Heteroaryl compounds useful for treating cognitive disorders

Abstract

The present invention relates to a compound of formula (I): [Formula 1] TIFF2024517223000480.tif85170(in the formula, 1 , X 2 , X 3 , R 3 , Ring A and Ring B are as described herein. The compound is an α5 subunit-containing GABA receptor antagonist, and a pharma- ceutical acceptable salt thereof. A The present invention relates to the preparation of compounds of formula (I), pharmaceutical compositions containing the compounds, and methods for treating depression and cognitive impairment, including cognitive impairment associated with psychotic disorders such as schizophrenia, and the like. A Further provided is their use as medicaments for the treatment of receptor-related diseases and disorders.

Description

[Technical field]

[0001] The present invention relates to a method for detecting γ-aminobutyric acid (GABA) type A receptors (GABA A R) Compounds that are negative allosteric modulators (NAMs), particularly α5 subunit-containing GABA A R(α5-GABA A The present invention relates to compounds that are selective for α5-GABA receptor agonists, their manufacture, pharmaceutical compositions containing the compounds and their use as medicaments. The compounds of the present invention are useful for treating cognitive disorders, including, for example, cognitive impairment, Alzheimer's disease or Huntington's disease. A It is useful in the treatment of diseases and conditions associated with R. [Background technology]

[0002] In the mammalian central nervous system, GABA is the major inhibitory neurotransmitter. Receptors for this neurotransmitter are of three major types: related members of the ligand-gated ion channel superfamily (which are often referred to as GABA receptors); A R and GABA C GABA receptors (type A and type C receptors, collectively referred to as GABARs, without reference to the pharmacology that distinguishes them) A R and GABA C R) and type B receptors (GABA receptors), which are members of the G protein-coupled receptor family. B It is classified as R.

[0003] GABA A GABA R is a membrane-bound heteropentamer composed of 19 known subunits. A R contains two α subunits, two β subunits and one γ subunit with two GABA binding sites formed at the interface of the α and β subunits. A There are numerous theoretical heteropentameric assemblies of R proteins, but only about 25 are thought to exist in the brain (Olsen RW and Sieghart W. 2008 Pharmacology Review 60 243-260).A The pharmacology of R is characterized as a GABA receptor that contains β and γ2 subunits along with either α1, α2, α3, or α5 (but not α4 or α6) subunits. A These different α-containing GABA receptors can be defined in terms of their sensitivity (or lack thereof) to benzodiazepines that act as positive allosteric modulators (PAMs) in R. A R mediates different physiological and pharmacological functions and may have different expression levels in various parts of the body.

[0004] GABA acting at the benzodiazepine recognition site A R PAMs and negative allosteric modulators (NAMs) have opposing pharmacological actions at the molecular and whole animal levels and in preclinical species and humans (Atack J. 2011 Current Topics in Medicinal Chemistry 11 1176-1202; Atack J. 2011 Current Topics in Medicinal Chemistry 11 1203-1214). For example, the nonselective GABA modulators exemplified by the benzodiazepine diazepam A R-PAMs are typically anxiolytic, sedative, and anticonvulsant drugs that impair cognitive function (Atack J. 2011 Current Topics in Medicinal Chemistry 11 1176-1202), but have nonselective GABAergic properties. A R NAMs are anxiogenic, convulsant-like, and cognitive enhancing, and there is evidence that, for example, the B-carboline FG7142 is anxiogenic and produces convulsant-like aura in normal volunteers (Dorrow, R. et al. 1983 Lancet 2 98-99). On the other hand, α5-GABAs such as α5IA, MRK016, and RG1662 A R NAMs do not have proconvulsant side effects and are not anxiogenic in humans (Atack, J. 2010 Pharmacology & Therapeutics 125 11-26).

[0005] α5-GABAA R is whole brain GABA A Although a relative minority of the R population, they are highly expressed in the hippocampus where they are likely related to cognition and other hippocampal functions. A R has been used in the treatment of Down syndrome (Martinez-Cue C.et al.2013 Journal of Neuroscience 33 3953-3966), depression (Zanos P.et al.2017 eNeuro 4 ENEURO.0285-16.2017), anesthetic-induced cognitive impairment (Zurek AAet al.2014 Journal of Clinical Investigation 124 5437-5441), stroke (Gacsalyi,I.2018 European Journal of Pharmacology 834 118-125), mild cognitive impairment and / or Alzheimer's disease (Atack J.et al.2009 Journal of Pharmacology and Experimental Therapeutics 331 470-484;Ballard T.et al.2009 Psychopharmacology 202 207-223;Kawaharada S.et al.2017 Neuropsychiatry 202 207-223;Kawaharada S.et al.2017 Neuropsychiatry 202 207-223;Kawaharada S.et al.2017 Neuropsychiatry 202 207-223;Kawaharada S.et al.2017 Neuropsychiatry 202 207-223). al.2018 Journal of Pharmacology and Experimental Therapeutics 366 58-65), alcohol-related disorders (Platt D.2005 et al.Journal of Pharmacology and Experimental Therapeutics 313 658-667) and disorders of brain function associated with neuroinflammation (Eimerbrink M.et al.2015 Behavioural Brain Research,288 50-53) or bacterial or viral infections such as HIV (Green and Thayer 2019 Neuropharmacology 149 161-168 and Jacob, 2019 Frontiers in Molecular Neuroscience,12 179).

[0006] α5-GABA A R modulators have entered clinical trials for a variety of indications, including Down syndrome (RG1662 / vasumisanil, NCT02024789), schizophrenia (RG1662 / vasumisanil, NCT02953639), stroke (S44819, NCT02877615) and Dup15q syndrome (NCT05307679).

[0007] Specific α5-GABA A R modulators are those described in WO 98 / 50385 (Merck Sharp & Dohme; WO 2018 / 104419, WO 2012 / 062687, WO 2010 / 127978, WO 2010 / 127976, WO 2010 / 127974, WO 2010 / 112475, WO 2010 / 097368, WO 2010 / 094669, WO 2009 / 071476, WO 2009 / 071477, WO 2009 / 071476, WO 2009 / 071464 (Hoffmann-La Roche); WO 2015 / 115673 (Ono Pharmaceuticals); WO 2014 / 001279 (Saniona); WO 2019 / 046300 (University of Maryland); and WO 2022 / 029170. Summary of the Invention [Problem to be solved by the invention]

[0008] Novel α5-GABA A R modulators, especially α5-GABA A There is still a need for R NAM. [Means for solving the problem]

[0009] According to the present invention, a compound of formula (I): [ka] (In the formula, Ring A is selected from A1, A2 and A3: [ka] is selected from R 1 is selected from phenyl and 5- or 6-membered heteroaryl; R 1 Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 optionally substituted with one or more substituents selected from; R 2 H, halo, C 1~4 Alkyl and C 1~4 Haloalkyl, -OR a2 , -SR a2 and -NR a2 R b2 is selected from C 1~4 Alkyl is halo, -OR a3 , -SR a3 and -NR a3 R b3 optionally substituted with one or more substituents selected from; R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -NR 5 R 6 , -SR 5 , 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-; R 4 and R5 are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms, and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-; R 6 , H, C 1~4 Alkyl and C 1~4 haloalkyl; R 3 , R 4 , R 5 or R 6 Any C in either 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl-, halo, -OR a4 , -SR a4 and -NR a4 R b4 optionally substituted with one or more substituents selected from; X 1 , X 2 and X 3 are independently N and CR 7 Selected from; R 7 Each occurrence independently represents H, halo, -CN, or C. 1~4 Alkyl, C 1~4 Haloalkyl, -OR 8 , -NR 8 R 9 and -S(O) x R 8 (wherein x is 0, 1 or 2); R 8 and R 9 are independently H, C 1~4 Alkyl and C 1~4 haloalkyl; R 7 , R 8 or R 9Any C in either 1~4 Alkyl is halo, -CN, -OR a5 , -S(O) x R a5 where x is 0, 1 or 2, and -NR a5 R b5 optionally substituted with one or more substituents selected from; Ring B is one or more R 10 C optionally substituted with 6~10 selected from aryl and 5- to 12-membered heteroaryl, where when Ring B is a heteroaryl, Ring B is attached to the remainder of the compound of formula (I) by a ring atom in the aromatic ring of the heteroaryl; R 10 Each occurrence independently represents halo, -CN, -NO 2 , =O, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Q 1 -L 1 -, -OR 11 , -S(O) x R 11 (wherein x is 0, 1 or 2), -NR 11 R a6 , -C(O)R 11 , -OC(O)R 11 , -C(O)OR 11 , -NR a6 C(O)R 11 , -NR a6 C(O)OR 11 , -C(O)NR 11 R a6 , -OC(O)NR 11 R a6 , -NR a6 SO 2 R 11 , -SO 2 NR 11 R a6 and -NR a6 C(O)NR 11 R a6 is selected from Said C 1~6 Alkyl, C 2~6Alkenyl and C 2~6 Alkynyl is defined as one or more R 12 optionally replaced by; R 11 are independently H, C 1~6 Alkyl and C 1~6 haloalkyl, 1~6 Alkyl is one or more R 13 optionally replaced by; Q 1 Each occurrence of is independently 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl, 4- to 9-membered heterocyclyl-C 1~3 Alkyl-, Phenyl, Phenyl-C 1~3 Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 alkyl-, Said C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl and 4- to 9-membered heterocyclyl-C 1~3 Alkyl- is one or more R 14 and optionally replaced by The phenyl, phenyl-C 1~3 Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 Alkyl- is one or more R 15 optionally replaced by; L 1 is a bond or -O-, -S(O) x - (wherein x is 0, 1 or 2), -NR a7 -, -C(O)-, -OC(O)-, -C(O)O-, -NR a7 C(O)-, -C(O)NR a7 -, -NR a7 C(O)O-, -OC(O)NR a7 -, -NR a7 SO 2 -, -SO 2 NR a7- and -NR a7 C(O)NR a7 - Selected from; R 12 , R 13 and R 14 Each occurrence independently represents halo, =O, -CN, -NO 2 , C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a8 , -S(O) 2 R a8 , -NR a8 R b8 , -C(O)R a8 , -OC(O)R a8 , -C(O)OR a8 , -NR a8 C(O)R b8 , -C(O)NR a8 R b8 , -NR a8 C(O)OR b8 , -OC(O)NR a8 R b8 , -NR a8 SO 2 R b8 and -SO 2 NR a8 R b8 Selected from; Said C 1~4 Alkyl is halo, -CN, -OR a9 , -NR a9 R b9 and -SO 2 R a9 optionally substituted by 1 or 2 substituents selected from R 15 Each occurrence independently represents halo, =O, -CN, -NO 2 , C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a10 , -S(O) 2 R a10 , -NR a10 R b10 , -C(O)R a10 , -OC(O)R a10 , -C(O)OR a10 , -NR a10 C(O)Rb10 , -C(O)NR a10 R b10 , -NR a10 C(O)OR b10 , -OC(O)NR a10 R b10 , -NR b10 SO 2 R a10 and -SO 2 NR a10 R b10 Selected from; Said C 1~4 Alkyl is halo, -CN, -OR a11 , -NR a11 R b11 and -SO 2 R a11 optionally substituted by 1 or 2 substituents selected from R a1 , R b1 , R a2 , R b2 , R a3 , R b3 , R a4 , R b4 , R a5 , R b5 , R a6 , R a7 , R a8 , R b8 , R a9 , R b9 , R a10 , R b10 , R a11 and R b11 Each occurrence of is independently H, C 1~4 Alkyl and C 1~4 haloalkyl; or Any -NR in the substituent a1 R b1 , -NR a2 R b2 , -NR a3 R b3 , -NR a4 R b4 , -NR a5 R b5 , -NR a8 R b8 , -NR a9 R b9 , -NRa10 R b10 , -NR a11 R b11 , -NR 5 R 6 , -NR 8 R 9 or -NR 11 R a6 can form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl being halo, ═O, C 1~4 Alkyl and C 1~4 haloalkyl) or a pharma- ceutically acceptable salt thereof, provided that (i) and (ii): (i) Ring A is A2, and R 2 If H, then R 3 -NR 5 R 6 rather than; and (ii) The compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0010] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0011] Also provided is a compound of the invention or a pharma- ceutically acceptable salt thereof for use as a medicament. In certain embodiments, the compound of the invention or a pharma- ceutically acceptable salt thereof is an α5-GABA A For use in the treatment of a disease or condition mediated by R.

[0012] α5-GABA A Also provided is a method of treating a disease or condition mediated by R in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention, or a pharma- ceutically acceptable salt thereof.

[0013] In certain embodiments, α5-GABA A There is provided a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of a neurological or neuropsychiatric disorder mediated by α5-GABA R. In certain embodiments, A The compound of the present invention or a pharma- ceutically acceptable salt thereof is provided for use in the prophylaxis or treatment of cognitive impairment associated with a neurological or neuropsychiatric disorder involving R. The neurological disorder may be a neurodevelopmental disorder, such as Down's syndrome, or a neurodegenerative disorder, such as Alzheimer's disease or Huntington's disease. Thus, the compound of the present invention or a pharma- ceutically acceptable salt thereof is also provided for use in the treatment of a neurological disorder (e.g., Down's syndrome). The compound of the present invention or a pharma- ceutically acceptable salt thereof is also provided for use in the treatment of a neurodegenerative disorder (e.g., Alzheimer's disease or Huntington's disease).

[0014] α5-GABA A Diseases or medical disorders mediated by R include Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive impairment (e.g., cognitive impairment associated with chemotherapy, anesthetics, bacterial or viral infections (e.g., HIV)), memory impairment, age-related cognitive impairment (i.e., mild cognitive impairment, MCI), bipolar disorder, autism, Down's syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or paraphrenia). The disorder may be selected from chronic encephalopathy, chronic knee pain, psychosis, post traumatic stress disorder, anxiety disorder, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, alcohol disorder (e.g. alcoholism), drug withdrawal, movement disorder, restless legs syndrome, cognitive impairment disorder, multi-infarct dementia, vascular dementia, mood disorder, depression, neuropsychiatric disorder, attention deficit hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive impairment associated with stroke, cognitive impairment associated with brain injury or trauma, cognitive impairment associated with brain tumour, attention disorder and Dup15q syndrome.

[0015] In certain embodiments, the compounds of the invention, or pharma- ceutically acceptable salts thereof, are for use in the treatment or prevention of depression, such as the treatment of treatment-resistant depression.

[0016] In certain embodiments, the compounds of the invention, or pharma- ceutically acceptable salts thereof, are for use in the treatment or prevention of post-operative cognitive dysfunction in a subject.

[0017] In certain embodiments, the compounds of the invention or pharma- ceutically acceptable salts thereof are for use in the treatment or prophylaxis of psychiatric or neurological symptoms induced by neuroinflammation, for example, the compounds of the invention or pharma- ceutically acceptable salts thereof are for use in the treatment of neuroinflammation-induced cognitive dysfunction.

[0018] In an embodiment, the compound of the invention, or a pharma- ceutically acceptable salt thereof, is for use in the treatment or prevention of cognitive impairment associated with a bacterial or viral infection in a subject.

[0019] In the following, embodiments of the present invention will be further described with reference to the accompanying drawings. [Brief description of the drawings]

[0020] [Figure 1] 1 shows raw whole-cell current traces recorded with a QPatch system from the same cell expressing α5β3γ2 GABAA receptors before and after addition of the compound described in Example 1 (1 μM) using the in vitro electrophysiological recording assay described herein. [Diagram 2] Figure 2 shows rescue of etomidate-mediated long-term potentiation (LTP) deficits by the compound of Example 1 in the mouse hippocampal brain slice LTP assay described herein. The Y-axis in Figure 2A shows field excitatory postsynaptic potential (fEPSP) slope expressed as % of control fEPSP before 4-theta burst stimulation (4-TBS). The Y-axis in Figure 2B shows fEPSP slope at time points 50-60 min after delivery of 4-TBS. [Diagram 3]Figure 2 shows occupancy of rat brain benzodiazepine (BZ) binding sites by the compound of Example 1 in the in vivo brain receptor occupancy assay described herein at doses ranging from 3-30 mg / kg (oral (po)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0022] References herein to "a compound of the invention" are references to any of the compounds disclosed herein, including a compound of Formulas (I)-(XXXI), a compound selected from Compound List 1, or a compound described in any of the Examples, or a pharma- ceutically acceptable salt, solvate, or salt of a solvate of any of them.

[0023] "α5-GABA A Reference to "GABA R" refers to a GABA receptor that contains at least one α5 subunit, e.g., one or two α5 subunits. A Point to R.

[0024] The term "negative allosteric modulator" or "NAM" refers to the α5-GABA A This refers to a drug that acts at an allosteric site on R and indirectly reduces the responsiveness of the receptor to the endogenous ligand (GABA).

[0025] The term "treating" or "treatment" refers to any beneficial effect of treating or ameliorating an injury, disease, condition or disease, including any objective or subjective parameter, such as relief; remission; reduction in symptoms or making the injury, condition or disease more tolerable to the patient; slowing the rate of degeneration or debilitation; reducing the progression of the disease or condition, making the end point of degeneration less debilitating; improving the physical or mental health of the patient. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical exam, neuropsychiatric exam, and / or psychiatric evaluation. The term "treating" and its conjugations include prevention (i.e., prophylaxis or prevention) of an injury, condition, condition or disease. For example, the term "treating" and its conjugations include the treatment of α5-GABA A This includes preventing a condition, pathology, or disease associated with R (e.g., reducing or preventing cognitive impairment associated with a condition or disease).

[0026] The term "cognitive dysfunction" or "cognitive impairment" refers to a disorder of cognitive function as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Examples of cognitive dysfunction include one or more disorders of executive function, learning, memory, perception, problem solving, language, or social cognition. Cognitive dysfunction can be associated with a neurocognitive disorder in which cognition is impaired (such as, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, or dementia). Cognitive dysfunction can also be associated with a neurodevelopmental disorder (such as, for example, Down's syndrome, autism, or attention deficit hyperactivity disorder (ADHD)).

[0027] Disease-related α5-GABA A The terms "associated with", "related to", "involved in" or "mediated by" in the context of R refer to the condition in which the disease is AIt means that the symptoms of a disease are caused (in whole or in part) by a receptor or the activity or function of a receptor. For example, α5-GABA A Symptoms of a disease or condition associated with R pathway activity include α5-GABA A It may be a symptom that is attributable (in whole or in part) to an increased level of activity of the R protein pathway. As used herein, what is described as being associated with a disease may be a target for the treatment of the disease if it is a causative agent. For example, α5-GABA A Diseases associated with increased levels of α5-GABA R activity A The patient may be treated with an agent effective to reduce the level of activity of R (eg, a compound described herein).

[0028] An "effective amount" is an amount sufficient to achieve a stated purpose. For example, an amount sufficient to achieve the intended effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce receptor signaling, increase receptor signaling, alleviate one or more symptoms of a disease or condition, or produce a disease-modifying effect (i.e., change the underlying pathophysiology of the disease). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, or to alleviate the progression of a disease, which may also be referred to as a "therapeutically effective amount." "Prevention" of one or more symptoms means reducing the severity or frequency of a symptom, or eliminating a symptom. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, has an intended prophylactic effect, such as preventing or delaying the occurrence (or recurrence) of an injury, disease, condition, or pathology, or reducing the likelihood of the occurrence (or recurrence) of an injury, disease, condition, or pathology, or a symptom thereof. The full prophylactic effect may not necessarily occur by administration of a single dose, but may occur after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more doses. The exact amount will depend on the purpose of the treatment and will be ascertainable by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0029] The therapeutically effective amount of a compound of the invention can be estimated initially from cell culture assays. The target concentration will be the concentration of active compound capable of achieving the therapeutic effect described herein, as measured using methods described herein or known in the art.

[0030] The therapeutically effective amount for use in humans can also be determined from animal models using known methods.For example, human doses can be formulated to achieve concentrations known to be effective in animals.Human doses can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upwards or downwards as described above.It is well within the capabilities of those skilled in the art to adjust doses to achieve maximum effectiveness in humans based on the above and other methods.

[0031] Dosage can vary depending on the patient's needs and the compound used. In the context of the present invention, the dosage administered to a patient is sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the existence, nature and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages that are less than the appropriate amount of the compound. Thereafter, dosage is increased by small increments until the optimum effect is achieved under different circumstances.

[0032] Dosage amount and interval may be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, or in response to disease biomarkers or other correlated or surrogate endpoints, which will provide a treatment regimen commensurate with the severity of the individual's condition.

[0033] A prophylactic or therapeutic treatment regimen preferably does not cause significant toxicity, yet is effective in treating the clinical symptoms exhibited by a particular patient. This determination of the dosing regimen is generally based on an evaluation of the active compound by considering factors such as the potency of the compound, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred method of administration and the toxicity profile of the selected agent.

[0034] The term "halo" or "halogen" refers to one of the halogens of Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0035] C m~n The term refers to a group having m to n carbon atoms.

[0036] "C 1~6 The term "alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. 1~4 "Alkyl" similarly refers to such groups containing up to four carbon atoms. Alkylene groups are divalent alkyl groups, which likewise may be linear or branched and may have two points of attachment to the remainder of the molecule. Additionally, the alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. For example, C 1~6 Alkylene is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 -or-CH 2 CH(CH 3 )CH 2The alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, substituents on the alkyl or alkylene groups can be halogens, such as fluorine, chlorine, bromine and iodine, OH, C 1 ~C 4 It can be -alkoxy, -NR'R''amino, where R' and R'' are independently H or alkyl. Other substituents of the alkyl group can be used instead.

[0037] "C 1~6 Haloalkyl", e.g. "C 1~4 The term "haloalkyl" refers to a hydrocarbon chain that is substituted with at least one halogen atom, selected independently at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position in the hydrocarbon chain. For example, C 1~6 Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. Haloalkyl groups include, for example, -CX 3 , -CHX 2 , -CH 2 CX 3 , -CH 2 CHX 2 or -CX(CH 3 )CH 3 where X is halo (e.g., F, Cl, Br, or I). Fluoroalkyl groups, i.e., a hydrocarbon chain substituted with at least one fluorine atom (e.g., -CF 3 , -CHF 2 , -CH 2 CF 3 or -CH 2 CHF 2 ).

[0038] "C 2~6 The term "alkenyl" includes branched or straight hydrocarbon chains containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond may be present as an E or Z isomer. The double bond may be in any possible position of the hydrocarbon chain. For example, "C 2~6 "Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. An alkenylene group is a divalent alkenyl group, which in turn can be linear or branched and can have two points of attachment to the remainder of the molecule. Furthermore, an alkenylene group can correspond, for example, to one of the alkenyl groups listed in this paragraph. For example, an alkenylene can be -CH=CH-, -CH 2 CH=CH-, -CH(CH 3 )CH=CH- or -CH 2 It can be CH=CH-. Alkenyl and alkenylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those described above as substituents for alkyl groups.

