Bicyclic heterocyclic compounds useful as monoacylglycerol lipase inhibitors

Abstract

The present invention provides new MAGL inhibitors having the general formula (II), wherein the variables are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds. TIFF2025503438000219.tif46161

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular monoacylglycerol lipase (MAGL) inhibitors useful for the treatment or prevention of MAGL-associated diseases or conditions, such as neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, inflammatory bowel syndrome, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, and / or visceral pain. [Background technology]

[0002] Endocannabinoids (ECs) are signaling lipids that exert their biological effects by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They regulate multiple physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA et al., Progress in lipid research 2016, 62, 107-28). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase MAGL. MAGL hydrolyzes 85% of 2-AG, while the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK et al., Science 2011, 334, 809). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, P.K. et al., Molecular Pharmacology 2010, 78, 996; Viader, A. et al., Cell Reports 2015, 12, 798). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes (LTs). AA oxidative metabolism is increased in inflamed tissues. Two major enzymatic pathways for arachidonic acid oxidation involved in the inflammatory process are cyclooxygenase, which produces PGs, and 5-lipoxygenase, which produces LTs. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, for example, in the cerebrospinal fluid of patients with neurodegenerative disorders, and are thought to contribute to the inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) exhibit a dramatic reduction in 2-AG hydrolase activity and a dramatic increase in 2-AG levels in the nervous system, whereas other arachidonoyl-containing phospholipids and neutral lipid species, including anandamide (AEA), and other free fatty acids, are unchanged.Conversely, levels of AA and AA-derived prostaglandins, as well as other eicosanoids including prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2), and thromboxane B2 (TXB2), are greatly reduced. Although the phospholipase A2 (PLA2) enzyme has been considered the major source of AA, cPLA2-deficient mice have unchanged AA levels in their brains, highlighting the importance of MAGL's role in regulating AA production and brain inflammatory processes.

[0003] Neuroinflammation is a common pathological feature of brain diseases, including, but not limited to, neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins regulates the neuroinflammatory process. The inflammatory progenitor lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is significantly blunted in Mgll- / - mice. LPS treatment also induces a widespread increase in inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), which are suppressed in Mgll- / - mice.

[0004] Neuroinflammation is characterized by the activation of innate immune cells in the central nervous system, microglia, and astrocytes. Anti-inflammatory drugs have been shown to suppress glial cell activation and disease progression in preclinical models, including Alzheimer's disease and multiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403). Importantly, genetic and / or pharmacological disruption of MAGL activity also inhibits LPS-induced microglial activation in the brain (Nomura, DK et al., Science 2011, 334, 809).

[0005] Furthermore, genetic and / or pharmacological disruption of MAGL activity has been shown to be protective in several animal models of neurodegeneration, including, but not limited to, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ et al., Nature Chemical Biology 2009, 5, 37). Systemic injection of such inhibitors recapitulates the Mgll- / - mouse phenotype in the brain, including increased 2-AG levels, decreased AA levels and related eicosanoid production, and suppression of cytokine production and microglial activation after LPS-induced neuroinflammation (Nomura, DK et al., Science 2011, 334, 809), confirming MAGL as a druggable target.

[0006] Following genetic and / or pharmacological disruption of MAGL activity, endogenous levels of 2-AG, a natural MAGL substrate, increase in the brain. 2-AG has been reported to have beneficial effects, for example, on pain-induced antinociception in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424) and on psychiatric disorders such as depression in chronic stress models (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763).

[0007] Furthermore, oligodendrocytes (OLs), myelinating cells in the central nervous system, and their precursors (OPCs) express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for both CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate the vulnerability of OLs and OPCs to excitotoxic injury and may therefore be neuroprotective (Bernal-Chico, A. et al., Glia 2015, 63, 163). Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the mouse brain, suggesting that MAGL inhibition may promote OPC differentiation into myelinating OLs in vivo (Alpar, A. et al., Nature Communications 2014, 5, 4421). Inhibition of MAGL has also been shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al., Journal of Neuroscience 2017, 37(35), 8385.).

[0008] Furthermore, metabolism, especially lipid metabolism, has recently been given great importance in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have shown that endocannabinoids have antitumor effects, including antiproliferative, apoptosis-inducing, and anti-metastatic effects. MAGL, as a key degradative enzyme for both lipid metabolism and the endocannabinoid system, further contributes to various aspects of tumorigenesis, including glioblastoma, as part of gene expression profiles (Qin, H. et al., Cell Biochem. Biophys. 2014, 70, 33; Nomura DK et al., Cell 2009, 140(1), 49-61; Nomura DK et al., Chem. Biol. 2011, 18(7), 846-856; Jinlong Yin et al., Nature Communications 2020, 11, 2978).

[0009] The endocannabinoid system is also involved in many gastrointestinal physiological and physiopathological functions (Marquez, Suarez, et al. 2009). All of these effects are primarily driven through cannabinoid receptors (CB1 and CB2). CB1 receptors are present throughout the gastrointestinal tract in animals and healthy humans, particularly in the enteric nervous system (ENS) and epithelial lining, as well as in smooth muscle cells of blood vessels in the colon wall (Wright, Rooney, et al. 2005, Duncan, Davison, et al. 2005). CB1 activation provides antiemetic, antimotility, and anti-inflammatory effects and helps regulate pain (Perisetti, Rimu, et al. 2020). CB2 receptors are expressed in immune cells such as plasma cells and macrophages, the lamina propria of the gastrointestinal tract (Wright, Rooney, et al. 2005), and the epithelium of human colonic tissue, primarily associated with inflammatory bowel disease (IBD). CB2 activation exerts anti-inflammatory effects by reducing pro-inflammatory cytokines. MAGL expression is increased in colonic tissues of UC patients (Marquez, Suarez, et al. 2009), and 2-AG levels are increased in the plasma of IBD patients (Grill, Hogenauer, et al. 2019). Several animal studies have demonstrated the potential of MAGL inhibitors for the symptomatic treatment of IBD. MAGL inhibition prevents TNBS-induced murine colitis and reduces local and circulating inflammatory markers via CB1 / CB2 MoA (Marquez, Suarez, et al. 2009). Furthermore, MAGL inhibition improves intestinal wall integrity and intestinal permeability via CB1-driven MoA (Wang, Zhang, et al. 2020).

[0010] In conclusion, inhibiting the action and / or activation of MAGL represents a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and psychiatric disorders.

[0011] WO2020065613 discloses certain MAGL inhibitors. However, although these MAGL inhibitors have properties that may make them suitable for the treatment of CNS indications such as depression and pain, they lack some properties (e.g., high passive permeability, P app) means that it is less suitable for indications that require, or at least benefit from, achieving higher exposure in the target tissue than in the rest of the body, such as inflammatory bowel disease. Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, there remains a high unmet medical need for novel MAGL inhibitors, especially those with different properties such that different exposures can be achieved in different tissues. [Means for solving the problem]

[0013] Surprisingly, starting from the compounds disclosed in WO2020065613, a number of chemical modifications have been made to improve passive permeability (P) while maintaining high cellular potency and excellent overall drug-like properties. app ) was able to be significantly reduced.

[0014] In a first aspect, the present invention provides a compound of formula (II) [ka] wherein the variables are as defined herein.

[0015] In further aspects, the invention provides pharmaceutical compositions comprising the compounds, methods for preparing the compounds, and methods of using the compounds in the treatment or prevention of diseases and disorders associated with MAGL. DETAILED DESCRIPTION OF THE INVENTION

[0016] definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0017] X is NR 9 and Y is C, the compound of formula (II) described herein can be represented by the formula (I) [ka] It is expressed by:

[0018] X is CR 9 and Y is N, the compound of formula (II) described herein can be represented by formula (IIa) [ka] It is expressed by:

[0019] Compounds of formula (II) described herein, where X and Y are both N, can be represented by the formula (IIb) [ka] It is expressed by:

[0020] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting, examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0021] The term "alkoxy" refers to an alkyl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. An alkoxy group contains 1 to 12 carbon atoms, unless otherwise specified. In some preferred embodiments, an alkoxy group contains 1 to 6 carbon atoms ("C 1-6 In other embodiments, alkoxy groups contain 1 to 4 carbon atoms. In still other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0022] The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by an alkoxy group. Preferably, "alkoxyalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by an alkoxy group. A particularly preferred, but non-limiting example of an alkoxyalkyl is 2-methoxyethyl.

[0023] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0024] The term "hydroxy" refers to the group --OH.

[0025] The term "carbamoyl" refers to the group -C(O)NH2.

[0026] The term "alkylsulfonimidoyl" refers to a group where R is alkyl. [ka] Refers to...

[0027] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, but non-limiting, example of cycloalkyl is cyclopropyl.

[0028] The term "triazolyl" is understood to include all possible substitutions of the three nitrogen atoms in the five-membered heteroaromatic ring. In particular, "triazolyl" includes 2H-triazol-4-yl, 1H-1,2,4-triazolyl, 1H-triazolyl and 4H-1,2,4-triazolyl.

[0029] The term "halocycloalkyl" refers to a cycloalkyl group in which at least one of the cycloalkyl group's hydrogen atoms has been replaced with a halogen atom, preferably fluoro. Preferably, "halocycloalkyl" refers to a cycloalkyl group in which one, two, or three of the cycloalkyl group's hydrogen atoms have been replaced with a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting, examples of halocycloalkyl are 2-fluorocyclopropyl and 2,2-difluorocyclopropyl.

[0030] The term "cyano" refers to a -CN (nitrile) group.

[0031] The term "oxo" refers to the group =O.

[0032] The term "(halo)alkylsulfonimidoyl" refers to the group [ka] Refers to...

[0033] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0034] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by hydroxy groups. A particularly preferred, but non-limiting example of a hydroxyalkyl is 1-hydroxyethyl.

[0035] The term "carbamoylalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms is replaced by a carbamoyl group. Preferably, "carbamoylalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms are replaced by a carbamoyl group. A particularly preferred, but non-limiting, example of a carbamoylalkyl is 2-amino-2-oxo-ethyl.

[0036] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

[0037] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0038] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0039] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0040] The term "treatment," as used herein, includes: (1) suppressing the symptom, disorder, or condition (e.g., in the case of maintenance treatment, arresting, reducing, or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof), and / or (2) alleviating the condition (i.e., causing regression of the symptom, disorder, or condition, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or physician. However, it will be understood that when a patient is administered a medication to treat a disease, the outcome need not necessarily be effective treatment.

[0041] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical symptoms or asymptomatic symptoms of the condition, disorder or condition.

[0042] The term "neuroinflammation," as used herein, refers to acute and chronic inflammation of nervous tissue, which is a major tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after central nervous system injury, for example, as a result of traumatic brain injury (TBI).

[0043] The term "traumatic brain injury" (also known as "TBI," "intracranial injury") relates to damage to the brain resulting from an external mechanical force such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0044] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0045] The term "mental disorder" (also called mental illness or mental disorder) relates to a behavioral or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0046] The term "pain" relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain. A particular example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0047] The term "neurotoxicity" relates to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, drug therapy, drug abuse, and organ transplants, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0048] The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0049] The term "mammal," as used herein, includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0050] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (II) [ka] (In the formula, L 1 is selected from a covalent bond, NHCH2, and CH2NH; R 8 is C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, (a) X is NR 9 and Y is C, (i) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 is based [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or (ii) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from phenyl and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 is based [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from cyano and hydroxy; R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (iii) A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 is based [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (iv) A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is hydroxy, carbamoyl-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 is based [ka] and R 6is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (b) X is CR 9 or N, and Y is N; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; A is selected from furanyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from triazolyl, imidazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, piperidine, piperazine, pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; R 1 is halogen, hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, C3-C 10-cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 and R 4 are each independently selected from absent or hydrogen, halogen, and cyano; R 5 is C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 8 is C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl), or a pharmaceutically acceptable salt thereof.

[0051] In a preferred embodiment, the invention comprises: X is NR 9 and Y is C, or X is CR 9 or N, and Y is N; L 1 is selected from a covalent bond, NHCH2, and CH2NH; R 8 C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, (i) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or (ii) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from phenyl and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from cyano and hydroxy; R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (iii) A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (iv) A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is hydroxy, carbamoyl-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the present invention provides X is CR 9 or N, Y is N, L 1 is selected from a covalent bond, NHCH2, and CH2NH; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; A is selected from furanyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from triazolyl, imidazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, piperidine, piperazine, pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; R 1 is halogen, hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, C3-C 10-cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 and R 4 are each independently selected from absent or hydrogen, halogen, and cyano; R 5 is C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 8 C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0053] In a particularly preferred embodiment, the present invention provides a compound in which X is NR 9 and Y is C, [ka] or a pharmaceutically acceptable salt thereof.

[0054] In one embodiment, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, wherein X is CR 9 and Y is N, [ka] or a pharmaceutically acceptable salt thereof. In one embodiment, the present invention provides a compound of formula (IIb) wherein X and Y are both N. [ka] or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the present invention provides (i) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or (ii) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from phenyl and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from cyano and hydroxy; R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention provides (i) A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or (ii) A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is hydroxy, carbamoyl-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, the present invention provides A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the present invention provides A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from phenyl and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from cyano and hydroxy; R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the present invention provides A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the present invention provides A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R 1is hydroxy, carbamoyl-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from absent or hydrogen, halogen, cyano, and C1-C6-alkyl; R 5 Based on [ka] and R 6 is selected from hydrogen, halogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkoxy, and halo-C-C-alkoxy, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11is selected from hydrogen, hydroxy and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the present invention provides (i)L 2 is selected from a covalent bond, OCH2, CH2O, NHCH2, CH2CH2; A is phenyl; B is selected from phenyl, pyridyl, triazolyl, and imidazolyl; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen or halogen, R 4 is hydrogen or halogen, R 5 Based on [ka] and R 6 is halogen or C1-C6 alkyl; R 7 is hydrogen or halogen, R 10 is selected from hydrogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkyl-SO-, oxo, hydroxy and cyano, R 11 is selected from hydrogen, C1-C6-alkyl, oxo, or (ii)L 2 is a covalent bond, A is phenyl; B is triazolyl or phenyl; C is pyridyl or phenyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen or halogen, R 7 is hydrogen, R 10 is hydroxy or cyano; R 11 is hydrogen or halogen, or (iii)L 2 is CH2 or CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen or halogen, R 7 is hydrogen or halogen, R 10 is hydrogen, R 11is hydrogen, or (iv) A is selected from pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is phenyl; R 1 is halo-C1-C6-alkyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is C1-C6-alkoxy, R 6 is a halogen, R 7 is hydrogen, or (v)L 2 is a covalent bond, A is pyridyl or phenyl; B is phenyl, triazolyl; C is triazolyl, pyrazolyl, or pyridyl; R 1 is hydroxy, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-SO2-NH-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, carbamoyl-C1-C6-alkyl, NH2SO2-, C3-C 10 -cycloalkyl, and the C3-C 10 -cycloalkyl is optionally substituted by one substituent selected from carbamoyl and C1-C6-alkyl-SO2-NH-, R 2 are hydrogen and halogens, R 3 is hydrogen, R 4 is hydrogen, R 5 is C1-C6-alkoxy or a group [ka] and R 6 is a halogen, R 7 is hydrogen or halogen, R 10 is hydrogen, hydroxy, R 11 is hydrogen, halogen, or (vi)L 2 is a covalent bond, A is pyrazinyl, B is phenyl or triazolyl; C is selected from azetidinyl, 1,2-dihydropyridine, pyrrolyl, and 2-thia-6-azaspiro[3.3]heptane; R 1 is halo-C1-C6-alkyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is selected from NH2SO2-, cyano and oxo; R 11 is hydrogen or oxo, or (vii)L 2 is selected from a covalent bond, CH2O, and CH2CH2; A is phenyl; B is phenyl or triazolyl; C is selected from 1,2-dihydropyridine, pyrrolidinyl, pyrrolyl, 2-thia-6-azaspiro[3.3]heptane, and triazolyl; R 1 NH2SO2-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C3-C 10 -cycloalkyl, wherein the C3-C 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is oxo or cyano, R 11 is hydrogen or oxo, or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the present invention provides L 2 is selected from a covalent bond, OCH2, CH2O, NHCH2, CH2CH2; A is phenyl; B is selected from phenyl, pyridyl, triazolyl, and imidazolyl; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen or halogen, R 4 is hydrogen or halogen, R 5 Based on [ka] and R 6 is halogen or C1-C6 alkyl; R 7 is hydrogen or halogen, R 10 is selected from hydrogen, C-C-alkyl, halo-C-C-alkyl, C-C-alkyl-SO-, oxo, hydroxy and cyano, R 11 is selected from hydrogen, C1-C6-alkyl, oxo, or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment, the present invention provides L 2 is a covalent bond, A is phenyl; B is triazolyl or phenyl; C is pyridyl or phenyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4is hydrogen, R 5 Based on [ka] and R 6 is hydrogen or halogen, R 7 is hydrogen, R 10 is hydroxy or cyano; R 11 is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the present invention provides L 2 is CH2 or CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen or halogen, R 7 is hydrogen or halogen, R 10 is hydrogen, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the present invention provides A is selected from pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is phenyl; R 1 is halo-C1-C6-alkyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 is C1-C6-alkoxy, R 6 is a halogen, R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, the present invention provides L 2 is a covalent bond, A is pyridyl or phenyl; B is phenyl, triazolyl; C is triazolyl, pyrazolyl, or pyridyl; R 1 is hydroxy, hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-SO2-NH-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, carbamoyl-C1-C6-alkyl, NH2SO2-, C3-C 10 -cycloalkyl, and the C3-C 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl and C-C-alkyl-SO-NH-, R 2 are hydrogen and halogens, R 3 is hydrogen, R 4 is hydrogen, R5 is C1-C6-alkoxy or a group [ka] and R 6 is a halogen, R 7 is hydrogen or halogen, R 10 is hydrogen, hydroxy, R 11 is hydrogen, halogen, or a pharmaceutically acceptable salt thereof.

[0067] In one embodiment, the present invention provides L 2 is a covalent bond, A is pyrazinyl, B is phenyl or triazolyl; C is selected from azetidinyl, 1,2-dihydropyridine, pyrrolyl, and 2-thia-6-azaspiro[3.3]heptane; R 1 is halo-C1-C6-alkyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is selected from NH2SO2-, cyano and oxo; R 11 is hydrogen or oxo, or a pharmaceutically acceptable salt thereof.

[0068] In one embodiment, the present invention provides L 2 is selected from a covalent bond, CH2O, and CH2CH2; A is phenyl; B is phenyl or triazolyl; C is selected from 1,2-dihydropyridine, pyrrolidinyl, pyrrolyl, 2-thia-6-azaspiro[3.3]heptane, and triazolyl; R 1 NH2SO2-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C3-C 10 -cycloalkyl, wherein the C3-C 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is oxo or cyano, R 11 is hydrogen or oxo, or a pharmaceutically acceptable salt thereof.

[0069] In a preferred embodiment, the present invention comprises: (i)L 2 is selected from a covalent bond, CH2O, and NHCH2; A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is oxo, R 11 is hydrogen, or (ii)L 2 is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen, R 7 does not exist, R 10 is hydroxy, R 11 is hydrogen or halogen, or (iii)L 2is CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is hydrogen, R 11 is hydrogen, or (iv)L 2 is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R 1 C3-C 10 -cycloalkyl, and the C3-C 10 -cycloalkyl is substituted by one C1-C6-alkyl-SO2-NH- substituent, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7is a halogen, R 10 is cyano, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0070] In a preferred embodiment, the present invention comprises: L 2 is selected from a covalent bond, CHO, and NHCH; A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is oxo, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0071] In a preferred embodiment, the present invention comprises: L 2 is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen, R 7 does not exist, R 10 is hydroxy, R 11 is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0072] In a preferred embodiment, the present invention comprises: L 2 is CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is a halogen, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is hydrogen, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0073] In a preferred embodiment, the present invention comprises: L 2 is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R 1 C3-C 10 -cycloalkyl, and the C3-C 10 -cycloalkyl is substituted by one C1-C6-alkyl-SO2-NH- substituent, R 2 is a halogen, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is a halogen, R 7 is a halogen, R 10 is cyano, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0074] In a particularly preferred embodiment, the present invention comprises: (i)L 2 is selected from a covalent bond, CH2O, and NHCH2; A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R 1 is fluoro, R 2 is fluoro, R 3 is hydrogen, R 4is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is oxo, R 11 is hydrogen, or (ii)L 2 is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R 1 is fluoro, R 2 is fluoro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen, R 7 does not exist, R 10 is hydroxy, R 11 is hydrogen or chloro, or (iii)L 2 is CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is fluoro, R 2 is fluoro, R 3is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is hydrogen, R 11 is hydrogen, or (iv)L 2 is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R 1 is cyclopropyl, which is substituted with one methyl-SO2-NH- substituent; R 2 is chloro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is cyano, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0075] In a particularly preferred embodiment, the present invention comprises: L 2 is selected from a covalent bond, CH2O, and NHCH2; A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R 1 is fluoro, R 2 is fluoro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is oxo, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0076] In a particularly preferred embodiment, the present invention comprises: L 2 is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R 1 is fluoro, R 2 is fluoro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is hydrogen, R 7does not exist, R 10 is hydroxy, R 11 is hydrogen or chloro; or a pharmaceutically acceptable salt thereof.

[0077] In a particularly preferred embodiment, the present invention comprises: L 2 is CH2CH2, A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R 1 is fluoro, R 2 is fluoro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is hydrogen, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0078] In a particularly preferred embodiment, the present invention comprises: L 2 is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R 1 is cyclopropyl, which is substituted with one methyl-SO2-NH- substituent; R 2 is chloro, R 3 is hydrogen, R 4 is hydrogen, R 5 Based on [ka] and R 6 is fluoro, R 7 is chloro, R 10 is cyano, R 11 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0079] In a preferred embodiment, the present invention provides L 1 is selected from a covalent bond and NHCH2, or a pharmaceutically acceptable salt thereof.

[0080] In a preferred embodiment, the present invention provides L 1 is NHCH2, or a pharmaceutically acceptable salt thereof.

[0081] In a particularly preferred embodiment, the present invention provides 1 is a covalent bond, or a pharmaceutically acceptable salt thereof.

[0082] In a preferred embodiment, the present invention provides R 8 is C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0083] In a particularly preferred embodiment, the present invention provides 8 is methyl, or a pharmaceutically acceptable salt thereof.

[0084] In a preferred embodiment, the present invention provides R 9 is C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0085] In a particularly preferred embodiment, the present invention provides 9 is methyl, or a pharmaceutically acceptable salt thereof.

[0086] In one embodiment, the present invention provides L 2 is selected from a covalent bond, CH2O, OCH2, CH2NH, NHCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; A is selected from furanyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from triazolyl, imidazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, piperidine, piperazine, pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; R 1 is halogen, hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, C3-C 10-cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-PO2-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl may be substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 and R 4 are each independently selected from absent or hydrogen, halogen, and cyano; R 5 C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 8 C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present invention provides a compound wherein A is (i) [ka] and R 1 is halo-C1-C6-alkyl, or (ii) cyclopropyl, where R 1 is halo-C1-C6-alkyl and R 2 , R 3 and R 4 are all hydrogen, or (iii) phenyl, and R 1 but halogen, carbamoyl-C1-C6-alkyl, C3-C 10 -cycloalkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy, NH2SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, C1-C6-alkyl-SO2-NH-C1-C6-alkyl-, hydroxy-C1-C6-alkyl and (C1-C6-alkyl)2-PO-C1-C6-alkyl-, and C3-C 10 -cycloalkyl is substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from hydrogen and halogen; or (iv) pyrazinyl, where R 1is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 does not exist, or (v) pyridyl, and R 1 is selected from hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl-SO2- and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; R 2 is selected from hydrogen and halogen, and R 3 and R 4 are both hydrogen; or (vi) pyrimidinyl, and R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 The present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0088] In one embodiment, the present invention provides a method for producing a compound comprising the steps of: [ka] or a pharmaceutically acceptable salt thereof. [ka]

[0089] In a preferred embodiment, the present invention comprises: A is phenyl; R 1 is halogen or C3-C substituted by one C1-C6-alkyl-SO2-NH- substituent 10 -cycloalkyl, R 2 is a halogen, R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0090] In a particularly preferred embodiment, the present invention comprises: A is phenyl; R 1 is fluoro or cyclopropyl substituted with one methyl-SO2-NH- substituent; R 2 is fluoro or chloro, R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0091] In one embodiment, the present invention provides B is selected from triazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, pyridyl, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; L 2 is selected from a covalent bond, CH2O, CH2, NHCH2, and CH2CH2; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11is selected from hydrogen, hydroxy and oxo, or a pharmaceutically acceptable salt thereof.

[0092] In one embodiment, the present invention provides a method for producing a compound comprising the steps of: [ka] or a pharmaceutically acceptable salt thereof. [ka] TIFF2025503438000065.tif196165

[0093] In a preferred embodiment, the present invention comprises: B is selected from triazolyl and phenyl; C is selected from imidazolidine, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyridyl, 1,2-dihydropyridine, and oxazolidine; L 2 is selected from a covalent bond, CH2O, NHCH2, and CH2CH2; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen and halogen; R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, halogen, cyano and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0094] In a particularly preferred embodiment, the present invention comprises: B is selected from triazolyl and phenyl; C is selected from imidazolidine, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyridyl, 1,2-dihydropyridine, and oxazolidine; L 2 is selected from a covalent bond, CH2O, NHCH2, and CH2CH2; R 5 However, methoxy and groups [ka] is selected from R 6 is selected from hydrogen and fluoro; R 7 is selected from hydrogen and chloro; R 10 is selected from hydrogen, chloro, cyano and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, the present invention provides X is NR 9 and Y is C, or X is CR 9 or N, Y is N, L 1 is selected from a covalent bond and NHCH; L 2 is selected from a covalent bond, CH2O, CH2, NHCH2, and CH2CH2; A is (i) [ka] and R 1 is halo-C1-C6-alkyl and R 2 , R 3 and R4 are not all present, or (ii) cyclopropyl, where R 1 is halo-C1-C6-alkyl and R 2 , R 3 and R 4 are all hydrogen, or (iii) phenyl, and R 1 but halogen, carbamoyl-C1-C6-alkyl, C3-C 10 -cycloalkyl, C1-C6-alkoxy-C1-C6-alkoxy, NH2SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, C1-C6-alkyl-SO2-NH-C1-C6-alkyl-, hydroxy-C1-C6-alkyl, and (C1-C6-alkyl)2-PO-C1-C6-alkyl-; 10 -cycloalkyl is substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 , R 3 , and R 4 are each independently selected from hydrogen and halogen; or (iv) pyrazinyl, where R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 does not exist, or (v) pyridyl, and R 1 is selected from hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl-SO2- and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; R 2 is selected from hydrogen and halogen, and R 3 and R 4 are both hydrogen; or (vi) pyrimidinyl, and R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R4 does not exist, B is selected from triazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, pyridyl, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 8 and R 9 are all C1-C6-alkyl, R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and oxo, or a pharmaceutically acceptable salt thereof.

[0096] In a preferred embodiment, the present invention comprises: X is NR 9 and Y is C, L 1 is a covalent bond, L 2 is selected from a covalent bond, CH2O, NHCH2, and CH2CH2; A is phenyl; B is selected from triazolyl and phenyl; C is selected from imidazolidine, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyridyl, 1,2-dihydropyridine, and oxazolidine; R 1 is halogen or C3-C substituted by one C1-C6-alkyl-SO2-NH- substituent 10 -cycloalkyl, R 2 is a halogen, R 3 and R 4 are all hydrogen, R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen and halogen; R 7 is selected from hydrogen and halogen; R 8 and R 9 are all C1-C6-alkyl, R 10 is selected from hydrogen, halogen, cyano and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0097] In a particularly preferred embodiment, the present invention comprises: X is NR 9 and Y is C, L 1 is a covalent bond, L 2 is selected from a covalent bond, CH2O, NHCH2, and CH2CH2; A is phenyl; B is selected from triazolyl and phenyl; C is selected from imidazolidine, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyridyl, 1,2-dihydropyridine, and oxazolidine; R 1 is fluoro or cyclopropyl substituted with one methyl-SO2-NH- substituent; R 2 is fluoro or chloro, R 3 and R 4 are all hydrogen, R 5 However, methoxy and groups [ka] is selected from R 6 is selected from hydrogen and fluoro; R 7 is selected from hydrogen and chloro; R 8 and R 9 are all methyl, R 10 is selected from hydrogen, chloro, cyano and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the present invention provides a method for producing a compound comprising: 1 is selected from a covalent bond and NHCH2, or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the present invention provides a method for producing a compound comprising: 2 is selected from a covalent bond, CH2O, CH2, NHCH2, and CH2CH2, or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment, the present invention provides a compound in which A is [ka] or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is cyclopropyl.

[0102] In a particularly preferred embodiment, the present invention provides compounds of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

[0103] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyrazinyl.

[0104] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyridyl.

[0105] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is pyrimidinyl.

[0106] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from triazolyl, phenyl, and pyridyl.

