The compound according to claim 1, which has the structure of formula (IB): in n is 1 or 2; R 2 Selected from: (a) (b) (c) as well as (d) and R 3 for in R a is H, halo or C 1-4 Alkyl; and R b C 1-4 Alkyl or OC 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18, wherein n is 1.

20. A pharmaceutical composition, comprising: (A) a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (B) at least one pharmaceutically acceptable excipient.

21. Use of at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity.

22. The use according to claim 21, wherein the MGL receptor-mediated disease, disorder or condition is selected from: (a) pain, psychiatric disorders, neurological disorders, cancer and ocular disorders; (b) major depressive disorder, refractory depression, anxious depression, autism spectrum disorder, Asperger's syndrome and bipolar disorder; and (c) inflammatory pain.

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