[0039] "C 2~6 The term "alkynyl" includes branched or straight hydrocarbon chains containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be in any available position of the hydrocarbon chain. For example, "C 2~6 Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl and hexynyl. Alkynylene groups are divalent alkynyl groups, which in turn can be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an alkynylene group can correspond, for example, to one of the alkynyl groups listed in this paragraph. For example, alkynylene can be -C≡C-, -CH 2 C≡C-, -CH 2 C≡CCH 2 -, -CH(CH 3 )CH≡C- or -CH 2 C≡CCH 3Alkynyl and alkynylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those described above as substituents for alkyl groups.

[0040] "C 3~6 The term "cycloalkyl" includes saturated hydrocarbon ring systems containing 3, 4, 5 or 6 carbon atoms. For example, "C 3 ~C 6 "Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane or bicyclo[1.1.1]pentane. 3 ~C 6 "Cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0041] The term "heterocyclyl", "heterocyclic" or "heterocycle" includes non-aromatic saturated or partially saturated monocyclic or fused, bridged or spiro bicyclic heterocyclic ring systems. Monocyclic heterocycles may contain about 3-12 (preferably 3-7) ring atoms with 1-5 (preferably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles may contain 7-12 member atoms in the ring. Bicyclic heterocyclic rings may be fused, spiro or bridged ring systems. Heterocyclyl groups may be 3-12 membered, e.g. 3-9 membered (e.g. 3-7 membered), non-aromatic monocyclic or bicyclic saturated or partially saturated groups containing 1, 2 or 3 heteroatoms independently selected from O, S and N in the ring system (in other words 1, 2 or 3 of the atoms forming the ring system are selected from O, S and N). Partially saturated means that the ring may contain one or two double bonds. This is especially true for monocyclic rings having 5 to 7 members. The double bond will typically be between two carbon atoms, but may be between a carbon atom and a nitrogen atom. Bicyclic ring systems may be spiro-fused, i.e., in which the rings are linked to each other through a single carbon atom; closely fused, i.e., in which the rings are linked to each other through two adjacent carbon and / or nitrogen atoms; or they may share a bridgehead, i.e., the rings are linked to each other through two non-adjacent carbon or nitrogen atoms (bridged ring systems). Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing at least one nitrogen in a ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, etc. Exemplary sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin.Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl and octahydrobenzothiazolyl. For sulfur-containing heterocycles, SO or SO. 2 Also included are sulfur oxide heterocycles containing groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Preferred values ​​for heterocyclyl groups with one or two oxos (=O), such as 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two or three heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle may be linked to another group through any suitable atom, such as a carbon or nitrogen atom. For example, the term "piperidino" or "morpholino" refers to a piperidin-1-yl or morpholin-4-yl ring linked through a ring nitrogen.

[0042] The term "bridged ring system" includes ring systems in which two rings share three or more atoms, see, for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Preferably, the bridge is formed between two non-adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridgehead atoms can be a bond or can include one or more atoms. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0043] The term "spirobibicyclic ring system" includes ring systems in which two rings share one common spiro carbon atom, i.e., a heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 6-oxa-2-azaspiro[3.4]octane, 2,7-diaza-spiro[4.4]nonane, 2-azaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0044] "Heterocyclyl-C m~n Alkyl" is C m~n Heterocyclyl groups covalently linked to alkylene groups, both of which are defined herein; heterocyclyl-C m~n The alkyl group is linked to the remainder of the molecule through a carbon atom in the alkylene group. m~n Alkyl, Heteroaryl-C m~n Alkyl" and "Cycloalkyl-C m~n "Alkyl" is defined in the same manner.

[0045] "-NRR replaced with -C m~n Alkyl" and "-OR substituted C m~n Alkyl" is similarly C m~n refers to an -NRR'' or -OR'' group covalently bonded to an alkylene group, where the group is linked to the remainder of the molecule through a carbon atom in the alkylene group.

[0046] The term "aromatic", when applied to a substituent as a whole, includes monocyclic or polycyclic ring systems having 4n+2 electrons in a conjugated pi system within the ring or ring system, and all atoms contributing to the conjugated pi system lie in the same plane.

[0047] The term "aryl" includes aromatic hydrocarbon ring systems. The ring systems have 4n+2 electrons in a conjugated pi-system within the ring, and all atoms contributing to the conjugated pi-system are in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0048] The term "heteroaryl" includes aromatic monocyclic or bicyclic rings incorporating one or more (e.g., 1 to 4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The ring or ring system has 4n+2 electrons in a conjugated pi system, and all atoms contributing to the conjugated pi system lie in the same plane.

[0049] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more usually 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, such as bicyclic structures formed from fused 5- and 6-membered rings or two fused 6-membered rings. Bicyclic heteroaryl groups can be closely fused, i.e., in which case the rings are connected to each other via two adjacent carbon and / or nitrogen atoms. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, heteroaryl rings will contain up to four, e.g., up to three heteroatoms, more usually up to two, e.g., a single heteroatom. In one embodiment, heteroaryl rings contain at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, will be less than five.

[0050] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, and benzofurazanyl. Examples of pyrazinyl include quinolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl and imidazo[1,2-b][1,2,4]triazinyl. Examples of heteroaryl groups containing at least one nitrogen in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl.

[0051] "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings are non-aromatic, saturated or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems may be closely fused, i.e., in which the rings are linked to each other via two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0052] When Ring B is heteroaryl and the heteroaryl ring system comprises an aromatic ring and a non-aromatic, saturated or partially saturated ring, Ring B may be joined via a ring atom in the aromatic ring of Ring B to the formula: [ka] For example, ring B may be bonded to a group of the formula: [ka] When the bicyclic heteroaryl group is a bicyclic heteroaryl group of the formula: * via one of the ring carbon atoms represented by formula (I) [ka] is attached to the remainder of the compound.

[0053] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0054] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0055] Particular examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0056] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0057] The term "oxo" or "=O" as used herein means an oxygen that is double bonded to a carbon atom.

[0058] The term "optionally substituted" includes either groups, structures or molecules that are substituted as well as those that are not substituted.

[0059] When an optional substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of the specified groups, which may be the same or different, or substituents selected from two or more of the specified groups. For example, "one or more optional substituents" can refer to one or two or three substituents (e.g., one substituent or two substituents).

[0060] When a moiety is substituted, it can be substituted at any point on the moiety that is chemically possible and consistent with valence requirements. A moiety can be substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents; optionally, there are 1 or 2 substituents on a group. When there are two or more substituents, the substituents can be the same or different.

[0061] Substituents are present only in positions where they are chemically possible, and one skilled in the art can determine (either experimentally or theoretically) without undue effort whether a substitution is chemically possible or not.

[0062] Ortho, meta and para substitutions are terms well understood in the art. For the avoidance of doubt, an "ortho" substitution is [ka] As shown by the bond ending in , a substitution pattern in which adjacent carbons bear substituents, whether they are a single group, such as the fluoro group in the example below, or other parts of the molecule. [ka]

[0063] "Meta" substitution is a substitution pattern in which two substituents are on carbons one carbon away from each other, i.e., there is a single carbon atom between the substituted carbons. In other words, there is a substituent on a second atom away from an atom that has another substituent. For example, the following group is meta substituted: [ka]

[0064] "Para" substitution is a substitution pattern in which two substituents are on carbons two carbons away from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom away from an atom that has another substituent. For example, the following group is para substituted: [ka]

[0065] Reference to the group -NRR' forming a 4-6 membered heterocyclyl refers to R and R' which, together with the nitrogen atom to which they are attached, form a 4-6 membered heterocyclyl group. For example, -NR a1 R b1 , -NR a2 R b2 , -NR a3 R b3 , -NR a4 R b4 , -NR a8 R b8 , -NR a9 R b9 , -NR a10 R b10 , -NR 5 R 6 , -NR 8 R 9 or -NR 11 R a6 Groups such as -NRR' include [ka] Similarly, the -NRR' group in a substituent can form a 4-6 membered heterocyclyl linked to a carbonyl, for example, -C(O)NRR ’ The base is [ka] -OC(O)NRR ’ , -SO 2 NRR ’ or -NRC(O)NRR ’And so forth, -NRR' groups within a substituent may similarly form a 4-6 membered heterocyclyl within such substituent.

[0066] [ka] Or " * A bond that terminates in " represents that the bond is attached to another atom that is not shown in the structure. A bond that terminates within a ring structure and does not terminate at an atom of the ring structure represents that the bond may be attached to any of the atoms in the ring structure, if allowed by valences.

[0067] Throughout the description and claims of this specification, the terms "comprise" and "contain" and variations thereof mean "including, but not limited to," and they are not intended to exclude (and do not exclude) other moieties, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular includes the plural unless the context requires otherwise. In particular, when the indefinite article is used, the specification should be understood to contemplate the plural as well as the singular, unless the context requires otherwise.

[0068] It should be understood that features, integers, properties, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, abstract and drawings) and / or all of the 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 inconsistent. The invention is not limited to the details of any of the above embodiments. The invention extends to any novel one or any novel combination of the features disclosed herein (including any accompanying claims, abstract and drawings) or any novel one or any novel combination of the steps of any method or process so disclosed.

[0069] The reader's attention is directed to all articles and documents filed contemporaneously herewith or prior to this application and published herein in connection with this application, and the contents of all such articles and documents are incorporated herein by reference.

[0070] The various functional groups and substituents which make up the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, e.g., less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 585, e.g., 575 or less.

[0071] A suitable or preferred feature of any compound of the invention may also be a suitable feature of any other embodiment.

[0072] The present invention contemplates pharma- ceutically acceptable salts of the compounds of the present invention. These may include acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds.

[0073] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, glucept, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0074] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. For a general overview of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0075] Pharmaceutically acceptable salts of the compounds of the invention can be prepared, for example, by one or more of the following methods: (i) by reacting a compound of the invention with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) by converting one salt of a compound of the invention into another salt by reaction with an appropriate acid or base or by using a suitable ion exchange column.

[0076] These methods are typically carried out in solution. The resulting salt precipitates and may be recovered by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to nearly non-ionized.

[0077] Compounds that have the same molecular formula but differ in the nature or sequence of bonds of their atoms or the arrangement of their atoms in space are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of one another are called "diastereomers" and those that are non-superimposable mirror images of one another are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog or the way the molecule rotates the plane of polarized light and are represented as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". When a compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the present invention may exist as a single stereoisomer or may be a mixture of stereoisomers, such as racemic mixtures and other enantiomeric and diastereomeric mixtures. When the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. When the compound is a single stereoisomer, the compound may further contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have an enantiomeric excess (ee) or diastereomeric excess (de) of 100%, but may have an ee or de of about at least 85%, such as at least 90%, at least 95%, or at least 99%.

[0078] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemic forms (see the description in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It should be understood that the present invention encompasses all optical, diastereomeric and geometric isomers and mixtures thereof.

[0079] Z / E (eg, cis / trans) isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0080] Conventional techniques for the preparation / isolation of individual enantiomers, if desired, include chiral synthesis or resolution of the racemate (or racemate of a salt or derivative) from a suitable optically pure precursor, for example using chiral high performance liquid chromatography (HPLC). Thus, the chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0-50% by volume of isopropanol, typically 2%-20% and in certain instances 0-5% by volume of an alkylamine, for example 0.1% diethylamine. Concentration of the eluate gives the enriched mixture.

[0081] Alternatively, the racemate (or a racemate precursor) can be reacted with a suitable optically active compound, for example an alcohol or, if the compound of the invention contains an acidic or basic moiety, a base or an acid, for example 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted into the corresponding pure enantiomer by means well known to those skilled in the art.

[0082] When any racemate crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (true racemate), where one homogeneous form of crystal containing both enantiomers is produced in equimolar amounts. The second type is the racemic mixture or conglomerate, where two forms of crystals, each containing a single enantiomer, are produced in equimolar amounts.

[0083] While both crystalline forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, 1994).

[0084] The compounds and salts described herein may be isotopically labeled (or "radiolabeled"). Thus, one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include: 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C. 13 C. 14 C. 15 O. 17 O. 18 O. 13 N, 15 N, 18 F, 36Cl, 123 I, 25 I, 32 P, 35 The radionuclide used will depend on the specific application of the radiolabeled derivative. For example, in an in vitro competitive assay, 3 H or 14 C is often useful. For radioimaging applications, 11 C or 18 F is often useful. In one embodiment, the radionuclide is 3 H. In one embodiment, the radionuclide is 14 C. In one embodiment, the radionuclide is 11 C. Further, in certain embodiments, the radionuclide is 18 It's F.

[0085] Isotopically labeled compounds may generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described, substituting an appropriate isotopically labeled reagent for the non-labeled reagent previously used.

[0086] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK / PD properties of the compound, and / or the toxicity of the compound. For example, deuteration may increase the half-life or decrease the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It should be understood that the present invention encompasses deuterated derivatives of the compound of formula (I). As used herein, the term deuterated derivative refers to a compound of the present invention in which at least one hydrogen atom is replaced with deuterium at a particular position. For example, C 1~4 -One or more hydrogen atoms in the alkyl group are replaced with deuterium to form deuterated C 1~4 -alkyl groups may be formed. For example, R 2 is methyl, the present invention relates to -CD 3 , -CHD 2 and -CH 2 D is also included.

[0087] Certain compounds of the present invention can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, and it is to be understood that the invention encompasses all such solvated forms.

[0088] It is also to be understood that certain compounds of the invention may exhibit polymorphism and that the invention encompasses all such forms.

[0089] The compounds of the present invention may exist in several different tautomeric forms, and reference to the compounds of the present invention includes all such forms. For the avoidance of doubt, if a compound may exist in one of several tautomeric forms and only one is specifically described or shown, nevertheless, all others are encompassed by the compounds of the present invention. Examples of tautomers include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro. [ka] for example [ka]

[0090] The in vivo effects of the compounds of the invention may be exerted in part by one or more metabolic products formed within the human or animal body following administration of the compounds of the invention.

[0091] It should further be understood that suitable pharma- ceutically acceptable prodrugs of the compounds of formula (I) also form an aspect of the present invention. Thus, the compounds of the present invention encompass prodrug forms of the compounds, and the compounds of the present invention may be administered in the form of prodrugs (i.e., compounds that are broken down in the human or animal body to release the compounds of the present invention). Prodrugs may be used to alter the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs may be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at carboxy or hydroxy groups in the compounds of the present invention, and in vivo cleavable amide derivatives that may be formed at carboxy or amino groups in the compounds of the present invention.

[0092] The present invention therefore includes the compounds of the invention as defined herein when made available by organic synthesis and when made available in the human or animal body by cleavage of a prodrug thereof. The present invention therefore includes compounds of formula (I) produced by organic synthetic means and also such compounds produced in the human or animal body by metabolism of a precursor compound, i.e. compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0093] Suitable pharma- ceutically acceptable prodrugs of the compounds of the invention are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and undue toxicity.

[0094] Various forms of prodrugs are described, for example, in the following documents: a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0095] Suitable pharma- ceutically acceptable prodrugs of the compounds of formula I having a carboxy group are, for example, their in vivo cleavable esters. In vivo cleavable esters of the compounds of the invention containing a carboxy group are, for example, pharma- ceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharma- ceutically acceptable esters for carboxy include C, such as methyl, ethyl, and tert-butyl. 1~6 C such as alkyl esters and methoxymethyl esters 1~6 C such as alkoxymethyl ester and pivaloyloxymethyl ester 1~6C such as alkanoyloxymethyl esters, 3-phthalidyl esters, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters 3~8 Cycloalkylcarbonyloxy-C 1~6 C alkyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters. 1~6 Alkoxycarbonyloxy-C 1~6 Alkyl esters are included.

[0096] Suitable pharma- ceutically acceptable prodrugs of the compounds of the present invention having a hydroxy group are, for example, their in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compounds of the present invention containing a hydroxy group are, for example, pharma- ceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include inorganic acid esters such as phosphate esters (including phosphoramidate cyclic esters). Further suitable pharma-ceutically acceptable ester-forming groups for hydroxy groups include C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1~10 Alkanoyl group, ethoxycarbonyl, N,N-(C 1~6 Alkyl) 2 C such as carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups 1~10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Suitable pharma- ceutical-acceptable ether forming groups for a hydroxy group include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl groups.

[0097] Suitable pharma- ceutically acceptable prodrugs of compounds of the invention having a carboxy group include, for example, in vivo cleavable amides thereof, amines such as ammonia, C-alkyl groups such as methylamines, etc. 1~4 (C) such as alkylamines, dimethylamine, N-ethyl-N-methylamine or diethylamine 1~4 Alkyl) 2 Amines, such as 2-methoxyethylamine 1~4 Alkoxy-C 2~4 Phenyl-C such as alkylamines and benzylamines 1~4 Amides formed with alkyl amines and amino acids such as glycine or their esters.

[0098] Suitable pharma- ceutically acceptable prodrugs of the compounds of the invention having an amino group are, for example, their in vivo cleavable amide or carbamate derivatives. Suitable pharma- ceutically acceptable prodrugs from an amino group include, for example, C-type prodrugs such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1~10 Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Suitable pharma- ceutically acceptable carbamates from an amino group include, for example, acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.

[0099] compound The following paragraphs are applicable to the compounds of the present invention.

[0100] In certain embodiments, the compound of formula (I) has formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0101] In certain embodiments, the compound of formula (I) has formula (III): [ka] or a pharma- ceutically acceptable salt thereof.

[0102] In certain embodiments, the compound of formula (I) has formula (IV): [ka] or a pharma- ceutically acceptable salt thereof.

[0103] In certain embodiments, the compound of formula (I) has formula (V): [ka] (In the formula, X 4 is CH or N; R 101 is selected from H and halo or a pharma- ceutically acceptable salt thereof.

[0104] In certain embodiments, the compound of formula (I) has formula (VI): [ka] or a pharma- ceutically acceptable salt thereof.

[0105] In certain embodiments, the compound of formula (I) has formula (VII): [ka] or a pharma- ceutically acceptable salt thereof.

[0106] In certain embodiments, the compound of formula (I) has formula (VIII): [ka] or a pharma- ceutically acceptable salt thereof.

[0107] In certain embodiments, the compound of formula (I) has formula (IX): [ka] or a pharma- ceutically acceptable salt thereof.

[0108] In certain embodiments, the compound of formula (I) has the formula (X): [ka] (In the formula, X 4 is CH or N; R 101 is selected from H and halo or a pharma- ceutically acceptable salt thereof.

[0109] In certain embodiments, the compound of formula (I) has formula (XI): [ka] or a pharma- ceutically acceptable salt thereof.

[0110] In certain embodiments, the compound of formula (I) has formula (XII): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0111] In certain embodiments, the compound of formula (I) has formula (XIII): [ka] (In the formula, R 41 is C 1~3is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0112] In certain embodiments, the compound of formula (I) has formula (XIV): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0113] In certain embodiments, the compound of formula (I) has formula (XV): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0114] In certain embodiments, the compound of formula (I) has formula (XVI): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl); X 4 is CH or N; R 101 is selected from H and halo or a pharma- ceutically acceptable salt thereof.

[0115] In certain embodiments, the compound of formula (I) has formula (XVII): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0116] In certain embodiments, the compound of formula (I) has formula (XVIII): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0117] In certain embodiments, the compound of formula (I) has formula (XIX): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0118] In certain embodiments, the compound of formula (I) has the formula (XX): [ka] (R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0119] In certain embodiments, the compound of formula (I) has formula (XXI): [ka] (In the formula, R 41 is C1~3 is alkyl (e.g., R 41 is methyl); X 4 is CH or N; R 101 is selected from H and halo or a pharma- ceutically acceptable salt thereof.

[0120] In certain embodiments, the compound of formula (I) has formula (XXII): [ka] (In the formula, R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0121] In certain embodiments, the compound of formula (I) has formula (XXIII): [ka] (wherein p is 0, 1, 2 or 3). or a pharma- ceutically acceptable salt thereof.

[0122] In certain embodiments, the compound of formula (I) has formula (XXIV): [ka] (wherein p is 0, 1, 2 or 3; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0123] In certain embodiments, the compound of formula (I) has formula (XXV): [ka] (wherein p is 0, 1, 2 or 3; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0124] In certain embodiments, the compound of formula (I) has the formula (XXVI): [ka] (wherein p is 0, 1, 2 or 3; X 5 is CH or N) or a pharma- ceutically acceptable salt thereof.

[0125] In certain embodiments, the compound of formula (I) has formula (XXVII): [ka] (wherein p is 0, 1, 2 or 3; X 5 is CH or N; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0126] In certain embodiments, the compound of formula (I) has formula (XXVIII): [ka] (wherein p is 0, 1, 2 or 3; X 5 is CH or N; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0127] In certain embodiments, the compound of formula (I) has formula (XXIX): [ka] (In the formula, X 5 is CH or N) or a pharma- ceutically acceptable salt thereof.

[0128] In certain embodiments, the compound of formula (I) has the formula (XXX): [ka] (In the formula, X 5 is CH or N; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0129] In certain embodiments, the compound of formula (I) has the formula (XXXI): [ka] (In the formula, X 5 is CH or N; R 41 is C 1~3 is alkyl (e.g., R 41 is methyl) or a pharma- ceutically acceptable salt thereof.

[0130] In certain embodiments, the compounds of the present invention include, for example, compounds of formula (I)-(XXXI) or pharma- ceutically acceptable salts thereof, in which, unless otherwise specified, ring A, ring B, ring R 1 , R 2 , R 3 , R 10 , X 1 , X 2 , X 3Each of has any of the meanings defined above or in any of the following statements in numbered paragraphs (1) to (203) below. These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may be combined (where chemically permissible) with features described in one or more of the other statements below. In particular, when a compound is exemplified or depicted herein, any two or more of the following statements describing the characteristics of that compound, expressed at any level of generality, may be combined to represent subject matter that is considered to form part of the disclosure of the present invention herein.

[0131] 1. Ring A has the structure: [ka] A1 of the formula: [ka] indicates the point of attachment as defined in formula (I).

[0132] 2. Ring A has the structure: [ka] A2 of the formula: [ka] indicates the point of attachment as defined in formula (I).

[0133] 3. Ring A is A3 and has the structure: [ka] wherein [ka] indicates the point of attachment as defined in formula (I).

[0134] 4.R 1 is phenyl.

[0135] 5.R 1 Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 For example, R 1 -OR and -HALO a1 R is a phenyl group substituted with one or more substituents selected from a1 is C 1~4 It can be haloalkyl. Thus, R 1 can be a halo-substituted phenyl group. For example, R 1 R may be a phenyl group substituted with -F or -Cl. 1 -OR a1 R may be phenyl substituted with 1 -OC 1~4 It can be phenyl substituted with haloalkyl. Thus, R 1 -OCF 3 It may be phenyl substituted with

[0136] 6.R 1 is 4-fluorophenyl.