[0107] In one embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is selected from azetidine, cyclopropyl, pyridyl, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl.

[0108] In one embodiment, the present invention provides a compound comprising R 5 C1-C6-alkoxy and groups [ka] or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the present invention provides a compound comprising R 6 is selected from hydrogen, halogen and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0110] In one embodiment, the present invention provides a compound comprising R 7 is selected from hydrogen and halogen, or a pharmaceutically acceptable salt thereof.

[0111] In one embodiment, the present invention provides a compound comprising R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C1-C6-alkyl-SO2-, NH2SO2- and halo-C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0112] In one embodiment, the present invention provides a compound comprising R 11 is selected from hydrogen, hydroxy and oxo, or a pharmaceutically acceptable salt thereof.

[0113] In a preferred embodiment, the present invention provides L 2 is selected from a covalent bond, CH2O, NHCH2, and CH2CH2, or a pharmaceutically acceptable salt thereof.

[0114] In a preferred embodiment, the present invention provides compounds of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from triazolyl and phenyl.

[0115] In a preferred embodiment, the present invention provides compounds of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is triazolyl.

[0116] In a particularly preferred embodiment, the present invention provides compounds of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is phenyl.

[0117] In a preferred embodiment, the present invention provides compounds of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is selected from imidazolidine, triazolyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyridyl, 1,2-dihydropyridine, and oxazolidine.

[0118] In a preferred embodiment, the present invention provides R 1 is halogen or C3-C substituted by one C1-C6-alkyl-SO2-NH- substituent 10 or a pharmaceutically acceptable salt thereof.

[0119] In a preferred embodiment, the present invention provides R 2 is a halogen; or a pharmaceutically acceptable salt thereof.

[0120] In a preferred embodiment, the present invention provides R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0121] In a preferred embodiment, the present invention provides R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0122] In a preferred embodiment, the present invention provides R 5 C1-C6-alkoxy and groups [ka] Selected from C, L 2 , R 10 , and R 11 or a pharmaceutically acceptable salt thereof.

[0123] In a preferred embodiment, the present invention provides R 5 is C1-C6-alkoxy; or a pharmaceutically acceptable salt thereof.

[0124] In a particularly preferred embodiment, the present invention provides 5 Based on [ka] and C, L 2 , R 10 and R 11 or a pharmaceutically acceptable salt thereof.

[0125] In a preferred embodiment, the present invention provides R 6 is selected from hydrogen and halogen, or a pharmaceutically acceptable salt thereof.

[0126] In a preferred embodiment, the present invention provides R 7 is selected from hydrogen and halogen, or a pharmaceutically acceptable salt thereof.

[0127] In a preferred embodiment, the present invention provides R 10is selected from hydrogen, halogen, cyano and oxo, or a pharmaceutically acceptable salt thereof.

[0128] In a preferred embodiment, the present invention provides R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0129] In a particularly preferred embodiment, the present invention provides 1 is fluoro or is cyclopropyl substituted with one methyl-SO2-NH- substituent, or a pharmaceutically acceptable salt thereof.

[0130] In a particularly preferred embodiment, the present invention provides 2 is fluoro or chloro; or a pharmaceutically acceptable salt thereof.

[0131] In a particularly preferred embodiment, the present invention provides 5 However, methoxy and groups [ka] or a pharmaceutically acceptable salt thereof.

[0132] In a particularly preferred embodiment, the present invention provides 6 is selected from hydrogen and fluoro, or a pharmaceutically acceptable salt thereof.

[0133] In a particularly preferred embodiment, the present invention provides 7 is selected from hydrogen and chloro, or a pharmaceutically acceptable salt thereof.

[0134] In a particularly preferred embodiment, the present invention provides10 is selected from hydrogen, chloro, cyano and oxo, or a pharmaceutically acceptable salt thereof.

[0135] In a particularly preferred embodiment, the present invention comprises: [ka] but [ka] and R 5 , R 6 , and R 7 or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the compound of formula (II) according to the present invention is A is phenyl; R 1 is a halogen, R 2 , R 3 and R 4 and each is hydrogen; or a pharmaceutically acceptable salt thereof.

[0137] In one embodiment, the compound of formula (II) according to the present invention is B is phenyl; R 5 is C1-C6-alkoxy, R 6 is a halogen, R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the compound of formula (II) according to the present invention is A is phenyl; R 1 is chloro, R 2 , R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0139] In one embodiment, the compound of formula (II) according to the present invention is B is phenyl; R 5 is methoxy, R 6 is chloro, R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment, the compound of formula (II) according to the present invention is A is phenyl; B is phenyl; R 1 is a halogen, R 2 , R 3 and R 4 are hydrogen, R 5 is C1-C6-alkoxy, R 6 is a halogen, R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0141] In one embodiment, the compound of formula (II) according to the present invention is A is phenyl; B is phenyl; R 1 is chloro, R 2 , R 3 and R 4 are hydrogen, R 5 is methoxy, R 6 is chloro, R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0142] In a first aspect, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: [ka] (In the formula, L 1 is selected from a covalent bond, NHCH2, and CH2NH; L 2 is selected from a covalent bond, CH2O, OCH2, CH2, CH2CH2, CF2CH2, and CH2CF2; A is selected from oxazolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from 2H-triazol-4-yl, imidazolyl, 1H-1,2,4-triazol-3-yl, phenyl, and pyridyl; C is selected from azetidine, cyclopropyl, piperidine, piperazine, pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, triazol-1-yl, 1H-triazol-4-yl, and 1H-1,2,4-triazol-3-yl; R 1 is halogen, hydroxy, carbamoyl-C1-C6-alkyl, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy, C3-C 10-cycloalkyl, NH2SO2-, C1-C6-alkyl-SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, (C1-C6-alkyl)2-PO-C1-C6-alkyl-, C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, halo-C1-C6-alkyl-sulfonimidoyl-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl is substituted by one substituent selected from carbamoyl, C1-C6-alkyl-SO2-, and C1-C6-alkyl-SO2-NH-, R 2 , R 3 and R 4 are each independently selected from hydrogen, halogen, and cyano; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 8 C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 9 C1-C6-alkyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C3-C 10 -cycloalkyl, and halo-C3-C 10 -cycloalkyl, R 10is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy, oxo and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0143] In a preferred embodiment, the present invention provides L 1 is a covalent bond, or a pharmaceutically acceptable salt thereof.

[0144] In one embodiment, A is (i) [ka] and R 1 is halo-C1-C6-alkyl, or (ii) cyclopropyl, where R 1 is halo-C1-C6-alkyl and R 2 , R 3 and R 4 are all hydrogen, or (iii) phenyl, and R 1 but halogen, carbamoyl-C1-C6-alkyl, C3-C 10 -cycloalkyl, C1-C6-alkoxy-C1-C6-alkoxy, NH2SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl is substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 is a halogen and R 3 and R 4 are both hydrogen, or (iv) pyrazinyl, where R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 does not exist, or (v) pyridyl, and R 1 is selected from hydroxy, carbamoyl-C1-C6-alkyl, and C1-C6-alkyl-SO2-; R 2 , R 3 and R 4 are all hydrogen, or (vi) pyrimidinyl, and R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 The present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0145] In one embodiment, A is (i) [ka] and R 1 is halo-C1-C6-alkyl, or (ii) phenyl, and R 1 Carbamoyl-C1-C6-alkyl, C3-C 10 -cycloalkyl, C1-C6-alkoxy-C1-C6-alkoxy, NH2SO2-, C1-C6-alkyl-SO2-C1-C6-alkyl-, C1-C6-alkyl-NH-SO2-C1-C6-alkyl-, and C1-C6-alkyl-SO2-NH-C1-C6-alkyl-; 10 -cycloalkyl is substituted by one substituent selected from carbamoyl, C-C-alkyl-SO-, and C-C-alkyl-SO-NH-; R 2 is a halogen and R 3 and R 4 are both hydrogen, or (iii) pyrazinyl, where R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 does not exist, or (iv) pyridyl, where R 1 is selected from hydroxy, carbamoyl-C1-C6-alkyl, and C1-C6-alkyl-SO2-; R 2 , R 3 and R 4 are all hydrogen, or (v) pyrimidinyl, and R 1 is halo-C1-C6-alkyl and R 2 and R 3 are all hydrogen, and R 4 The present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0146] In one embodiment, the present invention provides a method for producing a compound comprising the steps of: [ka] provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [ka]

[0147] In a preferred embodiment, the present invention comprises: A is phenyl; R 1 and R 2 are all halogens, R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0148] In a particularly preferred embodiment, the present invention comprises: A is phenyl; R1 and R 2 are all fluoro, R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0149] In one embodiment, the present invention provides B is selected from 1H-1,2,4-triazol-3-yl, phenyl, and pyridyl; C is selected from azetidine, cyclopropyl, pyridyl, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, triazol-1-yl, and 1H-1,2,4-triazol-3-yl; L 2 is selected from a covalent bond, CH2O, CH2, and CH2CH2; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen, halogen and C1-C6-alkyl, R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, cyano, hydroxy, halogen, oxo, C-C-alkyl-SO—, NHSO—, and halo-C-C-alkyl, R 11 is selected from hydrogen, hydroxy and oxo, or a pharmaceutically acceptable salt thereof.

[0150] In one embodiment, the present invention provides a method for producing a compound comprising the steps of: [ka] provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: [ka]

[0151] In a preferred embodiment, the present invention comprises: B is selected from 1H-1,2,4-triazol-3-yl and phenyl; C is selected from pyridyl, 1,2-dihydropyridine, and oxazolidine; L 2 is selected from a covalent bond and CHO-; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen and halogen; R 7 is selected from hydrogen and halogen; R 10 is selected from hydrogen, halogen and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0152] In a particularly preferred embodiment, the present invention comprises: B is selected from 1H-1,2,4-triazol-3-yl and phenyl; C is selected from pyridyl, 1,2-dihydropyridine, and oxazolidine; L 2 is selected from a covalent bond and CHO-; R 5 C1-C6-alkoxy and groups [ka] is selected from R 6 is selected from hydrogen and fluoro; R 7 is selected from hydrogen and chloro; R 10 is selected from hydrogen, chloro and oxo; R 11 is selected from hydrogen and hydroxy, or a pharmaceutically acceptable salt thereof.

[0153] In a preferred embodiment, the present invention provides R 8 is C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0154] In a particularly preferred embodiment, the present invention provides 8 is methyl, or a pharmaceutically acceptable salt thereof.

[0155] In a preferred embodiment, the present invention provides a compound comprising R 9 is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0156] In a particularly preferred embodiment, the present invention provides 9 is methyl, or a pharmaceutically acceptable salt thereof.

[0157] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from: 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]pyrrolidin-2-one; 5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one; 5-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]oxazolidin-2-one; 4-[3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile; 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one; N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile; 3-chloro-5-[6-[2-chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; N-[[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]methyl]methanesulfonamide; N-[1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; 5-[[3-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one; [2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; 2-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide; [2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 5-[[3-chloro-4-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one; (2-chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]-N-methyl-methanesulfonamide; [2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 3-chloro-5-[6-[2-chloro-5-fluoro-3-(1H-1,2,4-triazol-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; (2-chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 3-[3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-4-fluorophenyl]benzonitrile; [2-chloro-5-fluoro-3-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 4-[2-[3-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one; 1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-(2-oxo-1H-pyridin-4-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; 5-[2-chloro-3-[3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one; [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(5-fluoro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone; 2-[3-chloro-5-[(7R)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide; [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(6-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone; 5-[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one; (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 2-[3-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-5-fluorophenyl]acetamide; [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone; 4-[2-[3-chloro-4-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one; 1-[2-chloro-3-[2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]azetidine-3-sulfonamide; (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 3-chloro-5-[(7S)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; [2-chloro-3-(5,5-dimethyl-4H-isoxazol-3-yl)-5-fluorophenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; (2-chloro-3-methoxyphenyl)-[(7S)-2,7-dimethyl-3-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 3-chloro-5-[(7R)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; (2-chloro-3-methoxyphenyl)-[(7S)-3-(6-hydroxy-2-pyridyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-pyrrolidin-3-yl-1,2,4-triazol-3-yl)methanone; hydrochloride; 1-[3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-methylphenyl]imidazolidin-2-one; 3-chloro-5-[2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide; [3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[2-(triazol-1-ylmethyl)phenyl]methanone; 5-[[3-chloro-4-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one; [2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; N-[[3-chloro-5-[(7R)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]methyl]methanesulfonamide; 4-[2-[3-chloro-4-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one; [2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 2-[5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-3-pyridyl]acetamide; [2-chloro-3-(2,2-dioxo-2λ 6-thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 5-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one; 3-[3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one; (2-chloro-3-methoxyphenyl)-[(7S)-2,7-dimethyl-3-(5-methylsulfonyl-3-pyridyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [(7S)-3-[3-chloro-5-(2-methoxyethoxy)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone; 1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[(5-oxopyrrolidin-3-yl)methoxy]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; 1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; 1-[3-chloro-5-[(7R)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; 5-[2-chloro-3-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one; 5-[2-chloro-3-[(7R)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one; 1-[3-chloro-5-[(7S)-6-[2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; 1-[3-chloro-5-[(7R)-6-[2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide; 3-[5-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]imidazol-1-yl]-1H-pyridin-2-one; 3-[3-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one; [(7R)-3-[3-chloro-5-(2-methoxyethoxy)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone; N-[[2-chloro-6-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-4-pyridyl]methyl]methanesulfonamide; (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-4-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 4-[2-chloro-5-fluoro-3-[(7S)-3-[3-fluoro-5-[[methyl(dioxo)-λ 6 -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile; 4-[2-chloro-5-fluoro-3-[(7R)-3-[3-fluoro-5-[[methyl(dioxo)-λ 6 -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile; N-[1-[3-chloro-5-[6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; N-[1-[3-chloro-5-[(7R)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; N-[1-[3-chloro-5-[(7S)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; N-[1-[3-chloro-5-[(7R)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; N-[1-[3-chloro-5-[(7S)-6-[1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carbonyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile; 4-[2-chloro-3-[(7R)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile; N-[1-[3-chloro-5-[(7S)-6-[2,5-difluoro-3-(1H-pyrazol-4-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; [(7S)-3-[3-chloro-5-(2-hydroxy-2-methyl-propyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone; 3-[3-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one; 3-chloro-5-[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one; 3-chloro-5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one; 3-chloro-5-[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one; [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl)phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl)phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methylamino]pyrrolidin-2-one; Hydrochloride; 5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one; (5S)-5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one; (5R)-5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one; 4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]pyrrolidin-2-one; [2-chloro-3-(1,6-diazaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 2,2,2-trifluoroacetic acid; [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-4-pyridyl)-1,2,4-triazol-3-yl]methanone; (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one; (4R)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one; (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one; (2-chloro-3-methoxyphenyl)-[(8S)-3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone; and (2-Chloro-3-methoxyphenyl)-[(8S)-3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]methanone.

[0158] In preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]pyrrolidin-2-one; 5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one; 5-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]oxazolidin-2-one; 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one; [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone; N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide; [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl)phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methylamino]pyrrolidin-2-one; Hydrochloride; (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one; and (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one.

[0159] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

[0160] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is 5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one, or a pharmaceutically acceptable salt thereof.

[0161] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is 5-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]oxazolidin-2-one, or a pharmaceutically acceptable salt thereof.

[0162] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one, or a pharmaceutically acceptable salt thereof.

[0163] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, or a pharmaceutically acceptable salt thereof.

[0164] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone, or a pharmaceutically acceptable salt thereof.

[0165] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0166] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, or a pharmaceutically acceptable salt thereof.

[0167] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, or a pharmaceutically acceptable salt thereof.

[0168] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methylamino]pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof.

[0169] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, or a pharmaceutically acceptable salt thereof.

[0170] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein which is (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, or a pharmaceutically acceptable salt thereof.

[0171] In certain embodiments, the present invention provides pharmaceutically acceptable salts of compounds according to formula (I) described herein. In further particular embodiments, the present invention provides compounds according to formula (I) described herein in their free form (i.e., as a free base or free acid).

[0172] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that may be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0173] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0174] 1 1 C. 18 F, 15 O and 13Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting an appropriate isotopically labeled reagent for the previously employed non-isotopically labeled reagent.

[0175] Manufacturing method The preparation of the compounds of formula (II) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings indicated herein unless otherwise indicated.

[0176] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (such as those described in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, NY) may be introduced prior to a critical step by applying methods well known in the art. Such protecting groups may be removed at a later stage of the synthesis using standard methods described in the literature.

[0177] When the starting material or intermediate contains a stereocenter, the compound of formula (II) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with optically pure acids, or by separating the antipodes by specific chromatographic methods using either chiral adsorbents or chiral eluents. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (II) typically yields the respective diastereomerically / enantiomerically enriched compound of formula (II).

[0178] Those skilled in the art will recognize that in the synthesis of compounds of formula (II), unless otherwise desired, an "orthogonal protecting group strategy" is applied, which allows several protecting groups to be cleaved one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0179] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0180] More specifically, compounds of formula (II) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions that affect the described reactions, see, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999." The reactions could be easily carried out with or without a solvent. There are no particular restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The reaction time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0181] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section.

[0182] X is NR 9The present compounds of formula (II) (hereinafter "Formula (I)"), wherein Y is C, can be prepared by reacting the intermediate of formula 1 with a carboxylic acid of formula 2 by stirring in a polar solvent such as DMF or DMA in the presence of a base such as DIPEA or TEA and a coupling agent such as HATU or HOBT (Scheme 1). Optionally, carboxylic acid 2 can be treated with thionyl chloride or oxalyl chloride to generate the corresponding acyl chloride. Treatment with a base such as TEA in the presence of amine 1 also generates compounds of formula I. Optionally, R 1 is a protecting group (e.g., R 1 =NH2SO2-), a subsequent deprotection step also gave compounds of formula I. [ka]

[0183] Scheme 1 Or, L 1 is a covalent bond, A is a phenyl ring, and R 1 Compounds of general formula I, where is carbamoyl-C1-C6-alkyl (referred to herein as compound 3), can be prepared from ester 4 (Scheme 2). Ester 4 can be treated with ammonia and a coupling agent such as CDI. Alternatively, ester 4 can first be saponified to the corresponding carboxylic acid, which can then be treated with ammonia and a suitable coupling agent to give compound 3. [ka]

[0184] Scheme 2 Alternatively, ring B=1H-1,2,4-triazol-3-yl, L 2 = covalent bond, and R 10Compounds of general formula I, where ═ = pyrrolidinyl (represented herein as compound 5), can be prepared as shown in Scheme 3. N-Alkylation of bromide 7 with triazole 6 in the presence of a base affords intermediate 8 (and the corresponding regioisomer, not shown here). Intermediate 9 can be generated by saponification of ester 8 using a base such as NaOH or LiOH in a polar solvent such as THF, MeOH, or water (or a mixture thereof). Intermediate 10 can be prepared from the amide coupling of acid 9 and amine 1 using a suitable coupling reagent, such as HATU or HOBT, a base (e.g., TEA or DIPEA), in a polar protic solvent such as DMF or DMA. Intermediate 5 can be obtained after N-Boc deprotection of intermediate 10 under acidic conditions (e.g., HCl or TFA) in a solvent such as 1,4-dioxane or DCM. [ka]

[0185] Scheme 3 Or, L 1 Compounds of general formula I, in which R is a covalent bond and ring A is 1,3,4-oxadiazolyl (shown as compound 11), can be prepared by palladium-catalyzed cyanation of intermediate 12 using standard reaction conditions, such as 1,1'-bis(diphenylphosphino)ferrocene, zinc cyanide, tris(dibenzylideneacetone)dipalladium(0), and DMF (Scheme 4). N-Boc deprotection of the resulting intermediate 13 using an acid, such as HCl, TFA, or PTSA, affords the corresponding amine 14 (or its salt). Coupling of intermediate 14 and an acid of formula 2 with HATU or HOBT and TEA or DIPEA in DMF or DMA affords intermediate 15. [2+3] cycloaddition of intermediate 15 and sodium azide affords intermediate 16. Compound 11 can be obtained by treating intermediate 16 with, for example, an anhydride. [ka]

[0186] Scheme 4 Components of formula 1 can be prepared from intermediate 17 by N-Boc deprotection using an acid such as HCl or TFA in a solvent such as 1,4-dioxane or DCM (Scheme 5). 1 = -OMe, intermediate 17 can be treated with 12N HCl at 100 °C to both deprotect the N-Boc protecting group and remove the methyl group on the methoxy group, affording intermediate 1 with a pyridone. 1 This can be done prior to the N-Boc deprotection step, with simultaneous / subsequent deprotection using standard conditions. The chemistry described in Scheme 5 can also be applied to compounds of general formula IIa and IIb. [ka]

[0187] Scheme 5 Intermediate 17 can be prepared by Pd-catalyzed Suzuki-Miyaura cross-coupling of pinacol ester 18 (or the corresponding boronic acid) and triflate 12 (e.g., XPhosG3, K2CO3, 1,4-dioxane / water or Pd(PPh3)4, Na2CO3, THF / water) (Scheme 6). The preparation of intermediate 12 has been previously described elsewhere (Patentnr. WO2020 / 065613 A1, 2020). Boronic acids are commercially available or can be prepared from pinacol ester 18 after treatment with sodium metaperiodate and ammonium acetate. In some instances, boronic esters can be incorporated into intermediate 12, which can then be reacted with (het)aryl bromides to give intermediate 17. In other instances, bromides were used instead of triflates on intermediate 12 to prepare intermediate 17. [ka]

[0188] Scheme 6 Alternatively, Y is -C1-C6-(halo)-alkyl or -C3-C 10 The -(halo)-cycloalkyl intermediate 19 can be prepared from boronic acid 20 and triflate 12 using standard Suzuki-Miyaura cross-coupling conditions (e.g., Na2CO3, Pd(PPh3)4, DMF) to give alkene 21 (Scheme 7). Oxidative cleavage of alkene 21 using OsO4 and NaOI4 in 1,4-dioxane / water gives aldehyde 22. Reductive amination of intermediate 22 and a primary amine (e.g., using sodium cyanoborohydride in DCM) gives intermediate 19. In some instances, a bromide was used in place of the triflate on intermediate 12 to prepare intermediate 21. [ka]

[0189] Scheme 7 Building blocks of general formula 18 can be prepared from the corresponding bromides 23 by Miyaura borylation (e.g., KOAc, bis(pinacolato)diboron, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1,4-dioxane) (Scheme 8). [ka]

[0190] Scheme 8 Intermediate 24 can be prepared from (het)aryl bromides or chlorides 25 using sodium methanesulfinate in DMF (Scheme 9). [ka]

[0191] Scheme 9 Intermediate 26 can be prepared from benzylamine 27 by treatment with TEA and the appropriate sulfonyl chloride (Scheme 10). [ka]

[0192] Scheme 10 Intermediate 28 can be obtained from the corresponding sulfonyl chloride 29 by treatment with an appropriate amine (Scheme 11). [ka]

[0193] Scheme 11 Alternatively, intermediate 30 can be prepared from carboxylic acid 31 using thionyl chloride in MeOH (X = OMe) or ammonia (X = NH2) (Scheme 12). [ka]

[0194] Scheme 12 Intermediate 32 can be prepared from intermediate 33 using a sulfonium salt, such as methyl(diphenyl)sulfonium tetrafluoroborate and sodium bis(trimethylsilyl)azanide (Scheme 13). Intermediate 33 can be prepared, inter alia, by Suzuki-Miyaura cross-coupling of a halide with a boronic ester or boronic acid using standard reaction conditions. [ka]

[0195] Scheme 13 Intermediate 2 can be prepared by saponification of intermediate 34, where R = Me or Et, using NaOH or LiOH in THF / MeOH / water or any combination of one or more of the three solvents (Scheme 14). 5When intermediate 34 contains a methoxypyridine, both the methoxypyridine and the methyl or ethyl ester can be simultaneously deprotected using concentrated HCl at elevated temperature to give the corresponding pyridine-containing carboxylic acid 2 in one step. In some instances, this sequence occurs sequentially (deprotection followed by saponification, or vice versa). Similarly, for intermediate 34 bearing a protecting group (e.g., trityl), deprotection occurs during saponification. [ka]

[0196] Scheme 14 R=C1-6-alkyl (e.g., Me, Et), Ring B is phenyl or pyridyl, and R 5 L 2 Intermediate 35, defined by =OCH2, where ring C is a cyclic carbamate, lactam, or halocycloalkyl, can be prepared by alkylation of phenol 37 with intermediate 36 using a base such as cesium carbonate, potassium carbonate, or TEA in DMF or DMSO (Scheme 15). [ka]

[0197] Scheme 15 Intermediate 38 could be prepared starting from bromide 39 (Scheme 16). Bromide 39 can be treated with n-BuLi and DMF to give aldehyde 40. Aldehyde 40 can be treated with hydroxylamine hydrochloride and sodium acetate to give intermediate 41. Chlorination of intermediate 41 (using NCS) gives intermediate 42. Cycloaddition with 2-methylpropene and TEA gives intermediate 38. [ka]

[0198] Scheme 16 R=Me, Et, ring B is phenyl or pyridyl, R 5 is L2 Intermediate 34, where R is defined as a covalent bond and C is a heterocyclic amine such as azetidine, piperidine, piperazine, 2-thia-6-azaspiro[3.3]heptane, or 1,6-diazaspiro[3.3]heptane, can be prepared from the corresponding bromide 43 (Scheme 17). Introduction of these secondary amines can be achieved by standard Buchwald-Hartwig cross-coupling using the amine as a free base or salt (e.g., HCl), a base such as Pd(dba) or cesium carbonate, and a ligand such as xantphos in a solvent such as 1,4-dioxane. In some instances, when an amine with an additional protected functionality is used in the Buchwald-Hartwig coupling, an additional deprotection step is required after the cross-coupling, which is not shown here. Alternatively, when R = Me or Et, ring B is a (heteroaryl) ring such as phenyl or pyridyl, and R 5 L 2 When intermediate 34 is defined as = covalent bond and ring C is pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, phenyl, pyrrolyl, pyrazolyl, triazol-1-yl, 1H-triazol-4-yl, or 1H-1,2,4-triazol-3-yl, reaction with intermediate 43 provides the corresponding bi(hetero)aryl 34 (Scheme 17). Intermediate 34 can be prepared by standard Suzuki-Miyaura cross-coupling using bromide 43 and a boronic ester or acid, e.g., Pd(PPh3)4, sodium carbonate. In some instances, the bromide can also be converted to the corresponding boronic ester or acid. When ring C is a 1H-1,2,4-triazol-3-yl, a deprotection step is required after the cross-coupling. [ka]

[0199] Scheme 17 R = Me, Et, ring B is 2H-triazol-4-yl, imidazolyl, 1H-1,2,4-triazol-3-yl, R 5 L 2= covalent bond, ring C is 1,2-dihydropyridine, and R 10 Intermediate 44, where is oxo, can be prepared via Chan-Lam coupling of intermediate 45 and boronic acid 46 using standard conditions (e.g., Cu(OAc)2, pyridine in DCM) (Scheme 18). [ka]

[0200] Scheme 18 Intermediate 47, where R = Me or Et and X is a (hetero)cyclic or (hetero)aromatic compound, can be prepared by Sonogashira cross-coupling of iodide 48 and alkyne 49 using standard reaction conditions, such as Pd(PPh3)4, CuI, and TEA in ACN, to give intermediate 50, followed by hydrogenation (Scheme 19). [ka]

[0201] Scheme 19 Intermediate 51, where Y = imidazolidine, oxazolidine, pyrrolidinyl, can be prepared from aldehyde 52 and amine 53 in the presence of a reducing agent such as sodium cyanoborohydride in dichloromethane (Scheme 20). [ka]

[0202] Scheme 20 L 1= covalent bond, intermediate 54 can be prepared starting from carboxylic acid 55 and hydrazine 56 in the presence of a base such as trimethylamine or DIPEA and a coupling agent (e.g., HATU, HOBT) in dichloromethane to give intermediate 57 (Scheme 21). Treatment of intermediate 57 with an acid such as acetic acid and heating gives intermediate 58. Intermediate 54 can be obtained from building block 58 in a hydrogenation reaction using a heterogeneous catalyst such as Pt / C under a hydrogen atmosphere in a polar solvent such as MeOH. [ka]

[0203] Scheme 21 X is CR 9 and Y is N (hereinafter "Formula (IIa)"), or where X and Y are both N (hereinafter "Formula (IIb)"), can be prepared similarly to the procedures for making compounds of Formula (I) outlined above in Schemes 1-20. For example, by substituting a bromide for a triflate, such as intermediate 12, compounds of Formula IIb can be prepared.

[0204] In certain instances, compounds of formula I can be further functionalized to give other compounds of formula I. For example, compounds of formula I bearing (hetero)aryl bromides or iodides can be further functionalized with other groups, e.g., small amines, small alkyls, using metal-catalyzed cross-coupling conditions such as the Buchwald or Suzuki reaction.