[0137] 7.R 1 is a 5- or 6-membered heteroaryl group containing at least one ring nitrogen atom, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0138] 8.R 1 is a 5-membered heteroaryl group containing at least one ring nitrogen, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0139] 9.R 1 is a 6-membered heteroaryl group containing at least one ring nitrogen, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0140] 10.R 1 is a heteroaryl selected from isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0141] 11.R 1 is a heteroaryl selected from isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, said heteroaryl being halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0142] 12.R 1is a heteroaryl selected from pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl, said heteroaryl being halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0143] 13.R 1 is a heteroaryl selected from pyridyl, said heteroaryl being halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0144] 14.R 1 is heteroaryl as defined in any one of numbered paragraphs 7-13, wherein said heteroaryl is unsubstituted.

[0145] 15.R 1 is heteroaryl as defined in any one of numbered paragraphs 7 to 13, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 is substituted with one or two substituents selected from:

[0146] 16.R 1 is heteroaryl as defined in any one of numbered paragraphs 7 to 13, said heteroaryl being selected from halo, C 1~4 Alkyl, C 1~4 Haloalkyl and -OR a1 is substituted with one or two substituents selected from:

[0147] 17.R 1 is heteroaryl as defined in any one of numbered paragraphs 7-13, said heteroaryl being substituted with 1 or 2 substituents selected from halo.

[0148] 18.R 1 is heteroaryl as defined in any one of numbered paragraphs 7-13, said heteroaryl being substituted with one fluoro substituent.

[0149] 19.R 1 teeth, [ka] is selected from the group consisting of X 4 is CH or N; R 101 is H or halo; R 102 -OC 1~4 It is haloalkyl.

[0150] 20.R 1 The structure: [ka] wherein R 101 is H or halo. Therefore, R 101 can be F or Cl.

[0151] 21.R 1 teeth, [ka] is selected from the group consisting of [ka] indicates the point of attachment to ring A.

[0152] 22. Ring A is A1 and R 1 teeth, [ka] wherein: [ka] indicates the point of attachment to ring A.

[0153] 23. Ring A is A1 and R 1 teeth, [ka] wherein: [ka] indicates the point of attachment to ring A.

[0154] 24. Ring A is A2 and R 1 is unsubstituted phenyl.

[0155] 25. Ring A is A3 and R 1 teeth, [ka] wherein: [ka] indicates the point of attachment to ring A.

[0156] 26.R 2 Halo, C 1~4 Alkyl and C 1~4 Haloalkyl, -OR a2 , -SR a2 and -NR a2 R b2 Selected from C 1~4 Alkyl is halo, -OR a3 , -SR a3 and -NR a3 R b3 and optionally substituted with one or more substituents selected from:

[0157] 27.R 2 H, halo, C 1~4 Alkyl and C 1~4 Haloalkyl, -OR a2 , -SR a2 and -NR a2 R b2 is selected from.

[0158] 28.R 2 Halo, C 1~4 Alkyl and C 1~4 Haloalkyl, -OR a2 , -SR a2 and -NR a2 R b2 is selected from.

[0159] 29.R 2 is H.

[0160] 30.R 2 is C 1~4 It is an alkyl.

[0161] 31.R 2 is C 1~3 It is an alkyl.

[0162] 32.R 2 is methyl.

[0163] 33.R 2 is methyl and ring A is A1.

[0164] 34.R 2 is methyl and ring A is A2.

[0165] 35.R 2 is methyl and ring A is A3.

[0166] 36.R 2 is methyl, R 1 is as defined in any one of numbered paragraphs 4 to 25.

[0167] 37. Ring A is [ka] wherein: [ka] indicates the point of attachment as defined in formula (I).

[0168] 38. Ring A is [ka] is selected from.

[0169] 39.R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -NR 5 R 6 , -SR 5 , 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-, 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl- is any of halo, -OR a4 , -SR a4 and -NR a4 R b4 and optionally substituted with one or more substituents selected from:

[0170] 40.R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -SR 5, 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-, 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl- is any of halo, -OR a4 and -SR a4 and optionally substituted with one or more substituents selected from:

[0171] 41.R 3 is C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -SR 5 , 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-, 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl- is any of halo, -OR a4 and -SR a4 and optionally substituted with one or more substituents selected from:

[0172] 42.R 3 is a 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms, a 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 Alkyl- and -OR 4 is selected from.

[0173] 43.R 3 is a 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms, a 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-.

[0174] 44.R 3is a 4- to 7-membered heterocyclyl containing 1 or 2 ring oxygen atoms. 3 can be a 4- to 7-membered heterocyclyl containing one ring oxygen atom. Thus, R 3 may be selected from oxetanyl, tetrahydrofuranyl and pyranyl.

[0175] 45.R 3 is a 4- to 7-membered heterocyclyl-C containing 1 or 2 ring oxygen atoms 1~3 Preferably, R 3 is a 4- to 7-membered heterocyclyl-C containing one ring oxygen atom 1~3 It can be alkyl-. Thus, R 3 is oxetanyl-C 1~3 Alkyl-, tetrahydrofuranyl-C 1~3 Alkyl- and pyranyl-C 1~3 alkyl-.

[0176] 46.R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -NR 5 R 6 and -SR 5 C is selected from 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl- is any of halo, -OR a4 , -SR a4 and -NR a4 R b4 and optionally substituted with one or more substituents selected from:

[0177] 47.R 3 -OR 4 and -NR 5 R 6 is selected from.

[0178] 48.R 3 -OR 4 and -NR 5 R 6 Selected from R 4 is C 3~6 Cycloalkyl, C 1~4 Alkyl and -NR a4 R b4 C replaced by 2~4 alkyl; R a4 and R b4 are independently H and C 1~4 alkyl; R 5 and R 6 are independently H and C 1~4 is selected from alkyl.

[0179] 49.R 3 -NR 5 R 6 It is.

[0180] 50.R 3 is -NH 2 It is.

[0181] 51.R 3 -NR 5 R 6 Therefore, R 3 is -NH 2 This may not be the case.

[0182] 52.R 3 is C 1~4 May not be alkyl. 3 is C 1~4 Alkyl or -NR 5 R 6 This may not be the case.

[0183] 53.R 3 -OR 4 It is.

[0184] 54.R 3 -OR 4 and R 4 is C 1~4Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl containing 1 or 2 ring oxygen atoms, and 4- to 7-membered heterocyclyl-C containing 1 or 2 ring oxygen atoms 1~3 alkyl-, R 4 In the above C 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl-, halo, -OR a4 , -SR a4 and -NR a4 R b4 and optionally substituted with one or more substituents selected from:

[0185] 55.R 3 -OR 4 and R 4 is a 4- to 7-membered heterocyclyl containing 1 or 2 ring oxygen atoms or a 4- to 7-membered heterocyclyl-C containing 1 or 2 ring oxygen atoms 1~3 It is alkyl-.

[0186] 56.R 3 -OR 4 and R 4 is a 4- to 6-membered heterocyclyl containing 1 or 2 ring oxygen atoms. 3 -OR 4 and R 4 can be a 4- to 6-membered heterocyclyl containing one ring oxygen atom. Thus, R 3 -OR 4 and R 4 may be selected from oxetanyl, tetrahydrofuranyl and pyranyl.

[0187] 57.R 3 -OR 4 and R 4 is a 4- to 6-membered heterocyclyl-C containing 1 or 2 ring oxygen atoms 1~3R is alkyl. 3 -OR 4 and R 4 is a 4- to 6-membered heterocyclyl-C containing one ring oxygen atom 1~3 It can be alkyl-. Thus, R 3 -OR 4 and R 4 is oxetanyl-C 1~3 Alkyl-, tetrahydrofuranyl-C 1~3 Alkyl- and pyranyl-C 1~3 alkyl-.

[0188] 58.R 3 teeth, [ka] where: [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0189] 59.R 3 -OR 4 and R 4 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~3 alkyl-, R 4 In the above C 1~4 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl-C 1~3 Alkyl-, halo, -OR a4 , -SR a4 and -NR a4 R b4 and optionally substituted with one or more substituents selected from:

[0190] 60.R 3 -OR 4 and R 4 is C 1~4Alkyl, C 1~4 Haloalkyl and C 3~6 cycloalkyl.

[0191] 61.R 3 -OR 4 and R 4 is C 1~4 Alkyl and C 1~4 haloalkyl.

[0192] 62.R 3 -OR 4 and R 4 is C 1~4 It is an alkyl.

[0193] 63.R 3 -OR 4 and R 4 -OR a4 , -SR a4 and -NR a4 R b4 C substituted with one or more substituents selected from 2~4 It is an alkyl.

[0194] 64.R 3 -OR 4 and R 4 -OR a4 C replaced by 2~4 is alkyl, R a4 H and C 1~4 R is selected from alkyl. 4 -OR a4 C replaced by 2~4 is alkyl, R a4 can be H. Therefore, R 3 is -O(CH 2 ) 2 It can be OH. 4 -OR a4 C replaced by 2~4 is alkyl, R a4 is C 1~4 It can be alkyl. Thus, R 3 is -O(CH 2 ) 2 OCH3 It could be.

[0195] 65.R 3 -OR 4 and R 4 -NR a4 R b4 C replaced by 2~4 is alkyl, R a4 and R b4 are independently H and C 1~4 R is selected from alkyl. 4 -NR a4 R b4 C replaced by 2~4 is alkyl, R a4 is H and R b4 is C 1~4 It can be alkyl. Thus, R 3 is -O(CH 2 ) 2 NHCH 3 It could be.

[0196] 66.R 3 -OR 4 and R 4 is C 3~6 It is cycloalkyl.

[0197] 67.R 3 is selected from cyclopropoxy, cyclobutoxy and cyclopentoxy.

[0198] 68.R 3 is cyclobutoxy.

[0199] 69.R 3 -OC 1~3 Alkyl and -OC 3~4 cycloalkyl.

[0200] 70.R 3 is methoxy and -OCH(CH 3 ) 2 is selected from.

[0201] 71.R3 is selected from methoxy and -O-cyclobutyl.

[0202] 72.R 3 is methoxy.

[0203] 73.R 3 is -OCH(CH 3 ) 2 It is.

[0204] 74.R 3 is -O-cyclobutyl.

[0205] 75.R 3 is -OH.

[0206] 76.R 3 -NR 5 R 6 R 5 and R 6 are independently H and C 1~4 R may be selected from alkyl. 5 is H and R 6 is C 1~4 R can be alkyl. 5 is H and R 6 R can be methyl. 5 and R 6 is C 1~4 R can be alkyl. 5 is methyl, R 6 can be methyl.

[0207] 77.R 3 -OR 4 and -NR 5 R 6 is selected from R 4 is C 3~6 Cycloalkyl, C 1~4 Alkyl and -NR a4 R b4 C replaced by 2~4 alkyl, R a4 and R b4are independently H and C 1~4 alkyl; R 5 and R 6 are independently H and C 1~4 is selected from alkyl.

[0208] 78.R 3 -OR 4 and R 4 is C 3~6 Cycloalkyl, C 1~4 Alkyl and -OR a4 C optionally substituted with 2~4 R is selected from alkyl. 3 -OR 4 and R 4 is C 3~6 Cycloalkyl, C 1~4 It may be selected from alkyl.

[0209] 79.R 3 is methoxy, [ka] is selected from the group consisting of [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0210] 80.R 3 is methoxy, [ka] is selected from the group consisting of [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0211] 81.R 3 is methoxy, [ka] is selected from the group consisting of [ka] R indicates the point of attachment to the remainder of the compound of formula (I). 3 is methoxy, [ka] may be selected from:

[0212] 82.X 1 is N.

[0213] 83.X 1 CR 7 It is.

[0214] 84.X 1 is CH.

[0215] 85.X 1 CR 7 and R 7 , halo, -CN, -OR a5 , -S(O) x R a5 where x is 0, 1 or 2, and -NR a5 R b5 C optionally substituted with one or more substituents selected from 1~4 It is an alkyl.

[0216] 86.X 1 CR 7 and R 7 -NR a5 R b5 C replaced by 1~3 It is an alkyl.

[0217] 87.X 1 CR 7 and R 7 -NR a5 R b5 C replaced by 1~3 is alkyl, R a5 and Rb5 H and C 1~3 is selected from alkyl.

[0218] 88.X 1 CR 7 and R 7 -CH 2 N(CH 3 ) 2 It is.

[0219] 89.X 2 is N.

[0220] 90.X 2 CR 7 It is.

[0221] 91.X 2 is CH.

[0222] 92.X 3 is N.

[0223] 93.X 3 CR 7 It is.

[0224] 94.X 3 is CH.

[0225] 95.X 3 is N and X 1 and X 2 CR 7 It is.

[0226] 96.X 3 is N and X 1 CR 7 and X 2 is CH.

[0227] 97.X 3 is N and X 1 is CH and X 2 CR 7 It is.

[0228] 98.X3 is N and X 1 and X 2 is CH.

[0229] 99.X 2 and X 3 is N and X 1 CR 7 It is.

[0230] 100.X 2 and X 3 is N and X 1 CR 7 and R 7 -CH 2 N(CH 3 ) 2 It is.

[0231] 101.X 2 and X 3 is N and X 1 is CH.

[0232] 102.X 1 and X 2 is N and X 3 CR 7 It is.

[0233] 103.X 1 and X 2 is N and X 3 is CH.

[0234] 104.X 1 is N and X 2 and X 3 CR 7 It is.

[0235] 105.X 1 is N and X 2 is CH and X 3 CR 7 It is.

[0236] 106.X 1 is N and X 2 CR 7and X 3 is CH.

[0237] 107.X 1 is N and X 2 and X 3 is CH.

[0238] 108.X 2 is N and X 1 and X 3 CR 7 It is.

[0239] 109.X 2 is N and X 1 CR 7 and X 3 is CH.

[0240] 110.X 2 is N and X 1 is CH and X 3 CR 7 It is.

[0241] 111.X 2 is N and X 1 and X 3 is CH.

[0242] 112.X 1 , X 2 and X 3 is CH.

[0243] 113.R 7 Each occurrence of is independently H, C 1~4 Haloalkyl and -CN, -OR a5 , -S(O) x R a5 where x is 0, 1 or 2, and -NR a5 R b5 C optionally substituted with one or more substituents selected from 1~4 is selected from alkyl.

[0244] 114.R 7Each occurrence of is independently H, C 1~3 Haloalkyl and -OR a5 , -S(O) 2 R a5 and -NR a5 R b5 C optionally substituted with one substituent selected from 1~3 is selected from alkyl.

[0245] 115.R 7 Each occurrence of is independently H, C 1~4 Haloalkyl and C 1~4 is selected from alkyl.

[0246] 116.R 7 is H.

[0247] 117. Ring B may each contain one or more R 10 and monocyclic or bicyclic 5- to 12-membered heteroaryl optionally substituted with

[0248] 118. Each ring B contains one or more R 10 and monocyclic or bicyclic 5- to 11-membered heteroaryl optionally substituted with

[0249] 119. Each ring B contains one or more R 10 and monocyclic 5- or 6-membered heteroaryl, optionally substituted with

[0250] 120. Each ring B contains one or more R 10 and n is selected from 5- or 6-membered heteroaryl optionally substituted with

[0251] 121. Ring B contains one or more R 10 Ring B is selected from phenyl, 5- or 6-membered heteroaryl, and 9- or 10-membered bicyclic heteroaryl, each optionally substituted with one or more R 10and 9- or 10-membered bicyclic heteroaryl, optionally substituted with

[0252] 122. Ring B is one or more R 10 and bicyclic 8- to 10-membered heteroaryl optionally substituted with

[0253] 123. Ring B is one or more R 10 and wherein R is an integer from 1 to 10. In the formula:

[0254] 124. Ring B is one or more R 10 bicyclic 8-, 9- or 10-membered heteroaryl optionally substituted with

[0255] 125. Ring B is one or more R 10 bicyclic 9 or 10 membered heteroaryl optionally substituted with

[0256] 126. Ring B is one or more R 10 and n is an integer from 1 to 5. In the formula:

[0257] 127. Ring B is one or more R 10 and optionally substituted 10-membered bicyclic heteroaryl.

[0258] 128. Ring B is one or more R 10 and n is selected from 5-membered heteroaryl optionally substituted with

[0259] 129. Ring B is one or more R 10 and 6-membered heteroaryl optionally substituted with

[0260] 130. Ring B is as defined in any one of numbered paragraphs 117-129, wherein said heteroaryl contains 1 to 4 ring heteroatoms selected from O, S and N.

[0261] 131. Ring B is as defined in any one of numbered paragraphs 117-129, wherein said heteroaryl contains one ring nitrogen atom and optionally 1 to 3 ring heteroatoms selected from O, S and N.

[0262] 132. Ring B is as defined in any one of numbered paragraphs 117 to 129, wherein said heteroaryl contains one ring nitrogen atom and optionally one or two ring heteroatoms selected from O, S and N.

[0263] 133. Ring B is as defined in any one of numbered paragraphs 117-129, and said heteroaryl contains 1-4 ring nitrogen atoms. Thus, the heteroaryl may contain 1-3 ring nitrogen atoms. For example, the heteroaryl contains 1 or 2 ring nitrogen atoms.

[0264] 134. Ring B is as defined in any one of numbered paragraphs 117 to 133, and when Ring B is heteroaryl, said heteroaryl is bonded to the remainder of the compound of formula (I) via a ring carbon atom in an aromatic ring in Ring B.

[0265] 135. Ring B is as defined in any one of numbered paragraphs 117 to 133, and when Ring B is heteroaryl, said heteroaryl is bonded to the remainder of the compound of formula (I) via a ring nitrogen atom in an aromatic ring in Ring B.

[0266] 136. Ring B is as defined in any one of numbered paragraphs 117 to 135, and Ring B is selected from the group consisting of one or two R 10 Thus, ring B is optionally substituted with one R 10 Ring B may be substituted with one R 10 may be substituted with

[0267] 137. Ring B is [ka] is selected from In the formula, p' is 0 or 1; p″ is 0, 1 or 2; p''' is 0, 1, 2 or 3; and [ka] indicates the point of attachment to the remainder of the compound of formula (I). p', p'' and p''' can be 0 or 1. p', p'' and p''' can be 0.

[0268] 138. Ring B is [ka] is selected from In the formula, p' is 0 or 1; p″ is 0, 1 or 2; p''' is 0, 1, 2 or 3; and [ka] indicates the point of attachment to the remainder of the compound of formula (I). p', p'' and p''' can be 0 or 1. p', p'' and p''' can be 0.

[0269] 139. Ring B is [ka] is selected from wherein p″ is 0, 1 or 2; p''' is 0, 1, 2 or 3; and [ka] indicates the point of attachment to the remainder of the compound of formula (I). p'' and p''' can be 0 or 1. p'' and p''' can be 0.

[0270] 140. Ring B is [ka] where p″ is 0, 1 or 2; [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0271] 141. Ring B is [ka] where: [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0272] 142. Ring B is [ka] is selected from In the formula, p' is 0 or 1; p' is 0, 1 or 2; [ka] indicates the point of attachment to the remainder of the compound of formula (I). p′ and p″ can be 0 or 1. p′ and p″ can be 0.

[0273] 143. Ring B is one or more (e.g., 1, 2 or 3) R 10 Ring B is a 6-membered heteroaryl containing at least one nitrogen in the ring, optionally substituted with. Ring B can have 1, 2 or 3 ring nitrogen atoms. For example, Ring B has 1 or 2 ring nitrogen atoms.

[0274] 144. Ring B has the structure: [ka] having During the ceremony, X 10 , X 11 , X 12 , X 13 and X 14 is independently selected from CH and N; X 10 , X 11 , X 12 , X 13 and X 14 at least one of is N; p is 0, 1, 2, 3 or 4 (where chemically feasible); [ka] indicates the point of attachment to the remainder of the compound of formula (I). 10 , X 11 , X 12 , X 13 and X 14 If there are two or less of these, then it is N.

[0275] 145. Ring B is [ka] where p is 0, 1, 2 or 3; [ka] indicates the point of attachment to the remainder of the compound of formula (I). Typically, p is 0 or 1. For example, p is 0. For example, p is 1.

[0276] 146. Ring B has the structure: [ka] wherein X 10 , X 11 , X 13 and X 14 is independently selected from CH and N; X 10 , X 11 , X 13 and X 14at least one of is N; p is 0, 1, 2 or 3 (where chemically feasible); [ka] indicates the point of attachment to the remainder of the compound of formula (I). 10 , X 11 , X 12 , X 13 and X 14 If there are two or less of these, then it is N.

[0277] 147. Ring B is [ka] where p is 0 or 1; [ka] indicates the point of attachment to the remainder of the compound of formula (I). Optionally, p is 1, and thus ring B is [ka] may be selected from:

[0278] 148. Ring B is [ka] is selected from In the formula, p is 0 or 1; [ka] indicates the point of attachment to the remainder of the compound of formula (I). Optionally, p is 1, and thus ring B is [ka] may be selected from:

[0279] 149. Ring B is selected from a 5- or 6-membered heteroaryl ring, wherein the 5-membered heteroaryl is as defined in numbered paragraph (137) and the 6-membered heteroaryl is as defined in numbered paragraph (145).

[0280] 150. Ring B is selected from a 5- or 6-membered heteroaryl ring, wherein the 5-membered heteroaryl is as defined in numbered paragraph (138) and the 6-membered heteroaryl is as defined in numbered paragraph (145).

[0281] 151. Ring B is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, saturated 4- to 7-membered heterocyclyl, partially saturated 4- to 7-membered heterocyclyl and C 3~7 A fused bicyclic heteroaryl selected from phenyl or a 5- or 6-membered heteroaryl ring fused to a ring selected from cycloalkyl, and ring B is selected from one or more R 10 wherein at least one ring atom in Ring B is N, and Ring B is optionally substituted with a group, and Ring B is bonded to the remainder of the compound of Formula (I) through a ring atom in the aromatic ring of Ring B.

[0282] 152. Ring B is a fused bicyclic heteroaryl selected from a phenyl ring fused to a ring selected from a 5- or 6-membered heteroaryl, a 4- to 7-membered saturated heterocyclyl, and a 4- to 7-membered partially saturated heterocyclyl, wherein Ring B is selected from one or more R 10 group, and at least one ring atom in Ring B is N. Ring B is a bicyclic heteroaryl selected from a phenyl ring fused to a ring selected from a 5- or 6-membered heteroaryl, a 5- or 6-membered saturated heterocyclyl, and a 5- or 6-membered partially saturated heterocyclyl, and Ring B is optionally substituted with one or more R 10 Ring B is optionally substituted with a group and at least one ring atom in Ring B may be N. In any of the above cases, the Ring B group is bonded to the remainder of the compound of formula (I) by a ring carbon atom in the phenyl ring of the bicyclic Ring B group.

[0283] 153. Ring B has the structure: [ka] having During the ceremony, Ring B' is selected from a 5- or 6-membered heteroaryl ring, a 5- or 6-membered saturated heterocyclyl ring, and a 5- or 6-membered partially saturated heterocyclyl ring; p' and q' are independently selected from 0, 1, 2 or 3 (where chemically feasible); At least one ring atom in ring B' is N; Ring B is [ka] Preferably, p'+q' is ≦4, for example p'+q' is 0, 1 or 2.

[0284] 154. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of attachment to the carbon atom in the phenyl ring of Ring B to the remainder of the compound of formula (I); p' and q' are independently selected (where chemically possible) from 0, 1, 2 or 3. Suitably, p'+q' is ≦4. For example, p'+q' is 0, 1 or 2.

[0285] 155. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of attachment to the remainder of the compound of formula (I) or ring B; p' and q' are independently selected (where chemically possible) from 0, 1, 2 or 3. Suitably, p'+q' is ≦4. For example, p'+q' is 0, 1 or 2.

[0286] 156. Ring B is a 4- to 7-membered saturated heterocyclyl, a 4- to 7-membered partially saturated heterocyclyl, and C 3~6 a fused bicyclic heteroaryl selected from a 6-membered heteroaryl ring fused to a ring selected from a cycloalkyl, the bicyclic group being selected from one or more R 10 group, and at least one ring atom in Ring B is N. Ring B is selected from the group consisting of 5- or 6-membered saturated heterocyclyl, partially saturated 5- or 6-membered heterocyclyl and C 5~6 a fused bicyclic heteroaryl selected from a 6-membered heteroaryl ring fused to a ring selected from a cycloalkyl, the bicyclic group being selected from one or more R 10 group, and at least one ring atom in Ring B may be N. In any of the above cases, Ring B is bonded to the remainder of the compound of Formula (I) through a ring atom in the 6-membered heteroaryl ring of Ring B.

[0287] 157. Ring B has the structure: [ka] having During the ceremony, Ring B' is a 5- or 6-membered saturated heterocyclyl, a partially saturated 5- or 6-membered heterocyclyl or C 3~6 is cycloalkyl; X 15 , X 16 , X 17 and X 18 is independently selected from CH and N, with the proviso that X 15 , X 16 , X 17 and X 18 At least one, but not more than two, of the ring B is X 15 , X 16 , X 17 and X 18to the remainder of the compound of formula (I) via a ring carbon represented by one of: p' is 0, 1 or 2; q' is 0, 1, 2 or 3 (where chemically possible). Suitably, p'+q' is ≦4, for example 0, 1 or 2.

[0288] 158. Ring B is [ka] is selected from During the ceremony, p' is 0, 1 or 2 (if chemically possible); q' is 0, 1, 2 or 3 (if chemically possible); [ka] indicates the point of attachment from a ring carbon in the pyridyl ring of Ring B to the remainder of the compound of formula (I). Suitably p'+q' is ≦4, for example 0, 1 or 2.

[0289] 159. Ring B is [ka] is selected from During the ceremony, p' is 0, 1 or 2 (if chemically possible); q' is 0, 1, 2 or 3 (if chemically possible); [ka] indicates the point of attachment to the remainder of the compound of formula (I). Suitably, p'+q' is ≦4, for example 0, 1 or 2.

[0290] 160. Ring B is a 4- to 7-membered saturated heterocyclyl, a partially saturated 4- to 7-membered heterocyclyl, and C 3~6 A fused bicyclic heteroaryl selected from a 5-membered heteroaryl ring fused to a ring selected from cycloalkyl, and ring B is selected from one or more R 10group, and at least one ring atom in Ring B is N. Ring B is selected from the group consisting of 5- or 6-membered heterocyclyl, partially saturated 5- or 6-membered heterocyclyl and C 5~6 A fused bicyclic heteroaryl selected from a 5-membered heteroaryl ring fused to a ring selected from cycloalkyl, and ring B is selected from one or more R 10 group, and at least one ring atom in Ring B can be N. In each of the above fused bicyclic heteroaryl Ring B groups, Ring B is attached to the remainder of the compound of Formula (I) by a ring atom in the 5-membered heteroaryl ring of the Ring B group.

[0291] 161. Ring B has the structure: [ka] having During the ceremony, Ring B contains at least one ring nitrogen; Ring B' is a 5- or 6-membered saturated heterocyclyl ring, a 5- or 6-membered partially saturated heterocyclyl ring, and C 5~6 cycloalkyl; X 19 , X 20 , X 21 , X 22 and X 23 is a 5-membered heteroaryl ring; X 19 and X 23 is independently selected from C and N; X 20 , X 21 and X 22 is independently selected from CH, N, NH, O and S, with the proviso that X 20 , X 21 and X 22 is O, S, or NH; Ring B is X 20 , X 21 and X 22 is attached to the remainder of the compound of formula (I) by a ring carbon or nitrogen atom represented by one of p' is 0, 1 or 2; q' is 0, 1, 2, 3 or 4. Suitably, p'+q' is ≦4, for example, p'+q' is 0, 1 or 2.

[0292] 162. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of Ring B to the remainder of the compound of formula (I); Ring B is attached to the remainder of the compound by a ring carbon or nitrogen atom in the 5-membered heteroaryl ring in Ring B; p' is 0 or 1; q' is 0, 1, 2, 3 or 4. Suitably, p'+q' is ≦4, for example, p'+q' is 0, 1 or 2.

[0293] 163. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of ring B to the remainder of the compound of formula (I); p' is 0 or 1; q' is 0, 1, 2, 3 or 4. Suitably, p'+q' is ≦4, for example, p'+q' is 0, 1 or 2.

[0294] 164. Ring B is a fused bicyclic heteroaryl selected from a 5- or 6-membered heteroaryl fused to another 5- or 6-membered heteroaryl, and Ring B is selected from one or more R 10group, and at least one ring atom in Ring B is N. Ring B is a fused bicyclic heteroaryl selected from a 5-membered heteroaryl fused to a 6-membered heteroaryl, and Ring B is optionally substituted with one or more R 10 group, and at least one ring atom in Ring B can be N. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to another 6-membered heteroaryl, and Ring B is optionally substituted with one or more R 10 At least one ring atom in ring B may be N, optionally substituted with a group.

[0295] 165. Ring B is a fused bicyclic heteroaryl selected from a 5-membered heteroaryl fused to a 6-membered heteroaryl, where Ring B is bonded to the remainder of the compound of formula (I) via a ring carbon or ring nitrogen atom in the 5-membered heteroaryl, and Ring B contains at least one ring nitrogen atom (e.g., 1, 2, 3, or 4 ring nitrogen atoms) and optionally 1 or 2 ring atoms selected from O and S; Ring B contains one or more R 10 Groups are optionally substituted.

[0296] 166. Ring B is a fused bicyclic heteroaryl selected from a 5-membered heteroaryl fused to a 6-membered heteroaryl, and Ring B is bonded to the remainder of the compound of formula (I) via a ring carbon or ring nitrogen atom in the 5-membered heteroaryl; the 5-membered heteroaryl is selected from pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, and 1,2,4-triazole; The 6-membered heteroaryl is selected from pyridine, pyrimidine, pyridazine, and pyrazine; Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0297] 167. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to a 5-membered heteroaryl, where Ring B is bonded to the remainder of the compound of formula (I) via a ring carbon or ring nitrogen atom in the 6-membered heteroaryl, Ring B contains at least one ring nitrogen atom (e.g., 1, 2, 3, or 4 ring nitrogen atoms) and optionally, 1 or 2 ring atoms selected from O and S; Ring B contains one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0298] 168. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to a 5-membered heteroaryl, and Ring B is bonded to the remainder of the compound of formula (I) via a ring atom in the 6-membered heteroaryl; the 5-membered heteroaryl is selected from pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, and 1,2,4-triazole; The 6-membered heteroaryl is selected from pyridine, pyrimidine, pyridazine, and pyrazine; Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0299] 169. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to another 6-membered heteroaryl, where Ring B contains at least one ring nitrogen atom (e.g., 1, 2, 3, or 4 ring nitrogen atoms) and optionally 1 or 2 ring atoms selected from O and S; Ring B contains one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0300] 170. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to another 6-membered heteroaryl, each of said 6-membered heteroaryls being independently selected from pyridine, pyrimidine, pyridazine, and pyrazine; Ring B is one or more (e.g., 1, 2, 3, or 4) R10 Groups are optionally substituted.

[0301] 171. Ring B is a fused bicyclic heteroaryl selected from a 5-membered heteroaryl fused to a phenyl ring, said 5-membered heteroaryl group having 1, 2 or 3 ring heteroatoms selected from O, S and N; Ring B is a fused bicyclic heteroaryl selected from a 5-membered heteroaryl group having 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; 10 ring B is optionally substituted with one or more (e.g., 1, 2, 3, or 4) R 10 Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the 5-membered heteroaryl ring. Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the phenyl ring.

[0302] 172. Ring B is a fused bicyclic heteroaryl group selected from 5-membered heteroaryls fused to a phenyl ring, the 5-membered heteroaryl group being selected from pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole, and 1,2,4-triazole; Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0303] Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the 5-membered heteroaryl ring. Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the phenyl ring.

[0304] 173. Ring B is a fused bicyclic heteroaryl selected from a 6-membered heteroaryl fused to a phenyl ring, said 6-membered heteroaryl having 1, 2 or 3 ring heteroatoms selected from O, S and N; ... wherein said 6-membered heteroaryl has 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; 10 Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the 6-membered heteroaryl ring. Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the phenyl ring.

[0305] 174. Ring B is a fused bicyclic group selected from a 6-membered heteroaryl fused to a phenyl ring, said 6-membered heteroaryl group being selected from pyridine, pyrimidine, pyridazine and pyrazine; Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 Groups are optionally substituted.

[0306] Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the 6-membered heteroaryl ring. Ring B may be attached to the remainder of the compound of formula (I) through a ring atom in the phenyl ring.

[0307] 175. Tamaki is [ka] [ka] is selected from During the ceremony, p' is 0, 1, 2 or 3; q' is 0, 1 or 2 (where chemically feasible); [ka] indicates the point of attachment from a ring atom in the 5-membered heteroaryl ring of Ring B to the remainder of the compound of Formula (I).

[0308] 176. Ring B is [ka] is selected from During the ceremony, p' is 0, 1, 2 or 3; q' is 0, 1 or 2 (where chemically feasible); [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0309] 177. Ring B is [ka] [ka] is selected from p' is 0, 1, 2 or 3; q' is 0, 1 or 2 (where chemically feasible); [ka] indicates the point of attachment from a ring carbon atom in the 6-membered heteroaryl ring of Ring B to the remainder of the compound of Formula (I).

[0310] 178. Ring B is [ka] is selected from p' is 0, 1, 2 or 3; q' is 0, 1 or 2 (where chemically feasible); q″ is 0 or 1; [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0311] 179. Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 C optionally substituted with 6~10 It is aryl.

[0312] 180. Ring B is one or more (e.g., 1, 2, 3, or 4) R 10 is phenyl optionally substituted with Ring B is one R 10 Thus, ring B is a phenyl substituted with [ka] is selected from the group consisting of [ka] may represent the point of attachment to the remainder of the compound of formula (I). Preferably, ring B is [ka] It could be.

[0313] 181. Ring B is unsubstituted. Therefore, R 10 may not be present.

[0314] 182. Ring B is as defined in any one of numbered paragraphs 117 to 180; R 10 does not exist.

[0315] 183. Ring B is one or more R 10 For example, ring B is substituted with one or two R 10 Therefore, ring B is substituted with one R 10 may be substituted with

[0316] 184. Ring B is as defined in any one of numbered paragraphs 117 to 180, and Ring B is selected from the group consisting of one or two R 10 is replaced by.

[0317] 185.R 10 Each occurrence independently represents halo, -CN, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, Q 1 -L 1 -, -OR 11 , -S(O) x R 11 (wherein x is 0, 1 or 2), -NR 11 R a6 , -C(O)R 11 , -OC(O)R 11 , -C(O)OR 11 , -NR a6 C(O)R 11 , -NR a6C(O)OR 11 , -C(O)NR 11 R a6 , -OC(O)NR 11 R a6 , -NR a6 SO 2 R 11 , -SO 2 NR 11 R a6 C is selected from 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is defined as one or more R 12 Ring B can be as defined in any one of numbered paragraphs 117-184.

[0318] 186.R 10 Each occurrence independently represents halo, -CN, =O, C 1~6 Alkyl, -C 1~6 Alkyl-OR a8 , -C 1~6 Alkyl-NR a8 R b8 , -C 1~6 Alkyl-O(CO)R a8 , -C 1~6 Alkyl-(CO)OR a8 , -C 1~6 Alkyl-SO 2 R a8 , -OH, -OC 1~6 Alkyl, -OC 1~6 Haloalkyl, -OC 2~4 Alkyl-OR a8 , -OC 2~4 Alkyl-NR a8 R b8 , -NH 2 , -NR a6 C 1~6 Alkyl, -NR a6 C 2~4 Alkyl-OR a8 , -NR a6 C 2~4 Alkyl-NR a8 R b8 , C 1~6 Haloalkyl, -SC 1~6 Alkyl, -SC1~6 Haloalkyl, -S(O) 2 C 1~6 Alkyl, -S(O) 2 C 1~6 Haloalkyl-C(O)C 1~6 Alkyl, -C(O)C 1~6 Haloalkyl, -C(O)C 1~6 Alkyl-OR a8 , -C(O)C 1~6 Alkyl-NR a8 R b8 , -OC(O)C 1~6 Alkyl, -COOH, -C(O)OC 1~6 Alkyl, -NR a6 C(O)C 1~6 Alkyl, -NR a6 C(O)C 1~6 Alkyl-OR a8 , -NR a6 C(O)C 1~6 Alkyl-NR a8 R b8 , -NR a6 C(O)OR a8 , -C(O)NR a6 C 1~6 Alkyl, -C(O)NR a6 C 2~6 Alkyl-OR a8 , -C(O)NR a6 C 2~6 Alkyl-NR a8 R b8 , -OC(O)NR a8 R a6 , -NR a6 SO 2 R a8 , -SO 2 NR a8 R a6 and Q 101 -L 101 - Selected from; Q 101 is C 3~6 cycloalkyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl and 4-6 membered heterocyclyl are substituted with halo, ═O, C 1~4 Alkyl, -OR a8 , -NRa8 R b8 , -C(O)R a8 and -S(O) 2 R a8 and optionally substituted with one or more (e.g., one or two) substituents selected from The 5- or 6-membered heteroaryl may be halo, C 1~4 Alkyl, -OR a10 , -NR a10 R b10 , -C(O)R a10 and -S(O) 2 R a1 optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 101 is a bond or C 1~3 Alkylene, -O- and -NR a7 - is selected.

[0319] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0320] 187.R 10 Each occurrence independently represents halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkyl-NR a8 R b8 , -OH, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, -OC 2~4 Alkyl-NR a8 R b8 , -NH 2 , -NR a6 C 1~4 Alkyl, -NR a6 C 2~4 Alkyl-OR a8 , -NR a6 C 2~4 Alkyl-NR a8 R b8 , -C(O)C 1~4 Alkyl, -C(O)C 1~4 Haloalkyl, -C(O)C 1~4 Alkyl-NR a8R b8 , -COOH, -C(O)OC 1~4 Alkyl, -C(O)NR a6 C 1~4 Alkyl, -C(O)NR a6 C 2~4 Alkyl-OR a8 , -C(O)NR a6 C 2~4 Alkyl-NR a8 R b8 and Q 102 -L 102 - Selected from; Q 102 is selected from 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; The 4- to 6-membered heterocyclyl is independently halo, ═O, C 1~4 Alkyl, -OR a8 , -NR a8 R b8 and -C(O)R a8 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from The 5- or 6-membered heteroaryl is independently halo, C 1~4 Alkyl, -OR a10 and -NR a10 R b10 selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 102 is a bond or C 1~3 Alkylene, -O- and -NR a7 - is selected.

[0321] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0322] 188.R 10 Each occurrence independently represents halo, -CN, C1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkyl-NR a8 R b8 , -OH, -OC 1~4 Alkyl, -OC 1~4 Haloalkyl, -OC 2~4 Alkyl-NR a8 R b8 , -NH 2 , -NR a6 C 1~4 Alkyl, -NR a6 C 2~4 Alkyl-OR a8 , -NR a6 C 2~4 Alkyl-NR a8 R b8 , C 1~4 Haloalkyl, -C(O)C 1~4 Alkyl, -C(O)C 1~4 Haloalkyl, -C(O)C 1~4 Alkyl-NR a8 R b8 , -COOH, -C(O)OC 1~4 Alkyl, -C(O)NR a6 C 1~4 Alkyl, -C(O)NR a6 C 2~4 Alkyl-OR a8 , -C(O)NR a6 C 2~4 Alkyl-NR a8 R b8 and Q 103 -L 103 - Selected from; Q 103 is a 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is independently halo, ═O, C 1~4 Alkyl, -OR a8 , -NR a8 R b8 and -C(O)R a8 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 103is a bond or is selected from methylene, -O-, -NH-, and -NMe-. Ring B can be as defined in any one of numbered paragraphs 117 to 184.

[0323] 189.R 10 Each occurrence independently represents halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -C 1~4 Alkyl-NR a8 R b8 , -NH 2 , -NR a6 C 1~4 Alkyl, -NR a6 C 2~4 Alkyl-NR a8 R b8 , -C(O)C 1~4 Alkyl, -C(O)C 1~4 Alkyl-NR a8 R b8 , -C(O)NHR a6 , -C(O)N(R a6 ) C 1~4 Alkyl and -C(O)N(R a6 ) C 2~4 Alkyl-NR a8 R b8 Ring B can be as defined in any one of numbered paragraphs 117-184.

[0324] 190.R 10 Each occurrence independently represents halo, -CN, -NO 2 , =O, C 1~6 Alkyl, C 1~6 Haloalkyl, Q 1 -L 1 -, -OR 11 , -S(O) x R 11 (wherein x is 0, 1 or 2), -NR 11 R a61 , -C(O)R 11 , -C(O)OR 11 , -NR a61 C(O)R 11 and -C(O)NR 11 Ra61 Selected from; Said C 1~6 Alkyl is one or more R 12 optionally replaced by; R 11 are independently H, C 1~6 Alkyl and C 1~6 haloalkyl, 1~6 Alkyl is one or more R 13 optionally replaced by; Q 1 Each occurrence of is independently 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 9-membered heterocyclyl-C 1~3 selected from alkyl, 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl and 4- to 9-membered heterocyclyl-C 1~3 Alkyl is one or more R 14 and optionally replaced by The 5- or 6-membered heteroaryl may be one or more R 15 optionally replaced by; L 1 is a bond or -O- or -NR a71 Selected from; R 12 For each occurrence, -NR a81 R b81 , -C(O)OR a81 , -OR a81 Selected from; R 13 For each occurrence, -NR a81 R b81 -OR a81 Selected from; R 14 Each occurrence of is halo, =O, C 1~4 Alkyl, -NR a81 R b81 -OR a81 Selected from; R 15 Each time it occurs, it is called a halo, C 1~4 Alkyl, -NR a81 Rb81 -OR a81 Selected from; R a61 , R a71 , R a81 and R b81 are independently H and C 1~4 is selected from alkyl.

[0325] Ring B can be as defined in any one of numbered paragraphs 117 to 184. In this embodiment, Q 1 Each occurrence of is independently 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl-C 1~3 selected from alkyl-, 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl and 4- to 7-membered heterocyclyl-C 1~3 Alkyl- is one or more R 14 and optionally replaced by The 5- or 6-membered heteroaryl may be one or more R 15 may be optionally replaced by

[0326] 191.R 10 Each occurrence of is independently 1~6 Alkyl or Q 1 -L 1 - selected from Said C 1~6 Alkyl is one or more R 12 optionally replaced by; Q 1 is independently selected from 4- to 7-membered heterocyclyl having one ring nitrogen atom and optionally one ring atom selected from O, S and N; and Q 1 Halo, C 1~4 Alkyl, -NR a81 R b81 -OR a81 optionally substituted with one or two substituents selected from L 1is a bond or -O-; R 12 For each occurrence, -NR a81 R b81 Selected from; R a81 and R b81 are independently H and C 1~4 is selected from alkyl.

[0327] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0328] 192.R 10 Each occurrence of is independently 1 -L 1 - selected from Q 1 Each occurrence independently represents 4- to 9-membered heterocyclyl-C 1~3 alkyl-, said heterocyclyl having one ring nitrogen atom and optionally one ring atom selected from O, S and N; L 1 is a bond.

[0329] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0330] 193.R 10 -NR a81 R b81 , -C 1~3 Alkyl-NR a81 R b81 , -NR a81 -C 2~3 Alkyl-NR a81 R b81 , -C(O)C 1~3 Alkyl-NR a81 R b81 and -C(O)NR a81 C 2~3 Alkyl-NR a81 R b81 Selected from R a81 and R b81 are independently H and C 1~3is selected from alkyl.

[0331] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0332] 194.R 10 -NR a81 R b81 and R a81 and R b81 are independently H and C 1~3 is selected from alkyl.

[0333] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0334] 195.R 10 -NR a81 R b81 and -C 1~3 Alkyl-NR a81 R b81 Selected from R a81 and R b81 are independently H and C 1~3 R is selected from alkyl. 10 -C 1~3 Alkyl-NR a81 R b81 and R a81 and R b81 are independently H and C 1~3 It may be selected from alkyl.

[0335] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0336] 196.R 10 is fluoro, chloro, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, -NH 2 , -NH(Me), -N(Me) 2 , [ka] [ka] [ka] is selected from During the ceremony, [ka] indicates the point of attachment to ring B.

[0337] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0338] 197. Ring B is Q 1 -L 1 -One R selected from 10 The ring B is substituted with halo, C 1~3 Alkyl and C 1~3 Ring B may be as defined in any one of numbered paragraphs 117-184, and is optionally substituted with one or two further substituents selected from haloalkyl.

[0339] 198. Ring B is Q 101 -L 101 -One R selected from 10 The ring B is substituted with halo, C 1~3 Alkyl and C 1~3 optionally substituted with one or two further substituents selected from haloalkyl; Q 101 is C 3~6 cycloalkyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl and 4-6 membered heterocyclyl are substituted with halo, ═O, C 1~4 Alkyl, -OR a8 , -NR a8 R b8 , -C(O)R a8 and -S(O) 2 R a8 and optionally substituted with one or more (e.g., one or two) substituents selected from The 5- or 6-membered heteroaryl may be halo, C 1~4 Alkyl, -OR a10 , -NR a10 R b10 , -C(O)R a10 and -S(O) 2 R a1 optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 101 is a bond or C 1~3 Alkylene, -O- and -NR a7 - is selected.

[0340] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0341] 199. Ring B is Q 102 -L 102 -One R selected from 10 The ring B is substituted with halo, C 1~3 Alkyl and C 1~3 optionally substituted with one or two further substituents selected from haloalkyl; Q 102 is selected from 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; The 4- to 6-membered heterocyclyl is independently halo, ═O, C 1~4 Alkyl, -OR a8 , -NR a8 R b8 and -C(O)R a8 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from The 5- or 6-membered heteroaryl is independently halo, C 1~4 Alkyl, -OR a10 and -NR a10 R b10selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 102 is a bond or C 1~3 Alkylene, -O- and -NR a7 is selected from.