[0205] In some instances, compounds of Formula I or building blocks bearing esters can be further functionalized to the corresponding amides or carboxylic acids. Similarly, standard functional group interconversion techniques (e.g., conversion of halides to other groups, e.g., small amines, small alkyls using metal-catalyzed cross-coupling conditions such as the Buchwald or Suzuki reaction, conversion of boronic esters to boronic acids, conversion of bromides to boronic esters, S NBuilding blocks can be generated from commercially available fragments using techniques such as alkylation of hydroxyl or amine groups via the 2 reaction or reductive amination, acylation using activated carbonyl derivatives, or installation of a -SOMe group using literature techniques. Such techniques can also be used to elaborate fragments before, after, or within the synthetic sequences described above.

[0206] In certain instances, components described as electrophiles or nucleophiles in cross-coupling reactions (e.g., Suzuki cross-coupling) can also be modified to act as nucleophiles or electrophiles.

[0207] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) Amine 1 [ka] wherein the variables are as defined herein, Carboxylic Acid 2 [ka] wherein the variables are as defined herein; and reacting in the presence of a base and a coupling agent in a solvent to form said compound of formula (I), and optionally (b) contacting said compound of formula (I) with an acid to form a pharmaceutically acceptable salt thereof.

[0208] In one embodiment, the base used in the method is selected from DIPEA and TEA.

[0209] In one embodiment, the solvent used in the process is selected from DMF, DMA and CH3CN.

[0210] In one embodiment, the coupling agent used in the method is selected from HATU and HOBT.

[0211] In one aspect, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, when prepared according to any one of the methods described herein.

[0212] MAGL inhibitory activity The compounds of the invention are MAGL inhibitors. Thus, in one aspect, the invention provides the use of a compound of formula (II) as described herein to inhibit MAGL in a mammal.

[0213] In a further aspect, the present invention provides a compound of formula (II) as described herein for use in a method of inhibiting MAGL in a mammal.

[0214] In a further aspect, the present invention provides the use of a compound of formula (II) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0215] In a further aspect, the present invention provides a method of inhibiting MAGL in a mammal, comprising administering to the mammal an effective amount of a compound of formula (II) described herein.

[0216] Compounds of formula (II) were profiled for MAGL inhibitory activity by measuring enzymatic activity via mass spectrometry analysis of arachidonic acid generated by hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG). This assay is hereafter abbreviated as the "2-AG assay."

[0217] Compounds of formula (II) were profiled for MAGL inhibitory activity by measuring enzymatic activity via mass spectrometry analysis of arachidonic acid generated by hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG). This assay is hereafter abbreviated as the "2-AG assay." The 2-AG assay was performed in a 384-well polypropylene assay plate. Compound dilutions were made in 3-fold dilutions in 100% DMSO in the polypropylene plate to give a final concentration range in the assay of 12.5 μM to 0.8 pM. Compound dilutions were added to MAGL protein in assay buffer (50 mM TRIS, 1 mM EDTA, 0.01% (v / v) Tween-20, 2.5% (v / v) DMSO). After shaking, the plate was incubated at room temperature for 15 minutes. 2-arachidonoylglycerol in assay buffer was added to initiate the reaction. The final concentrations in the assay were 50 pM for MAGL protein and 8 μM for 2-arachidonoylglycerol. After shaking and incubation at room temperature for 30 min, the reaction was stopped by adding two assay volumes of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid formed was monitored by an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer. A C18 SPE cartridge (Agilent G9205A) was used in an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. Compound activity was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid].

[0218] [Table 1] TIFF2025503438000114.tif240165

[0219] In one aspect, the present invention provides compounds of formula (II) as described herein, and pharmaceutically acceptable salts or esters thereof, wherein the compounds of formula (II) and pharmaceutically acceptable salts or esters thereof have an IC for MAGL inhibition of less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM, as measured in the MAGL assay described herein. 50 It has.

[0220] In one embodiment, the compounds of formula (II) described herein and their pharmaceutically acceptable salts or esters have an IC of 0.000001 μM to 25 μM as measured in the MAGL assay described herein. 50 (MAGL inhibition) values, with certain compounds having IC values ​​between 0.000005 μM and 10 μM 50 Certain compounds have IC values ​​between 0.00005 μM and 5 μM. 50 It has a value.

[0221] P obtained as part of a one-way P-gp screen app (passive permeability measurements) Experiment Description A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp cultured on 96-well semi-permeable filter membrane plates, where these cells form a polarized monolayer with tight junctions, which act as a barrier between the apical and basolateral compartments.

[0222] P-gp is expressed in the apical membrane of the monolayer. The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of the cell-impermeable marker Lucifer Yellow and the reference P-gp substrate edoxaban, respectively.

[0223] The assay is fully automated on a Tecan liquid handling robot.

[0224] Data analysis and interpretation For substrate testing, the assay measures the unidirectional permeability (P) of test compounds by administering them to the apical (i.e., donor compartment) side of the cell monolayer in the absence and presence of the specific P-gp inhibitor zosuquidar and measuring the movement of the compound into the basolateral (i.e., receiver) compartment over a 3-hour incubation at 37°C. app The effect of P-gp is measured by expressing the apical efflux ratio (AP-ER, Equation 2). The mean permeability (P app is determined in the absence of P-gp via zosuquidar conditions. AP-ER and mean P app is used to classify compound properties for the degree of efflux and permeability (Table 2).

number

[0225] formula 1P app , A, C0, and dQ / dt represent the apparent permeability, filter surface area, initial concentration, and transport rate per unit time, respectively. app Values ​​are calculated based on a single time point.

number

[0226] Equation 2: Calculation of the apical-to-basolateral efflux ratio (AP-ER). Papp,inh(A>B) is the permeability value in the apical-to-basolateral direction in the presence of an inhibitor, and Papp(A>B) is the permeability value in the apical-to-basolateral direction in the absence of an inhibitor.

[0227] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0228] In one embodiment, the compounds of the invention are primarily "peripherally" active, i.e., they do not penetrate the blood-brain barrier or cross it only to a limited extent. Peripheral activity is achieved by the P appLow P as measured by assay app Characterized by value.

[0229] In a further aspect, the present invention provides a method for treating or preventing a disease or condition associated with MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof.

[0230] In one embodiment, the disease or condition associated with MAGL is selected from neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and inflammatory bowel disease.

[0231] In one embodiment, the disease or condition associated with MAGL is selected from neuroinflammatory and neurodegenerative diseases.

[0232] In one embodiment, the disease or condition associated with MAGL is a neurodegenerative disease.

[0233] In one embodiment, the disease or condition associated with MAGL is cancer.

[0234] In a particularly preferred embodiment, the disease or condition associated with MAGL is inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.

[0235] In a particularly preferred embodiment, the disease or condition associated with MAGL is ulcerative colitis.

[0236] In a particularly preferred embodiment, the disease or condition associated with MAGL is Crohn's disease.

[0237] In one embodiment, the disease or condition associated with MAGL is irritable bowel syndrome.

[0238] It is believed that continued dysregulation of MAGL-related cell systems in IBD patients in clinical remission leads to irritable bowel syndrome (IBS)-like symptoms, such as abdominal pain and diarrhea.Therefore, in a particularly preferred embodiment, the present invention provides a method for treating or preventing IBS-like symptoms, such as abdominal pain and diarrhea, in IBD patients in clinical remission.

[0239] In one embodiment, the disease or condition associated with MAGL is pain, particularly visceral pain.

[0240] In one embodiment, the disease or condition associated with MAGL is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome, and visceral pain.

[0241] In one embodiment, the disease or condition associated with MAGL is selected from multiple sclerosis, Alzheimer's disease, and Parkinson's disease.

[0242] In one embodiment, the disease or condition associated with MAGL is selected from inflammatory bowel disease, inflammatory bowel disease symptoms, intestinal motility, visceral pain, fibromyalgia, endometriosis, COPD, and asthma.

[0243] In one aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof for use in the above methods.

[0244] In one aspect, the present invention provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the above method.

[0245] In one aspect, the present invention provides the use of a compound of formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or condition associated with MAGL described herein.

[0246] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (II) as described herein and a therapeutically inert carrier.

[0247] In one embodiment, a pharmaceutical composition according to Example 118 or Example 119 is provided.

[0248] The compounds of formula (II) and their pharmaceutically acceptable salts and esters can be used as medicines (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories).However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0249] The compound of formula (II) and its pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0250] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols etc.

[0251] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0252] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0253] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0254] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0255] The dosage can vary widely and will of course be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual dosages, for example, of the same amount. However, it is clear that the upper limit given herein may be exceeded in indicated cases. [Example]

[0256] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0257] When preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization. The absolute stereochemistry of the examples was determined for Examples 1, 3, 4, 16, and 64 by co-crystal structures of the ligand complexed with the protein. Similarly, absolute stereochemistry was assigned to the remaining examples based on biological activity but was not experimentally verified. When mixtures of diastereomers were isolated, the absolute stereochemistry was arbitrarily assigned, and the diastereomers were designated A, B, C, or D.

[0258] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0259] Abbreviation ACN = acetonitrile, Ar = argon, Boc = tert-butyloxycarbonyl, CASRN = Chemical Abstracts Registry Number, CDI = N,N'-carbonyldiimidazole, CHCl3 = chloroform, Cu(OAc)2 = copper acetate, CuI = copper iodide, DCM = dichloromethane (CHCl2), DMA = N,N-dimethylacetamide, DME = dimethylethane, DMF = N,N-dimethylformamide, DMSO = dimethyl sulfoxide, DIPEA = N,N-diisopropylethylamine, EI = electron ionization, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, FC = flash chromatography, g = gram (s), GC = gas chromatography, h = hour, HATU = 1-[bis(dimethylamino)methylene-1H-1,2,3 triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high performance liquid chromatography, H3PO4 = phosphoric acid, IPA = isopropyl alcohol, K2CO3 = potassium carbonate, KOAc = potassium acetate, LiOH = lithium hydroxide, M = moles, MeOH = methanol, mg = milligram, MgSO4 = magnesium sulfate, min = minute, mL = milliliter, μL = microliter, mmHg = millimeters of mercury, MS = mass spectrometry or molecular sieves, MTBE = methyl tert-butyl ether, N = normal, NaOH = sodium hydroxide, n-BuLi = n-butyllithium, NaHSO4 = sodium hydrogen sulfate, Na2SO4 = sodium sulfate, NBS = N-bromosulfate succinimide, NCS = N-chlorosuccinimide, TEA = triethylamine, THF = tetrahydrofuran, NHCl = ammonium chloride, PE = petroleum ether, Pd(dba) = tris(dibenzylideneacetone)dipalladium(0), PTSA = p-toluenesulfonic acid, R = any group, RP = reverse phase, SFC = supercritical fluid chromatography, SiO = silica, tBu = tert-butyl, TEA = trimethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, XPhosG = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium methanesulfonate.

[0260] Example 1 N-[[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]methyl]methanesulfonamide [ka] A solution of N-[[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]methyl]methanesulfonamide, hydrochloride (320.0 mg, 0.789 mmol) in dry DMF (5.0 mL) was treated with HATU (390.2 mg, 1.03 mmol), TEA (495 μL, 3.55 mmol), and 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 147.3 mg, 0.789 mmol) under Ar at 25 °C. The mixture was stirred at this temperature for 12 h and then diluted with water. The aqueous phase was extracted with EtO (3×), and the combined organic layers were dried over NaSO, filtered, and evaporated. Purification by RP-HPLC afforded 65 mg of the racemate. Purification by chiral chromatography gave the title compound (20.9 mg, 4.9% yield) as a yellow oil. MS (ESI): m / z = 537.0 [M+H] + .

[0261] Step a): N-[[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]methanesulfonamide A solution of N-[(3-bromo-5-chloro-phenyl)methyl]methanesulfonamide (A.1) (3.6 g, 12.06 mmol) in 1,4-dioxane (140 mL) was treated with KOAc (3.55 g, 36.17 mmol), bis(pinacolato)diboron (3.21 g, 12.66 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.88 g, 1.21 mmol) under Ar at 25 °C. The mixture was heated to 110 °C and stirred at this temperature for 24 h before being filtered. The filtrate was evaporated and diluted with water and EtOAc. The organic layer was washed with brine and water and concentrated with Na2 S Drying over O4, filtering and evaporation gave the title compound (3.0 g, 61.2%) as a brown solid. MS (ESI): m / z = 345.0 [M+H] + .

[0262] Step b) tert-butyl 3-[3-chloro-5-(methanesulfonamidomethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1,2020) (1.50 g, 3.76 mmol) in 5:1 1,4-dioxane / water (18 mL) was treated with N-[[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]methanesulfonamide (1.36 g, 3.94 mmol), KCO (1.04 g, 7.51 mmol), and Xphos G3 (0.32 g, 0.376 mmol) under Ar at 25 °C. The mixture was heated to 110°C and stirred at this temperature for 24 hours, then cooled to 23°C, filtered and evaporated. The residue was dissolved in water and EtOAc and the aqueous phase was extracted with EtOAc (3 times). The combined organic layers were dried over Na2SO4, filtered and evaporated. Purification by FC afforded the title compound (220 mg, 7.5%) as a yellow lyophilized solid. MS (ESI): m / z 469.0 [M+H] + .

[0263] Step c): N-[[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]methyl] Methanesulfonamide; Hydrochloride A solution of tert-butyl 3-[3-chloro-5-(methanesulfonamidomethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (500.0 mg, 0.693 mmol) in MeOH (2.0 mL) was treated with HCl (4 M in 1,4-dioxane; 693 μL, 2.77 mmol) at 25° C. The mixture was heated to 50° C. and stirred at this temperature for 24 hours, after which it was evaporated to give the title compound (320.0 mg, 30.4%) as a dark brown oil. MS (ESI): m / z=369.0 [M+H] + .

[0264] As in Example 1, the examples in the table below were produced using the respective building blocks A.1 or A.2 and 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5).

[0265] [Table 2]

[0266] Example 4 3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide [ka] A solution of N'-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]sulfonyl-N,N-dimethyl-formamidine (260.0 mg, 0.460 mmol) in MeOH (3 mL) was treated with 12 N HCl (0.38 mL, 4.61 mmol) at 23 °C. The mixture was heated to 60 °C and stirred at this temperature for 10 hours, then concentrated. The residue was purified by RP-HPLC to give the racemate (134.8 mg, 56.88% yield) as a white solid. Purification by chiral chromatography gave the title compound (55.2 mg, 40.95% yield) as a yellow solid. MS (ESI): m / z = 511.0 [M+H] + .

[0267] Step a): tert-butyl 3-(3-chloro-5-sulfamoyl-phenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO 2020 / 065613 A1, 2020) (845.0 mg, 1.59 mmol) in dry DMF was treated with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (EN 300-12593930; 655.16 mg, 2.06 mmol) and sodium carbonate (336.37 mg, 3.17 mmol) under Ar at 25 °C. The solution was sparged with Ar for 10 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (91.68 mg, 0.080 mmol). The resulting mixture was stirred at 100° C. for 16 h, cooled to 25° C., and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / EtOAc) afforded the title compound (350 mg, 50.02% yield) as a crude white solid. MS (ESI): m / z=385.0 [M-Bu+H] + .

[0268] Step b): tert-Butyl 3-[3-chloro-5-[(E)-dimethylaminomethyleneamino]sulfonyl-phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 3-(3-chloro-5-sulfamoyl-phenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (30.0 mg, 0.070 mmol) in 1,1-dimethoxy-N,N-dimethyl-methanamine (0.18 mL, 1.36 mmol) was stirred at 20 °C for 5 h and then evaporated to give the title compound (30 mg, 88.9% yield) as a colorless foam. MS (ESI): m / z = 440.0 [M-Bu + H] + .

[0269] Step c): N'-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)phenyl]sulfonyl-N,N-dimethyl-formamidine; 2,2,2-trifluoroacetate A solution of tert-butyl 3-[3-chloro-5-[(E)-dimethylaminomethyleneamino]sulfonyl-phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (30.0 mg, 0.060 mmol) in DCM (1 mL) was treated with TFA (0.05 mL, 0.600 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated to give the title compound (B.1; 28 mg, 81.89% yield) as a pale yellow oil. MS (ESI): m / z = 396.0 / 398.2 [M+H] + .

[0270] Step d): N'-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]sulfonyl-N,N-dimethyl-formamidine A solution of 2-chloro-3-methoxybenzoic acid (CASRN33234-36-5; 93.31 mg, 0.500 mmol) in ACN (5 mL) was treated with HATU (209.16 mg, 0.550 mmol) and TEA (0.35 mL, 2.5 mmol) at 20° C. After stirring the mixture at this temperature for 10 minutes, N′-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)phenyl]sulfonyl-N,N-dimethyl-formamidine; 2,2,2-trifluoroacetate (255.0 mg, 0.500 mmol) was added and stirred at 20° C. for 10 hours. The mixture was evaporated, and the residue was dissolved in EtOAc. The solution was washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (260 mg, 79.4% yield) as a pale yellow foam. MS (ESI): m / z = 564.2 / 566.2 / 568.0 [M+H] + .

[0271] Example 5 (2-chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone; [ka] A solution of 3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (115.82 mg, 0.280 mmol) in DMF (5 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 51.91 mg, 0.280 mmol), HATU (137.5 mg, 0.360 mmol), and DIPEA (0.12 mL, 0.830 mmol) under Ar at 25 °C. The mixture was stirred at this temperature for 18 h and then poured into water. The aqueous phase was extracted with more EtOAc (3x), and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. Purification by RP-HPLC and chiral chromatography gave the title compound (41.9 mg, 27.46% yield) as a white solid. MS (ESI): m / z = 563.2 [M+H] + .

[0272] Step a): 2-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 1-bromo-3-chloro-5-(1-methylsulfonylcyclopropyl)benzene (A.3; 2.0 g, 6.50 mmol) in 1,4-dioxane (40 mL) was treated with bis(pinacolato)diboron (1804.42 mg, 7.11 mmol), potassium acetate (1.21 mL, 19.38 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (527.11 mg, 0.650 mmol) under Ar at 25 °C. The mixture was heated to 80 °C and stirred at this temperature for 16 h, then cooled, filtered, and evaporated. The residue was dissolved in EtOAc, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / MTBE) afforded the title compound (1.2 g, 49.48% yield) as a crude pale yellow solid, which was used directly in the next step.

[0273] Step b): tert-butyl 3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of 2-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1270.0 mg, 3.56 mmol) in 4:1 THF / water (50 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (1422.11 mg, 3.56 mmol) and sodium carbonate (754.79 mg, 7.12 mmol) under Ar at 25 °C. The mixture was sparged with Ar for 5 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (411.46 mg, 0.360 mmol). The mixture was heated to 70 °C and stirred at this temperature for 16 h, then cooled to 25 °C and filtered through a SiO pad. The filtrate was evaporated and purified by FC (SiO; CHCl / ACN) to give the title compound (1.3 g, 66.93% yield) as a white solid. MS (ESI): m / z = 424.0 [M-tBu+H] + .

[0274] Step c): 3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine; hydrochloride A solution of tert-butyl 3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (120.0 mg, 0.250 mmol) in 4 M HCl in 1,4-dioxane (1.0 mL, 4.0 mmol) was stirred at 23 °C for 16 h and then evaporated. Trituration with MTBE afforded the title compound (B.2; 105 mg, 97.85% yield) as a pale yellow solid. MS (ESI): m / z = 380.0 [M+H] + .

[0275] Example 6 (2-Chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; 2,2,2-trifluoroacetic acid (550.0 mg, 1.18 mmol) in DMF (3 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 219.33 mg, 1.18 mmol), DIPEA (0.82 mL, 4.7 mmol), and HATU (536.35 mg, 1.41 mmol) at 23 °C. The mixture was stirred at this temperature for 18 h and then purified by RP-HPLC and chiral chromatography to give the title compound (37.4 mg, 6.09% yield) as a yellow gum. MS (ESI): m / z = 522 [M+H] + .

[0276] Step a): 1-Bromo-3-chloro-5-(methylsulfonylmethyl)benzene A solution of 1-bromo-3-(bromomethyl)-5-chloro-benzene (CASRN: 762292-63-7; 6.3 g, 22.15 mmol) in DMF (12 mL) was treated with sodium methanesulfinate (3.39 g, 33.23 mmol) at 23 °C. The mixture was heated to 50 °C and stirred at this temperature for 18 h, then cooled. The mixture was diluted with water, and the resulting precipitate was filtered, rinsed with water, and dried to give the title compound (5.7 g, 90.73% yield) as a white solid. MS (ESI): m / z = 282.8 [MH] - .

[0277] Step b): 2-[3-chloro-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of 1-bromo-3-chloro-5-(methylsulfonylmethyl)benzene (5.6 g, 19.75 mmol) in 1,4-dioxane (200 mL) was treated with bis(pinacolato)diboron (5.27 g, 20.74 mmol), KOAc (3.7 mL, 59.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.81 g, 0.990 mmol) under Ar at 23 °C. The mixture was heated to 100 °C and stirred at this temperature for 16 h, then cooled and filtered through SiO. The filtrate was evaporated. Trituration with hexane afforded the title compound (4.37 g, 63.58% yield) as a crude light brown solid, which was used directly in the next step.

[0278] Step c): [3-chloro-5-(methylsulfonylmethyl)phenyl]boronic acid A solution of 2-[3-chloro-5-(methylsulfonylmethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.37 g, 13.22 mmol) in 3:1 THF / water (100 mL) was treated with sodium metaperiodate (8.48 g, 39.65 mmol) and ammonium acetate buffer (2.04 g, 26.43 mmol) at 25 °C. The mixture was stirred at this temperature for 18 h, then filtered and evaporated. Trituration with hexane afforded the title compound (3.4 g, 98.35% yield) as a crude gray solid, which was used directly in the next step.

[0279] Step d): tert-butyl 3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of [3-chloro-5-(methylsulfonylmethyl)phenyl]boronic acid (373.3 mg, 1.5 mmol) in dry DMF (10 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (500.0 mg, 1.25 mmol) and sodium carbonate (265.37 mg, 2.5 mmol) under Ar at 23 °C. The mixture was sparged with Ar for 10 minutes, then treated with tetrakis(triphenylphosphine)palladium(0) (144.67 mg, 0.130 mmol) and heated to 100 °C. The mixture was stirred at this temperature for 16 hours, cooled, filtered, and evaporated. Purification by RP-HPLC gave the title compound (236 mg, 41.52% yield) as a pale yellow solid. MS (ESI): m / z=452.2 [M−H] − .

[0280] Step e): 3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; 2,2,2-trifluoroacetic acid A solution of tert-butyl 3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (550.0 mg, 1.21 mmol) in DCM (5.5 mL) was treated with TFA (0.37 mL, 4.85 mmol) at 25 °C. The mixture was stirred at this temperature for 18 hours. Diethyl ether was added, and the resulting precipitate was filtered and dried to give the title compound (500 mg, 80.09% yield) as a white solid. MS (ESI): m / z = 354 [M+H] + .

[0281] Example 7 N-[1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]methanesulfonamide; hydrochloride (B.3; 150.0 mg, 0.350 mmol) in DMF (5 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN33234-36-5; 64.88 mg, 0.350 mmol), HATU (171.88 mg, 0.450 mmol), and TEA (0.15 mL, 1.04 mmol) at 25 °C. The mixture was stirred at this temperature for 18 h, then poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated. Purification by RP-HPLC afforded 200 mg of the racemate. Chiral chromatography gave the title compound (49.5 mg, 25.26% yield) as a light brown solid. MS (ESI): m / z = 563.2 [M+H] + .

[0282] Step a): N-[1-(3-bromo-5-chloro-phenyl)cyclopropyl]methanesulfonamide A solution of 1-(3-bromo-5-chloro-phenyl)cyclopropanamine; hydrochloride salt (CASRN: 2089255-58-1; 3.0 g, 10.6 mmol) in dry DCM (40 mL) was treated with TEA (3.69 mL, 26.5 mmol) at 23 °C. The mixture was stirred at this temperature for 10 minutes and cooled to 0 °C. The mixture was treated dropwise with a solution of methanesulfonyl chloride (0.98 mL, 12.72 mmol) in DCM (4 mL) at 0 °C. The mixture was stirred at 23 °C for 4 hours, then treated with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to give the title compound (3 g, 82.82% yield) as a white solid. MS (ESI): m / z = 324.0 [M+H] + .

[0283] Step b): N-[1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]methanesulfonamide A solution of N-[1-(3-bromo-5-chloro-phenyl)cyclopropyl]methanesulfonamide (3.0 g, 9.24 mmol) in 1,4-dioxane (30 mL) was treated with bis(pinacolato)diboron (2581.49 mg, 10.17 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (754.11 mg, 0.920 mmol), and potassium acetate (2.72 g, 27.72 mmol) under Ar at 23 °C. The mixture was heated to 80 °C and stirred at this temperature for 16 h, then cooled, filtered, and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / MTBE) gave the title compound (2 g, 55.31% yield) as a pale yellow solid. MS (ESI): m / z = 289.0 [M+H] + .

[0284] Step c): [3-chloro-5-[1-(methanesulfonamido)cyclopropyl]phenyl]boronic acid A solution of N-[1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]methanesulfonamide (1.6 g, 4.3 mmol) in acetone (20 mL) was treated with a solution of sodium metaperiodate (2762.2 mg, 12.91 mmol) and ammonium acetate buffer (663.63 mg, 8.61 mmol) in water (8 mL) at 23 °C. The mixture was stirred at this temperature for 3 hours, and water (4 mL) was added. The mixture was stirred at 40 °C for 24 hours. After the addition of 4 N aqueous HCl (3 mL), the organic phase was concentrated under reduced pressure, and the remaining aqueous solution was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to give the title compound (1.1 g, 79.43% yield) as a dark brown oil. MS(ESI): m / z=287.8[MH] -.

[0285] Step d): tert-butyl 3-[3-chloro-5-[1-(methanesulfonamido)cyclopropyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of [3-chloro-5-[1-(methanesulfonamido)cyclopropyl]phenyl]boronic acid (942.44 mg, 3.25 mmol) in 4:1 THF / water (5 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet n° WO2020 / 065613 A1, 2020) (1.0 g, 2.5 mmol) and sodium carbonate (530.0 mg, 5 mmol) under Ar at 23 °C. The mixture was sparged with Ar for 10 minutes, and tetrakis(triphenylphosphine)palladium(0) (290.0 mg, 0.250 mmol) was added. The mixture was heated to 70 °C and stirred at this temperature for 16 hours, then cooled, filtered through SiO2, and evaporated. Purification by FC (SiO2; CHCl3 / ACN) gave the title compound (900 mg, 72.61% yield) as a white solid. MS (ESI): m / z = 495.0 [M+H] + .

[0286] Step e): N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]methanesulfonamide; hydrochloride A solution of tert-butyl 3-[3-chloro-5-[1-(methanesulfonamido)cyclopropyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (780.0 mg, 1.58 mmol) in MeOH (5 mL) was treated with 4 M HCl in 1,4-dioxane (2.34 mL, 9.36 mmol). The mixture was stirred at 23 °C for 16 h and then evaporated. Trituration with MTBE afforded the title compound (B.3; 387.8 mg, 54.2% yield) as a pale yellow solid. MS (ESI): m / z = 395.0 [M+H] + .

[0287] Example 8 (2-Chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 2,7-dimethyl-3-[6-(trifluoromethyl)pyridin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine (400.0 mg, 1.35 mmol) in DMF (3.0 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 251.06 mg, 1.35 mmol), HATU (613.93 mg, 1.61 mmol), and DIPEA (0.94 mL, 5.38 mmol) under Ar at 25 °C. The mixture was stirred for an additional 18 h and then purified by RP-HPLC and chiral chromatography to give the title compound (117.4 mg, 18.73% yield) as a white solid. MS (ESI): m / z = 466.0 [M+H] + .

[0288] Step a): tert-butyl 2,7-dimethyl-3-[6-(trifluoromethyl)pyridin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyrazine (CASRN 2223053-21-0; 3.92 g, 10.01 mmol) in dry DMF (95.99 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet n° WO2020 / 065613 A1, 2020) (4.0 g, 10.01 mmol) and sodium carbonate (2.12 g, 20.03 mmol) under Ar at 25 °C. The mixture was sparged with Ar for 10 minutes and then treated with tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1 mmol). The resulting mixture was heated to 100°C and stirred at this temperature for 16 h, then cooled, filtered, and evaporated. Purification by FC (SiO2; hexane / MTBE) afforded the title compound (1.3 g, 31% yield) as a pale yellow solid. MS (ESI): m / z = 342.0 [(M-tBu+H] + .

[0289] Step b): 2,7-dimethyl-3-[6-(trifluoromethyl)pyridin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; hydrochloride tert-Butyl 2,7-dimethyl-3-[6-(trifluoromethyl)pyridin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (1298.4 mg, 3.27 mmol) was treated with 4 M HCl in 1,4-dioxane (16.23 mL) at 25 °C. The mixture was stirred at this temperature for 18 hours. The resulting suspension was filtered and washed with diethyl ether to give the title compound (B.3; 950 mg, 87.12% yield) as a white powder. MS (ESI): m / z = 298 [M + H] + .

[0290] As with Example 8, commercially available components were used to generate the examples in the table below.