[0342] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0343] 200. Ring B is Q 103 -L 103 -One R selected from 10 The ring B is substituted with halo, C 1~3 Alkyl and C 1~3 optionally substituted with one or two further substituents selected from haloalkyl; Q 103 is a 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is independently halo, ═O, C 1~4 Alkyl, -OR a8 , -NR a8 R b8 and -C(O)R a8 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted with one or more (e.g., 1 or 2) substituents selected from L 103 is a bond or is selected from methylene, --O--, --NH-- and --NMe--.

[0344] Ring B can be as defined in any one of numbered paragraphs 117-184.

[0345] 201. Ring B is [ka] [ka] [ka] [ka] [ka] is selected from During the ceremony, * indicates the point of attachment to the remainder of the compound of formula (I).

[0346] 202. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0347] 203. Ring B is [ka] is selected from During the ceremony, [ka] indicates the point of attachment to the remainder of the compound of formula (I).

[0348] 204. In the compound of formula (I), X 1 and X 3 is N and X 2 is CH.

[0349] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XII), (XIII), (XIV), (XV), (XVIII), (XIX), (XX), (XXIII), (XXIV), (XXV), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof; 1 is selected from phenyl and 5- or 6-membered heteroaryl containing at least one ring nitrogen; R 1 Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 and optionally substituted with one or more substituents selected from:

[0350] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof; 3 -OR 41 -OMe and -OCH(CH 3 ) 2 Therefore, R 3 -OR 41 can be -OMe. 3 -OR 41 is -OCH(CH 3 ) 2 It could be.

[0351] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof, wherein X is 1 CR 7 and X 2 is N. For example, X 1 CR 7 and R 7 H, halo and C 1~4 alkyl; X 2 is N. For example, X 1 is CH and X 2 is N. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0352] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof, wherein X is 1 is N and X 2 CR 7 For example, X 1 is N and X 2 CR 7 and R 7H, halo and C 1~4 For example, X is selected from alkyl. 1 is N and X 2 is CH. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0353] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof, wherein X is 1 and X 2 CR 7 In these embodiments, X 1 is CH and X 2 CR 7 It could be. X 1 CR 7 and X 2 can be CH. In these embodiments, R 7 H, halo and C 1~4 alkyl. Thus, X 1 and X 2 can be CH. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0354] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XXIII), (XXIV), (XXVI), (XXVII), (XXIX) or (XXX) or a pharma- ceutically acceptable salt thereof, wherein X is 1 , X 2 and X 3 is CH. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0355] In certain embodiments, a compound of the invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is as defined in any one of numbered paragraphs 117-184, 201 or 202.

[0356] In certain embodiments, the compound of the invention is a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is as defined in any one of numbered paragraphs 117-184, 201 or 202; R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR41 is -OMe).

[0357] In certain embodiments, the compound of the invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is as defined in any one of numbered paragraphs 117-184, 201 or 202; 1 and X 2 are both CH. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0358] In certain embodiments, the compound of the invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is as defined in any one of numbered paragraphs 117-184, 201 or 202; 1 is N and X 2 is CH. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0359] In certain embodiments, the compound of the invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is as defined in any one of numbered paragraphs 117-184, 201 or 202; 1 is CH and X 2 is N. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0360] In certain embodiments, the compound of the invention is a compound of formula (I), (XII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI) or a pharma- ceutically acceptable salt thereof, wherein ring A is as defined in any one of numbered paragraphs 37 and 38. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 In these embodiments, X is -OMe. 1 and X 2 may both be CH. In these embodiments, X 1 is CH and X 2 may be N. In these embodiments, X 1 is N and X 2 can be CH.

[0361] In certain embodiments, the compound of the present invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein ring B is selected from one or two R 10 Optionally substituted with R 10 is as defined in any one of numbered paragraphs 185 to 196. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe). Thus, in this embodiment, ring B can be unsubstituted. In this embodiment, ring B can be substituted with one or two R 10 is replaced by R 10 may be as defined in any one of numbered paragraphs 185 to 196.

[0362] In certain embodiments, the compound of the present invention is a compound of formula (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof; 10 is as defined in any one of numbered paragraphs 185 to 196. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe. Preferably, in these embodiments, p (if present) is 0, 1 or 2.

[0363] In certain embodiments, the compound of the invention is a compound of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XIII), (XIV), (XV), (XVIII), (XIX) or (XX) or a pharma- ceutically acceptable salt thereof; 1 is as defined in any one of numbered paragraphs 4 through 21; 2 is methyl. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0364] In certain embodiments, the compound of the present invention is a compound of formula (I), (II), (III), (IV), (V), (VII), (VIII), (IX), (X), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), or (XXI), or a pharma- ceutically acceptable salt thereof; 2 is not H. Therefore, R 2 may be as defined in any one of numbered paragraphs 26, 28, or 30-32.

[0365] In certain embodiments, the compound of the invention is a compound of formula (I), (XII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI) or a pharma- ceutically acceptable salt thereof, wherein Ring A is as defined in numbered paragraph 37 or 38. Ring A is as defined in numbered paragraph 37 and R 3 can be as defined in any one of numbered paragraphs 39 to 81. For example, ring A is as defined in numbered paragraph 37, and R 3 is methoxy.

[0366] In certain embodiments, the compound of the invention is a compound of formula (I), (II), (III), (IV), (VII), (VIII), (IX), (XIII), (XIV), (XV), (XVIII), (XIX) or (XX) or a pharma- ceutically acceptable salt thereof; 2 is as defined in any one of numbered paragraphs 26 to 32; 1 is selected from phenyl or 4-fluorophenyl. Suitably, in these embodiments, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 (e.g., R 3 -OR 41 is -OMe).

[0367] Suitably, in the compounds of formula (I), (IV), (IX), (XII), (XV), (XX), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) and (XXXI) or pharma- ceutically acceptable salts thereof, when ring A is of formula A3, R 2 -OR a2 , -SR a2 and -NR a2 R b2 For example, in these embodiments, when ring A is A3, R 2 Halo, C 1~4 Alkyl and C 1~4 When ring A is A3, R 2 can be H.

[0368] In certain embodiments, the compound of the present invention is a compound of formula (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX) or (XXXI), or a pharma- ceutically acceptable salt thereof; 10 -NR a81 R b81 and -C 1~3 Alkyl-NR a81 R b81and R a81 and R b81 are independently H and C 1~3 R is selected from alkyl. 10 -CH 2 -NR a81 R b81 and R a81 and R b81 are independently H and C 1~3 In this embodiment, R 3 -OR 41 -OMe, -OCH(CH 3 ) 2 and -Ocyclobutyl. For example, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 is selected from.

[0369] In certain embodiments, the compound of the present invention is a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI) or (XXII) or a pharma- ceutically acceptable salt thereof, wherein Ring B is -NR a81 R b81 and -C 1~3 Alkyl-NR a81 R b81 One R selected from 10 The substituents (wherein R a81 and R b81 are independently H and C 1~3 alkyl); and optionally halo and C 1~4 Ring B is substituted with one or two substituents selected from -NR a81 R b81 and -C 1~3 Alkyl-NR a81 R b81 Only one R is selected from 10 Substituted by the substituent, R a81 and R b81are independently H and C 1~3 R may be selected from alkyl. 10 -CH 2 -NR a81 R b81 and R a81 and R b81 are independently H and C 1~3 In this embodiment, R 3 -OR 41 -OMe, -OCH(CH 3 ) 2 and -O-cyclobutyl. For example, R 3 -OR 41 -OMe and -OCH(CH 3 ) 2 is selected from.

[0370] In another embodiment, the compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is selected from phenyl and 5- or 6-membered heteroaryl containing at least one nitrogen atom; R 1 Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a1 , -SR a1 and -NR a1 R b1 optionally substituted with one or more substituents selected from; R 2 H, halo, C 1~4 Alkyl and C 1~4 Haloalkyl, -OR a2 , -SR a2 and -NR a2 R b2 is selected from C 1~4 Alkyl is halo, -OR a3 , -SR a3 and -NR a3 R b3optionally substituted with one or more substituents selected from; R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, -OR 4 , -NR 5 R 6 , -SR 5 , 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-; R 4 and R 5 are independently H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms, and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms 1~3 alkyl-; R 6 , H, C 1~4 Alkyl and C 1~4 haloalkyl; X 1 , X 2 and X 3 are independently N and CR 7 Selected from; R 7 Each occurrence independently represents H, halo, -CN, or C. 1~4 Alkyl, C 1~4 Haloalkyl, -OR 8 , -NR 8 R 9 and -S(O) x R 8 (wherein x is 0, 1 or 2); R 8 and R 9 are independently H, C 1~4 Alkyl and C1~4 haloalkyl; R 7 , R 8 or R 9 Any C in either 1~4 Alkyl is halo, -CN, -OR a5 , -S(O) x R a5 where x is 0, 1 or 2, and -NR a5 R b5 optionally substituted with one or more substituents selected from; Ring B is one or more R 10 and 5- to 12-membered heteroaryl, optionally substituted with R 10 Each occurrence independently represents halo, -CN, -NO 2 , =O, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Q 1 -L 1 -, -OR 11 , -S(O) x R 11 (wherein x is 0, 1 or 2), -NR 11 R a6 , -C(O)R 11 , -OC(O)R 11 , -C(O)OR 11 , -NR a6 C(O)R 11 , -NR a6 C(O)OR 11 , -C(O)NR 11 R a6 , -OC(O)NR 11 R a6 , -NR a6 SO 2 R 11 , -SO 2 NR 11 R a6 and -NR a6 C(O)NR 11 R a6 is selected from Said C 1~6 Alkyl, C2~6 Alkenyl and C 2~6 Alkynyl is defined as one or more R 12 optionally replaced by; R 11 are independently H, C 1~6 Alkyl and C 1~6 haloalkyl, 1~6 Alkyl is one or more R 13 optionally replaced by; Q 1 Each occurrence of is independently 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl, 4- to 9-membered heterocyclyl-C 1~3 Alkyl-, Phenyl, Phenyl-C 1~3 Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 alkyl-, Said C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl and 4- to 9-membered heterocyclyl-C 1~3 Alkyl- is one or more R 14 and optionally replaced by The phenyl, phenyl-C 1~3 Alkyl, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 Alkyl is one or more R 15 optionally replaced by; L 1 is a bond or -O-, -S(O) x - (wherein x is 0, 1 or 2), -NR a7 -, -C(O)-, -OC(O)-, -C(O)O-, -NR a7 C(O)-, -C(O)NR a7 -, -NR a7 C(O)O-, -OC(O)NR a7 -, -NR a7 SO 2 -, -SO 2 NRa7 - and -NR a7 C(O)NR a7 - Selected from; R 12 , R 13 and R 14 Each occurrence independently represents halo, =O, -CN, -NO 2 , C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a8 , -S(O) 2 R a8 , -NR a8 R b8 , -C(O)R a8 , -OC(O)R a8 , -C(O)OR a8 , -NR a8 C(O)R b8 , -C(O)NR a8 R b8 , -NR a8 C(O)OR b8 , -OC(O)NR a8 R b8 , -NR a8 SO 2 R b8 and -SO 2 NR a8 R b8 Selected from; Said C 1~4 Alkyl is halo, -CN, -OR a9 , -NR a9 R b9 and -SO 2 R a9 optionally substituted by 1 or 2 substituents selected from R 15 Each occurrence independently represents halo, =O, -CN, -NO 2 , C 1~4 Alkyl, C 1~4 Haloalkyl, -OR a10 , -S(O) 2 R a10 , -NR a10 R b10 , -C(O)R a10 , -OC(O)R a10 , -C(O)OR a10 , -NR a10C(O)R b10 , -C(O)NR a10 R b10 , -NR a10 C(O)OR b10 , -OC(O)NR a10 R b10 , -NR b10 SO 2 R a10 and -SO 2 NR a10 R b10 Selected from; Said C 1~4 Alkyl is halo, -CN, -OR a11 , -NR a11 R b11 and -SO 2 R a11 optionally substituted by 1 or 2 substituents selected from R a1 , R b1 , R a2 , R b2 , R a3 , R b3 , R a4 , R b4 , R a5 , R b5 , R a6 , R a7 , R a8 , R b8 , R a9 , R b9 , R a10 , R b10 , R a11 and R b11 Each occurrence of is independently H, C 1~4 Alkyl and C 1~4 haloalkyl; or Any -NR in the substituent a1 R b1 , -NR a2 R b2 , -NR a3 R b3 , -NR a4 R b4 , -NR a5 R b5 , -NR a8 R b8 , -NR a9 R b9 , -NRa10 R b10 , -NR a11 R b11 , -NR 5 R 6 , -NR 8 R 9 or -NR 11 R a6 can form a 4- to 6-membered heterocyclyl, the 4- to 6-membered heterocyclyl being halo, ═O, C 1~4 Alkyl and C 1~4 Optionally substituted with one or more substituents selected from haloalkyl.

[0371] In this embodiment, R 3 is C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl- and -OR 4 For example, R 3 -OR 4 It could be.

[0372] In this embodiment, R 4 , H, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 6-membered heterocyclyl containing one or more ring oxygen atoms, and 4- to 6-membered heterocyclyl-C containing one ring oxygen atom 1~3 alkyl-.

[0373] In this embodiment, Q 1 Each occurrence of is independently 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl-, 4- to 7-membered heterocyclyl, 4- to 9-membered heterocyclyl-C 1~3 Alkyl-, Phenyl, Phenyl-C 1~3Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 alkyl-, Said C 3~6 Cycloalkyl, C 3~6 Cycloalkyl-C 1~3 Alkyl, 4- to 7-membered heterocyclyl and 4- to 7-membered heterocyclyl-C 1~3 Alkyl- is one or more R 14 and optionally replaced by The phenyl, phenyl-C 1~3 Alkyl, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C 1~3 Alkyl- is one or more R 15 may be optionally replaced by

[0374] In this embodiment, ring B can be as defined in any one of numbered paragraphs 117-184, 201 or 202.

[0375] In this embodiment, R 3 -OMe, -OCH(CH 3 ) 2 and -O-cyclobutyl. Thus, R 3 can be -OMe. 3 is -OCH(CH 3 ) 2 It can be. R 3 can be --O-cyclobutyl.

[0376] In this embodiment, R 3 -OMe, -OCH(CH 3 ) 2 and oxetan-3-yloxy-.

[0377] In another embodiment, the compound of formula (I) has the formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein R1 is phenyl optionally substituted with 1 or 2 substituents selected from halo; R 2 is C 1~4 is alkyl; R 3 -OR 4 and; R 4 is C 1~4 Alkyl and C 3~6 cycloalkyl; X 1 and X 2 is CH; X 3 is N; Ring B is [ka] Selected from; R 101 are independently H, C 1~4 Alkyl, -C 1~3 Alkyl-NR a82 R b82 , -NR a82 R b82 and Q 1 -L 1 - selected from Q 1 are halo and C, respectively. 1~4 selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted with 1 or 2 substituents selected from alkyl and =O; L 1 is a bond or -O-, -NH- and -N(C 1~3 alkyl)-; R a82 and R b82 are independently H and C 1~4 is selected from alkyl.

[0378] In this embodiment, R 3 -OMe, -OCH(CH 3 ) 2 and -O-cyclobutyl. Thus, R3 can be -OMe. 3 is -OCH(CH 3 ) 2 It can be. R 3 can be --O-cyclobutyl.

[0379] In this embodiment, R 101 -NR a82 R b82 , -C 1~3 Alkyl-NR a82 R b82 and Q 1 -L 1 - Selected from Q 1 is C 1~4 azetidinyl optionally substituted with one substituent selected from alkyl; 1 can be a bond or selected from -O- and -NH-. Thus, R 101 is -NH 2 , -N(Me)H, -N(Me) 2 , -CH 2 -NH 2 , -CH 2 -N(Me)H, -CH 2 -N(Me) 2 , azetidin-3-yl-O-, 1-methylazetidin-3-yl-O-, azetidin-3-yl-NH-, and 1-methylazetidin-3-yl-NH-. For example, R 101 -CH 2 -NH 2 It could be.

[0380] In this embodiment, R 1 is phenyl or 4-fluorophenyl; R 2 is methyl; R 3 is -OMe or -CH(CH 3 ) 2 and; X 1 and X 2 is CH; X 3 is N; Ring B is [ka] Selected from; R 101 are independently -NR a82 R b82 , -C 1~3 Alkyl-NR a82 R b82 and Q 1 -L 1 - Selected from; Q 1 is C 1~4 azetidinyl optionally substituted with one substituent selected from alkyl; L 1 is a bond or is selected from -O- and -NH-; R a82 and R b82 are independently H and C 1~4 It may be selected from alkyl.

[0381] In another embodiment, compound list 1: Compound List 1 [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0382] In another embodiment, there is provided a compound selected from any one of the Examples herein, or a pharma- ceutically acceptable salt thereof.

[0383] In another embodiment, [ka] or a pharma- ceutically acceptable salt thereof.

[0384] Certain compounds of the present invention have an α5-GABA binding activity of less than 30 nM (e.g., 10 nM or less) as measured in the in vitro radioligand binding assay described herein. A The preferred compounds of the present invention are GABA receptors containing α1, α2 or α3 subunits. A α5-GABA receptor A has a binding affinity and / or efficacy that is selective for R.

[0385] Pharmaceutical Compositions According to another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0386] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, MEAulton, Churchill Livingstone, 1988.

[0387] The compositions of the invention may be in a form suitable for oral use (for example as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as a cream, ointment, gel, or aqueous or oily solution or suspension), for administration by inhalation (for example as a finely divided powder or liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intraperitoneal administration or as a suppository for rectal administration).

[0388] The compositions of the invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0389] An effective amount of a compound of the invention for use in the treatment of disease is an amount sufficient to alleviate the symptoms or slow the progression of the disease in a warm-blooded animal, particularly a human.

[0390] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.1 mg to 0.5 g of active agent (more preferably, 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of an excipient, which may vary between about 5 and about 98 percent by weight of the total composition.

[0391] The size of a dose of the compounds of the invention for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the animal's or patient's condition, its age and sex, and the route of administration, in accordance with well known principles of medicine.

[0392] When using a compound of the invention for therapeutic or prophylactic purposes, it will generally be administered to provide a daily dose within the relevant range, for example, a daily dose selected from 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, or 5 mg / kg to 10 mg / kg body weight, assuming divided administration if necessary. Generally, lower doses will be administered when a parenteral route is used. Thus, for example, for intravenous, subcutaneous, intramuscular or intraperitoneal administration, a dose within the relevant range, for example, 0.1 mg / kg to 30 mg / kg body weight, may be suitable. Similarly, for administration by inhalation, a dose within the relevant range, for example, 0.05 mg / kg to 25 mg / kg body weight, may be suitable. When administered orally, the total daily dose of the compound of the invention may be selected, for example, from 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg, or 25 mg to 500 mg. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of a compound of the invention. In certain embodiments, the compound of the invention is administered parenterally, for example, by intravenous administration. In another particular embodiment, the compound of the invention is administered orally.

[0393] Therapeutic uses and applications According to another aspect, the present invention provides a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0394] A further aspect of the present invention is the use of α5-GABA A There is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of a disease or medical disorder mediated by R.

[0395] α5-GABA in subjects A Also provided is a method for preventing or treating a disease or medical disorder mediated by R, comprising administering to a subject an effective amount of a compound of the invention, or a pharma- ceutically acceptable salt thereof.

[0396] α5-GABA AThere is also provided the use of a compound of the invention, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease or medical disorder mediated by R.

[0397] In the following sections of this application, the compounds of the present invention or their pharmaceutically acceptable salts are referred to for use in the prevention or treatment of certain diseases or conditions. It should be understood that any reference herein to a compound for a certain use is also intended to refer to (i) the use of the compounds of the present invention or their pharmaceutically acceptable salts in the manufacture of a medicament for the prevention or treatment of that disease or disorder; and (ii) a method for the prevention or treatment of a disease or disorder in a subject, comprising administering a therapeutically effective amount of the compounds of the present invention or their pharmaceutically acceptable salts to the subject.

[0398] In certain embodiments, α5-GABA A There is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of cognitive impairment associated with a disease or medical disorder mediated by R.

[0399] In certain embodiments, α5-GABA A There is provided a compound of the present invention, or a pharma- ceutically acceptable salt thereof, for use in the prophylaxis or treatment of a neurological or neuropsychiatric disorder mediated by α5-GABA R. In certain embodiments, A The present invention provides a compound or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of cognitive dysfunction associated with a neurological or neuropsychiatric disorder mediated by R. The neurological disorder may be a neurodevelopmental disorder (e.g., attention deficit disorder (ADHD), Down's syndrome, learning disability, cerebral palsy, autism, or speech disorder). The neurological disorder may be a neurodegenerative disorder (e.g., Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or Creutzfeldt-Jakob disease (CJD)). In a particular embodiment, the neurological disorder is Huntington's disease).

[0400] α5-GABA ADiseases or medical disorders mediated by R include Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive impairment (e.g., cognitive impairment associated with chemotherapy, anesthetics, bacterial or viral infections (e.g., HIV), memory impairment, age-related cognitive impairment (i.e., mild cognitive impairment, MCI), bipolar disorder, autism, Down's syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder or may be selected from chronic neuroinflammatory cognitive impairment associated with stroke, cognitive impairment associated with brain injury or trauma, cognitive impairment associated with brain tumor, and attention disorder.

[0401] In certain embodiments, the present invention relates to a method for treating a variety of conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive impairment (e.g., cognitive impairment associated with chemotherapy, anesthetics, or bacterial or viral infection (e.g., HIV), memory impairment, age-related cognitive impairment (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, Down's syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or paraphrenia), psychosis, post-traumatic stress disorder. In one embodiment, the compound of the present invention, or a pharmacologic agent thereof, is provided for use in the prevention or treatment of cognitive impairment, anxiety disorder, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, alcohol disorder (e.g., alcoholism), drug withdrawal, movement disorder, restless legs syndrome, cognitive impairment disorder, multi-infarct dementia, vascular dementia, mood disorder, depression, neuropsychiatric disorder, attention deficit hyperactivity disorder, neuropathic pain, chronic neuroinflammatory cognitive impairment associated with stroke, cognitive impairment associated with brain injury or trauma, cognitive impairment and attention disorder associated with brain tumors.

[0402] In certain embodiments, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the prevention or treatment of cognitive impairment associated with Alzheimer's disease.

[0403] In certain embodiments, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the prevention or treatment of cognitive impairment associated with Huntington's disease.

[0404] Chromosome 15q11.2-13.1 duplication syndrome (Dup15q syndrome) is a rare disorder resulting from a duplication of a portion of the 15q11.2-13.1 chromosome. Dup15q syndrome is characterized by hypotonia and gross and fine motor delays, variable intellectual disability, autism spectrum disorder, and epilepsy, including infantile spasms. Excess α5-GABA AReceptor function has been confirmed in Dup15q syndrome (Frohlich et al. Mechanisms underlying the EEG biomarker in Dup15q syndrome. Molecular Autism 10, 29 (2019)). A A phase II clinical trial using R NAM is also planned (NCT05307679).

[0405] In certain embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof for use in treating Dup15q syndrome. The compound of the present invention may be for use in treating children with DUP15g syndrome, for example children aged 2-11 years. The compound of the present invention may reduce or eliminate one or more neurodevelopmental features associated with Dup15q syndrome, such as hypotension, motor retardation, or intellectual development (e.g., speech or language retardation, cognitive impairment, or problems with social interaction).

[0406] In certain embodiments, the compound of the present invention or its pharma- ceutically acceptable salt is provided for use in preventing or treating chemotherapy-induced cognitive impairment in a subject in need thereof.Examples of chemotherapy that can induce cognitive impairment include amphetamines, dopaminergic agents, ketamine, corticosteroids and anticonvulsants.

[0407] In certain embodiments, the compounds of the invention are for use in the treatment of depression, such as the treatment of treatment-resistant depression.

[0408] Neuroinflammation can induce psychiatric and neurological symptoms, such as cognitive impairment, and α5-GABA ATreatment with R NAM may be beneficial (Jacob, 2019 Frontiers in Molecular Neuroscience, 12 179). Thus, in certain embodiments, the compounds of the present invention are provided for use in the prevention or treatment of psychiatric and / or neurological symptoms associated with neuroinflammation. In certain embodiments, the compounds of the present invention are for use in the treatment or prevention of cognitive impairment associated with neuroinflammation. The neuroinflammation may be chronic neuroinflammation. The neuroinflammation may be caused by or associated with, for example, stroke, bacterial infection, viral infection, traumatic brain injury, or autoimmune disease (e.g., systemic lupus erythematosus).

[0409] It is well known that bacterial or viral infections can result in both acute and chronic cognitive impairment in subjects who are or have been infected with bacteria or viruses. In particular, viral infections can result in so-called "post-viral syndrome" in which subjects who have been infected with the virus develop chronic symptoms after the viral infection. Such symptoms include chronic fatigue, joint pain, cognitive impairment or flu-like symptoms. There is increasing evidence that certain subjects infected with the SARS-CoV-2 virus develop chronic symptoms, including cognitive impairment in the so-called "long COVID" or "post-COVID syndrome" (Raveendran, et al., 2021 Diabetes & metabolic syndrome, 15(3), 869-875. Thus, the compounds of the present invention may be useful for the treatment or prevention of cognitive impairment caused by or associated with viral or bacterial infection.

[0410] In a particular embodiment there is provided a compound of the invention for use in the treatment or prevention of psychiatric and / or neurological symptoms (particularly cognitive impairment) caused by or associated with a viral or bacterial infection.

[0411] In certain embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are due to a bacterial infection (e.g., Chlamydia pneumoniae, Helicobacter pylori, Borrelia spp. (e.g., B. burgdorferi, B. mayonii, B. afzelii, or B. garinii), Treponema pallidum, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Listeria monocytogenes, Brucella spp., Mycobacterium tuberculosis, Salmonella spp., or any combination thereof. spp. and Rickettsia spp.)

[0412] In some embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a viral infection. In some embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a viral infection. In some embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a viral infection, such as a coronavirus, a coronavirus from the Coronaviridae family (e.g., Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus), a coronavirus from the Picornaviridae family (e.g., Enteroviruses, such as Rhinovirus, Human Rhinovirus (HRV)), a virus from the Flaviviridae family (e.g., Zika virus (ZIKV), Dengue fever (e.g., DENV), or a combination of viruses from the Coronaviridae family (e.g., HIV ... 1-4), West Nile virus (WNV), Yellow Fever virus (YFV, e.g. Yellow Fever 17D virus), Japanese encephalitis virus (JEV), Hepatitis C virus (HCV), Filoviridae (e.g. Ebolavirus), Togaviridae (e.g. Alphaviruses such as Chikungunya virus (CHIKV), Sindbis virus and Ross River virus), Herpesviruses (e.g. γ-herpesvirus, human herpesvirus 8, herpesvirus 1, herpesvirus 2, varicella zoster virus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV)), Adenoviridae (e.g. human adenovirus (HAdV)), lentiviruses (e.g. HIV) and influenza viruses.

[0413] In certain embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a virus selected from cytomegalovirus (CMV); herpes simplex virus-1 (HSV-1), HIV, hepatitis, varicella-zoster virus, Zika virus, Epstein-Barr virus, or a coronavirus (e.g., SARS-CoV-2) or a variant thereof.

[0414] In certain embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a coronavirus (e.g., Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) or Middle East Respiratory Syndrome coronavirus (MERS-CoV)) or a variant thereof.

[0415] In certain embodiments, the psychiatric and / or neurological symptoms (e.g., cognitive impairment) are caused by or associated with a coronavirus that causes Severe Acute Respiratory Syndrome (SARS), such as a SARS or MERS virus, e.g., SARS-CoV, SARS-CoV-2, or MERS-CoV. Preferably, the viral infection is caused by or associated with SARS-CoV-2 or a variant thereof.

[0416] In certain embodiments, the compounds of the invention are for use in the treatment or prevention of cognitive impairment caused by or associated with a respiratory viral infection, such as Severe Acute Respiratory Syndrome (SARS). In certain embodiments, the compounds of the invention are for use in the treatment or prevention of cognitive impairment caused by or associated with COVID-19.

[0417] In a particular embodiment, the compounds of the present invention are for use in the treatment or prevention of psychiatric and / or neurological symptoms (particularly cognitive impairment) in a subject with a viral or bacterial infection. In this embodiment, the psychiatric and / or neurological symptoms are caused by or associated with a bacterial or viral infection. In this embodiment, the subject may have an acute viral or bacterial infection. The infection may be a symptomatic bacterial or viral infection. Alternatively, the infection may be an asymptomatic bacterial or viral infection. In this embodiment, the subject may have a viral infection. In this embodiment, the subject may have a bacterial infection.

[0418] In certain embodiments, the compounds of the present invention are for use in the prevention or treatment of psychiatric and / or neurological symptoms (particularly cognitive impairment) in a subject with post-viral or post-bacterial syndrome. In this embodiment, the subject may have post-viral syndrome. In this embodiment, the subject may have post-bacterial syndrome. In this embodiment, the compound is administered to the subject after an initial acute bacterial or viral infection, for example when the subject has recovered from the initial acute symptoms of viral or bacterial infection and / or when the subject is substantially free of infectious bacteria or viruses (e.g. when the subject has substantially no or very low viral / bacterial load after initial infection). The bacterial / viral load in the subject can be determined using well-known methods, for example suitable diagnostic tests such as bacterial culture methods and / or PCR-based methods. The initial (acute) infection can be, for example, due to any of the bacteria or viruses described herein. The initial acute bacterial or viral infection can be a symptomatic bacterial or viral infection. Alternatively, the initial infection can be an asymptomatic bacterial or viral infection.

[0419] In certain embodiments, the compounds of the present invention are for use in treating cognitive impairment in a subject, where the subject has developed cognitive impairment after SARS-CoV-2 infection. Thus, the compounds of the present invention may be for use in treating or preventing cognitive impairment caused by or associated with COVID-19. For example, the compounds of the present invention may be for use in treating a subject who has developed cognitive impairment after COVID-19 infection.

[0420] Postoperative Cognitive Dysfunction (POCD) Postoperative cognitive dysfunction refers to cognitive dysfunction following anesthesia and surgery. POCD is a widely recognized clinical phenomenon that encompasses acute or persistent deficits in attention, concentration, learning and memory following surgery that are not due to obvious complications or injury resulting from the surgery.

[0421] POCD is a transient disorder that generally resolves within 3 months in younger patients. However, POCD in elderly patients occurs much more frequently, with 41% of patients over 60 years old exhibiting symptoms 7 days after surgery. POCD in elderly patients can also be long-lasting, with >10% of patients exhibiting symptoms 3 months after surgery. POCD is associated with an increased risk of death both within 3 months and 1 year after surgery. POCD may also be a risk factor for the development or acceleration of dementia (Monk et al. Anesthesiology 2008,108(1),18-30; Moller et al. The Lancet 1998,351(9106),857-861; and Needham et al., British Journal of Anaesthesia,2017 Volume 119,i115-i125). Cardiopulmonary bypass (CPB) surgery has the strongest association with POCD, especially since it is one of the most common medical conditions and surgeries worldwide. CPB procedures are performed approximately 200,000 times per year in the United States alone, with an average incidence of 62 per 100,000 inhabitants in Western countries (Melly et al. J. Thorac. Dis. 2018, 10(3), 1960-1967).

[0422] General anesthetics have been implicated as a cause of POCD due to the observation that the duration of anesthesia correlates positively with the occurrence of postoperative cognitive impairment in patients (Moller 1998 supra). A single exposure to an anesthetic can cause retrograde and anterograde memory impairments that persist for days to weeks in rodent models (Crosby et al., Anesth. Analg., 2005, 101(5), 1389-92; and Culley et al. Anesth. Analg., 2003, 96(4), 1004-9).

[0423] Many general anesthetics activate the inhibitory γ-aminobutyric acid type A receptor (GABA A R) (Antkowiaket al., Curr. Opin. Anaesthesiol. 2016, 29(4), 447-453). During anesthesia, GABA A Increased activity of GABA R contributes to the desired and pronounced neuroinhibitory properties of anesthetic drugs. After cessation of administration of the anesthetic drug, A Positive allosteric regulation of GABA R function is rapidly restored, thus returning receptor activity to baseline and A It has been speculated that α5-GABA R does not contribute to the unwanted persistent cognitive impairment following anesthesia (Belelli et al., Br. J. Pharmacol. 1996, 118(3), 563-76). However, this hypothesis is supported by the fact that α5-GABA A This was recently suggested by the observation that α5-GABA R-deficient mice showed no symptoms of cognitive impairment in a novel object recognition experiment after exposure to isoflurane. In contrast, wild-type mice showed cognitive decline, suggesting a role for α5-GABA R in anesthetic-induced cognitive impairment. A This suggests a role for R (Zurek et al. Anesth. Analg. 2012, 114(4), 845-855). Changes in long-term potentiation in rat amygdala brain slices were also observed after repeated, but not single, doses of isoflurane (Long et al., Neural Plast. 2016, 8524560-8524560).

[0424] A single treatment of mice with the injectable anesthetic etomidate inhibited α5-GABA receptor agonism for at least one week. A Tonic inhibitory currents generated by R and α5-GABA A R increased cell surface expression (Zurek 2012, supra). A Sustained increases in α5-GABA R activity impaired memory and synaptic plasticity in the hippocampus. Similarly, the inhalation anesthetic isoflurane inhibited α5-GABA R activity in the hippocampus. A α5-GABA induced a sustained increase in tonic currents and cell surface expression of R. A R function did not return to baseline after the anesthetic was removed, suggesting a mechanism to explain persistent memory impairment after general anesthesia. The study also showed that memory in mice after a single etomidate treatment in a novel object recognition task was impaired for up to 72 hours. However, at the 1-week time point, memory was restored despite still elevated tonic currents. Given that homeostatic plasticity has been widely demonstrated in the hippocampus, persistent increases in tonic currents may induce compensatory changes that contribute to memory recovery. α5-GABA A R α5-GABA with NAM L-655,708 A Inhibition of α5-GABA R completely abolished etomidate-induced memory impairment. Further studies showed that inhibition of α5-GABA R in non-pyramidal cells A suggested that R may be most important for the effects on LTP seen with etomidate, but other anesthetics were not evaluated (Rodgers et al., The Journal of Neuroscience: the official journal of the Society for Neuroscience 2015,35(26),9707-9716).

[0425] In isoflurane-anesthetized aged rats, L-655,708 was able to prevent but not reverse cognitive impairment in the Morris water maze experiment, in contrast to young rats, where the compound was able to both prevent and reverse cognitive effects (Zhao et al., Neural Regen. Res. 2019, 14(6), 1029-1036).

[0426] Additionally, benzodiazepine use is associated with an increased risk of developing POCD, and studies suggest that 2.5 mg of midazolam more than doubles the risk of developing POCD. A R are non-specific positive allosteric modulators of R, suggesting that excessive stimulation of these receptors may cause or exacerbate POCD.

[0427] POCD may also be associated with inflammation resulting from surgery. A comprehensive review of the mechanisms underlying the inflammation hypothesis for POCD was recently published by Safavynia and Goldstein (Frontiers in psychiatry 2019,9,752-752). It is believed that peripheral surgical trauma induces central nervous system inflammation through damage to the blood-brain barrier (BBB), which in turn causes dysfunction of neuronal activity, leading to POCD. Furthermore, TNFα may decrease inhibitory neurotransmission by downregulating GABA receptors, upsetting the delicate balance between excitatory and inhibitory neurotransmission, ultimately promoting glutamate toxicity (Pribiag et al., J.Neurosci. 2013,33(40),15879-93).

[0428] Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction is mediated by α5-GABA A The inhibition of α5-GABA R function in hippocampal neurons restored this function (Wang et al., Cell reports 2012, 2(3), 488-496). AThe tonic inhibitory current generated by R was increased by the major inflammatory cytokine interleukin-1β via the p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β upregulates α5-GABAergic receptor signaling in the hippocampus. A It also increased the surface expression of the receptor (Wang et al. supra).

[0429] GABA-induced currents in cultured hippocampal and cortical neurons induced by etomidate or isoflurane were increased by pretreatment with the inflammatory cytokine interleukin-1β. Also, the in vivo immobilization properties of etomidate, but not isoflurane, were increased by lipopolysaccharide, suggesting that inflammation increases sensitivity to some anesthetics (Avramescu et al.,Anesthesiology 2016,124(2),417-27).

[0430] LPS treatment significantly increased the levels of benzodiazepine site modulators (diazepam and brotizolam) and GABA receptor antagonists compared to vehicle-treated mice. A In mice treated with the R agonist (muscimol), the duration of the loss of righting reflex (LORR) induced by pentobarbital was significantly increased. These effects were consistent with those of bicuculline, GABA A The inflammation-induced impairment of contextual fear memory using LPS was inhibited by Gabra5 antagonists (Kitamura et al., European Journal of Pharmacology 2019, 842, 231-238). - / - L-655,708-induced α5-GABA expression in wild-type mice was absent, whereas L-655,708-induced α5-GABA expression in wild-type mice was absent. A This was prevented by inhibition of GABA and GABA R (Wang et al., Cell reports 2012,2(3),488-496). A Increased extracellular levels of membrane expression of the α5 subunit of the receptor were also observed in a rat model of neuroinflammation (Agusti et al., CNS Neurosci. Ther. 2017, 23(5), 386-394).

[0431] According to a further aspect, there is provided a compound of the invention, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of POCD in a subject.

[0432] In certain embodiments, the subject has undergone or is scheduled to undergo major surgery, such as surgery of at least 1 hour duration. Examples of surgery include cardiac; vascular; ear, nose and throat; plastic surgery; gynecological; orthopedic; urological; or ophthalmological surgery. In certain embodiments, the subject has undergone or is scheduled to undergo cardiac surgery, such as coronary artery bypass surgery. In certain embodiments, the subject has undergone or is scheduled to undergo orthopedic surgery, such as hip or knee replacement surgery.

[0433] In certain embodiments, the subject is anesthetized with an anesthetic selected from a general anesthetic, e.g., an intravenous anesthetic (e.g., etomidate, propofol, fospropofol, a barbiturate (e.g., amobarbital, methohexital, thiamylal, or thiopental), a benzodiazepine (e.g., diazepam, lorazepam, or midazolam), a triazolobenzodiazepine (e.g., alprazolam), a thienotriazolodiazepine (e.g., brotizolam), dexmedetomidine, ketamine, and an opioid (e.g., fentanyl, alfentanil, remifentanil, or sufentanil); and an inhalation anesthetic (e.g., nitrous oxide, xenon, cyclopropane, or a volatile anesthetic (e.g., a halogenated anesthetic (e.g., halothane, enflurane, isoflurane, sevoflurane, or desflurane)).

[0434] In certain embodiments, the POCD is anesthetic-induced POCD, such as POCD induced by or associated with a general anesthetic (e.g., one or more of the general anesthetics listed above). In certain embodiments, the POCD is inflammation-induced POCD, such as inflammation induced by or associated with major surgery (e.g., one or more of the surgical procedures listed above).

[0435] The compound of the present invention or a pharma- ceutically acceptable salt thereof may be administered to a subject before, after, or during surgery. In certain embodiments, the compound of the present invention or a pharma- ceutically acceptable salt thereof may be administered to a subject before surgery. In certain embodiments, the compound of the present invention or a pharma- ceutically acceptable salt thereof may be administered to a subject during surgery. In certain embodiments, the compound of the present invention or a pharma- ceutically acceptable salt thereof may be administered to a subject after surgery.

[0436] In certain embodiments, the subject is at least 60 years of age. In certain embodiments, the subject is less than 60 years of age, for example, between 18 and 59 years of age.

[0437] The degree of cognitive impairment associated with surgery and the efficacy of the compounds of the present invention in treating POCD can be assessed using a suitable clinical scoring system. For example, subjects can be assessed and scored before and after surgery. For example, subjects can be scored 1, 2, 3, 4, 5, 6 or 7 days before surgery. Patients can be scored 1, 2, 3, 4, 5, 6 or 7 days, 1, 2, 3, 6 or 12 months after surgery. The severity of POCD in subjects can be determined by comparing the clinical scores before and after surgery. Similarly, the efficacy of the compounds of the present invention in treating or preventing POCD can be determined by comparing the clinical scores before and after treatment with the compounds of the present invention. Suitable scoring systems for assessing cognitive function are well known, including, for example, the CogState Brief Battery (CBB) (Maruff et al., 2013, BMC psychology vol.1,1 30). Immediate memory, visuospatial and delayed memory domains can be assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (Karantzoulis et al., 2013, Arch. Clin. Neuropsychol.; 28(8):837-44). Speech fluency and executive function can be assessed using the Controlled Oral Word Association Test (COWAT) (Malek-Ahmadi et al., 2011, Dement. Geriatr. Cogn. Disord.; 32(4):235-40). Visuospatial and executive function can be assessed using the Trail Making Test A and B (TMT) (Terada et al., 2013, Psychiatry Res.; 213(3):249-55).

[0438] Selectivity GABA ANon-selective inhibition of R may result in undesirable side effects, such as proconvulsant and / or anxiogenic effects. A R inhibition is a non-selective GABA A It is expected that these compounds will provide beneficial therapeutic effects, such as improved cognition, while avoiding or minimizing the risk of undesirable side effects (e.g., proconvulsant and / or anxiogenic effects) associated with R inhibition.

[0439] Thus, preferred compounds of the present invention are GABA receptor antagonists that do not contain the α5 subunit. A From R, GABA A For example, the compounds of the present invention may be used to inhibit GABA receptors containing α1, α2, α3, α4, or α6 subunits. A From R, α5-GABA A R. In certain embodiments, the compounds of the present invention have selective affinity for and / or selectively inhibit the function of GABA receptors containing the α1-, α2-, or α3-subunits, as measured using the in vitro radioligand binding assays described herein. A at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold lower (e.g., about 20 to about 1000-fold lower) than the Ki for the α5-GABA receptor A It has an affinity (Ki) for R.

[0440] In certain embodiments, the compounds of the present invention exhibit an α5 GABA receptor antagonist activity as measured in the in vitro electrophysiological recording assay described herein. A Preferred compounds of the present invention exhibit GABAergic RNA Mn activity, as measured in the in vitro electrophysiological recording assays described herein. A From R, α5-GABA A Selectively inhibits the function of R.

[0441] Preferred compounds of the present invention are GABA containing α1-, α2- or α3-subunits. A From R, α5-GABA A It has selective affinity for α5-GABA A Selectively inhibits the function of R.

[0442] In certain embodiments, such selective compounds may be used in the treatment or prevention of any of the diseases or conditions described herein.

[0443] Combination Therapy The compounds of the invention may be used alone to provide a therapeutic effect. The compounds of the invention may also be used in combination with one or more additional therapeutic agents.

[0444] In certain embodiments, the additional therapeutic agent is selected from one or more of the following: Antidepressants, such as tricyclic antidepressants (e.g. desipramine, imipramine, amitriptyline or nortriptyline); Serotonin reuptake inhibitors, such as sertraline, desmethylsertraline or fluoxetine; Typical or atypical antipsychotics; · Inhibitors of acetylcholinesterase (e.g., galantamine or donepezil); Anti-inflammatory drugs; GABA other than the compounds of the present invention A R modulators, e.g. GABA A GABA acts through a different binding site on the R receptor A R regulator or GABA A GABA acts through a different subunit in R A R regulators; antiepileptic drugs (e.g. acetazolamide, brivaracetam, cannabidiol, carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, everolimus, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, padosevonil, perampanel, phenobarbital, phenytoin, piracetam, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproic acid, vigabatrin or zonisamide); or Agents that inhibit the rate of metabolism of the compounds of this invention.

[0445] Such combination therapy may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ the compounds of this invention within the therapeutically effective dosage ranges described above and the other pharma- ceutical active agent(s) within their approved dosage ranges.

[0446] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration. In one embodiment of the present invention, "combination" refers to simultaneous administration. In another embodiment of the present invention, "combination" refers to separate administration. In a further embodiment of the present invention, "combination" refers to sequential administration. If administration is sequential or separate, the delay in administering the second component should not be such as to impair the beneficial effect of the combination.

[0447] In some embodiments where combination therapy is used, the amount of the compound of the present invention and the amount of the other pharmacologic active agent, when combined, are therapeutically effective for treating the targeted disorder in a patient. In this context, the combined amount is a "therapeutically effective amount" if, when combined, they are sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder; cure the disorder; halt, completely stop or slow the progression of the disorder; or reduce the risk of the disorder worsening. Typically, such an amount can be determined by those skilled in the art, for example, by starting from the dosage ranges described herein for the compound of the present invention and the approved or otherwise published dosage ranges for the other pharmacologic active compound.

[0448] Biological assays The biological effect of a compound may be assessed using one or more of the assays described herein.

[0449] cell line Mouse L(tk - Human α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2 GABA produced by transfection of individual subunits in the dexamethasone-inducible expression vector pMSGneo in α1β3γ2 cells. A Mouse L(tk - ) cells (Hadingham et al., 1993, Mol. Pharmacol. 43:970-975 and 1993, Mol. Pharmacol. 44:1211-1218) were used for binding and functional assays. For certain compounds, human α1β3γ2L, α2β3γ2L, α3β3γ2L and α5β3γ2L GABA A HEK293 cells stably expressing the receptors were used to assess their functional effects in SyncroPatch electrophysiology assays.

[0450] cell culture Human α1β3γ2, α2β3γ2, α3β3γ2, α5β3γ2 GABA A L(tk- ) Cells were incubated at 4 °C in 5% CO 2 The cells were maintained in DMEM F12 medium supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin and 1 mg / mL Geneticin G418 in an incubator at 37° C. with a humidified atmosphere containing

[0451] For QPatch electrophysiology studies, 1 μM dexamethasone was administered in the L(tk - ) was added to the culture medium of the cells. Cells were typically used for electrophysiology experiments 72-96 h after splitting.