[0291] [Table 3]

[0292] Example 11 (2-Chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 2-chloro-3-methoxybenzoic acid (CASRN33234-36-5; 320.9 mg, 1.72 mmol) in DCM (5 mL) was treated with DMF and oxalyl chloride (0.15 mL, 1.72 mmol) dropwise under Ar at 20 °C. The mixture was stirred at this temperature for 1 hour and then evaporated. A solution of (2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)methyl-[1-(trifluoromethyl)cyclopropyl]ammonium dichloride (310.0 mg, 0.860 mmol) in DCM (10 mL) was treated with DIPEA (0.6 mL, 3.43 mmol) at 20 °C. The mixture was then cooled to 0 °C and treated dropwise with the acyl chloride prepared above. The mixture was warmed to 20°C and stirred at this temperature for 5 hours, then evaporated. Purification by RP-HPLC and chiral chromatography afforded the title compound (134.6 mg, 52.3% yield) as a brown solid. MS (ESI): m / z = 457.0 / 459.0 [M+H] + .

[0293] Step a): tert-Butyl 2,7-dimethyl-3-[(E)-styryl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of (E)-phenylethenylboronic acid (1867.27 mg, 12.62 mmol) in DMF (30 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (4200.0 mg, 10.52 mmol), sodium carbonate (2229.19 mg, 21.03 mmol), and tetrakis(triphenylphosphine)palladium(0) (607.6 mg, 0.530 mmol) in DMF (30 mL) under Ar at 20° C. The resulting mixture was heated to 100° C. and stirred at this temperature for 15 hours, then cooled and diluted with water. The aqueous phase was extracted with more EtOAc (3x) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. Purification by FC (SiO2; hexane / EtOAc 3:1) afforded the title compound (3200 mg, 83.42% yield) as a yellow solid. ESI (MS): m / z = 354.2 [M+H] + .

[0294] Step b): tert-Butyl 3-formyl-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-[(E)-styryl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (3200.0 mg, 9.05 mmol) in 5:1 1,4-dioxane / water (60 mL) was treated with osmium tetroxide (115.08 mg, 0.450 mmol) and sodium metaperiodate (5809.27 mg, 27.16 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred at this temperature for 5 h. A precipitate formed. The precipitate was filtered off, and the filtrate was diluted with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. Purification by FC (SiO2; hexane / EtOAc 3:1) afforded the title compound (C.1) (1022 mg, 36.76% yield) as a yellow oil. MS (ESI): m / z = 224.2 [M-Bu + H]+ .

[0295] Step c): tert-Butyl 2,7-dimethyl-3-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 3-formyl-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (300.0 mg, 1.07 mmol) in 1,2-dichloroethane (8 mL) was treated with [1-(trifluoromethyl)cyclopropyl]ammonium chloride (190.85 mg, 1.18 mmol) and acetic acid (144 μL, 0.25 mmol) at 25 °C. The mixture was stirred for 30 minutes and then treated with sodium triacetoxyborohydride (796.68 mg, 3.76 mmol). The resulting mixture was stirred at 20 °C for an additional 15 hours and then diluted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over Na2SO4, filtered, and evaporated to give the title compound (390 mg, 93.49% yield) as a pale yellow oil. ESI (MS): m / z = 389.3 [M+H] + .

[0296] Step d): (2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]ylidin-6-ium-3-yl)methyl-[1-(trifluoromethyl)cyclopropyl]ammonium; dichloride A solution of tert-butyl 2,7-dimethyl-3-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (340.0 mg, 0.880 mmol) in DCM (10 mL) was treated with hydrochloric acid (4 M in 1,4-dioxane) (2.19 mL, 8.75 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated to give the title compound (310 mg, 98.04% yield) as a crude pale yellow powder. MS (ESI): m / z = 289.2 [M+H] + .

[0297] Example 12 (2-Chloro-3-methoxyphenyl)-[(7S)-2,7-dimethyl-3-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of (2-chloro-3-methoxyphenyl)-[2,7-dimethyl-3-(2H-tetrazol-5-yl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (230.0 mg, 0.590 mmol) in toluene (10 mL) was treated with trifluoroacetic anhydride (0.1 mL, 0.710 mmol) at 20 °C. The mixture was stirred at this temperature for 1 hour, then heated to 100 °C and stirred for an additional 10 hours. The mixture was then cooled and evaporated. Purification by RP-HPLC and chiral chromatography afforded the title compound (51.8 mg, 29.3% yield) as a light brown foam. MS (ESI): m / z = 456.2 / 458.2 [M+H] + .

[0298] Step a): tert-Butyl 3-cyano-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (3000.0 mg, 7.51 mmol) in DMF (25 mL) was treated with zinc cyanide (0.52 mL, 8.26 mmol), 1,1'-bis(diphenylphosphino)ferrocene (416.42 mg, 0.750 mmol), and tris(dibenzylideneacetone)dipalladium(0) (343.92 mg, 0.380 mmol) under Ar at 20 °C. The resulting mixture was heated to 100 °C and stirred at this temperature for 10 h, then cooled and poured into water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / EtOAc 5:1) afforded the title compound (1100 mg, 49.97% yield) as a pale yellow solid. MS (ESI): m / z = 221.0 [M-Bu + H] + .

[0299] Step b): 2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-carbonitrile; chloride A solution of tert-butyl 3-cyano-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (300.0 mg, 1.09 mmol) in DCM (5 mL) was treated with HCl (4 M in 1,4-dioxane) (2.71 mL, 10.86 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated to give the title compound (230 mg, 91.44% yield) as a white solid. MS (ESI): m / z = 177.2 [M + H] + .

[0300] Step c): 6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3-carbonitrile A solution of 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 201.79 mg, 1.08 mmol) in DCM (5 mL) was treated dropwise with oxalyl chloride (0.14 mL, 1.62 mmol) at 20° C., stirred at this temperature for 1 hour, and evaporated. The residue was dissolved in DCM (10 mL), cooled to 0° C., and then treated with 2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-carbonitrile; chloride (230.0 mg, 1.08 mmol) and DIPEA (0.75 mL, 4.33 mmol). The mixture was warmed to 20° C. and stirred at this temperature for 5 hours. The reaction mixture was diluted with water, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound (340 mg, 78.96% yield) as a yellow solid. MS (ESI): m / z = 345.2 / 347.2 [M+H] + .

[0301] Step d): (2-chloro-3-methoxyphenyl)-[2,7-dimethyl-3-(2H-tetrazol-5-yl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone A solution of 6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-3-carbonitrile (240.0 mg, 0.700 mmol) in DMF (5 mL) was treated with ammonium chloride (55.85 mg, 1.04 mmol) and sodium azide (0.04 mL, 1.04 mmol) at 20 °C. The mixture was heated to 100 °C and stirred at this temperature for 10 hours, then cooled. The mixture was diluted with brine and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over Na SO , filtered, and evaporated to give the title compound (230 mg, 69.61% yield) as a pink solid. MS (ESI): m / z = 386.0 / 388.0 [MH] - .

[0302] Example 13 (2-Chloro-3-methoxyphenyl)-[(7S)-3-(6-hydroxy-2-pyridyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 2-chloro-3-methoxybenzoic acid (CASRN33234-36-5; 152.76 mg, 0.820 mmol) in DMF (3 mL) was treated with 6-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)pyridin-2-ol (200.0 mg, 0.820 mmol), TEA (0.57 mL, 4.09 mmol), and HATU (373.55 mg, 0.980 mmol) at 23 °C. The mixture was stirred at this temperature for 16 h and then purified by RP-HPLC and chiral chromatography to give the title compound (105.8 mg, 38.09% yield) as a brown solid. ESI (MS): m / z = 413.0 / 415.0 [M+H] + .

[0303] Step a): tert-butyl 3-(6-methoxy-2-pyridyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (1.0 g, 2.25 mmol) in dry DMF (15 mL) was treated with 6-methoxypyridine-2-boronic acid pinacol ester (CASRN: 1034297-69-2; 688.69 mg, 2.93 mmol) and sodium carbonate (477.67 mg, 4.51 mmol) under Ar at 23 °C. The mixture was sparged with Ar for 10 minutes, then treated with tetrakis(triphenylphosphine)palladium(0) (260.4 mg, 0.230 mmol) and heated to 100 °C. The mixture was stirred at this temperature for 16 hours, then cooled and filtered. Purification by RP-HPLC gave the title compound (559 mg, 69.21% yield) as a light brown oil. MS (ESI): m / z = 359.4 [M+H] + .

[0304] Step b): 6-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)pyridin-2-ol A solution of tert-butyl 3-(6-methoxy-2-pyridyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (559.0 mg, 1.56 mmol) in 12 N HCl (7.8 mL, 77.98 mmol) was heated to 100 °C and stirred at this temperature for 16 h. The mixture was then cooled, evaporated, and purified by RP-HPLC to give the title compound (159.5 mg, 41.86% yield) as a light brown solid. ESI (MS): m / z = 245.2 [M+H] + .

[0305] Example 14 2-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide [ka] A solution of methyl 2-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetate (80.0 mg, 0.160 mmol) in THF (10 mL) was treated with ammonia (1.0 mL, 14.68 mmol) and then heated to 50 °C. The mixture was stirred at this temperature for 30 minutes and then treated with CDI (51.64 mg, 0.320 mmol) in one portion. The mixture was stirred at this temperature for an additional 18 hours and then evaporated. Purification by RP-HPLC afforded the title compound (57.2 mg, 72.68% yield) as a white solid. MS (ESI): m / z = 488 [M+H] + .

[0306] Step a): Methyl 2-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate A solution of methyl 2-(3-bromo-5-chlorophenyl)acetate (CASRN: 960305-70-8; 500.0 mg, 1.9 mmol) in 1,4-dioxane (20 mL) was treated with bis(pinacolato)diboron (505.91 mg, 1.99 mmol) and potassium acetate (0.36 mL, 5.69 mmol) under Ar at 23 °C. The mixture was sparged with Ar and then treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (154.83 mg, 0.190 mmol) and heated to 110 °C. The mixture was stirred at this temperature for 16 h, cooled, filtered, and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound (500 mg, 74.67% yield). MS (ESI): m / z = 310.0 [M+H] + .

[0307] Step b): [3-chloro-5-(2-methoxy-2-oxo-ethyl)phenyl]boronic acid A solution of methyl 2-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (2.5 g, 8.05 mmol) in 2.5:1 THF / water (56 mL) was treated with sodium metaperiodate (5.17 g, 24.15 mmol) and ammonium acetate buffer (1.24 g, 16.1 mmol) at 25 °C. The mixture was stirred at this temperature for 18 h, then filtered and evaporated. Purification by RP-HPLC afforded the title compound (400 mg, 21.1% yield) as a pale yellow solid. MS (ESI): m / z = 227.8 [M−H] - .

[0308] Step c): tert-butyl 3-[3-chloro-5-(2-methoxy-2-oxoethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of [3-chloro-5-(2-methoxy-2-oxo-ethyl)phenyl]boronic acid (400.38 mg, 1.75 mmol) in dry DMF (10 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (700.0 mg, 1.75 mmol) and sodium carbonate (371.52 mg, 3.51 mmol) under Ar at 23 °C. The mixture was sparged with Ar and then treated with tetrakis(triphenylphosphine)palladium(0) (202.53 mg, 0.180 mmol) and heated to 100 °C. The mixture was stirred at this temperature for 16 h, cooled, filtered, and evaporated. FC (SiO2; hexane / EtOAc) gave the title compound (170 mg, 22.35% yield) as a pale yellow solid. MS (ESI): m / z = 434.0 [M+H] + .

[0309] Step d): Methyl 2-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]acetate; hydrochloride A 4M solution of tert-butyl 3-[3-chloro-5-(2-methoxy-2-oxo-ethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (170.0 mg, 0.390 mmol) in 1,4-dioxane (2 mL) was stirred at 25° C. for 18 hours. EtO was added, and the resulting precipitate was filtered and dried to give the title compound (100 mg, 62.04% yield) as a white solid. MS (ESI): m / z = 334.0 / 336.0 [M+H] + .

[0310] Step e): Methyl 2-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetate A solution of methyl 2-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]acetate (1081.08 mg, 2.4 mmol) in DMF (8 mL) was treated with 2-chloro-3-methoxybenzoic acid; hydrochloride (534.56 mg, 2.4 mmol), HATU (1093.5 mg, 2.88 mmol), and DIPEA (1.67 mL, 9.59 mmol) at 23 °C. The mixture was stirred at this temperature for 18 hours and then purified by RP-HPLC to give the racemate (373 mg, 30.98% yield) as a light brown solid. Purification by chiral chromatography gave the title compound (153 mg, 12.35% yield) as a white solid. MS (ESI): m / z = 503.0 [M+H] + .

[0311] Example 15 2-[3-chloro-5-[(7R)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide [ka] The title compound was prepared similarly to Example 14. 149 mg, 12.2% yield, white solid. MS (ESI): m / z = 503.0 [M+H] + .

[0312] Example 16 1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide [ka] A solution of 1-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxylic acid (99.81 mg, 0.190 mmol) in dry THF (10 mL) was treated with CDI (47.28 mg, 0.290 mmol) at 25 °C. The mixture was stirred at this temperature for 15 h, then treated with ammonia hydrate (296.25 mg, 1.94 mmol) and stirred for 15 h. The mixture was evaporated, and the residue was dissolved in EtOAc. The organic layer was washed with 0.1 N HCl, saturated aqueous NaHCO3, and brine, dried over Na2SO4, filtered, and evaporated. Purification by chiral chromatography afforded the title compound (27.6 mg, 27.65% yield) as a light brown solid. MS (ESI): m / z = 513.0 [M+H] + .

[0313] Step a): Methyl 1-(3-bromo-5-chloro-phenyl)cyclopropanecarboxylate A solution of 1-(3-bromo-5-chloro-phenyl)cyclopropanecarboxylic acid (CASRN: 1505800-30-5; 500.0 mg, 1.81 mmol) in MeOH (1 mL) was treated dropwise with thionyl chloride (259.07 mg, 2.18 mmol) at 0 °C. The mixture was then heated to 50 °C and stirred at this temperature for 16 h before being evaporated. The residue was dissolved in DCM, washed with water, dried over Na2SO4, filtered, and evaporated to give the title compound (520 mg, 94.02% yield) as a white solid. MS (ESI): m / z = 289.0 / 290.8 [M+H] + .

[0314] Step b): Methyl 1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate A solution of bis(pinacolato)diboron (456.05 mg, 1.8 mmol) in 1,4-dioxane (30 mL) was treated with methyl 1-(3-bromo-5-chlorophenyl)cyclopropanecarboxylate (520.0 mg, 1.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1465.45 mg, 1.8 mmol), and potassium acetate (0.11 mL, 1.8 mmol) under Ar at 23 °C. The mixture was heated to 110 °C and stirred at this temperature for 16 h, then filtered and evaporated. The residue was partitioned with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / MTBE) afforded the title compound (400 mg, 62.86% yield) as a crude white solid, which was used directly in the next step.

[0315] Step c): tert-butyl 3-[3-chloro-5-(1-methoxycarbonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1,2020) (310.0 mg, 0.780 mmol) in dry DMF (30 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (89.69 mg, 0.080 mmol), sodium carbonate (164.53 mg, 1.55 mmol) and methyl 1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (313.53 mg, 0.930 mmol) under Ar at 23 °C. The mixture was heated to 100°C and stirred at this temperature for 16 hours, then cooled, filtered and evaporated. Purification by FC (SiO2; hexane / EtOAc) afforded the title compound (300 mg, 84% yield) as a light brown solid. MS (ESI): m / z = 460.2 [M+H] + .

[0316] Step d): Methyl 1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropanecarboxylate; hydrochloride A solution of tert-butyl 3-[3-chloro-5-(1-methoxycarbonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (300.0 mg, 0.650 mmol) in 4 M HCl in 1,4-dioxane (2.0 mL, 8 mmol) at 23 °C. The mixture was stirred for 16 h and then evaporated. Trituration with MTBE gave the title compound (200 mg, 73.51% yield) as a white powder. MS (ESI): m / z = 360.0 [M+H] + .

[0317] Step e): Methyl 1-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxylate A solution of methyl 1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropanecarboxylate; hydrochloride (200.0 mg, 0.500 mmol) in DMF (5 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 94.16 mg, 0.500 mmol), HATU (287.8 g, 0.757 mmol), and TEA (0.25 mL, 1.77 mmol) at 23 °C. The mixture was stirred at this temperature for 16 h and then poured into water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated. Purification by RP-HPLC afforded the title compound (129 mg, 48.37% yield) as a pale yellow oil. MS (ESI): m / z = 529.0 [M+H] + .

[0318] Step f): 1-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxylic acid A solution of methyl 1-[3-chloro-5-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxylate (129.0 mg, 0.240 mmol) in 2.5:2.5:1 THF / MeOH / water (6 mL) was treated with LiOH monohydrate (25.61 mg, 0.610 mmol) at 25 °C. The mixture was heated to 50 °C and stirred at this temperature for 16 hours before evaporation. The residue was diluted with water and the pH adjusted to 3. The mixture was extracted with MTBE, and the combined organic layers were dried over Na SO , filtered, and evaporated to give the title compound (100 mg, 79.63% yield) as a white solid. MS (ESI): m / z = 514.2 [M+H] + .

[0319] Example 17 2-[3-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-5-fluorophenyl]acetamide [ka] A solution of 2-[3-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)-5-fluorophenyl]acetamide chloride (86.0 mg, 0.250 mmol) in DMF (0.500 mL) was treated with 2-chloro-3-methoxybenzoic acid (CASRN 33234-36-5; 47.36 mg, 0.250 mmol), HATU (115.82 mg, 0.300 mmol), and TEA (0.18 mL, 1.27 mmol) at 20 °C. The mixture was stirred for 10 h, filtered, and evaporated. Purification by RP-HPLC afforded the title compound (70 mg, 58.56% yield) as a light brown solid. Chiral chromatography afforded the desired enantiomer (23.1 mg, 33.0% yield) as a yellow solid. MS (ESI): m / z = 471.0 / 473.0 [M+H] + .

[0320] Step a): 2-(3-bromo-5-fluoro-phenyl)acetamide A solution of 2-(3-bromo-5-fluoro-phenyl)acetic acid (CASRN: 202001-01-2; 1.2 g, 5.15 mmol) in DCE (5 mL) was treated with a drop of DMF and thionyl chloride (0.56 mL, 7.72 mmol) at 23 °C. The mixture was heated to 80 °C and stirred at this temperature for 2 hours, then evaporated. The residue was evaporated with toluene and dissolved in THF (5 mL). The mixture was added dropwise to an aqueous solution of ammonia (25%; 30.0 mL, 5.15 mmol) at -5 °C. The mixture was stirred at 20 °C for 2 hours. The precipitate was filtered and dried to give the title compound (900 mg, 73.66% yield) as a pale yellow powder. MS (ESI): m / z = 232.0 / 234.0 [M+H] + .

[0321] Step b): 2-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide A solution of 2-(3-bromo-5-fluorophenyl)acetamide (200.0 mg, 0.860 mmol) in 1,4-dioxane (5 mL) was treated with bis(pinacolato)diboron (262.64 mg, 1.03 mmol) and potassium acetate (0.13 mL, 2.15 mmol) under Ar at 23 °C. The mixture was sparged with Ar and then treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (70.38 mg, 0.090 mmol) and heated to 100 °C. The mixture was stirred at this temperature for 5 h, cooled, and filtered through Celite. The filtrate was evaporated to give the title compound (250 mg, 88.23% yield) as a dark brown solid. MS (ESI): m / z = 279.0 [M+H] + .

[0322] Step c) tert-butyl 3-[3-(2-amino-2-oxo-ethyl)-5-fluoro-phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (180.0 mg, 0.340 mmol) in dry DMF (2 mL) was treated with 2-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (146.01 mg, 0.440 mmol) and sodium carbonate (38.26 mg, 0.360 mmol) under Ar at 23 ° C. The mixture was sparged with Ar for 10 min, treated with tetrakis(triphenylphosphine)palladium(0) (10.43 mg, 0.010 mmol), and heated to 100 ° C. The mixture was stirred at this temperature for 16 hours, then cooled, filtered and evaporated. Purification by RP-HPLC afforded the title compound (81.1 mg, 57.29% yield) as a light brown foam. MS (ESI): m / z = 347.2 [M-Bu + H] + .

[0323] Step d): 2-[3-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)-5-fluorophenyl]acetamide; chloride A solution of tert-butyl 3-[3-(2-amino-2-oxo-ethyl)-5-fluoro-phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (115.5 mg, 0.290 mmol) in DCM (1 mL) was treated with 4 M HCl in 1,4-dioxane (0.72 mL, 2.87 mmol) at 20 ° C. The mixture was stirred at this temperature for 10 hours and then evaporated to give the title compound (96 mg, 96.16% yield) as a light brown solid. MS (ESI): m / z = 303.0 [M + H] + .

[0324] Example 18 2-[5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-3-pyridyl]acetamide [ka] A solution of 2-chloro-3-methoxybenzoic acid (CASRN33234-36-5; 102.6 mg, 0.550 mmol) in DCM (1 mL) was treated with 1 drop of DMF and oxalyl chloride (0.09 mL, 1.1 mmol) at 20° C. The mixture was stirred at this temperature for 1 hour and then concentrated. The residue was then dissolved in DCM (2 mL) and added to a solution of 2-[5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)pyridin-1-ium-3-yl]acetamide dichloride (197.0 mg, 0.550 mmol) and DIPEA (0.38 mL, 2.2 mmol) in DCM (5 mL) at 0° C. The mixture was warmed to 20° C., stirred at this temperature for 10 hours, and then evaporated. Purification by RP-HPLC followed by chiral chromatography gave the title compound (74.3 mg, 40.2% yield) as a yellow viscous oil. MS (ESI): m / z=454.0 / 456.2 [M+H] + .

[0325] Step a): Methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]acetate A solution of methyl 2-(5-bromo-3-pyridyl)acetate (CASRN: 118650-08-1; 750.0 mg, 3.26 mmol) in 1,4-dioxane (15 mL) was treated with bis(pinacolato)diboron (952.03 mg, 3.75 mmol) and potassium acetate (0.61 mL, 9.78 mmol) under Ar at 20 °C. The mixture was sparged with Ar and treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (266.23 mg, 0.330 mmol). The mixture was heated to 100 °C and stirred at this temperature for 15 h before being evaporated. The residue was dissolved in EtOAc, filtered through celite, and evaporated. Trituration with hexane gave the title compound (770 mg, yield 80.54%) as a brown solid. MS (ESI): m / z = 277.0 [M] + .

[0326] Step b): tert-butyl 3-[5-(2-methoxy-2-oxo-ethyl)-3-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of methyl 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]acetate (767.87 mg, 2.49 mmol) in DMF (7 mL) was treated with tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevetn° WO 2020 / 065613, 2020) (830.0 mg, 2.08 mmol) and sodium carbonate (440.53 mg, 4.16 mmol) under Ar at 20 °C. The mixture was sparged with Ar and then treated with tetrakis(triphenylphosphine)palladium(0) (120.07 mg, 0.100 mmol). The resulting mixture was heated to 100° C. and stirred at this temperature for 15 h, then cooled and diluted with water (10 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. Purification by RP-HPLC afforded the title compound (225 mg, 27.04% yield) as a brown foam. MS (ESI): m / z=401.2 [M+H] + .

[0327] Step c): tert-butyl 3-[5-(2-amino-2-oxo-ethyl)-3-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 3-[5-(2-methoxy-2-oxo-ethyl)-3-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (225.0 mg, 0.560 mmol) in ammonia (25% in MeOH) (4.78 mL, 56.18 mmol) was stirred at 20 °C for 10 h and then evaporated to give the title compound (214 mg, 98.81% yield) as a light brown foam. MS (ESI): m / z = 386.2 [M + H] + .

[0328] Step d): 2-[5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)pyridin-1-ium-3-yl]acetamide; dichloride A solution of tert-butyl 3-[5-(2-amino-2-oxo-ethyl)-3-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (214.0 mg, 0.560 mmol) in DCM (2 mL) was treated with 4 M HCl in 1,4-dioxane (1.39 mL, 5.55 mmol) at 20 °C. The mixture was stirred at this temperature for an additional 15 h and then evaporated to give the title compound (197 mg, 99.04% yield) as a pale yellow solid. MS (ESI): m / z = 286.2 [M+H] + .

[0329] Example 19 [2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 2-chloro-3-(2,2-diketo-2λ6-thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoic acid (C.1) (54.67 mg, 0.171 mmol) in dry DMF (1.5 mL) was treated with HATU (78.02 mg, 0.205 mmol) and DIPEA (291.93 μL, 1.71 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for 10 min, then treated with 1:5 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine / 2,2,2-trifluoroacetic acid (Patentnr. WO2020 / 065613 A1,2020) (B.5; 150 mg, 0.171 mmol) and stirred for an additional 20 h. Purification by FC (SiO2; DCM / MeOH) afforded the title compound (28 mg, 43.47% yield) as a white solid. MS (ESI): m / z = 565.2 [M+H] + .

[0330] Examples 20 and 21 [2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 20) and [2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 21) [ka] Example 19 was purified by chiral chromatography to give the title compound (Example 20) (26 mg, 26.91%) as a white solid, and the title compound (Example 21) (27 mg, 27.95%) as a white solid. MS (ESI): m / z = 565.2 [M+H] + .

[0331] Similar to Examples 19-21, the examples in the table below were prepared using amine B.5 and acid CX or commercially available acid.

[0332] [Table 4] TIFF2025503438000136.tif218165 TIFF2025503438000137.tif218165 TIFF2025503438000138.tif222165 TIFF2025503438000139.tif207165 TIFF2025503438000140.tif231165 TIFF2025503438000141.tif50165

[0333] Example 53 4-[3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile [ka] Example 53 was produced as a by-product during the synthesis of Example 36 and was isolated during purification (34.7 mg, 10.0% yield).

[0334] Example 54 [3-(3,5-Difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-pyrrolidin-3-yl-1,2,4-triazol-3-yl)methanone; Hydrochloride (one diastereomer, unknown stereochemistry) [ka] A solution of tert-butyl (3S)-3-[5-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]pyrrolidine-1-carboxylate (104.0 mg, 0.200 mmol) in MeOH (0.500 mL) was treated with 10 M aqueous HCl (0.2 mL, 1.97 mmol) at 23 °C. The mixture was stirred at this temperature for 16 h and then evaporated. RP-HPLC afforded the title compound (39.7 mg, 43.41% yield) as a light brown solid. MS (ESI): m / z = 428.2 [M+H] + .

[0335] Step a): Ethyl 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate and ethyl 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate A solution of ethyl 1H-1,2,4-triazole-3-carboxylate (CASRN: 4928-88-5; 699.64 mg, 4.96 mmol) in DMF (10 mL) was treated with tert-butyl 3-bromopyrrolidine-1-carboxylate (CASRN: 939793-16-5; 1.24 g, 4.96 mmol) and potassium carbonate (1370.33 mg, 9.91 mmol) at 25° C. The mixture was stirred at this temperature for 16 h and then purified by FC (SiO2; hexane / EtOAc) to give first eluting ethyl 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate (390 mg, 25.35% yield) as a colorless oil and second eluting ethyl 1-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate (210 mg, 13.65% yield) as a colorless oil. For both examples, MS (ESI) m / z = 311.2 [M+H] + .

[0336] Step b): Methyl 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate A solution of methyl 2-pyrrolidin-3-yl-1,2,4-triazole-3-carboxylate dihydrochloride (1.0 g, 3.72 mmol) in DCM (15 mL) was treated with methyl 2-pyrrolidin-3-yl-1,2,4-triazole-3-carboxylate dihydrochloride (1.0 g, 3.72 mmol) and BocO (1.02 mL, 4.46 mmol) at 23 °C. The mixture was stirred at this temperature for a further 16 h and then evaporated. Purification by FC (SiO; hexane / EtOAc 1:1) afforded the title compound (950 mg, 86.28% yield) as a colorless oil. MS (ESI): m / z = 297.2 [M+H] + .

[0337] Step c): tert-butyl 3-[(1S)-5-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]pyrrolidine-1-carboxylate A solution of 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine (399.84 mg, 1.52 mmol) (prepared from hydrochloride salt and NaOH solution and extracted with DCM) in 1,2-dichloroethane (5 mL) was treated with trimethylaluminum (2.0 M in heptane) (1.01 mL, 2.02 mmol) and methyl 2-(1-tert-butoxycarbonylpyrrolidin-3-yl)-1,2,4-triazole-3-carboxylate (300.0 mg, 1.01 mmol) under Ar at 0° C. The mixture was heated to 60° C. and stirred at this temperature for 16 h, then cooled to 0° C. and treated with water (1 mL). The mixture was stirred for 10 min, filtered through celite, and evaporated. Purification by RP-HPLC and chiral chromatography gave the title compound (104 mg, 25.0% yield) as a brown oil. MS (ESI): m / z = 529.4 [M+H] + .

[0338] Example 55 N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of HATU (42.31 mg, 0.111 mmol) in DMF (0.813 mL) was treated with DIPEA (119.84 mg, 158.31 μL, 0.927 mmol) and 2-chloro-5-fluoro-3-(6-keto-1H-pyridin-3-yl)benzoic acid (C.5; 24.82 mg, 0.093 mmol) under Ar at 23 ° C. The mixture was stirred at this temperature for 10 minutes, after which N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]methanesulfonamide; hydrochloride (B.2; 40 mg, 0.093 mmol) was added and stirred for an additional 18 hours. Purification by RP-HPLC gave the title compound (29 mg, 48.52%) as an off-white lyophilized powder. MS (ESI): m / z = 644.4 [M+H] + .

[0339] Similar to Example 55, the examples in the table below were made using amine BX and carboxylic acid CY.

[0340] [Table 5] TIFF2025503438000146.tif102165

[0341] Example 62 3-chloro-5-[(7S)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide [ka] Example 59 (30 mg, 0.06 mmol) was separated by chiral chromatography to give the title compound (6.7 mg, 22.3% yield) as an off-white amorphous solid. MS (ESI): m / z = 527.3 [M+H] + .

[0342] Example 63 3-chloro-5-[(7R)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide [ka] Example 59 (30 mg, 0.06 mmol) was separated by chiral chromatography to give the title compound (5.7 mg, 19.0% yield) as an off-white amorphous solid. MS (ESI): m / z = 527.3 [M+H] + .

[0343] Example 64 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid (C.11; 35.68 mg, 0.135 mmol) under Ar at 23 °C. After stirring the mixture at this temperature for 10 min, 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 45 mg, 0.135 mmol) was added and stirred for an additional 18 h. Purification by RP-HPLC afforded the racemate as a white lyophilizate (45 mg). Purification by chiral chromatography gave the title compound (16.2 mg, 22.09%) as a white solid. MS (ESI): m / z = 544.3 [M+H] + .

[0344] Example 65 [2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 2-chloro-3-(2,2-diketo-2λ) at 23 °C under Ar. 6 The mixture was treated with 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; hydrochloride (B.3; 45 mg, 0.135 mmol) and stirred for an additional 18 hours. Purification by RP-HPLC afforded the racemic product as a white lyophilizate (62 mg). Purification by chiral chromatography afforded the title compound (17 mg, 21.05%) as a white solid. MS (ESI): m / z = 599.4 [M+H] + .

[0345] Example 66 [2-chloro-3-(2,2-dioxo-2λ 6 -Thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 2-chloro-3-(2,2-diketo-2λ6-thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorobenzoic acid (C.1; 43.11 mg, 0.135 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for 10 min, after which 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 45 mg, 0.135 mmol) was added and stirred for an additional 18 h. Purification by RP-HPLC afforded the racemic product as a white lyophilizate (62 mg). Purification by chiral chromatography gave the title compound (23.4 mg, 29.0%) as a white solid. MS (ESI): m / z = 599.4 [M+H] + .

[0346] Example 67 3-[3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 1-(2-keto-1H-pyridin-3-yl)-1,2,4-triazole-3-carboxylic acid (C.7; 27.8 mg, 0.135 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for 10 min, after which 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 45 mg, 0.135 mmol) was added and stirred for an additional 18 h. Purification by RP-HPLC afforded the racemate as a white lyophilizate (35 mg). Purification by chiral chromatography gave the title compound (10 mg, 15.28%) as an off-white solid. MS (ESI): m / z = 486.4 [M+H] + .

[0347] Example 68 5-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 2-chloro-5-fluoro-3-(6-keto-1H-pyridin-3-yl)benzoic acid (C.5; 36.09 mg, 0.135 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for 10 minutes, after which 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 45 mg, 0.135 mmol) was added and stirred for an additional 18 hours. Purification by RP-HPLC and chiral chromatography afforded the title compound (11 mg, 14.92%) as a light brown powder. MS (ESI): m / z = 547.4 [M+H] + .

[0348] The following compounds were made similarly to the compounds above. [Table 6] TIFF2025503438000155.tif229165

[0349] Example 80 N-[[2-chloro-6-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-4-pyridyl]methyl]methanesulfonamide [ka] A solution of 2-chloro-3-methoxybenzoic acid (21.07 mg, 0.11 mmol) in DCM (1 mL) was treated with oxalyl chloride (0.01 mL, 0.14 mmol) at 23 °C. The mixture was stirred at this temperature for 1 hour and then evaporated. The residue was dissolved in DCM (1 mL). N-[[2-chloro-6-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)pyridin-1-ium-4-yl]methyl]methanesulfonamide; dichloride (50.0 mg, 0.11 mmol) and triethylamine (0.08 mL, 0.56 mmol) were added to the solution, and the resulting mixture was stirred at 20 °C for 10 hours and then evaporated. The residue was purified by RP-HPLC to give the title compound (46.0 mg, 75.66%) as a light brown solid. MS (ESI): m / z = 538.0 [M+H] +

[0350] Step a): tert-Butyl 2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (8.0 g, 20.03 mmol) in 1.33 L of EtOAc was treated with molecular sieves (17.64 g, 40.05 mmol), triethylamine (4.19 mL, 30.04 mmol), and 10% Pd / C (8.0 g) under Ar. The mixture was then hydrogenated at 1500 mmHg (with balloon) at 25°C for 18 hours. The mixture was filtered and evaporated to give the title compound (5.0 g, 98.35% yield) as a pale yellow viscous oil. MS (ESI): m / z = 196 [M-tBu+H] +

[0351] Step b): tert-Butyl 3-bromo-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of tert-butyl 2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (3.0 g, 11.94 mmol) in ACN (30 mL) was treated with NBS (2.1 g, 11.94 mmol) at 23 °C. The mixture was stirred at this temperature for 15 h, then evaporated and dissolved in EtOAc. The organic layer was washed with water and brine, then dried over Na2SO4, filtered, and evaporated to give the title compound (3.3 g, 78.44% yield) as a pale yellow solid. MS (ESI): m / z = 274.0 / 276.0 [M-Bu+H] +

[0352] Step c): (6-tert-butoxycarbonyl-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl)boronic acid A solution of tert-butyl 3-bromo-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (4.1 g, 12.42 mmol) in THF (50 mL) was treated dropwise with a 2.5 M n-butyllithium solution in THF (6.21 mL, 15.52 mmol) at −78° C. under Ar. After stirring at this temperature for 1 h, trimethyl borate (3.87 g, 37.25 mmol) was added, and the resulting solution was stirred at −78° C. for 8 h and at 20° C. for 10 h. The mixture was then carefully treated with 1 N aqueous HCl and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and evaporated to give the title compound (2.78 g, 66.31% yield) as a yellow foam. MS (ESI): m / z = 296.2 [M+H] +

[0353] Step d): N-[(2,6-dichloro-4-pyridyl)methyl]methanesulfonamide A suspension of (2,6-dichloropyridin-1-ium-4-yl)methylammonium dichloride (1.69 g, 6.76 mmol) in DCM (30 mL) was cooled to 0° C. and triethylamine (3.77 mL, 27.05 mmol) was added. The mixture was stirred for 30 minutes, and methanesulfonyl chloride (0.58 mL, 7.44 mmol) was added dropwise, maintaining the temperature below 5° C. The mixture was then warmed to 20° C. and stirred at that temperature for 5 hours. The mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate and evaporated to give the title compound (1.49 g, 85.52% yield) as a brown solid. MS (ESI): m / z = 255.0 / 257.0 [M+H] +

[0354] Step e): tert-Butyl 3-[6-chloro-4-(methanesulfonamidomethyl)-2-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A solution of (6-tert-butoxycarbonyl-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl)boronic acid (450.0 mg, 1.52 mmol) in 1,4-dioxane (15 mL) was treated with N-[(2,6-dichloro-4-pyridyl)methyl]methanesulfonamide (330.63 mg, 1.3 mmol) and potassium carbonate (526.81 mg, 3.81 mmol, 2.5 equiv.) at 23 °C. The mixture was sparged with Ar and then treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (124.42 mg, 0.15 mmol). The resulting mixture was stirred in a sealed vessel at 100 °C for 15 h, then cooled and evaporated. The residue was dissolved in EtOAc, and the resulting suspension was filtered through celite. The filtrate was concentrated, and the residue was purified by RP-HPLC to give the title compound (130.3 mg, 17.67%) as a light brown foam. MS (ESI): m / z = 414.0 / 416.0 [M-Bu+H] +

[0355] Step f): N-[[2-chloro-6-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium-3-yl)pyridin-1-ium-4-yl]methyl]methanesulfonamide; dichloride A solution of tert-butyl 3-[6-chloro-4-(methanesulfonamidomethyl)-2-pyridyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (130.3 mg, 0.28 mmol) in DCM (2 mL) was treated with hydrochloric acid (4 M in 1,4-dioxane) (0.69 mL, 2.77 mmol) at 20 °C. The mixture was stirred at this temperature for 20 h and then evaporated to give the title compound (120.0 mg, 94.23%) as a light brown solid. MS (ESI): m / z = 370.0 / 372.0 [M+H] +

[0356] Example 81 (2-Chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-4-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone [ka] A solution of 2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-4-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 200.0 mg, 0.6 mmol) in DMF (3 mL) was treated with 2-chloro-3-methoxybenzoic acid (123.0 mg, 0.66 mmol), HATU (341.79 mg, 0.9 mmol), and N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) at 23 °C. The mixture was stirred at this temperature for an additional 18 h and then purified by RP-HPLC. Chiral chromatography afforded the title compound (44.2 mg, 15.83% yield) as a white solid. MS (ESI): m / z = 466 [M+H] +

[0357] Example 82 and Example 83 4-[2-chloro-5-fluoro-3-[(7S)-3-[3-fluoro-5-[[methyl(dioxo)-λ 6 -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile (Example 82) and 4-[2-chloro-5-fluoro-3-[(7R)-3-[3-fluoro-5-[[methyl(dioxo)-λ 6 -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile (Example 83) [ka] A solution of 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid (C.11; 149.47 mg, 0.51 mmol), 3-[3-(dimethylphosphorylmethyl)-5-fluoro-phenyl]-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (189.0 mg, 0.51 mmol) and triethylamine (0.35 mL, 2.54 mmol) in DMF (3 mL) was treated with HATU (212.6 mg, 0.56 mmol) and stirred at 20 ° C. for 16 hours. Purification by RP-HPLC followed by chiral chromatography gave Example 82 (51.0 mg, 30.37% yield) and Example 83 (52.4 mg, 32.17% yield) as light brown solids. MS (ESI): m / z = 582.2 [M+H] +

[0358] Step a): 1-Bromo-3-(dimethylphosphorylmethyl)-5-fluoro-benzene A solution of 1-bromo-3-(bromomethyl)-5-fluoro-benzene (10.0 g, 37.32 mmol) in THF (150 mL) was treated with a solution of NaHMDS in THF (27.99 mL, 55.99 mmol). The mixture was stirred for 30 minutes, then treated in portions with dimethylphosphine oxide (4.37 g, 55.99 mmol) and stirred for 16 hours. Water (1 mL) was then added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated. Trituration with hexane afforded the title compound (1.15 g, 11.62%) as a white solid. MS (ESI): m / z = 265 / 267 [M+H] +

[0359] Step b): 2-[3-(dimethylphosphorylmethyl)-5-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A solution of bis(pinacolato)diboron (1.44 g, 5.66 mmol), potassium acetate (0.71 mL, 11.32 mmol), 1-bromo-3-(dimethylphosphorylmethyl)-5-fluoro-benzene (1.0 g, 3.77 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (153.93 mg, 0.19 mmol) in 1,4-dioxane (15 mL) was sparged with Ar, sealed, and heated at 100 °C for 16 h. The mixture was cooled, filtered, and evaporated to give the crude title compound (1.07 g, 87.0% yield) as a brown solid. MS (ESI): m / z = 313.2 [M+H] +

[0360] Step c): tert-butyl-3-[3-(dimethylphosphorylmethyl)-5-fluorophenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A degassed suspension of 2-[3-(dimethylphosphorylmethyl)-5-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (570.1 mg, 1.64 mmol), tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (505.0 mg, 1.26 mmol), and sodium carbonate (268.0 mg, 2.53 mmol) in toluene (15 mL) / water (1.5 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (73.1 mg, 0.06 mmol). The resulting mixture was stirred at 80 °C for 15 h, then cooled and evaporated. Purification by RP-HPLC gave the title compound (287.0 mg, 52.12% yield) as a brown oil. MS (ESI): m / z = 380.2 [M-Bu+H] +

[0361] Step d): 3-[3-(dimethylphosphorylmethyl)-5-fluorophenyl]-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; hydrochloride A solution of tert-butyl 3-[3-(dimethylphosphorylmethyl)-5-fluorophenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (630.0 mg, 1.45 mmol) in DCM (3 mL) was treated with a solution of HCl in dioxane (3.62 mL, 14.47 mmol). The mixture was stirred at 20° C. for 10 hours and then evaporated. Purification by RP-HPLC afforded the title compound (398.5 mg, 70.38% yield) as a light brown solid. MS (ESI): m / z=336.2 [M+H] +

[0362] Example 84 N-[1-[3-chloro-5-[6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid (C.11; 149.47 mg, 0.51 mmol), N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]-methanesulfonamide; hydrochloride (B.2; 189.0 mg, 0.51 mmol) and triethylamine (0.35 mL, 2.54 mmol) in DMF (3 mL) was treated with HATU (212.6 mg, 0.56 mmol) at 20 ° C. The mixture was stirred at this temperature for another 16 hours and then purified by RP-HPLC to give the title compound (136.0 mg, 44.13% yield) as a pink solid. MS (ESI): m / z = 641.2 [M+H] +

[0363] Example 85 and Example 86 N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 85) and N-[1-[3-chloro-5-[(7R)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 86). [ka] N-[1-[3-chloro-5-[6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 84; 163 mg, 0.3 mmol) was purified by chiral HPLC to give Example 85 (51.0 mg, 30.37% yield) and Example 86 (52.4 mg, 32.17% yield) as light brown solids. MS (ESI): m / z = 641.2 [M + H] +

[0364] Example 87 N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]methanesulfonamide hydrochloride (B.2; 60 mg, 0.139 mmol) in N,N-dimethylformamide (1.18 mL) and n-ethyldiisopropylamine (237.47 μL, 1.39 mmol) was treated with 2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoic acid; 2,2,2-trifluoroacetic acid (C.18; 53.53 mg, 0.140 mmol) and HATU (106.52 mg, 0.280 mmol) at 23 °C. The mixture was stirred for 18 h and then purified by RP-HPLC to give the title compound (19.4 mg, 21.6%) as a colorless foam. MS (ESI): m / z=644.3 [M+H] +

[0365] Step a): 1-[(4-methoxyphenyl)methyl]-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]triazole A solution of 2,2,6,6-tetramethylpiperidine (9.32 mL, 55.24 mmol) in THF (550 mL) under Ar was cooled to −30° C. and then treated dropwise with a 2.5 M solution of n-butyllithium in THF (22.1 mL, 55.24 mmol). The mixture was stirred at this temperature for 30 min, then cooled to −78° C. and treated dropwise with a solution of 1-[(4-methoxyphenyl)methyl]triazole-4-carbaldehyde (CASRN: 853807-54-2; 10.0 g, 46.04 mmol) in THF (100 mL). The mixture was stirred at this temperature for 30 min and then treated dropwise with a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (13.57 g, 50.64 mmol) in THF (50 mL). The mixture was slowly warmed to 23 °C and stirred at this temperature for an additional 16 h, then cooled to 0 °C and treated dropwise with saturated aqueous NH4Cl (150 mL). The mixture was stirred for 1 h and then filtered. Water (200 mL) was added to the filtrate and the mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; PE / MTBE) afforded the title compound (4.4 g, 26.61% yield) as a white solid. MS (ESI): m / z = 342.2 [M+H] +

[0366] Step b): Methyl 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]vinyl]benzoate A suspension of 1-[(4-methoxyphenyl)methyl]-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]triazole (3.0 g, 8.79 mmol), methyl 3-bromo-2-chloro-5-fluorobenzoate (2.59 g, 9.67 mmol), and potassium carbonate (2.43 g, 17.58 mmol) in 1,4-dioxane (40 mL) and water (5 mL) was sparged with Ar for 5 min and then treated with Pd(dppf)Cl·CHCl (1.44 g, 1.76 mmol). The mixture was stirred under Ar at 80 °C for 18 h, then cooled and filtered through SiO (25 g), rinsing with dioxane (100 mL). The filtrate was evaporated. Purification by FC (SiO2; CHCl3 / MTBE) gave the title compound (1.65 g, 44.37% yield) as a pale yellow solid. MS (ESI): m / z = 402.0 [M+H] +

[0367] Step c): Methyl 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl]benzoate A solution of methyl 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]vinyl]benzoate (1650.0 mg, 4.11 mmol) and Rh / C (10%) (500 mg) in 150 mL of EtOAc was hydrogenated at 7600 mmHg (10 bar) at 25° C. for 18 hours. The reaction mixture was filtered and evaporated to give the title compound (1.60 g, 89.73% yield) as a dark green oil. MS (ESI): m / z = 404.0 [M+H] +

[0368] Step d): 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl]benzoic acid A mixture of methyl 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl]benzoate (1.5 g, 3.71 mmol) in 4:1 methanol / water (25 mL) was treated with a solution of lithium hydroxide monohydrate (264.96 mg, 6.31 mmol) in THF (20 mL) at 23 °C. The mixture was stirred at this temperature for 18 h and then evaporated. The residue was treated with water, and the resulting solution was acidified with citric acid (aq) and extracted with TBME (2 × 50 mL). The combined organic layers were dried over Na SO , filtered, and evaporated to give the title compound (1.35 g, 88.58% yield) as a pale gray solid. MS (ESI): m / z = 390.2 [M+H] +

[0369] Step e): 2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoic acid; 2,2,2-trifluoroacetic acid (C.18) A solution of 2-chloro-5-fluoro-3-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl]benzoic acid (1350.0 mg, 3.46 mmol) and anisole (1.88 mL, 17.32 mmol) in trifluoroacetic acid (5.34 mL, 69.26 mmol) was stirred at 70 °C for 120 h (sealed tube). The mixture was then cooled and purified by RP-HPLC to give the title compound (C.18; 116.9 mg, 8.36% yield) as a white solid. MS (ESI): m / z = 270.0 [M+H] +

[0370] Example 88 and Example 89 N-[1-[3-chloro-5-[(7S)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 88) and N-[1-[3-chloro-5-[(7R)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 89) [ka] N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide (Example 87; 18 mg, 0.027 mmol) was separated by chiral SFC to give Example 88 (4.4 mg, 24%) and Example 89 (6.9 mg, 38%) as white solids. MS (ESI): m / z = 644.3 [M + H] +

[0371] Example 90 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile [ka] A mixture of 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid (C.11; 162.03 mg, 0.55 mmol), 2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.6; 185.0 mg, 0.55 mmol), and triethylamine (0.38 mL, 2.76 mmol) in DMF (3 mL) was treated with HATU (230.47 mg, 0.61 mmol). The mixture was stirred at 20 °C for 16 h and then purified by RP-HPLC and chiral HPLC to give the title compound (54.9 mg, 33%) as a white solid. MS (ESI): m / z = 546.0 [M+H] +

[0372] Step a): tert-Butyl 2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A degassed suspension of 2,3,4,5-tetrafluorophenylboronic acid (631.1 mg, 3.25 mmol), tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (1.0 g, 2.5 mmol), and sodium carbonate (530.75 mg, 5.01 mmol) in DMF (10 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (144.67 mg, 0.13 mmol) at 23 ° C. The resulting mixture was stirred at 100 ° C. for 15 hours, then cooled and purified by RP-HPLC to give the title compound (223.0 mg, 22.3% yield) as a brown oil. MS (ESI): m / z = 344.2 [M-Bu + H] +

[0373] Step b): 2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; hydrochloride salt (B.6) A solution of tert-butyl 2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (223.0 mg, 0.56 mmol) in DCM (0.5 mL) was treated with 1,4-dioxane HCl solution (0.7 mL, 2.79 mmol) at 23 °C. The resulting mixture was stirred at this temperature for 16 h and then evaporated to give the title compound (B.6; 185 mg, 99% yield) as a brown solid. MS (ESI): m / z = 300.0 [M-Bu + H] +

[0374] Example 91 N-[1-[3-chloro-5-[(7S)-6-[1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carbonyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of HATU (42.31 mg, 0.111 mmol) in ultra-dry N,N-dimethylformamide (0.813 mL) was treated with n-ethyldiisopropylamine (158.31 μL, 0.927 mmol) and 1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carboxylic acid (C.10; 22.31 mg, 0.093 mmol) under Ar at 23 °C. After stirring the mixture at this temperature for 10 min, N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]cyclopropyl]methanesulfonamide hydrochloride (B.2; 40 mg, 0.093 mmol) was added and the mixture was stirred for an additional 18 h. Purification by RP-HPLC and chiral HPLC gave the title compound (15.6 mg, 25.88%) as a white solid. MS (ESI): m / z = 615.2 [M−H] -

[0375] Example 92 and Example 93 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile (Example 92) and 4-[2-chloro-3-[(7R)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile (Example 93) [ka] A solution of 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid (C.11; 150.0 mg, 0.57 mmol) in DMF (2 mL) was added to 2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.7; 180.1 mg, 0.57 mmol), triethylamine (0.4 mL, 2.83 mmol), and HATU (237.07 mg, 0.62 mmol) at 20 °C. The mixture was stirred at this temperature for 16 h. Purification by RP-HPLC and chiral chromatography afforded Example 92 (67 mg, 42% yield) and Example 93 (64 mg, 40% yield) as white solids. MS (ESI): m / z = 528.0 [M+H] +

[0376] Step a): tert-Butyl 2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A degassed suspension of 3,4,5-trifluorophenylboronic acid (0.63 g, 3.61 mmol), tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1, 2020) (1.2 g, 3.0 mmol), and sodium carbonate (636.9 mg, 6.01 mmol) in DMF (15 mL) was treated with tetrakis(triphenylphosphine)palladium(0) (173.6 mg, 0.15 mmol). The resulting mixture was stirred at 100 °C for 15 h, then cooled and diluted with water (30 mL). The mixture was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. Purification by FC (SiO2; hexane / EtOAc) gave the title compound (980.0 mg, 79.28% yield) as a white solid. MS (ESI): m / z = 326.0 [M+H-tBu] +

[0377] Step b): 2,7-dimethyl-3-(3,4,5-trifluorophenyl)-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine; hydrochloride salt (B.7) A solution of tert-butyl 2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (980.0 mg, 2.57 mmol) in DCM (10 mL) was treated with hydrochloric acid (4 M in dioxane) (6.42 mL, 25.7 mmol). The mixture was stirred at 20 °C for 16 h and then evaporated to give the title compound (B.7; 680.0 mg, 83.29% yield) as a pale yellow solid. MS (ESI): m / z = 282.0 [M+H] +

[0378] Example 94 N-[1-[3-chloro-5-[(7S)-6-[2,5-difluoro-3-(1H-pyrazol-4-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide [ka] A solution of 2,5-difluoro-3-(1H-pyrazol-4-yl)benzoic acid (C.19; 31.18 mg, 0.139 mmol) in ultra-dry tetrahydrofuran (2 mL) was treated with HATU (63.46 mg, 0.167 mmol) and DIPEA (97.17 μL, 0.556 mmol) under Ar at 20 °C. The mixture was stirred at this temperature for 10 min and then treated with N-[1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]-cyclopropyl]methanesulfonamide; hydrochloride (B.2; 60 mg, 0.139 mmol). The mixture was stirred at this temperature for 18 h and then diluted with EtOAc. The organic layer was washed with water (1×) and brine (3×), dried over Na2SO4, filtered, and evaporated. Purification by RP-HPLC and chiral SFC gave the title compound (4 mg, 4.55%) as an off-white solid. MS (ESI): m / z = 599.4 [M−H] -

[0379] Step a): Methyl 2,5-difluoro-3-(1H-pyrazol-4-yl)benzoate A solution of methyl 3-bromo-2,5-difluorobenzoate (CASRN: 1524902-93-9; 2.0 g, 7.97 mmol) and 4-pyrazoleboronic acid pinacol ester (CASRN: 269410-08-4; 1.5 g, 7.97 mmol) and KCO (2.2 g, 15.93 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (650.15 mg, 0.8 mmol) under N at 23 °C. The mixture was stirred at 100 °C under N for 12 h, then filtered and evaporated. Purification by RP-HPLC afforded the title compound (110.0 mg, 5.8% yield) as a pale yellow solid. MS (ESI): m / z = 239.3 [M+H] +

[0380] Step b): 2,5-Difluoro-3-(1H-pyrazol-4-yl)benzoic acid (C.19) A solution of methyl 2,5-difluoro-3-(1H-pyrazol-4-yl)benzoate (50.0 mg, 0.21 mmol) in methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) was treated with LiOH monohydrate (44.04 mg, 1.05 mmol) at 23 °C. The mixture was stirred at that temperature for 6 hours and then extracted with EtOAc. The aqueous phase was acidified to pH 4 with 1N aqueous HCl, and the aqueous phase was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (C.19; 35.0 mg, 74%) as a white solid. MS (ESI): m / z = 225.0 [M+H] +

[0381] Example 95 [(7S)-3-[3-chloro-5-(2-hydroxy-2-methyl-propyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone [ka] A solution of 2-chloro-3-methoxybenzoic acid (150.0 mg, 0.8 mmol) in DMF (2 mL) was treated with 1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]-2-methyl-propan-2-ol: hydrochloride salt (B.8; 372.13 mg, 0.8 mmol), triethylamine (0.56 mL, 4.02 mmol), and HATU (336.23 mg, 0.88 mmol). The mixture was stirred at 20 °C for 16 h and purified by RP-HPLC and chiral SFC to give the title compound (110 mg, 38%) as a pale yellow gum. MS (ESI): m / z = 502.2 [M+H] +

[0382] Step a): 1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-propan-2-ol A mixture of bis(pinacolato)diboron (1.88 g, 7.4 mmol), potassium acetate (0.92 mL, 14.8 mmol), 1-(3-bromo-5-chlorophenyl)-2-methyl-propan-2-ol (CASRN: 2229628-26-4; 1.3 g, 4.93 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (201.24 mg, 0.25 mmol) in 1,4-dioxane (25 mL) was degassed with Ar and stirred at 100° C. under Ar for 16 h. The mixture was evaporated. Purification by FC (SiO; hexane / EtOAc) afforded the title compound (1.01 g, 62.63% yield) as a white solid, which was used directly in the next step. GC-MS(EI): m / z=294.1[M-OH] +

[0383] Step b): tert-butyl 3-[3-chloro-5-(2-hydroxy-2-methylpropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate A suspension of tert-butyl 2,7-dimethyl-3-(trifluoromethylsulfonyloxy)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (Brevet no. WO2020 / 065613 A1,2020) (1.01 g, 2.53 mmol), 1-[3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methyl-propan-2-ol (1.02 g, 3.29 mmol), and sodium carbonate (536.06 mg, 5.06 mmol) in dry DMF (6 mL) was sparged with Ar and then treated with tetrakis(triphenylphosphine)palladium(0) (146.11 mg, 0.13 mmol). The mixture was stirred at 100° C. for 16 h, then cooled, diluted with water (50 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. FC (SiO; hexane / EtOAc) afforded the title compound (330.0 mg, 27.36% yield) as a pale yellow oil. MS (ESI): m / z=434.2 [M+H] +

[0384] Step c): 1-[3-chloro-5-(2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-3-yl)phenyl]-2-methyl-propan-2-ol; Hydrochloride salt (B.8) A solution of tert-butyl 3-[3-chloro-5-(2-hydroxy-2-methyl-propyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carboxylate (375.0 mg, 0.79 mmol) in DCM (2 mL) was treated with hydrochloric acid (4 M in dioxane) (1.97 mL, 7.86 mmol). The mixture was stirred at 20 °C for 16 h and evaporated to give the title compound (B.4; 311.0 mg, 85.44% yield) as a pale yellow solid. MS (ESI): m / z = 334.2 [M+H] +

[0385] Example 96 3-[3-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one [ka] A solution of HATU (61.52 mg, 0.162 mmol) in DMF (1.2 mL) was treated with DIPEA (230.21 μL, 1.35 mmol) and 1-(2-keto-1H-pyridin-3-yl)-1,2,4-triazole-3-carboxylic acid (C.7; 27.8 mg, 0.135 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for 10 min, after which 2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.3; 45 mg, 0.135 mmol) was added and stirred for an additional 18 h. Purification by RP-HPLC afforded the racemate as a white lyophilizate (35 mg). Purification by chiral chromatography gave the title compound (10 mg, 15.28%) as an off-white solid. MS (ESI): m / z = 486.4 [M+H] +