[0452] In vitro radioligand binding assay (α5-GABA A R Ki) Human Recombinant GABA A The affinity (Ki) of the compound for the benzodiazepine site of R was evaluated using the results of a selective benzodiazepine antagonist [ 3 H]Ro15-1788([ 3 H]flumazenil).

[0453] Human recombinant GABA containing α1β3γ2, α2β3γ2, α3β3γ2, and α5β3γ2 subunits A R expressing L(tk - ) The cells were harvested and the membranes were washed with phosphate buffer (K 2 PO 4 10 mM, pH 7.0) was prepared for each receptor combination (Hadingham et al. (1992) Proc. Natl. Acad. Sci. USA; 89(14):6378-82). 3 The protein concentration, receptor expression and Kd of [H]Ro15-1788 were determined before the Ki values ​​of the compounds were evaluated. For Kd evaluation, saturation binding curves were performed at various concentrations of [ 3 H]Ro15-1788 (82.5 Ci / mM) and nonspecific binding was determined in the presence of 1 μM TP003.

[0454] [3 H]Ro15-1788([ 3 H]flumazenil) is tritiated at the N-methyl group as shown: [ka]

[0455] TP003 has the formula: [ka] Non-selective GABA A It is an R benzodiazepine site agonist.

[0456] For Ki evaluation, cell membranes were incubated with 4 nM [ 3 H]Ro15-1788. Non-specific binding was determined with 1 μM TP003. All incubations were performed in assay buffer for 1 h at 4° C. The total assay volume was 0.5 mL, containing 100 μg membrane protein / well for α1β3γ2, α2β3γ2, α3β3γ2 and 50 μg membrane protein / well for α5β3γ2. Incubations were terminated by filtration onto Whatman GF / B filters and washing with ice-cold Tris-HCl buffer (50 mM, pH=7.4), and the radioactivity of the filters was measured using liquid scintillation counting.

[0457] [ 3 % inhibition of [H]Ro15-1788 binding was calculated based on compound concentration and calculated IC 50 The IC was plotted as a function of 50 From the above, the affinity (Ki) is calculated as follows: 3 H]The Kd value obtained for Ro15-1788 was used to calculate the Kd using the method of Cheng and Prusoff.

[0458] The compounds of the present invention tested in the above assays are APreferred compounds have been found to have affinity for α1-, α2- and α3-GABA R. A From R, α5-GABA A It has selectivity for R (20-1000 times).

[0459] In vitro electrophysiological recording assay (α5-GABA A R (relative effectiveness) The efficacy of modulators was assessed using either the automated patch clamp platform QPatch16 (Sophion, Copenhagen, Denmark) or SyncroPatch 384i (Nanion Technologies, Germany). Cells were harvested from flasks by enzymatic dissociation and resuspended in serum-free medium.

[0460] For QPatch recordings, all experiments were performed at room temperature (20-22 °C) using standard whole-cell procedures and physiological solutions. A gigaseal was formed upon execution of a combined suction / voltage protocol, followed by increased suction resulting in a whole-cell configuration. Recorded currents were acquired at 1 KHz and filtered at 0.3 KHz with a Bessel filter. Whole-cell currents were measured at a holding potential of -65 mV.

[0461] For syncropatch recordings, a stacking additive protocol was used, in which GABA was rapidly applied and then washed out of the cell. All experiments were performed at room temperature (20-22 °C) using standard whole-cell procedures. Recorded currents were acquired at 2 kHz and filtered with a Bessel filter. Whole-cell currents were measured at a holding potential of -80 mV.

[0462] For QPatch recordings, the extracellular solution was (in mM): 145 NaCl, 4 KCl, 1 MgCl 2 , 2CaCl 2 , 10 HEPES, 10 D-glucose (pH 7.4), and the intracellular solution contained (in mM): 96 KCl, 28 CsCl, 25 KOH, 4.3 CaCl 2, 1.4MgCl 2 , 10 EGTA, 10 HEPES, 3 MgATP (pH 7.2). The osmolality of the extracellular and intracellular solutions was 305 and 295 mOsm, respectively.

[0463] For syncropatch recordings, the extracellular recording solution was 140 mM NaCl, 4 mM KCl, 2 mM CaCl. 2 , 1 mM MgCl 2 The intracellular recording solution contained 90 mM KCl, 50 mM KF, 1.5 mM MgCl, 10 mM HEPES, and 5 mM glucose (pH 7.4 and an osmolality of approximately 300-310 mOsm / L). 2 , 11.1 mM EGTA and 10 mM HEPES (pH 7.2 and an osmolality of approximately 300 mOsm / L). 2 mM NaATP was added to the intracellular solution on the day of the study.

[0464] The effects of modulators are assessed in the presence of submaximal GABA concentrations, typically resulting in activation of 10–20% of the response evoked by a saturating GABA concentration (GABA EC 10~20 For QPatch recordings, GABA ECs were used to examine and ensure baseline current stability before compound addition. 10~20 Five consecutive single applications, each of 2 seconds duration with a minimum 1 minute washout period between, were performed prior to compound addition. 10~20 For SyncroPatch recordings, GABA ECs were applied using the pipetting system of the QPatch system at least 1 min prior to co-application with 20 Alone was applied three times (1 second long applications with wash steps in between) before compound addition. This was followed by a 1-2 minute preincubation with test compound and then GABA EC 10~20 Finally, after a further washing step, a saturating concentration of GABA was applied to allow accurate assessment for each cell of the baseline activation percentage induced by submaximal GABA applied.

[0465] Compounds were first dissolved in DMSO as 10 mM stocks and then further diluted to test concentrations such that the final DMSO concentration in the extracellular recording solution was kept constant at 0.1% for QPatch recordings or 0.2% for SyncroPatch recordings.

[0466] The % effectiveness of a regulator is calculated according to the formula: [((compound peak current-leak)-(GABA peak current-leak)) / (GABA peak current-leak)] * 100 The relative potency of a compound was calculated by normalizing its potency to that of methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), which produced an attenuation of GABA-evoked current of -57±4% (n=5) by a separately determined potency of DMCM, where "Leak" is the leak baseline current at -65 mV, "Compound Peak Current" is the current evoked by co-application of compound and GABA, and "GABA Peak Current" is the current evoked by GABA alone during the fifth GABA application. Results were presented as "relative potency" for each compound, generally at concentrations 100-fold or greater than their determined Ki. The relative potency of a compound was calculated by normalizing its potency to that of methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), which produced an attenuation of GABA-evoked current of -57±4% (n=5).

[0467] The compounds of the present invention tested in the above assays are A It was found to have RNAM activity and selectivity for the α5 subtype over α1, α2 and α3.

[0468] Electrophysiology in hippocampal slices - Long-term potentiation assay Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity that is associated with both learning and memory formation. The intravenous general anesthetic etomidate impairs LTP in CA1 pyramidal neurons when acutely applied to in vitro mouse hippocampal slice preparations. This effect of etomidate is mediated by the α5-GABA A It was stopped by R NAM, and the α5 - / -This did not occur in comparable recordings made from mice, which may suggest a role for α5-GABA in this form of synaptic plasticity. A These results suggest an important role for α5-GABA R (Martin et al. 2009, Anesthesiology; 111: 1025-1035; Zurek et al. 2014, J Clin Invest; 124(12): 5437-5441). A The efficacy of R NAMs was assessed by determining their ability to rescue LTP suppressed by the presence of etomidate.

[0469] Wild-type male mice (C57Bl6J) aged 2–5 months were decapitated after cervical dislocation, and their brains were rapidly removed and placed in ice-cold oxygenated (95% O) bronchial buffer with the osmolality of aCSF adjusted to 300–310 mOsm. 2 , 5% CO 2 ) in artificial cerebrospinal fluid (aCSF) (composition in mM: 124 NaCl, 3 KCl, 1.75 MgCl 2 , 1 CaCl 2 , 1.25 NaH 2 PO 4 , 26 NaHCO 3 and 10 D-glucose). Brain slices (400 μm) containing sagittal sections of the hippocampus were prepared using a VT1000E tissue slicer (Leica). After a 1-h recovery period in oxygenated aCSF, slices were transferred to a submerged recording chamber where they were supplemented with 1 mM MgCl 2 and 2.5 mM CaCl 2 The mice were continuously perfused with oxygenated aCSF containing

[0470] For electrophysiological recordings, single slices were transferred to a submerged recording chamber (Scientific Systems Design, Mississauga, Ontario, Canada). The oxygenated aCSF solution was maintained at 32°C by a temperature control device (Digitimer Proportional Temperature Controller PTC03). Slices were oxygenated in the perfusion system with aCSF (flow rate approximately 2 ml / min).

[0471] To monitor basal synaptic transmission, bipolar stimulating electrodes, either hand-made from Teflon-coated tungsten strands (Advent research materials, Ltd, Eynsham, Oxfordshire, UK) or commercially available electrodes (World Precision Instruments, Florida, USA), were used to stimulate the Schaffer collateral commissure pathway from area CA3 to area CA1 of the hippocampus. Stimuli were delivered to the slices every 30 seconds to record dynamic changes in neurally evoked field excitatory postsynaptic potentials (fEPSPs). Stimuli were delivered by a constant-current insulated electronic stimulator (Digitimer Ltd, model DS2, Hertfordshire, UK). The stimulation current was adjusted to produce a response with an fEPSP slope that was 40% of the maximum population spike-free response. fEPSPs were recorded using aCSF-filled borosilicate glass microelectrodes (Kind precision glass, Inc., Claremont, USA) placed into the apical dendritic layer of CA1 pyramidal cells.

[0472] For control LTP experiments, fEPSPs from stimuli delivered at 1 / 30 sec were monitored over a 15-20 min period to ensure stability of the recordings (fEPSP slope and amplitude) before inducing LTP. A theta burst stimulation (TBS) protocol was then delivered (4 pulses at 100 Hz, repeated 10 times with 200 ms intervals between groups of 4 pulses; 4-TBS) to induce control maximal LTP, before switching back to single stimuli delivered again at 1 / 30 sec.

[0473] fEPSP measurements (1 / 30 sec) were monitored for an additional 60 min after delivery of 4-TBS. Analysis of fEPSP was performed using WinLTP software (Anderson, https: / / www.winltp.com / ). Statistical analysis of LTP was performed using GraphPad Prism statistical software, and comparison of drug effects on the extent of LTP was measured by one-way ANOVA at 50-60 min post-4-TBS and compared to control baseline fEPSP.

[0474] Etomidate alone or α5-GABA A The effects of etomidate on LTP in the presence of R NAM were assessed by administering vehicle, etomidate, or etomidate + α5-GABA for at least 30 min prior to delivery of 4-TBS. A was investigated by applying RNAM.

[0475] Etomidate was prepared as a 10 mM stock in H 2 α5-GABA was dissolved in O. A A stock solution of R NAM (10 mM; in 100% DMSO) was diluted as required with a maximum final concentration of vehicle 0.01%.

[0476] Certain compounds of the invention were tested in the above assay and found to partially or completely reverse the LTP inhibition caused by etomidate.

[0477] In vivo brain receptor occupancy assay The occupancy of benzodiazepine binding sites in rat brain by compounds was measured using the 3 This radioligand was assayed by its ability to inhibit the in vivo binding of α5 subunit-containing GABA receptor agonist [H]L-655,708. A It is selective for the benzodiazepine site of the receptor (Quirk et al. 2001, Journal of Neurochemistry, 77 445-51) and inhibits the in vivo α5-GABA AIt has been used previously to measure R occupancy (Atack et al. 2005, Neuropharmacology, 49 220-229).

[0478] Male Sprague-Dawley rats (250-310 g, 4-6 per group) were orally (5 mL / kg) administered either vehicle (0.5% methylcellulose) or test compound suspended in vehicle (1, 3, and 10 mg / kg) 30 min to 4 h before sacrifice. 3 To define the level of non-specific binding of [H]L-655,708, a separate group of animals received a 10 mg / kg oral (po) dose of TPA023 (5 ml / kg) composed in 0.5% methylcellulose (Atack et al. 2008 CNS Neuroscience Therapeutics 14 25-35). Compound-pretreated animals were then administered [H]L-655,708 at 1 min prior to sacrifice. 3 A tail vein injection of [H]L-655,708 (0.5 μL / g, 30 Ci / mM, diluted 1:60 in 0.9% NaCl solution) was given.

[0479] The animals were then killed by stunning and decapitation, and the whole brain was rapidly removed, the cerebellum and brain stem discarded, and the forebrain was left, which was weighed and homogenized in 10 volumes of ice-cold homogenization buffer (10 mM potassium phosphate buffer, pH 7.4, containing 100 mM KCl). Aliquots of the homogenate (500 μL) were then either added directly to scintillation vials (total radioactivity) or filtered and washed with 5 ml of Tris-HCL buffer (50 mM, pH 7.4) onto Whatman glass microfiber GF / B filters. The washed filters were then placed into scintillation vials (3 filters per vial) and scintillation fluid was added to all vials, which were then counted in a Perkin-Elmer Tricarb 2900TR scintillation counter (membrane-bound radioactivity).

[0480] Percent occupancy was defined as the percentage of specific binding in the vehicle-treated group that was inhibited by drug treatment. Thus, the in vivo binding of the modulator in drug-treated animals was calculated as follows: % binding = [(cpm vehicle - cpm sample) / (cpm vehicle - cpm NSB)] * 100, where "cpm vehicle", "cpm sample" and "cpmNSB" are the average numbers in vehicle, modulator and TPA023 treated animals, respectively.

[0481] Certain compounds of the invention were tested in the above assay and were assayed to determine in vivo brain α5-GABA receptor activity when administered orally. A This indicates the involvement of R.

[0482] Other in vivo assays The in vivo biological effects of the compounds can be evaluated using other assays, some of which can be the T-maze spontaneous alternation task, a widely used behavioral test to assess cognitive performance in rodents and in vivo EEG recordings that give a measure of the brain networks involved. The spontaneous alternation task in the T-maze is a hippocampal-dependent task that is amenable to a variety of pharmacological treatments that affect memory processes, and has been shown to be associated with the use of α5-GABA. A RNAMs can be tested in this assay for amelioration of induced cognitive impairment (Gerlai, 1998 Behav. Brain Res.; 95(1):91-101; Andriambeloson et al., 2014, Pharmacol. Res. Perspect; 2(4):e00048).

[0483] Performing in vivo EEG recordings from rodents reflects in vivo changes in brain activity. A R may be another suitable assay to evaluate the effects of NAMs (Zanos et al., 2017, eNeuro;4(1):ENEURO.0285-16.2017).

[0484] synthesis In the description of the synthetic methods described below and in the synthetic methods mentioned used to prepare starting materials, it should be understood that all proposed reaction conditions, including the choice of solvents, reaction atmosphere, reaction temperature, duration of experimental and work-up procedures, can be selected by one skilled in the art.

[0485] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reactants and reaction conditions employed.

[0486] Necessary starting materials are obtainable by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process forms and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those shown which are within the skill of one of ordinary skill in the art of organic chemistry.

[0487] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the art of chemistry will understand when such protection is required and how such protecting groups can be installed and subsequently removed.

[0488] For examples of protecting groups, see one of the many general texts on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to those skilled in the art of chemistry as suitable for the removal of the protecting group in question, such method being selected so as to effect removal of the protecting group with minimal disturbance of groups elsewhere in the molecule.

[0489] Thus, if reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0490] By way of example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl or trifluoroacetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, for example benzyloxycarbonyl or aroyl groups, for example benzoyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or alkoxycarbonyl groups or aroyl groups, can be removed by hydrolysis with a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed by hydrogenation, for example in a catalyst such as palladium on carbon, or by deprotection with a Lewis acid, for example BF 3 .OEt 2 A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0491] Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkanoyl groups, for example acetyl, aroyl groups, for example benzoyl, or arylmethyl groups, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, such as alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable base, for example an alkali metal hydroxide, for example lithium hydroxide, or sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, for example benzyl groups, can be removed by hydrogenation, for example, over a catalyst such as palladium on carbon.

[0492] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or ethyl group, which may be removed by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group, which may be removed by treatment with an acid, for example an organic acid, such as trifluoroacetic acid, or for example a benzyl group, which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0493] Resins may also be used as protecting groups.

[0494] General synthesis route The compounds of the present invention may be prepared by several synthetic routes, including but not limited to the following.

[0495] A compound of formula (I), where ring B is linked to the remainder of the compound of formula (I) by a ring nitrogen in ring B, can be prepared by reacting a compound of formula (A): [ka] (wherein Lg1 is a suitable leaving group; Ring A, R 3 , X 1 , X 2 and X 3 has any of the meanings defined herein, except that any functional groups are protected as necessary), into a compound of formula (B): [ka] wherein Ring B has any of the meanings defined herein except that any functional groups are optionally protected, and with the proviso that Ring B bears an -NH- group; and optionally thereafter performing one or more of the following steps: converting a compound of formula (I) into another compound of formula (I); and / or removing any protecting groups; and / or Formation of pharma- ceutically acceptable salts It can be prepared by

[0496] Lg1 is a suitable leaving group, such as halo, in particular Br or I. Suitably, the reaction is carried out in the presence of a suitable catalyst (e.g., copper(I) iodide and L-proline) and a suitable base (e.g., potassium carbonate or tripotassium phosphate) in a suitable solvent (e.g., DMSO, DMF or NMP).

[0497] Compounds of formula (A) can be prepared, for example, using Reaction Scheme 1: Reaction Scheme 1: [ka] In the formula, rings A, R 3 , X 1 , X 2 and X 3 has any of the meanings defined herein, except that any functional groups are protected as necessary; Lg 1 is a suitable leaving group.

[0498] Notes on Reaction Scheme 1 (1): A carboxylic acid (B) is coupled with an aniline (C). The reaction is preferably carried out in the presence of a suitable activating agent (e.g., EDC, HATU, HBTU, PyBroP or T3P). The coupling reaction is preferably carried out in a suitable solvent (e.g., DCM, DMF, THF or EtOAc) and in the presence of a suitable base (e.g., an organic amine such as triethylamine, N,N-diisopropylethylamine or DMAP).

[0499] (2): Carboxylic acid (B) can be converted to the corresponding acid chloride (D) using well-known methods, such as by reacting (B) with a suitable reagent, such as thionyl chloride or oxalyl chloride, in a suitable solvent, such as DCM or toluene. Optionally, the reaction is carried out in the presence of a suitable catalyst, such as DMF.

[0500] (3): An acid chloride (D) is reacted with an aniline (C). The reaction is preferably carried out in a suitable solvent (e.g., DCM or THF) in the presence of a suitable base (e.g., an organic amine (e.g., triethylamine or N,N-diisopropylethylamine) or a carbonate base (e.g., potassium carbonate).

[0501] (4): Carboxylic acid (B) is preferably reacted with an activating agent such as 1,1′-carbonyldiimidazole (CDI) in a suitable solvent such as THF, 1,4-dioxane or DCM to give the CDI adduct (E).

[0502] (5) Adduct (E) is reacted with aniline in the presence of a suitable base (e.g., lithium bis(trimethylsilyl)amide) in a suitable solvent (e.g., THF or dioxane) to give compound (A).

[0503] Carboxylic acid (B), aniline (C) and ring B are commercially available or can be prepared using known methods. For example, carboxylic acid (B) can be prepared using methods similar to those described in the literature (e.g., WO 2018 / 104419, WO 2012 / 062687, WO 2010 / 127978 and Cheng HMet al. 2012 Journal of Medicinal Chemistry 55 2144-2153).

[0504] The compound of formula (I), where ring B is linked to the remainder of the compound of formula (I) by a ring carbon atom in ring B, can be prepared by reacting with a compound of formula (A1): [ka] (In the formula, Lg 2 is halo or triflate; Ring A, R 3 , X 1 , X 2 and X 3have any of the meanings defined herein, except that any functional groups are protected as necessary), into a compound of formula (F): [ka] wherein Ring B has any of the meanings defined herein, except that any functional groups are optionally protected; Bx is a boronic acid or ester thereof, or a trifluoroborate salt; and optionally thereafter performing one or more of the following steps: converting a compound of formula (I) into another compound of formula (I); and / or removing any protecting groups; and / or Formation of pharma- ceutically acceptable salts It can be prepared by

[0505] The coupling reaction is preferably carried out using Suzuki coupling reaction. Preferably, the coupling reaction is carried out in the presence of a metal catalyst, for example, a palladium catalyst such as [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a suitable base, for example, carbonate (potassium carbonate or cesium carbonate), tripotassium phosphate, potassium acetate or an organic amine base, for example, triethylamine. The coupling reaction is preferably carried out in a suitable solvent, for example, toluene, THF, dioxane, dimethoxyethane or water.

[0506] The group Bx is a boronic acid (-B(OH) 2 Alternatively, Bx can be a boronic acid ester, such as a catechol boronic acid ester, a pinacol boronic acid ester, an alkyl diol ester (e.g., a 1,3-propanediol ester or a neopentyl glycol ester). In certain embodiments, Bx is a trifluoroborate (e.g., potassium trifluoroborate).

[0507] Compounds of formula (F) are commercially available or can be prepared using well-known methods.

[0508] A compound of formula (I), where ring B is linked to the remainder of the compound of formula (I) by a ring carbon atom in ring B, can be converted to a compound of formula (G): [ka] (Wherein, Bx is a boronic acid or ester thereof, or a trifluoroborate salt; Ring A, R 3 , X 1 , X 2 and X 3 have any of the meanings defined herein, except that any functional groups are protected as necessary), into a compound of formula (H): [ka] wherein Ring B has any of the meanings defined herein, except that any functional groups are optionally protected; Lg 2 is halo or triflate; and optionally thereafter performing one or more of the following steps: converting a compound of formula (I) into another compound of formula (I); and / or removing any protecting groups; and / or Formation of pharma- ceutically acceptable salts It can be prepared by

[0509] The coupling reaction can be carried out using methods similar to those described above for the coupling of (A) and (F).

[0510] Compounds of formula (G) can be prepared by converting a compound of formula (A) to its corresponding boronic acid or boronic ester using a suitable boron reagent (e.g., 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane) in the presence of a suitable catalyst (e.g., [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a suitable base (e.g., potassium acetate). The reaction is preferably carried out in the presence of a suitable solvent (e.g., dioxane or DMSO). Compounds of formula (H) are commercially available or can be prepared using well-known methods.

[0511] Compounds of formula (I) may also be prepared according to Reaction Scheme 2: Reaction Scheme 2: [ka] (In the formula, ring A, ring B, R 3 , X 1 , X 2 and X 3 has any of the meanings defined herein, except that any functional groups are protected as necessary; and optionally thereafter performing one or more of the following steps: converting a compound of formula (I) into another compound of formula (I); and / or removing any protecting groups; and / or Forming pharma- ceutically acceptable salts.

[0512] The reaction conditions for steps (1), (2), (3), (4) and (5) are similar to those described for Reaction Scheme 1 above.

[0513] Compounds of formula (J) are commercially available or can be prepared using well-known methods, such as those described in the Examples herein. EXAMPLES

[0514] [Table 1]

[0515] [Table 2]

[0516] naming Exemplary compounds were named using Dotmatics ELN or Perkin-Elmer ChemDraw software. Other compounds, particularly commercially available reagents, use either names generated by Dotmatics ELN or Perkin-Elmer ChemDraw software or names commonly found in online databases and catalogs.