[0386] Example 97 3-chloro-5-[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one [ka] A suspension of 2-chloro-3-(5-chloro-6-oxo-1H-pyridin-3-yl)-5-fluorobenzoic acid (C.20; 323.0 mg, 1.07 mmol) in DMF (5 mL) was treated with HATU (487.86 mg, 1.28 mmol), triethylamine (0.6 mL, 4.28 mmol), and 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (B.5; 320.5 mg, 1.07 mmol). The mixture was stirred at 20 °C for 10 h and then filtered. The filtrate was evaporated and purified by RP-HPLC to give the title compound (244.4 mg, 41.76% yield) as a light brown solid. MS (ESI): m / z = 547.2 [M+H] +

[0387] Step a): Methyl-2-chloro-3-(5-chloro-6-methoxy-3-pyridyl)-5-fluorobenzoate A solution of methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN: 1805582-40-4; 800.0 mg, 2.99 mmol) and 3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CASRN: 1083168-91-5; 1.05 g, 3.89 mmol) in 1,4-dioxane (25 mL) was treated with a solution of potassium carbonate (1.24 g, 8.97 mmol) in water (5 mL). The mixture was sparged with Ar and treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (244.06 mg, 0.3 mmol). The mixture was stirred at 110 °C for 15 h, then cooled, filtered, and evaporated. The residue was dissolved in EtOAc and filtered through celite. The mixture was evaporated and purified by RP-HPLC to give the title compound (405.0 mg, 41.02% yield) as a white solid. MS (ESI): m / z=330.0 [M+H] +

[0388] Step b): 2-chloro-3-(5-chloro-6-oxo-1H-pyridin-3-yl)-5-fluoro-benzoic acid A mixture of methyl 2-chloro-3-(5-chloro-6-methoxy-3-pyridyl)-5-fluorobenzoate (405.0 mg, 1.23 mmol) and 12N aqueous HCl (10.22 mL, 122.68 mmol) was heated at 90°C for 15 hours, then cooled, diluted with water, and filtered. The precipitate was washed with ACN and dried to give the title compound (C.20; 323.0 mg, 81.75% yield) as a light brown solid. MS (ESI): m / z = 302.0 [M+H] +

[0389] Example 98 and Example 99 3-chloro-5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one (Example 98) and 3-chloro-5-[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-3H-pyridin-2-one (Example 99) [ka] Example 97 (87.7 mg, 0.16 mmol) was purified by chiral SFC to give Example 98 (35.1 mg, 40.34% yield) and Example 99 (38.1 mg, 41.6% yield). MS (ESI): m / z = 547.2 [M+H] +

[0390] Example 100 and Example 101 [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 100) and [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 101). [ka] A solution of 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.5; 168.19 mg, 0.56 mmol), HATU (256.02 mg, 0.67 mmol), and triethylamine (0.39 mL, 2.81 mmol) in DMF (2 mL) was treated with 1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carboxylic acid (C.10; 135.0 mg, 0.56 mmol). The resulting mixture was stirred at 20 °C for 16 h and then purified by RP-HPLC to give the racemic mixture (150.0 mg, 55.02% yield) as an orange solid. Chiral separation afforded Example 100 (86.5 mg, 25.28% yield) and Example 101 (121.4 mg, 35.49% yield) as light brown solids. MS (ESI): m / z = 486.2 [M+H] +

[0391] Example 102 and Example 103 [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 102) and [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 103) [ka] A solution of 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.5; 200.0 mg, 0.67 mmol), 2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]benzoic acid hydrochloride (C.21; 223.95 mg, 0.73 mmol), and HATU (380.55 mg, 1.0 mmol) in DMF (3 mL) was treated with N,N-diisopropylethylamine (0.58 mL, 3.34 mmol) at 23 °C. The mixture was stirred at this temperature for 18 hours. Purification by RP-HPLC and chiral chromatography afforded Example 102 (36.0 mg, 10.5% yield) and Example 103 (30.3 mg, 8.84% yield) as light brown solids. MS (ESI): m / z = 514.0 [M+H] + Step a): Methyl 2-chloro-5-fluoro-3-(2-trimethylsilylethynyl)benzoate A solution of trimethylsilylacetylene (5.59 mL, 39.26 mmol) in DMF (14 mL) and triethylamine (182.38 mL, 1308.51 mmol) was treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.13 g, 2.62 mmol), copper iodide (249.21 mg, 1.31 mmol), and triethylamine (182.38 mL, 1308.51 mmol) at 23 °C. The mixture was sparged with Ar and stirred at 88 °C for 18 h, then cooled, filtered, and evaporated. The residue was dissolved in water and extracted with MTBE. The combined organic layers were dried over NaSO, filtered, and evaporated to give the title compound (6.7 g, 86.3% yield) as a brown oil. GC-MS(EI):m / z=284.0[M] +

[0392] Step b): Methyl 2-chloro-3-ethynyl-5-fluoro-benzoate A solution of methyl 2-chloro-5-fluoro-3-(2-trimethylsilylethynyl)benzoate (3.81 g, 13.38 mmol) in THF (127 mL) was treated dropwise with tetrabutylammonium fluoride (20.07 mL, 20.07 mmol), stirred at 23 °C for 3 h, and then evaporated. The residue was dissolved in EtOAc (500 mL), and the organic layer was washed with water (2 × 1 L) and brine (1 × 500 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the title compound (2.8 g, 98.45% yield) as a dark brown liquid. GC-MS (EI): m / z = 212.0 [M] +

[0393] Step c): Methyl 2-chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethynyl]benzoate A solution of 4-iodo-1-tetrahydropyran-2-yl-pyrazole (1.96 g, 7.06 mmol) in DMF (5.6998 mL) and triethylamine (32.78 mL, 235.18 mmol) was treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (384 mg, 0.47 mmol), copper iodide (89.58 mg, 0.47 mmol), and methyl 2-chloro-3-ethynyl-5-fluorobenzoate (1.0 g, 4.7 mmol) and sparged with Ar. The mixture was stirred at 88 °C for 18 h, then cooled and filtered. The filtrate was evaporated, and the residue was dissolved in water. The aqueous layer was extracted with MTBE, and the organic layer was dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; hexane / EtOAc) gave the title compound (900.0 mg, 2.48 mmol, 52.74% yield) as a pale yellow viscous oil. MS (ESI): m / z = 362.1 [M+H] +

[0394] Step d): Methyl 2-chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]benzoate A solution of methyl 2-chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethynyl]benzoate (900.0 mg, 2.48 mmol) and Rh / C (10%) (150.0 mg) in 100 mL of EtOAc was hydrogenated at 3800 mmHg (in an autoclave) at 25 °C for 18 hours. The mixture was filtered and evaporated to give the title compound (900.0 mg, 90.99% yield) as a pale yellow viscous oil. MS (ESI): m / z = 367.0 [M+H] +

[0395] Step e): 2-chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]benzoic acid A solution of methyl 2-chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]benzoate (900.0 mg, 2.45 mmol) in THF (48 mL), methanol (48 mL), and water (12 mL) was treated with lithium hydroxide monohydrate (412 mg, 9.81 mmol) at 23 °C. The mixture was stirred at this temperature for 18 hours, then diluted with EtOAc and treated with saturated citric acid solution. The layers were separated, and the organic layer was washed with water. The combined aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (900.0 mg, 96.7% yield) as a pale yellow solid. MS (ESI): m / z = 353.0 [M+H] +

[0396] Step f): 2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]benzoic acid; hydrochloride 2-Chloro-5-fluoro-3-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]benzoic acid (600.0 mg, 1.7 mmol) was treated with 4N HCl in 1,4-dioxane (10 mL), and the mixture was stirred at 23° C. for 48 hours and then filtered. The precipitate was washed with ether and dried to give the title compound (C.21; 407.7 mg, 78.6% yield) as a white solid. MS (ESI): m / z = 270.0 [M+H] +

[0397] Example 104 and Example 105 [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 104) and [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone (Example 105) [ka] A solution of 2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoic acid, 2,2,2-trifluoroacetic acid (C.18; 95.0 mg, 0.25 mmol), 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.5; 74.22 mg, 0.25 mmol), and HATU (122 mg, 0.32 mmol) in DMF (5 mL) was treated with triethylamine (0.21 mL, 1.49 mmol) at 23 ° C. The mixture was stirred at this temperature for 48 hours and then purified by RP-HPLC and chiral chromatography to give Example 104 (20.4 mg, 16.0% yield) as a light gray solid and Example 105 (26.7 mg, 20.94% yield) as a light brown solid. MS(ESI): m / z=515.2 [M+H] +

[0398] Example 106 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methylamino]pyrrolidin-2-one; Hydrochloride [ka] A solution of tert-butyl N-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methyl]-N-(5-oxopyrrolidin-3-yl)carbamate (12.5 mg, 0.02 mmol) in DCM (0.5 mL) was treated with hydrochloric acid (4 M in dioxane) (0.05 mL, 0.2 mmol). The mixture was stirred at 20 °C for 16 hours and evaporated to give the title compound (9.9 mg, 80.14% yield) as a white solid. MS (ESI): m / z = 532.2 [M + H] +

[0399] Step a): Methyl 2-chloro-5-fluoro-3-[[(5-oxopyrrolidin-3-yl)amino]methyl]benzoate A solution of 4-aminopyrrolidin-2-one hydrochloride (CASRN: 167465-93-2; 83.1 mg, 0.6 mmol) in 1:2.5 DCM / IPA (14 mL) was treated with trimethylamine (0.09 mL, 0.7 mmol), methyl 2-chloro-5-fluoro-3-formylbenzoate (CASRN: 2384295-46-7; 155 mg, 0.6 mmol), and sodium cyanoborohydride (114.7 mg, 3 mmol) at 23 °C. The mixture was stirred at this temperature for 16 hours and then diluted with water and EtOAc. The organic layer was washed with saturated aqueous NaHCO and brine, dried over sodium sulfate, filtered, and evaporated to give the title compound (185 mg, 86%) as a light brown oil. 1 H NMR(400MHz,DMSO-d6)δ=7.58(dd,J=3.1,9.4Hz,1H),7.53-7.48(m,2H),3.86(s,3H),3.78(d,J=3 .5Hz,2H),3.48-3.36(m,2H),3.01(dd,J=3.7,8.9Hz,1H),2.41-2.31(m,1H),2.03-1.95ppm(m,1H)

[0400] Step b): 2-chloro-5-fluoro-3-[[(5-oxopyrrolidin-3-yl)amino]methyl]benzoic acid A solution of methyl 2-chloro-5-fluoro-3-[[(5-oxopyrrolidin-3-yl)amino]methyl]benzoate (240.0 mg, 0.678 mmol) in MeOH (2.0 mL) was treated with NaOH (32.5 mg, 0.814 mmol) at 23 ° C. The mixture was stirred at this temperature for 16 hours and then evaporated to give the title compound (150.0 mg, 62% yield) as a pale yellow viscous oil. MS (ESI): m / z = 287.1 [M + H] +

[0401] Step c): 3-[[tert-butoxycarbonyl-(5-oxopyrrolidin-3-yl)amino]methyl]-2-chloro-5-fluoro-benzoic acid A solution of 2-chloro-5-fluoro-3-[[(5-oxopyrrolidin-3-yl)amino]methyl]benzoic acid (100.0 mg, 0.35 mmol) in DCM (5 mL) was treated with di-t-butyl dicarbonate (76.13 mg, 0.35 mmol). The mixture was cooled to 0° C. and triethylamine (0.07 mL, 0.52 mmol) was added dropwise. The mixture was warmed to 20° C. and stirred for 16 hours, then diluted with water. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated to give the title compound (96.0 mg, 64.04% yield). MS (ESI): m / z=387.2 [M+H] +

[0402] Step d): tert-butyl N-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methyl]-N-(5-oxopyrrolidin-3-yl)carbamate A solution of 3-[[tert-butoxycarbonyl-(5-oxopyrrolidin-3-yl)amino]methyl]-2-chloro-5-fluorobenzoic acid (96.0 mg, 0.25 mmol) in DMF (1 mL) was treated with 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (B.5; 74.4 mg, 0.25 mmol), triethylamine (0.1 mL, 0.74 mmol), and HATU (113.24 mg, 0.3 mmol) at 20 ° C. The mixture was stirred at this temperature for 10 hours and then purified by RP-HPLC to give the title compound (11.5 mg, 6.96% yield) as a yellow viscous oil. MS (ESI): m / z = 532.2 [M + H-Boc] +

[0403] Example 107 (5R)-5-[[2,5-Dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one [ka] A solution of 2,5-dichloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoic acid (205.0 mg, 0.57 mmol) and 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (B.5; 170.64 mg, 0.57 mmol) in DMF (0.5 mL) was treated with triethylamine (0.24 mL, 1.71 mmol) and HATU (259.74 mg, 0.68 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated. Purification by RP-HPLC and chiral SFC afforded the title compound (69 mg, 26%) as a yellow solid. MS (ESI): m / z = 551.0 [M+H] +

[0404] Step a): Ethyl 2,5-dichloro-3-(oxiran-2-ylmethoxy)benzoate A solution of ethyl 2,5-dichloro-3-hydroxybenzoate (CASRN: 1806282-15-4; 850.0 mg, 3.62 mmol) and epichlorohydrin (0.85 mL, 10.85 mmol) in acetone (30 mL) was treated with potassium carbonate (999.53 mg, 7.23 mmol). The mixture was heated at 60 °C for 16 h, cooled, and filtered. The filtrate was concentrated, and the residue was dissolved in EtOAc. The organic layer was washed with aqueous KCO, water, and brine, dried over sodium sulfate, and evaporated to give the title compound (1.05 g, 89.76% yield) as a pale yellow oil. MS (ESI): m / z = 242.0 [M+H] +

[0405] Step b): Ethyl 2,5-dichloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate A solution of ethyl 2,5-dichloro-3-(oxiran-2-ylmethoxy)benzoate (1050.0 mg, 3.61 mmol), urethane (321 mg, 3.61 mmol), and triethylamine (0.1 mL, 0.72 mmol) in DMF (10 mL) was heated at 130° C. for 15 h. The mixture was then cooled and evaporated. Purification by RP-HPLC afforded the title compound (375.0 mg, 30.59% yield) as a pale yellow solid. MS (ESI): m / z=334.0 [M+H] +

[0406] Step c): 2,5-dichloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoic acid A solution of ethyl 2,5-dichloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate (375.0 mg, 1.12 mmol) in THF (3 mL) / water (3 mL) was treated with lithium hydroxide (67.2 mg, 2.81 mmol) at 0° C. The mixture was warmed to 20° C., stirred at that temperature for 16 hours, and evaporated. The residue was dissolved in water (15 mL) and acidified to pH=2 with 1N aqueous HCl. The precipitate was filtered and dried under reduced pressure to give the title compound (205.0 mg, 50.72% yield) as a white powder. MS (ESI): m / z=307.1 [M+H] +

[0407] Examples 108 and 109 (Arbitrary Assignment of Stereochemistry) (5S)-5-[[2,5-Dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one (Example 108) and (5R)-5-[[2,5-Dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one (Example 109) [ka] Example 107 (5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one) (110 mg, 0.2 mmol) was separated by chiral SFC to give Example 108 (39.7 mg, 36.1%) and Example 109 (39.2 mg, 35.6%) as white solids. MS (ESI): m / z = 551.0 [M+H] +

[0408] Example 110 5-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one [ka] A solution of 2-chloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoic acid (200.0 mg, 0.74 mmol) and 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (B.5; 220.69 mg, 0.74 mmol) in DMF (4 mL) was treated with triethylamine (0.41 mL, 2.94 mmol) and HATU (335.93 mg, 0.88 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated. Purification by RP-HPLC and SFC afforded the title compound (122 mg, 39%) as a light brown solid. MS (ESI): m / z = 517.2 [M+H] +

[0409] Step a): Methyl 2-chloro-3-(oxiran-2-ylmethoxy)benzoate A solution of methyl 2-chloro-3-hydroxybenzoate (200.0 mg, 1.07 mmol) and epichlorohydrin (198.34 mg, 2.14 mmol) in ACN (5 mL) was treated with potassium carbonate (370.35 mg, 2.68 mmol). The mixture was heated at 80° C. for 15 hours, then cooled and filtered. The filtrate was evaporated to give the title compound (170 mg, 56%) as a colorless oil. MS (ESI): m / z=242.0 [M+H] +

[0410] Step b): Methyl 2-chloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate A solution of methyl 2-chloro-3-(oxiran-2-ylmethoxy)benzoate (170.0 mg, 0.56 mmol), urethane (49.93 mg, 0.56 mmol), and triethylamine (0.02 mL, 0.11 mmol) in DMF (4 mL) was heated at 130° C. for 15 h. The mixture was cooled and evaporated. Purification by RP-HPLC afforded the title compound (64.0 mg, 39.97% yield) as a white solid. MS (ESI): m / z=286.0 [M+H] +

[0411] Step c): 2-chloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoic acid A solution of methyl 2-chloro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate (50.0 mg, 0.18 mmol) in THF (1 mL) / water (1 mL) was treated with lithium hydroxide (0.0 mL, 0.53 mmol) at 20° C. The mixture was stirred at this temperature for 15 hours and then evaporated. The residue was dissolved in water (5 mL) and acidified to pH=2 with 1N HCl (aq). The precipitate was filtered and dried under reduced pressure to give the title compound (34.0 mg, 71.51% yield) as a white powder. MS (ESI): m / z=270.0 [M−H] -

[0412] Example 111 [2-chloro-3-(1,6-diazaspiro[3.3]heptan-6-yl)-5-fluorophenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone;2,2,2-trifluoroacetic acid [ka] A solution of tert-butyl 6-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1,6-diazaspiro[3.3]heptane-1-carboxylate (60.0 mg, 0.1 mmol) in DCM (1 mL) was treated with trifluoroacetic acid (0.04 mL, 0.49 mmol) and stirred at 25 °C for 18 h, then evaporated. Purification by RP-HPLC afforded the title compound (2.8 mg, 4.56% yield) as a light brown solid. MS (ESI): m / z = 516.0 [M+H] +

[0413] Step a): tert-butyl 6-(2-chloro-5-fluoro-3-methoxycarbonyl-phenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate In a sealed tube, methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN: 1805582-40-4; 1.14 g, 4.26 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (123.14 mg, 0.210 mmol), tris(dibenzylideneacetone)dipalladium(0) (194.88 mg, 0.210 mmol), tert-Butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate; hydrochloride (1998.12 mg, 8.51 mmol), cesium carbonate (5.55 g, 17.03 mmol), and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (123.14 mg, 0.210 mmol) and 1,4-dioxane (91.08 mL) were added. The mixture was sparged with argon, heated to 100 °C, and stirred at this temperature for 18 h, then cooled and evaporated. Purification by FC (SiO; hexane / MTBE) afforded the title compound (750 mg, 45.79% yield) as a pale yellow solid. MS (ESI): m / z = 385.0 [M+H] +

[0414] Step b): 3-(1-tert-butoxycarbonyl-1,6-diazaspiro[3.3]heptan-6-yl)-2-chloro-5-fluoro-benzoic acid A solution of tert-butyl 6-(2-chloro-5-fluoro-3-methoxycarbonyl-phenyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (900.0 mg, 2.34 mmol) in THF (14.4 mL), methanol (14.4 mL), and water (3.6 mL) was treated with hydroxylithium hydrate (392.53 mg, 9.35 mmol) at 23 °C. The mixture was stirred for 18 hours and then diluted with EtOAc and citric acid (aq). The layers were separated, and the organic layer was washed with water. The combined aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (800.0 mg, 85.79% yield) as a pale yellow solid. MS (ESI): m / z = 371 [M+H] +

[0415] Step c): tert-butyl 6-[2-chloro-5-fluoro-3-[rac-(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1,6-diazaspiro[3.3]heptane-1-carboxylate A solution of 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.5; 150.0 mg, 0.5 mmol) in DMF (3 mL) was treated with 3-(1-tert-butoxycarbonyl-1,6-diazaspiro[3.3]heptan-6-yl)-2-chloro-5-fluorobenzoic acid (204.11 mg, 0.55 mmol), HATU (285.41 mg, 0.75 mmol), and N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) at 23 ° C. The mixture was stirred at this temperature for 18 hours and then purified by RP-HPLC and chiral SFC to give the title compound (61.0 mg, 19.79% yield) as a light brown solid. MS (ESI): m / z = 514.0 [M+H] +

[0416] Example 112 [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-4-pyridyl)-1,2,4-triazol-3-yl]methanone [ka] A solution of 1-(2-hydroxy-4-pyridyl)-1,2,4-triazole-3-carboxylic acid (115.0 mg, 0.56 mmol) in DMF (2 mL), 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine hydrochloride (B.5; 167.21 mg, 0.56 mmol), triethylamine (0.39 mL, 2.79 mmol), and HATU (233.31 mg, 0.61 mmol) in DMF (3 mL) was stirred at 20 °C for 16 h. Purification by RP-HPLC and chiral SFC afforded the title compound (30.2 mg, 41%) as a yellow solid. MS (ESI): m / z = 452.6 [M+H] +

[0417] Step a): Methyl 1-(2-methoxy-4-pyridyl)-1,2,4-triazole-3-carboxylate A suspension of methyl 1H-1,2,4-triazole-3-carboxylate (415.52 mg, 3.27 mmol), 2-methoxypyridine-4-boronic acid (500.0 mg, 3.27 mmol), pyridine (0.79 mL, 9.81 mmol), cupric acetate (890.71 mg, 4.9 mmol), and molecular sieves (4 Å, 500 mg) in DCM (20 mL) was stirred (open to air) at 30 °C for 16 h. The resulting mixture was filtered, evaporated, and purified by RP-HPLC to give the title compound (105.0 mg, 13.71% yield) as a pale yellow solid. MS (ESI): m / z = 235.2 [M+H] +

[0418] Step b): 1-(2-hydroxy-4-pyridyl)-1,2,4-triazole-3-carboxylic acid A solution of methyl 1-(2-methoxy-4-pyridyl)-1,2,4-triazole-3-carboxylate (190.0 mg, 0.81 mmol) in concentrated hydrochloric acid (4.87 mL, 48.67 mmol) was stirred at 90° C. for 16 hours. The resulting precipitate was filtered, washed with water, and air-dried to give the title compound (115.0 mg, 65.32% yield) as a white solid. MS (ESI): m / z = 286.0 [M+H]+

[0419] Example 113 and Example 114 (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one (Example 113) and (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one (Example 114) [ka] A solution of 2-chloro-5-fluoro-3-[[(4S)-2-oxoimidazolidin-4-yl]methoxy]benzoic acid (45.0 mg, 0.16 mmol) in DMF (1 mL) was treated with HATU (71.13 mg, 0.19 mmol), 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (B.5; 46.73 mg, 0.16 mmol), and triethylamine (0.09 mL, 0.62 mmol) at 20 ° C. The mixture was stirred at this temperature for 15 hours and then evaporated. Purification by RP-HPLC gave (4S)-4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one (33.9 mg, 40.73% yield) as a pink solid. Further purification by chiral SFC gave Example 113 (6.6 mg, 19.47% yield) and Example 114 (6.9 mg, 20.15% yield) as light brown solids. MS (ESI): m / z = 534.2 [M + H] +

[0420] Step a): 4-(bromomethyl)imidazolidin-2-one A solution of triphenylphosphine (3.73 g, 14.21 mmol) in DCM (30 mL) was treated dropwise with bromine (0.73 mL, 14.21 mmol) under Ar at −10° C. The mixture was stirred at this temperature for 30 min, and 4-(hydroxymethyl)imidazolidin-2-one (CASRN: 2248182-92-3; 1100.0 mg, 9.47 mmol) was added. The mixture was warmed to 25° C. and stirred for 15 h before being evaporated. Purification by FC (SiO; ACN / MTBE) afforded the title compound (330.0 mg, 19.46% yield) as a white solid. MS (ESI): m / z=179.0 [M+H] +

[0421] Step b): Ethyl 2-chloro-5-fluoro-3-[[(4S)-2-oxoimidazolidin-4-yl]methoxy]benzoate A solution of ethyl 2-chloro-5-fluoro-3-hydroxybenzoate (CASRN: 2090950-46-0; 362.68 mg, 1.66 mmol, 0.9 equiv.) in DMF (5 mL) was treated with potassium carbonate (509.53 mg, 3.69 mmol). The mixture was stirred at 20° C. for 1 hour, and then 4-(bromomethyl)imidazolidin-2-one (330.0 mg, 1.84 mmol) was added. The resulting mixture was heated at 100° C. for 15 hours, cooled, filtered, and the filtrate was evaporated. Purification by RP-HPLC afforded ethyl 2-chloro-5-fluoro-3-[(2-oxoimidazolidin-4-yl)methoxy]benzoate (112.0 mg, 18.28% yield) as a white solid. Further purification by chiral SFC gave the title compound (54 mg, 48%) as a white solid. MS m / z: 317.3 / 319.3 [M+H]+

[0422] Step c): 2-chloro-5-fluoro-3-[[(4S)-2-oxoimidazolidin-4-yl]methoxy]benzoic acid A solution of ethyl 2-chloro-5-fluoro-3-[[(4S)-2-oxoimidazolidin-4-yl]methoxy]benzoate (54.0 mg, 0.17 mmol) in THF (0.5 mL) / water (0.5 mL) was treated with lithium hydroxide (12.2 mg, 0.51 mmol). The mixture was stirred at 20 °C for 15 h, diluted with water, adjusted to pH = 3 with 1 N HCl (aq), and evaporated to give the title compound (45.0 mg, 82.29% yield) as a pale yellow solid. MS (ESI): m / z = 287.0 [MH] -

[0423] Example 115 (4R)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one [ka] A solution of 2-chloro-5-fluoro-3-[[(4R)-2-oxoimidazolidin-4-yl]methoxy]benzoic acid (80.0 mg, 0.18 mmol) in DMF (0.5 mL) was treated with HATU (82.19 mg, 0.22 mmol), 3-(3,5-difluorophenyl)-2,7-dimethyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridin-6-ium chloride (54.0 mg, 0.18 mmol), and triethylamine (0.1 mL, 0.72 mmol) at 20° C. The mixture was stirred at this temperature for 10 hours, then filtered and evaporated. Purification by RP-HPLC afforded (4R)-4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one (45.0 mg, 45.76% yield) as a white solid. Further purification by chiral SFC afforded the title compound (18.6 mg, 36.51% yield). MS (ESI): m / z = 534.2 [M+H] +

[0424] Step a): 4-(bromomethyl)imidazolidin-2-one A solution of triphenylphosphine (3.73 g, 14.21 mmol) in DCM (30 mL) was treated dropwise with bromine (0.73 mL, 14.21 mmol) under Ar at −10° C. The mixture was stirred at this temperature for 30 min, and 4-(hydroxymethyl)imidazolidin-2-one (CASRN: 2248182-92-3; 1100.0 mg, 9.47 mmol) was added. The mixture was warmed to 25° C. and stirred for 15 h before being evaporated. Purification by FC (SiO; ACN / MTBE) afforded the title compound (330.0 mg, 19.46% yield) as a white solid. MS (ESI): m / z=179.0 [M+H] +

[0425] Step b): Ethyl 2-chloro-5-fluoro-3-[[(4S)-2-oxoimidazolidin-4-yl]methoxy]benzoate A solution of ethyl 2-chloro-5-fluoro-3-hydroxybenzoate (CASRN: 2090950-46-0; 362.68 mg, 1.66 mmol, 0.9 equiv.) in DMF (5 mL) was treated with potassium carbonate (509.53 mg, 3.69 mmol). The mixture was stirred at 20° C. for 1 hour, and then 4-(bromomethyl)imidazolidin-2-one (330.0 mg, 1.84 mmol) was added. The resulting mixture was heated at 100° C. for 15 hours, cooled, filtered, and the filtrate was evaporated. Purification by RP-HPLC afforded ethyl 2-chloro-5-fluoro-3-[(2-oxoimidazolidin-4-yl)methoxy]benzoate (112.0 mg, 18.28% yield) as a white solid. Further purification by chiral SFC gave the title compound (41 mg, 37%) as a white solid. MS m / z: 317.3 [M+H] +

[0426] Step c): 2-chloro-5-fluoro-3-[[(4R)-2-oxoimidazolidin-4-yl]methoxy]benzoic acid A solution of ethyl 2-chloro-5-fluoro-3-[[(4R)-2-oxoimidazolidin-4-yl]methoxy]benzoate (104.0 mg, 0.33 mmol) in THF (1 mL) / water (1 mL) was treated with lithium hydroxide hydrate (0.01 mL, 0.49 mmol) at 23 °C. The mixture was stirred at 35 °C for 10 hours and then treated with saturated aqueous KHSO4 to adjust the pH to 4. The mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to give the title compound (90.0 mg, 60.58% yield) as a pale yellow foam. MS (ESI): m / z = 287.0 [MH] -

[0427] Example 116 (2-chloro-3-methoxyphenyl)-[(5S)-9-(3-chlorophenyl)-5-methyl-1λ 5 ,4,7,8-Tetrazabicyclo[4.3.0]nona-1(9),6-dien-4-yl]methanone [ka] A solution of 3-(3-chlorophenyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.5 g, 2.01 mmol) and 2-chloro-3-methoxybenzoic acid (0.41 g, 2.21 mmol) in N,N-dimethylformamide (15 mL) was treated with HATU (0.99 g, 2.61 mmol) and triethylamine (0.98 mL, 7.04 mmol). The mixture was stirred at 23 °C for 18 h, then poured into water and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated. Purification by RP-HPLC and chiral SFC afforded the title compound (108.0 mg, 12.46% yield) as a white solid. MS (ESI): m / z = 417.0 [M+H] +

[0428] Step a): 3-chloro-N'-(3-methylpyrazin-2-yl)benzohydrazide (3-Methylpyrazin-2-yl)hydrazine (CASRN: 19848-54-5; 9.99 g, 80.48 mmol) was added to a solution of 3-chlorobenzoic acid (CASRN: 535-80-8; 10.5 g, 67.06 mmol), 1-hydroxybenzotriazole (13.59 g, 100.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.93 g, 150.89 mmol), and triethylamine (28.04 mL, 201.19 mmol) in dichloromethane (700 mL). The reaction mixture was stirred at 23° C. for 8 hours and then diluted with water and dichloromethane. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to give the title compound (12.6 g, 61.51% yield) as a brown solid. MS (ESI): m / z = 263.0 [M+H] +

[0429] Step b): 3-(3-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyrazine A solution of 3-chloro-N'-(3-methylpyrazin-2-yl)benzohydrazide (12.3 g, 46.82 mmol) in acetic acid (25 mL) was refluxed for 18 h, then cooled and evaporated. The residue was dissolved in DCM and saturated aqueous NaHCO3. The organic layer was washed with water, dried over sodium sulfate, and concentrated. Purification by FC (SiO2; CHCl3 / ACN) afforded the title compound (5.2 g, 43.12% yield) as a pale yellow solid. MS (ESI): m / z = 317.0 [M+H] +

[0430] Step c): 3-(3-chlorophenyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine A solution of 3-(3-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]pyrazine (3.0 g, 12.26 mmol) and a catalytic amount of Pt in methanol (100 mL) was stirred under H2 (50 bar) at 23 °C for 18 h. The reaction mixture was filtered and evaporated. Crystallization from hexane afforded the title compound (1.06 g, 33.02% yield) as a white solid. MS (ESI): m / z = 249.0 [M+H] +

[0431] Example 117 (2-Chloro-3-methoxyphenyl)-[(8S)-3-(3-chlorophenyl)-8-methyl-2,5,6,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl]methanone [ka] A solution of 3-(3-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine; hydrochloride (150.0 mg, 0.53 mmol) and 2-chloro-3-methoxybenzoic acid (98.49 mg, 0.53 mmol) in DMF (8 mL) was treated with 2-chloro-3-methoxybenzoic acid (98.49 mg, 0.53 mmol) and triethylamine (0.26 mL, 1.85 mmol). The mixture was stirred at 23 °C for 18 h, poured into water, and extracted with EtOAc. The combined organic layers were washed with water, dried under anhydrous sodium sulfate, and evaporated. Purification by RP-HPLC and chiral SFC afforded the title compound (43.8 mg, 19.73% yield) as a white solid. MS (ESI): m / z = 418.0 [M+H] +

[0432] Step a): tert-butyl 8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate A solution of 8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (CASRN: 91476-83-4; 3.63 g, 26.45 mmol) in CHCl (50 mL) was treated with di-t-butyl dicarbonate (6.06 g, 27.78 mmol) at 23 °C. The mixture was stirred at this temperature for 16 h and then evaporated to give the title compound (4.5 g, 67.69% yield) as a brown oil. MS (ESI): m / z = 238.2 [M+H] +

[0433] Step b): tert-Butyl 3-bromo-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate A solution of tert-butyl 8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (377.69 mg, 1.59 mmol) in CCl4 (15 mL) was treated with NBS (283.27 mg, 1.59 mmol) under Ar at 23 °C. The mixture was stirred at reflux for 1 h, then poured into water (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to give the title compound (400 mg, 76.3% yield) as a light brown solid. MS (ESI): m / z = 316.0 [M+H] +

[0434] Step c): tert-butyl 3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate A suspension of tert-butyl 3-bromo-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (400.0 mg, 1.27 mmol), 3-chlorophenylboronic acid (296.73 mg, 1.9 mmol), and sodium carbonate (670.41 mg, 6.33 mmol) in DME (16 mL) and water (8 mL) was sparged with Ar and then treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (103.23 mg, 0.13 mmol). The mixture was stirred at 80 °C for 16 h, then cooled, filtered through silica, and washed with DME (50 mL). The filtrate was evaporated and purified by RP-HPLC to give the title compound (200.0 mg, 43.18% yield). MS (ESI): m / z = 348.1 [M+H] +

[0435] Step d): 3-(3-chlorophenyl)-8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine; hydrochloride A solution of tert-butyl 3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carboxylate (200.0 mg, 0.57 mmol) in 5 mL of 4N HCl in 1,4-dioxane was stirred at 23° C. for 32 hours and then evaporated to give the title compound (150.0 mg, 89.05% yield) as a white powder. MS (ESI): m / z = 248.2 [M+H] +

[0436] Composition of Components Component A.1 N-[(3-bromo-5-chloro-phenyl)methyl]methanesulfonamide A solution of (3-bromo-5-chloro-phenyl)methanamine (CASRN 917388-35-3; 2.0 g, 9.07 mmol) in CHCl (40 mL) was treated dropwise with TEA (1.39 mL, 9.98 mmol) and methanesulfonyl chloride (0.70 mL, 9.07 mmol) under Ar at 0 °C. The mixture was warmed to 25 °C and stirred at this temperature for 12 h before being diluted with CHCl. ​​The organic layer was washed with saturated aqueous citric acid and brine, dried over NaSO, filtered, and evaporated to give the title compound (2.7 g, 94.7%) as a white solid. MS (ESI): m / z = 298.0 [M+H] + .

[0437] Component A.2 1-(3-Bromo-5-chloro-phenyl)-N-methyl-methanesulfonamide A solution of (3-bromo-5-chloro-phenyl)methanesulfonyl chloride (CASRN 1499398-66-1; 300.0 mg, 0.990 mmol) in THF (10 mL) was treated dropwise with monomethylamine (2 M in THF; 306.52 mg, 9.87 mmol) under Ar at 25 °C. The mixture was stirred at this temperature for 18 h, then evaporated and dissolved in EtOAc. The organic layer was washed with aqueous hydrochloric acid (1 N) and saturated aqueous sodium chloride, dried over Na2SO4, filtered, and evaporated to give the title compound (240 mg, 81.45% yield) as a white solid. MS (ESI): m / z = 298.0 [MH] - .

[0438] Component A.3 1-Bromo-3-chloro-5-(1-methylsulfonylcyclopropyl)benzene A solution of methyl(diphenyl)sulfonium tetrafluoroborate (4.31 g, 14.95 mmol) in dry THF (40 mL) was treated with 1-bromo-3-chloro-5-(1-methylsulfonylvinyl)benzene (3.4 g, 11.5 mmol) and sodium bis(trimethylsilyl)azanilide (9.2 mL, 18.4 mmol) under Ar at 0 °C. The mixture was stirred at this temperature for 10 min, then warmed to 25 °C and stirred for an additional 10 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL), diluted with water (150 mL), and the organics were extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with water, dried over NaSO, filtered, and evaporated. Purification by FC (SiO; hexane / EtOAc) afforded the title compound (2 g, 53.35% yield) as a crude light brown solid, which was used directly in the next step.

[0439] Step a): 1-Bromo-3-chloro-5-(1-methylsulfonylvinyl)benzene A solution of 2-(3-bromo-5-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CASRN 488850-91-5; 8.4 g, 26.46 mmol) in 4:1 THF / water (50 mL) was treated with 1-bromo-1-methylsulfonylethylene (5386.63 mg, 29.11 mmol) and potassium carbonate (7315.02 mg, 52.93 mmol) under Ar at 25 °C. The mixture was sparged with Ar for 5 minutes and then treated with 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2159.48 mg, 2.65 mmol). The mixture was stirred at 70 °C for 16 hours and then filtered through a silica pad. The filtrate was evaporated and purified by FC (SiO2; PE / MTBE) to afford the title compound (3.4 g, 41.29% yield) as a crude light brown oil which was used directly in the next step.

[0440] Component C.1 2-chloro-3-(2,2-dioxo-2λ6-thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoic acid Methyl 2-chloro-3-(2,2-dioxo-2λ) 6 A solution of 1-thia-6-azaspiro[3.3]heptan-6-yl)-5-fluorobenzoate (900.0 mg, 2.7 mmol) in 4:4:1 THF / MeOH / water (101.25 mL) was treated with LiOH hydrate (339.44 mg, 8.09 mmol) at 23 °C and stirred at this temperature for 18 hours. The reaction mixture was evaporated, then diluted with water (11.25 mL) and acidified with 2N HCl until a precipitate formed. The precipitate was filtered off, washed with water, and dried to give the title compound (680 mg, 74.93% yield) as a white solid. MS (ESI): m / z 320.2 [M+H] + .

[0441] Step a): Methyl 2-chloro-3-(2,2-dioxo-2λ 6 -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoate A sealed tube was charged with methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN 1805582-40-4; 1.5 g, 5.61 mmol), tris(dibenzylideneacetone)dipalladium(0) (256.76 mg, 0.280 mmol), 2λ6-thia-6-azaspiro[3.3]heptane 2,2-dioxide; hydrochloride salt (CASRN 1263182-09-7; 2.06 g, 11.22 mmol), cesium carbonate (7.31 g, 22.43 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (162.24 mg, 0.280 mmol), and 1,4-dioxane (120 mL) under Ar at 23 °C. The mixture was sparged with Ar for 15 min and then heated at 100 °C for 18 h. The mixture was cooled and evaporated. Purification by FC (SiO; CHCl / ACN) afforded the title compound (1.1 g, 56.24% yield) as a pale yellow solid. MS (ESI): m / z = 334.0 [M+H] + .

[0442] Component C.2 2-Chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)benzoic acid A solution of methyl 2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)benzoate (1.1 g, 3.42 mmol) in 5:1 THF / water (48 mL) was treated with LiOH monohydrate (358.63 mg, 8.55 mmol) at 23 °C. The mixture was heated to 50 °C and stirred at this temperature for 4 hours, then concentrated under reduced pressure and acidified to pH 4 with saturated aqueous citric acid. The resulting suspension was stirred at 23 °C for 30 minutes and then filtered. The cake was washed with water and dried to give the title compound (840 mg, 75.85% yield) as a light gray solid. MS (ESI): m / z = 308.0 [M+H] + .

[0443] Step a): Methyl 2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)benzoate A solution of methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN 1805582-40-4; 1250.0 mg) in 1,4-dioxane (60 mL) was treated with 3-methylsulfonylazetidine hydrochloride (CASRN 1400764-60-4; 1203.24 mg, 7.01 mmol), Xantphos (216.32 mg, 0.370 mmol), tris(dibenzylideneacetone)dipalladium (213.97 mg, 0.230 mmol), and cesium carbonate (3045.27 mg, 9.35 mmol) under Ar at 23 °C. The mixture was sparged with Ar for 10 minutes, heated at 90 °C for 24 hours, and then cooled. The mixture was filtered through a silica pad, washed with 1,4-dioxane (100 mL), and evaporated. The residue was diluted with EtOAc (100 mL) and the organic layer was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2) afforded the title compound (1.1 g, 71.69% yield) as a pale yellow solid. MS (ESI): m / z = 322.0 [M+H] + .

[0444] Component C.3 2-Chloro-5-fluoro-3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzoic acid A solution of ethyl 2-chloro-5-fluoro-3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzoate (0.8 g, 2.35 mmol) in a 2:1 EtOH / water mixture at 23 °C was treated with lithium hydroxide (0.04 mL, 4.7 mmol). The mixture was heated to 40 °C and stirred at this temperature for 12 h before being concentrated under reduced pressure. Water and MTBE were added, and the resulting mixture was acidified with saturated citric acid. The aqueous phase was extracted with more EtOAc (3x), and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude product was recrystallized from hexane to give the title compound (0.400 g, 51.76% yield) as a pink solid. MS (ESI): m / z = 311.0 [MH] - .

[0445] Step a): Ethyl 2-chloro-5-fluoro-3-[[1-(trifluoromethyl)cyclopropyl]methoxy]benzoate A solution of ethyl 2-chloro-5-fluoro-3-hydroxybenzoate (CASRN 2090950-46-0; 0.63 g, 2.88 mmol) and cesium carbonate (2.82 g, 8.65 mmol) in DMF (10 mL) was treated with [1-(trifluoromethyl)cyclopropyl]methyl 4-methylbenzenesulfonate (CASRN 865833-72-3; 1.02 g, 3.46 mmol) at 23 °C. The reaction mixture was heated to 100 °C and stirred at this temperature for 24 h, then cooled and partitioned with EtOAc and water. The organic layer was washed with brine (3 times), dried over Na2SO4, filtered, and evaporated to give the title compound (0.880 g, 71.7% yield) as a brown liquid. MS (ESI): m / z = 341.0 [M+H] + .

[0446] Component C.4 2-chloro-3-(5,5-dimethyl-4H-isoxazol-3-yl)-5-fluoro-benzoic acid A solution of methyl 2-chloro-3-(5,5-dimethyl-4H-isoxazol-3-yl)-5-fluorobenzoate (480.0 mg, 1.68 mmol) in 4:4:1 THF / MeOH / water (9 mL) was treated with lithium hydroxide monohydrate (140.99 mg, 3.36 mmol) at 25 °C. The mixture was stirred at this temperature for 18 h, then concentrated under reduced pressure and acidified to pH = 4 with HCl (1 N). The resulting suspension was stirred for 30 min and then filtered. The precipitate was washed with water and dried to give the title compound (332 mg, 71.28% yield) as a white solid. MS (ESI): m / z = 272.0 [M+H] + .

[0447] Step a): Methyl 2-chloro-5-fluoro-3-formyl-benzoate A solution of methyl 3-bromo-2-chloro-5-fluoro-benzoate (CASRN: 1805582-40-4; 10.0 g, 37.39 mmol) in THF (250 mL) was treated dropwise with n-BuLi (17.95 mL, 44.86 mmol) at −78° C. under Ar. The mixture was stirred at this temperature for 30 min and then treated dropwise with a solution of DMF (8.68 mL, 112.16 mmol) in THF (50 mL). The mixture was warmed to 25° C. and stirred at this temperature for 3 h before being treated with saturated aqueous NH4Cl (50 mL). The layers were separated and the organic layer was washed with brine (20 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4 and evaporated. Purification by FC (SiO2) gave the title compound (1.2 g, 13.34% yield) as a pale yellow solid. MS (ESI): m / z = 216.0 [M+H] + .

[0448] Step b): Methyl 2-chloro-5-fluoro-3-[(E)-hydroxyiminomethyl]benzoate A solution of methyl 2-chloro-5-fluoro-3-formyl-benzoate (1200.0 mg, 5.54 mmol) (90% purity) in 2:1:1 THF / EtOH / water (28 mL) was treated with hydroxylamine hydrochloride (770.01 mg, 11.08 mmol) and sodium acetate (1363.51 mg, 16.62 mmol) at 23 °C. The mixture was stirred at this temperature for 24 h and then evaporated. The residue was partitioned between DCM (100 mL) and water (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (2x), and the combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (1.1 g, 77.15% yield) as a crude yellow solid. MS (ESI): m / z = 230.2 [M−H] - .

[0449] Step c): Methyl 2-chloro-3-[(Z)-C-chloro-N-hydroxy-carbonimidoyl]-5-fluoro-benzoate A solution of methyl 2-chloro-5-fluoro-3-[(E)-hydroxyiminomethyl]benzoate (1.2 g, 5.18 mmol) (85% purity) in DMF (20 mL) was treated in portions with NCS (0.69 g, 5.18 mmol) under Ar at 25 °C and stirred at this temperature for 3 h. The mixture was then diluted with water (100 mL) and extracted with TBME (3 × 50 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried over NaSO, and evaporated to give the title compound (1.25 g, 77.08% yield) as a pale yellow solid. MS (ESI): m / z = 267.2 [M+H] + .

[0450] Step d): Methyl 2-chloro-3-(5,5-dimethyl-4H-isoxazol-3-yl)-5-fluoro-benzoate A solution of methyl 2-chloro-3-[(Z)-C-chloro-N-hydroxy-carbonimidoyl]-5-fluoro-benzoate (1.25 g, 4.7 mmol) in DCM (50 mL) was treated with 2-methylpropene (1.05 g, 18.79 mmol) and TEA (1.31 mL, 9.4 mmol) under Ar at -10 °C. The mixture was warmed to 25 °C and stirred at this temperature for 24 h before being evaporated. Purification by RP-HPLC afforded the title compound (490 mg, 35.77% yield) as a yellow oil. MS (ESI): m / z = 286.0 [M+H] + .

[0451] Component C.5 2-Chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoic acid Methyl 2-chloro-5-fluoro-3-(6-methoxy-3-pyridyl)benzoate (2550.0 mg, 8.62 mmol) was treated with 12N HCl (136.0 mL, 1632 mmol) at 25° C. The mixture was heated to 88° C. and stirred at this temperature for 18 hours, then cooled and diluted with 400 mL of ice-cold water. The precipitate was filtered and dried to give the title compound (1027 mg, 40.97% yield) as a pale yellow solid. MS (ESI): m / z=268 [M+H] + .

[0452] Step a): Methyl 2-chloro-5-fluoro-3-(6-methoxy-3-pyridyl)benzoate A solution of methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN: 1805582-40-4; 4.0 g, 14.95 mmol) and 2-methoxy-5-pyridineboronic acid (CASRN 163105-89-3; 2.97 g, 19.45 mmol) in 4:1 DME / water (100 mL) was sparged with Ar for 10 min and then treated with bis(triphenylphosphine)palladium(II) chloride (629.79 mg, 0.900 mmol) and sodium carbonate (3.96 g, 37.39 mmol). The mixture was heated to 100 °C and stirred at this temperature for 18 h, then cooled, filtered, and evaporated. Purification by FC (SiO) afforded the title compound (2550 mg, 57.67% yield) as a white solid. MS (ESI): m / z = 296 [M+H] + .

[0453] Component C.6 Chloro-5-fluoro-3-(2-oxo-1H-pyridin-4-yl)benzoic acid Methyl 2-chloro-5-fluoro-3-(2-methoxy-4-pyridyl)benzoate (1410.0 mg, 4.77 mmol) was treated with 12N HCl (75.2 mL, 902.4 mmol) at 25° C. The mixture was heated to 88° C. and stirred at this temperature for 18 hours, then cooled and diluted with 400 mL of ice-cold water. The precipitate was filtered and dried to give the title compound (524.2 mg, 37.04% yield) as a pale yellow solid. MS (ESI): m / z=268 [M+H] + .

[0454] Step a): Methyl 2-chloro-5-fluoro-3-(2-methoxy-4-pyridyl)benzoate A solution of 2-methoxypyridine-4-boronic acid (CASRN 762262-09-9; 2.97 g, 19.44 mmol) in 4:1 DME / water (100 mL) was treated with methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN: 1805582-40-4; 4.0 g, 14.95 mmol), sodium carbonate (3.96 g, 37.39 mmol), and bis(triphenylphosphine)palladium(II) chloride (629.79 mg, 0.900 mmol) under Ar at 25 °C. The mixture was heated to 100 °C and stirred at this temperature for 18 h, then cooled, filtered, and evaporated. Purification by RP-HPLC afforded the title compound (1.48 g, 32.05% yield) as a pale yellow solid. MS (ESI): m / z = 296 [M+H] + .

[0455] Component C.7 1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carboxylic acid A solution of methyl 1-(2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (1090.0 mg, 4.65 mmol) in 12N HCl (50 mL) was stirred at 70° C. for 18 hours and then cooled. The precipitate was filtered, washed with water, and dried to give the title compound (603.2 mg, 59.73% yield) as a pale gray solid. MS (ESI): m / z = 207.0 [M+H] + .

[0456] Step a): Methyl 1-(2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1H-1,2,4-triazole-3-carboxylate (CASRN: 4928-88-5; 2.49 g, 19.61 mmol) and 2-methoxypyridine-3-boronic acid (CASRN: 163105-90-6; 3.0 g, 19.61 mmol) in DCM (180 mL) was treated with pyridine (4.76 mL, 58.83 mmol), 4Å MS (3 g), and Cu(OAc) (3.56 g, 19.61 mmol) at 23 °C. The mixture was heated to 30 °C and stirred at this temperature for 48 h before being filtered through Celite. The filtrate was washed with saturated aqueous ammonium hydroxide, and the organic layer was dried over NaSO, filtered, and evaporated to give the title compound (1.4 g, 27.74% yield) as a crude white solid. MS (ESI): m / z = 235.0 [M+H] + .

[0457] Component C.8 1-(6-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carboxylic acid A solution of methyl 1-(6-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (1.1 g, 4.7 mmol) in 12 N HCl (50 mL) was heated to 70° C. and stirred at this temperature for 18 hours, then cooled. The precipitate was filtered, washed with water, and dried to give the title compound (572.9 mg, 56.21% yield) as a pale gray solid. MS (ESI): m / z=207.0 [M+H] + .

[0458] Step a): Methyl 1-(6-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1H-1,2,4-triazole-3-carboxylate (CASRN: 4928-88-5; 2.5 g, 19.7 mmol) and 2-methoxy-5-pyridineboronic acid (CASRN: 163105-89-3; 3.01 g, 19.67 mmol) in DCM (150 mL) was treated with pyridine (4.77 mL, 59.01 mmol), 4Å MS (2.5 g), and Cu(OAc) (3.57 g, 19.67 mmol) at 25 °C. The mixture was heated to 30 °C and stirred at this temperature for 48 h before filtering through Celite. The filtrate was washed with saturated aqueous ammonium hydroxide, and the organic layer was dried over NaSO, filtered, and evaporated to give the title compound (2.2 g, 42.5% yield) as a crude white solid. MS (ESI): m / z = 235.2 [M+H] + .

[0459] Component C.9 1-(5-fluoro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carboxylic acid A solution of sodium 1-(5-fluoro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (435.0 mg, 1.34 mmol) in 12 N hydrochloric acid (8.03 mL, 80.26 mmol) was heated to 90 °C and stirred at this temperature for 16 hours, then cooled. The precipitate was filtered, washed with water, and dried to give the title compound (220 mg, 66.04% yield) as a white solid. MS (ESI): m / z = 225.0 [M+H] + .

[0460] Step a): Methyl 1-(5-fluoro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1H-1,2,4-triazole-3-carboxylate (CASRN: 4928-88-5; 1.6 g, 12.58 mmol) in DCM (100 mL) was treated with (5-fluoro-2-methoxy-3-pyridyl)boronic acid (CASRN: 957120-32-0; 2.15 g, 12.58 mmol), pyridine (3.05 mL, 37.73 mmol), cupric acetate (3.43 g, 18.87 mmol), and 4Å MS (3 g) at 23 °C. The mixture was heated to 30 °C and stirred at this temperature for 16 h, then filtered and evaporated. Purification by RP-HPLC afforded the title compound (282 mg, 8.53% yield) as a white solid. MS (ESI): m / z = 253.2 [M+H] + .

[0461] Step b): Sodium; 1-(5-fluoro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1-(5-fluoro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (393.0 mg, 1.56 mmol) in MeOH (2 mL) was treated with a solution of NaOH (93.5 mg, 2.34 mmol) in water (1 mL) at 20 °C. The mixture was stirred at this temperature for an additional 16 h and then evaporated. Purification by RP-HPLC afforded the title compound (435 mg, 85.84% yield) as a white solid. MS (ESI): m / z = 239.2 [M+H] + .

[0462] Component C.10 1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carboxylic acid A solution of sodium 1-(5-chloro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (210.0 mg, 0.610 mmol) in 12 N hydrochloric acid (3.04 mL, 30.37 mmol) was heated to 90° C. and stirred at this temperature for 16 hours, then cooled. The precipitate was filtered, washed with water, and dried to give the title compound (102.6 mg, 70.21% yield) as a white solid. MS (ESI): m / z = 241.0 [M+H] + .

[0463] Step a): Methyl 1-(5-chloro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1H-1,2,4-triazole-3-carboxylate (CASRN: 4928-88-5; 0.68 g, 5.34 mmol) in DCM (100 mL) was treated with 5-chloro-2-methoxypyridine-3-boronic acid (CASRN: 943153-22-8; 1.0 g, 5.34 mmol), pyridine (1.29 mL, 16.01 mmol), cupric acetate (1453.89 mg, 8 mmol), and 4Å MS (3 g) at 20°C. The mixture was heated to 30°C and stirred at this temperature for 16 hours, after which it was evaporated. The residue was diluted with aqueous HCl (5%; 50 mL), and the resulting precipitate was filtered and dried to give the title compound (210 mg, 13.48% yield) as a white solid. MS (ESI): m / z = 269.2 [M+H] + .

[0464] Step b): Sodium; 1-(5-chloro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate A solution of methyl 1-(5-chloro-2-methoxy-3-pyridyl)-1,2,4-triazole-3-carboxylate (210.0 mg, 0.720 mmol) in MeOH (2 mL) was treated with a solution of NaOH (43.15 mg, 1.08 mmol) in water (1 mL) at 20 °C. The mixture was stirred at this temperature for an additional 16 h and then evaporated to give the title compound (210 mg, 84.46% yield) as a crude white solid. MS (ESI): m / z = 255 [M+H]+ .

[0465] Component C.11 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoic acid A solution of 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluorobenzoic acid methyl ester (2730 mg, 9.8 mmol) in 1:1 1,4-dioxane / water (30 mL) was treated with LiOH monohydrate (739.95 mg, 17.63 mmol) at 23 °C. The mixture was stirred at this temperature for 6.5 hours and then concentrated under reduced pressure. The remaining aqueous solution was treated dropwise with 1 M HCl (17.63 mL, 17.63 mmol) and water (20 mL). The resulting thick slurry was filtered, and the cake was washed with water and dried to give the title compound (2.489 g, 96.0% yield) as a white solid. MS (ESI): m / z = 263.1 [MH] - .

[0466] Step a): Methyl 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate A solution of methyl 3-bromo-2-chloro-5-fluorobenzoate (CASRN: 1805582-40-4; 58.0 g, 216.84 mmol) in 1,4-dioxane (966.67 mL) was treated with bis(pinacolato)diboron (60.57 g, 238.52 mmol), potassium acetate (63.84 g, 650.52 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (17.69 g, 21.68 mmol) under Ar at 23 °C. The mixture was sparged with Ar and then heated to 100 °C and stirred at this temperature for 16 h. The mixture was then cooled, filtered through SiO2, and evaporated. Purification by FC (SiO2; hexane / MTBE) gave the title compound (18385 mg, 25.34% yield) as a pale yellow oil. MS (ESI): m / z = 314.0 [M+H] + .

[0467] Step b): Methyl 2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoate A solution of 4-bromo-1H-pyrrole-2-carbonitrile (CASRN: 1221435-18-2; 1.55 g, 9.06 mmol) in 2-MeTHF (20 mL) was treated with an aqueous solution (6 mL) of methyl 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.0 g, 9.54 mmol) and sodium carbonate (1.52 g, 14.31 mmol) under Ar at 23 °C. The mixture was sparged with Ar and then treated with di-tert-butyl(cyclopenta-1,4-dien-1-yl)phosphane; dichloropalladium; and iron (249.42 mg, 0.380 mmol). The mixture was heated to 60 °C and stirred at this temperature for 3 hours, then cooled. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. Purification by FC (SiO2; hexane / EtOAc) afforded the title compound (1600 mg, 58.93% yield) as a white powder. MS (ESI): m / z = 277.0 / 279.0 [M−H] - .

[0468] Component C.12 Chloro-5-fluoro-3-[(5-oxopyrrolidin-3-yl)methoxy]benzoic acid A solution of ethyl 2-chloro-5-fluoro-3-[(5-oxopyrrolidin-3-yl)methoxy]benzoate (774.0 mg, 2.45 mmol) in MeOH (5 mL) was treated with a solution of NaOH (147.09 mg, 3.68 mmol) in water (5 mL) at 23 °C. The mixture was stirred for 16 h and then evaporated. The residue was dissolved in HCl (pH = 3). The resulting precipitate was filtered off and dried to give the title compound (503 mg, 68.47% yield) as a white solid. MS (ESI) m / z = 288.0 [M + H] + .

[0469] Step a): Ethyl 2-chloro-5-fluoro-3-[(5-oxopyrrolidin-3-yl)methoxy]benzoate A solution of 4-(bromomethyl)pyrrolidin-2-one (814.37 mg, 4.57 mmol) in DMF (10 mL) was treated with ethyl 2-chloro-5-fluoro-3-hydroxybenzoate (1.0 g, 4.57 mmol) and cesium carbonate (2.98 g, 9.15 mmol) at 23 °C. The mixture was heated to 90 °C and stirred at this temperature for 16 h, then filtered and evaporated. Purification by RP-HPLC afforded the title compound (774 mg, 53.59% yield) as a light brown solid. MS (ESI): m / z = 316.0 [M+H] + .

[0470] Component C.13 3-chloro-2-[(2-oxooxazolidin-5-yl)methoxy]pyridine-4-carboxylic acid A solution of 3-chloro-2-fluoro-pyridine-4-carboxylic acid (CASRN: 741683-19-2; 824.48 mg, 4.7 mmol) in DMF (30 mL) was treated with 5-(hydroxymethyl)oxazolidin-2-one (CASRN: 7517-99-9; 500.0 mg, 4.27 mmol) and cesium carbonate (2.78 g, 8.50 mmol) at 23 °C. The mixture was heated to 80 °C and stirred at this temperature for 10 h, then cooled. The mixture was quantitatively acidified with NaHSO and extracted with EtOAc / water. The organic layer was separated, washed with water and brine, dried over NaSO, filtered, and evaporated. Purification by RP-HPLC afforded the title compound (234 mg, 18.09% yield) as a white solid. MS (ESI): m / z = 273.0 [M+H] + .

[0471] Component C.14 2-chloro-4-[2-(5-oxopyrrolidin-3-yl)ethyl]benzoic acid A solution of methyl 2-chloro-4-[2-(5-oxopyrrolidin-3-yl)ethyl]benzoate (1050.0 mg, 3.73 mmol) in 4:4:1 THF / MeOH / water (36 mL) was treated with lithium hydroxide monohydrate (203.3 mg, 4.85 mmol) at 25 °C. The mixture was stirred at this temperature for 18 h, then concentrated under reduced pressure and acidified to pH 4 with 1 M HCl. The resulting suspension was stirred for 30 min and filtered. The precipitate was washed with water and dried to afford the title compound (738.8 mg, 70.34% yield) as a white solid. MS (ESI): m / z = 266.0 [M−H] − .

[0472] Step a): Methyl 2-chloro-4-[2-(5-oxopyrrolidin-3-yl)ethynyl]benzoate A solution of methyl 2-chloro-4-iodobenzoate (CASRN: 156573-32-9; 1600.0 mg, 5.4 mmol) in ACN (70 mL) was treated with TEA (0.75 mL, 5.4 mmol) and 4-ethynylpyrrolidin-2-one (CASRN: 2098062-96-3; 588.92 mg, 5.4 mmol) under Ar at 23 °C. The mixture was sparged with Ar for 3 min and then treated with Pd(PPh) (438.19 mg, 0.380 mmol) and CuI (102.78 mg, 0.540 mmol). The mixture was heated to 50 °C and stirred at this temperature for 16 h, then filtered through a silica pad and evaporated. Purification by FC (SiO2; CHCl3 / ACN) gave the title compound (1050 mg, 66.56% yield) as a pale gray solid. MS (ESI): m / z = 278.0 / 280.0 [M+H] + .

[0473] Step b): Methyl 2-chloro-4-[2-(5-oxopyrrolidin-3-yl)ethyl]benzoate A solution of methyl 2-chloro-4-[2-(5-oxopyrrolidin-3-yl)ethynyl]benzoate (1050.0 mg, 3.78 mmol) in EtOAc (70 mL) was treated with Rh / C (10%) (300.0 mg) and hydrogen gas. The mixture was stirred at atmospheric pressure for 18 h, then returned to Ar, filtered, and evaporated to give the title compound (1000 mg, 87.3% yield) as a pale yellow oil. MS (ESI): m / z = 282.0 / 284.0 [M+H] + .

[0474] Component C.15 2-Chloro-5-fluoro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoic acid A solution of ethyl 2-chloro-5-fluoro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate (430.0 mg, 1.35 mmol) in 1:1 MeOH / water (1 mL) was treated with NaOH (81.21 mg, 2.03 mmol) at 20 °C. The mixture was stirred at this temperature for 10 h and then evaporated. The residue was dissolved in water (3 mL) and acidified to pH = 4 with H3PO4 solution. The mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (248 mg, 44.79% yield) as a yellow solid. MS (ESI): m / z = 290.0 / 292.0 [M+H] + .

[0475] Step a): Ethyl 2-chloro-5-fluoro-3-[(2-oxooxazolidin-5-yl)methoxy]benzoate A solution of ethyl 2-chloro-5-fluoro-3-hydroxybenzoate (CASRN: 2090950-46-0; 815.0 mg, 3.73 mmol) in DMA (10 mL) was treated with 5-(bromomethyl)-1,3-oxazolidin-2-one (CASRN: 51337-32-7; 1006.59 mg, 5.59 mmol) and cesium carbonate (2429.38 mg, 7.46 mmol) at 23 °C. The mixture was heated to 90 °C, stirred for 16 h, and then filtered. The filtrate was evaporated. Purification by RP-HPLC afforded the title compound (597 mg, 50.4% yield) as a dark brown solid. MS (ESI): m / z = 318.0 / 320.0 [M+H] + .

[0476] Component C.16 2-Chloro-5-fluoro-3-...

Claims

1. Formula (II) 【Chemistry 1】 (In the formula, L １ is a covalent bond, NHCH ２ , and C.H. ２ NH; R ８ is C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, and halo-C ３ -C １０ -cycloalkyl, R ９ is hydrogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, and halo-C ３ -C １０ -cycloalkyl, (a) X is NR ９ and Y is C, and (i) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R １ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ is the base 【Chemistry 2】 and R ６ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy, oxo and C １ -C ６ - alkyl, or (ii) A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from phenyl and pyridyl; R １ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ is the base 【Transformation 3】 and R ６ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is selected from cyano and hydroxy; R １１ is hydrogen, hydroxy, and C １ -C ６ - alkyl, or (iii) A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R １ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ is the base 【Chemistry 4】 and R ６ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy, and C １ -C ６ - alkyl, or (iv) A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R １ is hydroxy, carbamoyl-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, NH ２ SO ２ -, C １ -C ６ -Alkyl-SO ２ -, C １ -C ６ -Alkyl-SO ２ -C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ -PO-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-PO ２ -C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, halo-C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-SO ２ -C １ -C ６ -alkyl-, and C １ -C ６ -Alkyl-SO ２ -NH-C １ -C ６ -alkyl-, wherein C ３ -C １０ -Cycloalkyl is carbamoyl, C １ -C ６ -Alkyl-SO ２ -, and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ is the base 【Transformation 5】 and R ６ is hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy, and C １ -C ６ - alkyl; or (b) X is CR ９ or N, Y is N; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from A is selected from furanyl, thienyl, oxazolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from triazolyl, imidazolyl, phenyl and pyridyl; C is selected from azetidine, cyclopropyl, piperidine, piperazine, pyridyl, pyrazine, pyrimidine, 1,2-dihydropyridine, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, pyrrolyl, pyrrolidinyl, pyrazolyl, and triazolyl; R １ is halogen, hydroxy, carbamoyl-C １ -C ６ -Alkyl, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, C ３ -C １０ -cycloalkyl, NH ２ SO ２ -, C １ -C ６ -Alkyl-SO ２ -, C １ -C ６ -Alkyl-SO ２ -C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ -PO-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-PO ２ -C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, halo-C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-SO ２ -C １ -C ６ -alkyl-, and C １ -C ６ -Alkyl-SO ２ -NH-C １ -C ６ -alkyl-, wherein C ３ -C １０ -Cycloalkyl is carbamoyl, C １ -C ６ -Alkyl-SO ２ -, and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ , R ３ and R ４ are each independently selected from absent or hydrogen, halogen, and cyano; R ５ is C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ - alkyl and groups 【Transformation 6】 is selected from R ６ is hydrogen, halogen, and C １ -C ６ - alkyl, R ７ is selected from hydrogen and halogen; R ８ is C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, and halo-C ３ -C １０ -cycloalkyl, R ９ is hydrogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, and halo-C ３ -C １０ -cycloalkyl, R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy, oxo and C １ -C ６ -alkyl) or a pharmaceutically acceptable salt thereof.

2. Represented by formula (I), X is NR ９ and Y is C, or a pharmaceutically acceptable salt thereof. 【Transformation 7】

3. Represented by formula (IIa), X is CR ９ and Y is N, or a pharmaceutically acceptable salt thereof. 【Transformation 8】

4. 2. The compound of formula (II) according to claim 1, wherein X and Y are both N, as represented by formula (IIb), or a pharmaceutically acceptable salt thereof. 【Chemistry 9】

5. A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, and oxazolidine; R １ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ But, 【Chemistry 10】 and R ６ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy, oxo and C １ -C ６ 5. The compound of formula (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

6. A is selected from furanyl, thienyl, phenyl, and pyridyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from phenyl and pyridyl; R １ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ Based on 【Chemistry 11】 and R ６ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is selected from cyano and hydroxy; R １１ is hydrogen, hydroxy and C １ -C ６ 5. The compound of formula (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

7. A is selected from oxazolyl, pyrrolyl, pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R １ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ Based on 【Chemistry 12】 and R ６ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy and C １ -C ６ 5. The compound of formula (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

8. A is selected from oxazolyl, furanyl, thienyl, pyrrolyl, 1,3,4-oxadiazolyl, cyclopropyl, phenyl, pyrazinyl, pyridyl, and pyrimidinyl; B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, and imidazolyl; L ２ is a covalent bond, CH ２ O, OCH ２ , C.H. ２ NH, NHCH ２ , C.H. ２ , C.H. ２ CH ２ , C.F. ２ CH ２ , and C.H. ２ CF ２ is selected from C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine, phenyl, and pyridyl; R １ hydroxy, carbamoyl-C １ -C ６ -Alkyl, hydroxy-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -Alkyl, C ３ -C １０ -cycloalkyl, NH ２ SO ２ -, C １ -C ６ -Alkyl-SO ２ -, C １ -C ６ -Alkyl-SO ２ -C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ -PO-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-PO ２ -C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, halo-C １ -C ６ -Alkyl-sulfonimidoyl-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-SO ２ -C １ -C ６ -alkyl-, and C １ -C ６ -Alkyl-SO ２ -NH-C １ -C ６ -alkyl-, wherein C ３ -C １０ -Cycloalkyl is carbamoyl, C １ -C ６ -Alkyl-SO ２ -, and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ , R ３ , and R ４ are each independently absent or selected from hydrogen, halogen, cyano, and C １ -C ６ - alkyl, R ５ Based on 【Chemistry 13】 and R ６ But hydrogen, halogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy, and halo-C １ -C ６ -alkoxy, R ７ is selected from hydrogen and halogen; R １０ is hydrogen, cyano, hydroxy, halogen, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, NH ２ SO ２ -, and halo-C １ -C ６ - alkyl, R １１ is hydrogen, hydroxy and C １ -C ６ 5. The compound of formula (II) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

9. (i) L ２ is a covalent bond, OCH ２ , C.H. ２ O, NHCH ２ , C.H. ２ CH ２ is selected from A is phenyl; B is selected from phenyl, pyridyl, triazolyl, imidazolyl; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen or halogen, R ４ is hydrogen or halogen, R ５ Based on 【Chemistry 14】 and R ６ is halogen or C １ ~C ６ is alkyl, R ７ is hydrogen or halogen, R １０ But hydrogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, oxo, hydroxy and cyano; R １１ But hydrogen, C １ -C ６ - alkyl, oxo, or (ii) L ２ is a covalent bond, A is phenyl; B is triazolyl or phenyl; C is pyridyl or phenyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 15】 and R ６ is hydrogen or halogen, R ７ is hydrogen, R １０ is hydroxy or cyano; R １１ is hydrogen or halogen, or (iii) L ２ But CH ２ or CH ２ CH ２ and A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 16】 and R ６ is hydrogen or halogen, R ７ is hydrogen or halogen, R １０ is hydrogen, R １１ is hydrogen, or (iv) A is selected from pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is phenyl; R １ But, Halo-C １ -C ６ - alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ But C １ -C ６ -alkoxy, R ６ is a halogen, R ７ is hydrogen, or (v) L ２ is a covalent bond, A is pyridyl or phenyl; B is phenyl, triazolyl; C is triazolyl, pyrazolyl, or pyridyl; R １ But hydroxy, hydroxy-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, C １ -C ６ -Alkyl-SO ２ -, C １ -C ６ -Alkyl-SO ２ -C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-SO ２ -NH-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-SO ２ -C １ -C ６ -Alkyl-, carbamoyl-C １ -C ６ -Alkyl, NH ２ SO ２ -, C ３ -C １０ -cycloalkyl, wherein said C ３ -C １０ -Cycloalkyl includes carbamoyl and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ are hydrogen and halogens, R ３ is hydrogen, R ４ is hydrogen, R ５ But C １ -C ６ -alkoxy or group 【Chemistry 17】 and R ６ is a halogen, R ７ is hydrogen or halogen, R １０ is hydrogen, hydroxy, R １１ is hydrogen, halogen, or (vi) L ２ is a covalent bond, A is pyrazinyl, B is phenyl or triazolyl; C is selected from azetidinyl, 1,2-dihydropyridine, pyrrolyl, and 2-thia-6-azaspiro[3.3]heptane; R １ But, Halo-C １ -C ６ - alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on [Chemistry 18] and R ６ is a halogen, R ７ is a halogen, R １０ But NH ２ SO ２ -, cyano and oxo; R １１ is hydrogen or oxo, or (vii) L ２ is a covalent bond, CH ２ O, and CH ２ CH ２ is selected from A is phenyl; B is phenyl or triazolyl; C is selected from 1,2-dihydropyridine, pyrrolidinyl, pyrrolyl, 2-thia-6-azaspiro[3.3]heptane, and triazolyl; R １ But NH ２ SO ２ -, C １ -C ６ -Alkyl-PO ２ -C １ -C ６ -Alkyl-, C ３ -C １０ -cycloalkyl, wherein said C ３ -C １０ -Cycloalkyl is carbamoyl, C １ -C ６ -Alkyl-SO ２ -, and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 19】 and R ６ is a halogen, R ７ is a halogen, R １０ is oxo or cyano, R １１ 2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or oxo.

10. L ２ is a covalent bond, OCH ２ , C.H. ２ O, NHCH ２ , C.H. ２ CH ２ is selected from A is phenyl; B is selected from phenyl, pyridyl, triazolyl, imidazolyl; C is selected from azetidine, cyclopropyl, 2-thia-6-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, pyrrolidinyl, pyrrolyl, 1,2-dihydropyridine, 4,5-dihydroisoxazole, imidazolidine, oxazolidine; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen or halogen, R ４ is hydrogen or halogen, R ５ Based on 【Chemistry 20】 and R ６ is halogen or C １ -C ６ is alkyl, R ７ is hydrogen or halogen, R １０ But hydrogen, C １ -C ６ -Alkyl, halo-C １ -C ６ -Alkyl, C １ -C ６ -Alkyl-SO ２ -, oxo, hydroxy and cyano; R １１ But hydrogen, C １ -C ６ 10. The compound of formula (II) according to claim 9, wherein R is selected from the group consisting of -alkyl, oxo, or a pharmaceutically acceptable salt thereof.

11. L ２ is a covalent bond, A is phenyl and: B is triazolyl or phenyl; C is pyridyl or phenyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 21】 and R ６ is hydrogen or halogen, R ７ is hydrogen, R １０ is hydroxy or cyano; R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or halogen.

12. L ２ But CH ２ or CH ２ CH ２ and A is phenyl; B is phenyl and: C is triazolyl or pyrazolyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 22】 and R ６ is hydrogen or halogen, R ７ is hydrogen or halogen, R １０ is hydrogen, R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

13. A is selected from pyrazinyl, cyclopropyl, 1,3,4-oxadiazolyl, and pyrimidinyl; B is phenyl; R １ Halo-C １ -C ６ - alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ is C １ -C ６ -alkoxy, R ６ is a halogen, R ７ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

14. L ２ is a covalent bond, A is pyridyl or phenyl; B is phenyl, triazolyl; C is triazolyl, pyrazolyl, or pyridyl; R １ But hydroxy, hydroxy-C １ -C ６ -Alkyl, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, C １ -C ６ -Alkyl-SO ２ -, C １ -C ６ -Alkyl-SO ２ -C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-SO ２ -NH-C １ -C ６ -Alkyl-, C １ -C ６ -Alkyl-NH-SO ２ -C １ -C ６ -Alkyl-, carbamoyl-C １ -C ６ -Alkyl, NH ２ SO ２ -, C ３ -C １０ -cycloalkyl, wherein said C ３ -C １０ -Cycloalkyl includes carbamoyl and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ are hydrogen and halogens, R ３ is hydrogen, R ４ is hydrogen, R ５ But C １ -C ６ -alkoxy or group 【Chemistry 23】 and R ６ is a halogen, R ７ is hydrogen or halogen, R １０ is hydrogen, hydroxy, R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen.

15. L ２ is a covalent bond, A is pyrazinyl, B is phenyl or triazolyl; C is selected from azetidinyl, 1,2-dihydropyridine, pyrrolyl, and 2-thia-6-azaspiro[3.3]heptane; R １ Halo-C １ -C ６ - alkyl, R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 24】 and R ６ is a halogen, R ７ is a halogen, R １０ But NH ２ SO ２ -, cyano and oxo; R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or oxo.

16. L ２ is a covalent bond, CH ２ O, and CH ２ CH ２ is selected from A is phenyl; B is phenyl or triazolyl; C is selected from 1,2-dihydropyridine, pyrrolidinyl, pyrrolyl, 2-thia-6-azaspiro[3.3]heptane, and triazolyl; R １ But NH ２ SO ２ -, C １ -C ６ -Alkyl-PO ２ -C １ -C ６ -Alkyl-, C ３ -C １０ -cycloalkyl, wherein said C ３ -C １０ -Cycloalkyl is carbamoyl, C １ -C ６ -Alkyl-SO ２ -, and C １ -C ６ -Alkyl-SO ２ -NH-, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 25】 and R ６ is a halogen, R ７ is a halogen, R １０ is oxo or cyano, R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or oxo.

17. (i) L ２ is a covalent bond, CH ２ O, and NHCH ２ is selected from A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 26】 and R ６ is a halogen, R ７ is a halogen, R １０ is oxo, R １１ is hydrogen, or (ii) L ２ is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 27】 and R ６ is hydrogen, R ７ does not exist, R １０ is hydroxy, R １１ is hydrogen or halogen, or (iii) L ２ is CH ２ CH ２ and A is phenyl; B is phenyl and: C is triazolyl or pyrazolyl; R １ is a halogen, R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 28】 and R ６ is a halogen, R ７ is a halogen, R １０ is hydrogen, R １１ is hydrogen, or (iv) L ２ is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R １ is C ３ -C １０ -cycloalkyl, wherein said C ３ -C １０ -Cycloalkyl is one C １ -C ６ -Alkyl-SO ２ is substituted with an —NH— substituent; R ２ is a halogen, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 29】 and R ６ is a halogen, R ７ is a halogen, R １０ is cyano, R １１ 10. The compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

18. (i) L ２ is a covalent bond, CH ２ O, and NHCH ２ is selected from A is phenyl; B is phenyl; C is selected from pyrrolidinyl, 1,2-dihydropyridine, imidazolidine, and oxazolidine; R １ is fluoro, R ２ is fluoro, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Transformation 30】 and R ６ is fluoro, R ７ is chloro, R １０ is oxo, R １１ is hydrogen, or (ii) L ２ is a covalent bond, A is phenyl; B is triazolyl; C is pyridyl; R １ is fluoro, R ２ is fluoro, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 31】 and R ６ is hydrogen, R ７ does not exist, R １０ is hydroxy, R １１ is hydrogen or chloro, or (iii) L ２ is CH ２ CH ２ and A is phenyl; B is phenyl; C is triazolyl or pyrazolyl; R １ is fluoro, R ２ is fluoro, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Chemistry 32】 and R ６ is fluoro, R ７ is chloro, R １０ is hydrogen, R １１ is hydrogen, or (iv) L ２ is a covalent bond, A is phenyl; B is phenyl; C is pyrrolyl; R １ is cyclopropyl, and said cyclopropyl is one methyl-SO ２ is substituted with an —NH— substituent; R ２ is chloro, R ３ is hydrogen, R ４ is hydrogen, R ５ Based on 【Transformation 33】 and R ６ is fluoro, R ７ is chloro, R １０ is cyano, R １１ 18. The compound of formula (II) according to claim 17, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

19. L １ is a covalent bond and NHCH ２ 2. The compound of formula (II) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

20. L １ 20. The compound of formula (II) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein is a covalent bond.

21. R ８ is C １ -C ６ 2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -alkyl.

22. R ８ 22. The compound of formula (II) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein is methyl.

23. R ９ is C １ -C ６ 2. The compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -alkyl.

24. R ９ 24. The compound of formula (II) according to claim 23, or a pharmaceutically acceptable salt thereof, wherein is methyl.

25. 2. A compound of formula (II) according to claim 1, selected from the following: 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]pyrrolidin-2-one, 5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one, 5-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]oxazolidin-2-one, 4-[3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile, 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one, N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile, 3-chloro-5-[6-[2-chloro-5-fluoro-3-(6-oxo-1H-pyridin-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile, N-[[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]methyl]methanesulfonamide, N-[1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, 5-[[3-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one, [2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, 2-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide, [2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 5-[[3-chloro-4-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one, (2-chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]-N-methyl-methanesulfonamide, [2-chloro-5-fluoro-3-(3-methylsulfonylazetidin-1-yl)phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 3-chloro-5-[6-[2-chloro-5-fluoro-3-(1H-1,2,4-triazol-3-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, (2-chloro-3-methoxy-phenyl)-[(7S)-3-[3-chloro-5-(methylsulfonylmethyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 3-[3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-4-fluoro-phenyl]benzonitrile, [2-chloro-5-fluoro-3-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 4-[2-[3-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one, 1-[3-chloro-5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-(2-oxo-1H-pyridin-4-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, 5-[2-chloro-3-[3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(5-fluoro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone, 2-[3-chloro-5-[(7R)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]acetamide, [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(6-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone, 5-[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyridin-2-one, (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 2-[3-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-5-fluorophenyl]acetamide, [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone, 4-[2-[3-chloro-4-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one, 1-[2-chloro-3-[2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]azetidine-3-sulfonamide, (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-5-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 3-chloro-5-[(7S)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, [2-chloro-3-(5,5-dimethyl-4H-isoxazol-3-yl)-5-fluoro-phenyl]-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 3-chloro-5-[(7R)-2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, (2-chloro-3-methoxy-phenyl)-[(7S)-3-(6-hydroxy-2-pyridyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-pyrrolidin-3-yl-1,2,4-triazol-3-yl)methanone, hydrochloride salt, 1-[3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-methyl-phenyl]imidazolidin-2-one, 3-chloro-5-[2,7-dimethyl-6-[1-(2-oxo-1H-pyridin-3-yl)-1,2,4-triazole-3-carbonyl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]benzenesulfonamide, [3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[2-(triazol-1-ylmethyl)phenyl]methanone, 5-[[3-chloro-4-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-2-pyridyl]oxymethyl]oxazolidin-2-one, [2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, N-[[3-chloro-5-[(7R)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]methyl]methanesulfonamide, 4-[2-[3-chloro-4-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]ethyl]pyrrolidin-2-one, [2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 2-[5-[(7S)-6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-3-pyridyl]acetamide, [2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 5-[2-chloro-3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, 3-[3-[(7S)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one, (2-chloro-3-methoxyphenyl)-[(7S)-2,7-dimethyl-3-(5-methylsulfonyl-3-pyridyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [(7S)-3-[3-chloro-5-(2-methoxyethoxy)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone, 1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[(5-oxopyrrolidin-3-yl)methoxy]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, 1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, 1-[3-chloro-5-[(7R)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, 5-[2-chloro-3-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, 5-[2-chloro-3-[(7R)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, 1-[3-chloro-5-[(7S)-6-[2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, 1-[3-chloro-5-[(7R)-6-[2-chloro-3-(2,2-dioxo-2λ ６ -thia-6-azaspiro[3.3]heptan-6-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropanecarboxamide, 3-[5-chloro-4-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]imidazol-1-yl]-1H-pyridin-2-one, 3-[3-[(7S)-3-[3-chloro-5-(1-methylsulfonylcyclopropyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one, [(7R)-3-[3-chloro-5-(2-methoxyethoxy)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone, N-[[2-chloro-6-[6-(2-chloro-3-methoxy-benzoyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]-4-pyridyl]methyl]methanesulfonamide, (2-chloro-3-methoxy-phenyl)-[(7S)-2,7-dimethyl-3-[2-(trifluoromethyl)pyrimidin-4-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 4-[2-chloro-5-fluoro-3-[(7S)-3-[3-fluoro-5-[[methyl(dioxo)-λ ６ -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile, 4-[2-chloro-5-fluoro-3-[(7R)-3-[3-fluoro-5-[[methyl(dioxo)-λ ６ -phosphanyl]methyl]phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenyl]-1H-pyrrole-2-carbonitrile, N-[1-[3-chloro-5-[6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, N-[1-[3-chloro-5-[(7R)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, N-[1-[3-chloro-5-[6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, N-[1-[3-chloro-5-[(7S)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, N-[1-[3-chloro-5-[(7R)-6-[2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(2,3,4,5-tetrafluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile, N-[1-[3-chloro-5-[(7S)-6-[1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazole-3-carbonyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, 4-[2-chloro-3-[(7S)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile, 4-[2-chloro-3-[(7R)-2,7-dimethyl-3-(3,4,5-trifluorophenyl)-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]-1H-pyrrole-2-carbonitrile, N-[1-[3-chloro-5-[(7S)-6-[2,5-difluoro-3-(1H-pyrazol-4-yl)benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, [(7S)-3-[3-chloro-5-(2-hydroxy-2-methyl-propyl)phenyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-(2-chloro-3-methoxy-phenyl)methanone, 3-[3-[(7R)-2,7-dimethyl-3-[6-(trifluoromethyl)pyrazin-2-yl]-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-1,2,4-triazol-1-yl]-1H-pyridin-2-one, 3-chloro-5-[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-3H-pyridin-2-one, 3-chloro-5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-3H-pyridin-2-one, 3-chloro-5-[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-3H-pyridin-2-one, [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]methylamino]pyrrolidin-2-one, hydrochloride salt, 5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one, (5S)-5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one, (5R)-5-[[2,5-dichloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]oxazolidin-2-one, 4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]phenoxy]methyl]pyrrolidin-2-one, [2-chloro-3-(1,6-diazaspiro[3.3]heptan-6-yl)-5-fluoro-phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 2,2,2-trifluoroacetic acid, [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-4-pyridyl)-1,2,4-triazol-3-yl]methanone, (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, (4R)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, (2-chloro-3-methoxy-phenyl)-[(8S)-3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone, and (2-Chloro-3-methoxy-phenyl)-[(8S)-3-(3-chlorophenyl)-8-methyl-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]methanone.

26. 20. A compound of formula (II) according to claim 19, selected from the following: or a pharmaceutically acceptable salt thereof: 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]pyrrolidin-2-one, 5-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, 5-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]oxazolidin-2-one, 4-[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenyl]-1H-pyridin-2-one, [1-(5-chloro-2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]-[1-(2-hydroxy-3-pyridyl)-1,2,4-triazol-3-yl]methanone, N-[1-[3-chloro-5-[(7S)-6-[2-chloro-3-(5-cyano-1H-pyrrol-3-yl)-5-fluoro-benzoyl]-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-3-yl]phenyl]cyclopropyl]methanesulfonamide, [2-chloro-5-fluoro-3-[2-(1H-pyrazol-4-yl)ethyl]phenyl]-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, [2-chloro-5-fluoro-3-[2-(1H-triazol-4-yl)ethyl]phenyl]-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl]methanone, 4-[[2-chloro-3-[3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluorophenyl]methylamino]pyrrolidin-2-one, hydrochloride salt, (4S)-4-[[2-chloro-3-[(7S)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one, and (4S)-4-[[2-chloro-3-[(7R)-3-(3,5-difluorophenyl)-2,7-dimethyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridine-6-carbonyl]-5-fluoro-phenoxy]methyl]imidazolidin-2-one.

27. 10. A method for preparing a compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof, comprising: (a) Amine 1 【Transformation 34】 (In the formula, R １ ~R ４ , R ８ , R ９ , A and L １ is as defined in claim 1), Carboxylic Acid 2 【Chemistry 35】 (In the formula, R ５ ~R ７ and B is as defined in claim 1), reacting in a solvent in the presence of a base and a coupling agent to form a compound of formula (II) as described above, and optionally (b) contacting the compound of formula (II) with an acid to form a pharmaceutically acceptable salt thereof. A method comprising:

28. 28. A compound of formula (II) according to claim 1 when prepared according to the method of claim 27.

29. 10. A compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

30. A pharmaceutical composition comprising a compound of formula (II) according to claim 1 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

31. 10. A pharmaceutical composition comprising a compound of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use in a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, inflammatory bowel disease, irritable bowel syndrome and / or diarrhea in a mammal.

32. 32. A compound of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined in claim 30 for use in the method as defined in claim 31.

33. 10. Use of a compound of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, inflammatory bowel disease, irritable bowel syndrome and / or diarrhea in a mammal.

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