[0517] NMR All NMR spectra were obtained using a Varian VNMRS 600; Varian VNMRS 500; Bruker Avance III 500 or Bruker Avance 400 spectrometer. Chemical shifts are given in parts per million (ppm, δ) relative to residual isotopic solvent, e.g. as described in Gottlieb et al. J. Org Chem. (1997) 62 7512. The observed multiplicity of a particular signal is abbreviated by s (singlet); br (broad); d (doublet); t (triplet); q (quartet); m (multiplet); or combinations thereof. The number of protons (n) for a given resonance signal is indicated by nH. Coupling constants (J) are given in Hz and are reported to one decimal place.

[0518] mass spectrometry Mass spectrometry data were recorded as part of the LCMS analysis obtained using a Waters 2695 HPLC coupled to a Thermo LCQ ESI-MS or APCI-MS mass spectrometer; a Shimadzu Prominence Series coupled to an LCMS-2020 ESI and APCI mass spectrometer or a Waters Acquity H-class plus UPLC coupled to a Waters Acquity QDa API-ES mass detector. Molecular ions only, percentages from the molecular ion and other major peaks are reported as mass / charge (m / z) ratios.

[0519] Example 1 N-(6-imidazol-1-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 1-N-(6-bromo-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide 5-Methyl-3-phenyl-1,2-oxazole-4-carboxylic acid (10 g, 49.25 mmol) was dissolved in SOCl 2 (39.5 mL, 541.77 mmol). The mixture was divided across 4 x 20 mL Biotage microwave vials and heated to 65 °C overnight using an aluminum heating block. After cooling to room temperature, the vials were combined and the excess SOCl 2 The residue was dissolved in DCM (10 mL) and a solution of 6-bromo-2-methoxy-3-pyridinamine (10 g, 49.25 mmol) and Et in DCM (50 mL) pre-cooled in an ice bath. 3 N (8.2 mL, 59.1 mmol) was added dropwise to the solution. After the addition was complete (ca. 10 min), the cooling bath was removed and the mixture was allowed to stir at room temperature for 2 h. The reaction mixture was diluted with DCM (60 mL) and washed successively with water (2×50 mL), 2 M NaOH solution (2×40 mL), 1 M HCl solution (3×40 mL) and brine (40 mL). The organic extracts were washed with MgSO4 It was dried over, filtered and concentrated under reduced pressure to give N-(6-bromo-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (Intermediate 1) (18.14 g, 90% yield) as a brown solid. 1 H NMR (500 MHz, chloroform-d) δ 8.54 (d, J = 8.2 Hz, 1H), 7.65-7.53 (m, 6H), 7.02 (d, J = 8.2 Hz, 1H), 3.60 (s, 3H), 2.81 (s, 3H). m / z 390.0 81 [M+H] for Br + .

[0520] Process 2 Intermediate 1 (1.00 g, 2.58 mmol), imidazole (220 mg, 3.23 mmol), L-proline (120 mg, 1.04 mmol) and K in DMSO (10 mL) 2 CO 3 A suspension of (720 mg, 5.21 mmol) was sparged with nitrogen for 10 min. Copper iodide (200 mg, 1.05 mmol) was added to the mixture, which was heated to 80 °C in a sealed 20 mL microwave vial with conventional heating overnight. The mixture was partitioned between 200 mL EtOAc, 200 mL water, and 100 mL brine. The mixture was filtered through Celite, separated, and the aqueous phase was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with 100 mL 1:1 water:brine and diluted with MgSO 4The solid was dried over ice, filtered and concentrated under reduced pressure. Purification by flash silica column chromatography on an ISCO system (24 g silica, elution with a 0-5% MeOH / DCM gradient) gave approximately 800 mg of an orange solid, which was redissolved in refluxing isopropanol (10 mL). Approximately 10 mL of water was added to induce precipitation. After returning to reflux, the solution was hot filtered and cooled first to room temperature and then in a freezer at -20°C for 30 minutes. The solid was isolated by filtration and washed with 20 mL of cold (-20°C) isopropanol to give N-(6-imidazol-1-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (550 mg, 56% yield). 1 H NMR (500 MHz, DMSO-d 6 )δ 9.62(s,1H), 8.50(s,1H), 8.35(d,J=8.2Hz, 1H), 7.92(s,1H), 7.74-7.69(m,2H), 7 .60-7.50(m,3H), 7.38(d,J=8.2Hz, 1H), 7.11(s,1H), 3.92(s,3H), 2.65(s,3H).m / z 376.1[M+H] + .

[0521] Example 2 N-(4-imidazol-1-yl-2-methoxy-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Process 1 To a solution of 4-fluoro-2-methoxy-1-nitro-benzene (1.00 g, 5.8 mmol) in DMF (20 mL), 2 CO 3 (808 mg, 5.8 mmol) and imidazole (480 mg, 7.0 mmol) were added. The reaction was stirred at room temperature for 16 hours. The mixture was poured into water (15 mL) and the resulting solid was isolated by filtration to give 1-(3-methoxy-4-nitro-phenyl)imidazole (600 mg, 45% yield). 1H NMR (500 MHz, chloroform-d) δ 8.03 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.33 (s, 1H), 7.26 (s, 1H), 7.07 (d, J = 6.8 Hz, 2H), 4.04 (s, 3H). m / z 220.1 [M+H] + .

[0522] Process 2 A solution of 1-(3-methoxy-4-nitro-phenyl)imidazole (350 mg, 1.6 mmol) in MeOH was degassed by bubbling nitrogen gas through it for 3 min. Palladium on carbon (34 mg, 0.03 mmol) was added, the atmosphere was replaced with hydrogen, and the reaction was stirred for 2 h under H 2 The mixture was stirred under (balloon). TLC showed the reaction was complete. The reaction mixture was filtered through Celite and the clear filtrate was concentrated under reduced pressure to give 4-imidazol-1-yl-2-methoxy-aniline (230 mg, 72% yield) as a light pink solid. 1 H NMR (500MHz, chloroform-d) δ 7.72(s,1H), 7.16(dt,J=10.0, 1.2Hz, 2H), 6.81-6.76(m,2H), 6.73(d,J=8.1Hz, 1H), 3.91(s,2H), 3.88(s,3H).m / z 190.1[M+H] + .

[0523] Process 3 To a solution of 5-methyl-3-phenyl-1,2-oxazole-4-carboxylic acid (107.4 mg, 0.53 mmol) in DMF (5 mL) was added DIPEA (0.52 mL, 3 mmol) and HATU (301 mg, 0.79 mmol). The reaction mixture was stirred at room temperature for 10 min before 4-imidazol-1-yl-2-methoxy-aniline (100 mg, 0.53 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was concentrated to dryness. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organics were washed with brine and MgSO 4The mixture was dried over hexane, filtered, and concentrated under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a 2% MeOH / DCM gradient) afforded N-(4-imidazol-1-yl-2-methoxy-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (95 mg, 46% yield) as a yellow solid. 1 H NMR (500MHz, chloroform-d)δ 8.56(d,J=8.7Hz, 1H), 7.82(s,2H), 7.67-7.52(m,5H), 7.29-7.13(m,2 H), 6.99-6.91(m,1H), 6.82-6.70(m,1H), 3.51(s,3H), 2.82(s,3H).m / z 375.1[M+H] + .

[0524] Example 3 N-(2-imidazol-1-yl-4-methoxy-pyrimidin-5-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 2-imidazol-1-yl-(5-methyl-3-phenyl-isoxazol-4-yl)methanone To a solution of 5-methyl-3-phenyl-1,2-oxazole-4-carboxylic acid (2.00 g, 9.84 mmol) in THF (25 mL) was added 1,1'-carbonyldiimidazole (1.60 g, 9.84 mmol) in portions. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (30 mL) and saturated NaHCO 3 (30 mL), water (30 mL) and brine (30 mL), and then MgSO 4 It was dried over, filtered and concentrated under reduced pressure to give imidazol-1-yl-(5-methyl-3-phenyl-isoxazol-4-yl)methanone (Intermediate 2) (1.92 g, 73%) as an off-white solid. 1H NMR (500 MHz, chloroform-d): δ 7.78 (t, J = 1.1 Hz, 1H), 7.46-7.49 (m, 2H), 7.39-7.44 (m, 1H), 7.34-7.38 (m, 2H), 7.29 (t, J = 1.5 Hz, 1H), 6.95 (dd, J = 1.7, 0.8 Hz, 1H,), 2.63 (s, 3H). m / z 254.0 [M+H] + .

[0525] Step 2 - Synthesis of intermediate 3-N-(2-chloro-4-methoxy-pyrimidin-5-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide To a solution of 2-chloro-4-methoxy-pyrimidin-5-amine (1.00 g, 6.27 mmol) in THF (10 mL) was added slowly 1 M lithium bis(trimethylsilyl)amide solution in THF (9.4 mL, 9.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 40 min and then warmed to room temperature over 10 min. The reaction mixture was then cooled back to 0 °C before adding a solution of intermediate 2 (1.90 g, 7.52 mmol) in THF (50 mL). The reaction mixture was stirred at 0 °C for 10 min and then allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (100 mL) and the organics were washed with water (2 x 15 mL) followed by saturated brine solution (1 x 25 mL). The organics were dried (MgSO 4 ) and concentrated under reduced pressure. The crude residue was triturated with MeOH (20 mL) to give N-(2-chloro-4-methoxy-pyrimidin-5-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (Intermediate 3). 1 H NMR (600 MHz, chloroform-d) δ 9.38 (s, 1H), 7.65-7.61 (m, 1H), 7.60-7.57 (m, 4H), 7.41 (s, 1H), 3.70 (s, 3H), 2.82 (s, 3H). m / z 345.1 [M+H] + .

[0526] Process 3 To a solution of intermediate 3 (500 mg, 1.45 mmol) in DMSO (12 mL) was added imidazole (198 mg, 2.9 mmol) and K2 CO 3 (601 mg, 4.35 mmol) was added. The reaction mixture was then heated to 100 °C overnight. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (25 mL) and the organics were washed with water (2 x 5 mL) and then with saturated brine solution (1 x 20 mL). The organics were dried (MgSO 4 ) and concentrated under reduced pressure. The crude material was purified by flash silica column chromatography on an ISCO system (1-2% MeOH / DCM gradient) to give N-(2-imidazol-1-yl-4-methoxy-pyrimidin-5-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (123 mg, 21% yield). 1 H NMR (600 MHz, chloroform-d) δ 9.43 (s, 1H), 8.46 (t, J = 1.0 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.68-7.49 (m, 5H), 7.44 (s, 1H), 7.10 (d, J = 1.1 Hz, 1H), 3.76 (s, 3H), 2.84 (s, 3H). m / z 377.1 [M+H] + .

[0527] Example 4 N-[2-Methoxy-6-(1-methylpyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (60 mg, 0.15 mmol) and potassium phosphate tribasic (66 mg, 0.31 mmol) in 1,4-dioxane (2 mL) was treated with a solution of 1-methyl-1H-pyrazole-4-boronic acid (23 mg, 0.19 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then treated with Pd(dppf)Cl 2(combined with DCM, 13 mg, 0.02 mmol), sealed in a microwave tube and heated at 110° C. for 3 h. The reaction mixture was reduced under reduced pressure and taken up in DCM. Water was added and the organics were separated using a phase separator. The organics were removed under reduced pressure to give an oil which was purified by flash silica column chromatography on an ISCO system (0-80% EtOAc / PE gradient) to give N-[2-methoxy-6-(1-methylpyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (36 mg, 57% yield). 1 H NMR (600MHz, chloroform-d)δ 8.60(d,J=8.1Hz, 1H), 7.85(s,1H), 7.75(s,1H), 7.68(s,1H), 7.66-7.58(m,3H), 7.56( dd,J=8.1,6.6Hz,2H),7.00(d,J=8.1Hz,1H),3.92(s,3H),3.64(s,3H),2.82(s,3H).m / z 390.0[M+H] + .

[0528] Example 5 N-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-4-methyl-1-phenyl-1H-1,2,3-triazole-5-carboxamide [ka] Process 1 In a 100 mL RBF, add 5-fluoro-2-nitroanisole (10 g, 58.44 mmol), imidazole (4.77 g, 70.12 mmol), K 2 CO 3 (8.08 g, 58.44 mmol) and DMF (50 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was treated with water (30 mL) and stirred for 30 min. The suspension was filtered under reduced pressure and the solid cake was washed with water and then air-dried to give 1-(3-methoxy-4-nitrophenyl)-1H-imidazole (10.1 g, 75% yield) as a brown solid. 1 H NMR (500 MHz, DMSO-d 6)δ 8.48(s,1H), 8.05(dd,J=8.8, 1.7Hz, 1H), 7.94(s,1H), 7.56(d,J=2.1Hz, 1H), 7.41(dt,J=8.9, 2.0Hz, 1H), 7.15(s,1H), 4.01(s,3H).m / z 219.9[M+H] + .

[0529] Process 2 A 100 mL RBF was charged with 1-(3-methoxy-4-nitrophenyl)-1H-imidazole (1.33 g, 6.07 mmol), palladium on carbon (32.3 mg, 5% mmol) and EtOH (30 mL) under nitrogen. The reaction flask was then filled with H 2 Purge with a balloon and incubate overnight at room temperature in H 2 The reaction flask was purged with nitrogen and then the reaction mixture was filtered through Celite, washing with MeOH followed by DCM. The filtrate was then concentrated under reduced pressure to give 4-(1H-imidazol-1-yl)-2-methoxyaniline (1.05 g, 87% yield) as a brown oil. 1 H NMR (500 MHz, DMSO-d 6 ):δ 8.01(s,1H), 7.53(s,1H), 7.00(d,2H), 6.87(d,J=8.3, 1.7Hz, 1H), 6.67(d,J=8.3, 1.3Hz, 1H), 4.87(s,2H), 3.81(s,3H).m / z 189.9[M+H] + .

[0530] Process 3 A 10 mL microwave vial was charged with 4-(1H-imidazol-1-yl)-2-methoxyaniline (100 mg, 0.53 mmol), 4-methyl-1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (112.8 mg, 0.55 mmol), HATU (221.1 mg, 0.58 mmol), DIPEA (0.20 mL, 1.16 mmol) and DMF (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL), the phases were shaken and the organic layer was separated. The organic layer was further washed with brine (30 mL) and MgSO 4The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The crude residue was dissolved in DMSO (1 mL) and purified on a Shimadzu MDAP preparative purification system operating in positive mode. The product-containing fractions were combined and concentrated under reduced pressure to give N-(4-(1H-imidazol-1-yl)-2-methoxyphenyl)-4-methyl-1-phenyl-1H-1,2,3-triazole-5-carboxamide (60 mg, 29% yield) as an off-white solid. 1 H NMR (600 MHz, methanol-d 4 ):δ 8.27(s,1H), 8.14(d,J=8.5Hz, 1H), 7.64-7.56(m,6H), 7.23(s,1H), 7.19(s,1H), 7.16(d,J=8.6Hz, 1H), 3.87(s,3H), 2.58(s,3H).m / z 375.0[M+H] + .

[0531] Example 6 N-[6-(3,5-dimethylisoxazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Intermediate 1 (50 mg, 0.13 mmol), potassium phosphate tribasic (55 mg, 0.26 mmol) and (3,5-dimethylisoxazol-4-yl)boronic acid (28 mg, 0.15 mmol) were added to a microwave vial, backfilled with nitrogen and 1,4-dioxane (2 mL) was added. The mixture was purged with nitrogen (10 min) and then diluted with Pd(dppf)Cl. 2(combined with DCM, 11 mg, 0.01 mmol) was added and the vial was sealed. The mixture was purged for an additional 10 min and then reacted in a microwave reactor at 110° C. for 2 h. The solvent was removed by Genevac and to the resulting solid were added DCM and water. The biphasic solution was stirred vigorously and then passed through a phase separator. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica column chromatography on an ISCO system to give N-[6-(3,5-dimethylisoxazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (11 mg, 20% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.69 (d, J = 8.1 Hz, 1H), 7.72 (s, 1H), 7.66-7.60 (m, 3H), 7.60-7.55 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 3.63 (s, 3H), 2.83 (s, 3H), 2.56 (s, 3H), 2.42 (s, 3H). m / z 403.0 [MH] - .

[0532] Example 7 N-(2-Methoxy-6-pyrimidin-5-yl-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (500 mg, 1.29 mmol) and pyrimidine-5-boronic acid (191.5 mg, 1.55 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was treated with KOAc (505.5 mg, 5.15 mmol) and the reaction mixture was purged with nitrogen for 10 min. The reaction mixture was then treated with Pd-118 (84 mg, 0.13 mmol), sealed and heated at 80 °C for 3 h and then at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a brown solid. The residue was partitioned between EtOAc (150 mL) and water (150 mL) and the phases were shaken and separated. The organic phase was washed with brine (50 mL) and dried (MgSO 4), filtered and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash silica column chromatography on an ISCO system using collect all function (40 g silica, elution with 0-20% EtOAc / PE gradient) to give N-(2-methoxy-6-pyrimidin-5-yl-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (382 mg, 73% yield). 1 H NMR (600 MHz, chloroform-d) δ 9.25 (s, 2H), 9.17 (s, 1H), 8.77 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.66-7.61 (m, 3H), 7.58 (ddd, J = 7.7, 6.5, 2.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H), 2.83 (s, 3H). m / z 388.0 [M+H] +

[0533] Example 8 N-[2-Methoxy-6-(3-nitrophenyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Intermediate 1 (50 mg, 0.13 mmol), potassium phosphate tribasic (55 mg, 0.26 mmol) and (3-nitrophenyl)boronic acid (28 mg, 0.15 mmol) were added to a microwave vial, backfilled with nitrogen and 1,4-dioxane (2 mL) was added. The mixture was purged with nitrogen (10 min) and then diluted with Pd(dppf)Cl. 2(combined with DCM, 11 mg, 0.01 mmol) was added and the vial was sealed. The reaction mixture was purged for an additional 10 min and then reacted in a microwave reactor at 110° C. for 2 h. The solvent was removed by Genevac and to the resulting solid were added DCM and water. The biphasic solution was stirred vigorously and then passed through a phase separator. The filtrate was concentrated under reduced pressure and the residue was purified by flash silica column chromatography on an ISCO system to give N-[2-methoxy-6-(3-nitrophenyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (45 mg, 77% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.83-8.78 (m, 1H), 8.77 (d, J = 8.1 Hz, 1H), 8.28-8.24 (m, 1H), 8.17 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.80 (s, 1H), 7.68-7.62 (m, 3H), 7.62-7.54 (m, 3H), 7.42 (d, J = 8.1 Hz, 1H), 3.73 (s, 3H), 2.84 (s, 3H). m / z 429.0 [M+H] + .

[0534] Example 9 N-(3-Methoxy-5-pyrimidin-5-yl-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 4-N-(5-bromo-3-methoxy-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide To a solution of 5-bromo-3-methoxypyridin-2-amine (500 mg, 2.46 mmol) in DMF (15 mL) was added intermediate 2 (623 mg, 2.46 mmol). The reaction mixture was heated at 80° C. overnight. Heating was then increased to 120° C. for an additional 48 h. The reaction mixture was concentrated to dryness and the residue was purified by flash silica column chromatography (gradient 25-40% EtOAc / PE) to give N-(5-bromo-3-methoxy-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (intermediate 4) as a white solid (345 mg, 35% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.06 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.70-7.58 (m, 2H), 7.57-7.47 (m, 3H), 7.08 (d, J = 1.9 Hz, 1H), 3.52 (s, 3H), 2.81 (s, 3H). m / z 389.9 [M+H] + .

[0535] Process 2 A solution of potassium phosphate tribasic (54.6 mg, 0.26 mmol), pyrimidine-5-boronic acid (19.1 mg, 0.15 mmol) and intermediate 4 (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (4.2 mg, 0.01 mmol) was added quickly, the solution was degassed again for 10 min and the mixture was allowed to stir at 100 °C overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-(3-methoxy-5-pyrimidin-5-yl-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (32 mg, 61% yield) as a white solid. 1H NMR (600MHz, chloroform-d)δ 9.23(s,1H), 8.88(s,2H), 8.24(d,J=2.0Hz, 1H), 8.00(s,1H), 7.65(d,J=7.4Hz, 2H), 7.58( m / z 388.0[M+H] + .

[0536] Example 10 N-[2-Methoxy-6-(2-methoxythiazol-5-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of Intermediate 1 (60 mg, 0.15 mmol) and 2-methoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (45 mg, 0.19 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was treated with potassium phosphate tribasic (98 mg, 0.46 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then treated with Pd(dppf)Cl 2 (combined with DCM, 13 mg, 0.02 mmol), sealed and heated at 110° C. overnight. The reaction mixture was concentrated under reduced pressure and taken up in DCM (10 mL). Water (10 mL) was added and the organics were separated using a phase separator. The organics were concentrated under reduced pressure and the residue was purified by flash silica column chromatography on an ISCO system (12 g silica, elution with a 0-40% EtOAc / PE gradient) to give N-[2-methoxy-6-(2-methoxythiazol-5-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (15 mg, 21% yield). 1H NMR (600 MHz, chloroform-d) δ 8.63 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.64-7.59 (m, 3H), 7.59-7.52 (m, 2H), 7.48 (s, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.08 (s, 3H), 3.62 (s, 3H), 2.82 (s, 3H). m / z 423.0 [M+H] + .

[0537] Example 11 N-[6-(5-amino-3-pyridyl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (34 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and taken up in DCM (10 mL). Water (10 mL) was added and the organics were separated using a phase separator. The organics were concentrated under reduced pressure to give a dark oil which was purified by flash silica column chromatography on an ISCO system (12 g silica, elution with a 0-50% EtOAc / PE gradient) to give N-[6-(5-amino-3-pyridyl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (43 mg, 79% yield). 1H NMR (600MHz, chloroform-d)δ 8.71(d,J=8.2Hz, 1H), 8.59(d,J=1.8Hz, 1H), 8.06(d,J=2.7Hz, 1H), 7.76(s,1H), 7.63(tt, J=8.7, 1.5Hz, 3H), 7 .61-7.55(m,2H), 7.53(dd,J=2.7, 1.8Hz, 1H), 7.32(d,J=8.2Hz, 1H), 3.75(s,2H), 3.70(s,3H), 2.84(s,3H).m / z 402.0[M+H] + .

[0538] Example 12 N-[2-Methoxy-4-(1-methylpyrazol-4-yl)phenyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 5-N-(4-bromo-2-methoxy-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide To a mixture of 4-bromo-o-anisidine (1.00 g, 4.95 mmol), DIPEA (1.72 mL, 9.9 mmol) in DCM (40 mL) was added dropwise a 0.4 M solution of 5-methyl-3-phenyl-isoxazole-4-carbonyl chloride (12.37 mL, 4.95 mmol) in DCM (synthesized according to step 1, example 1). The reaction mixture was stirred at room temperature overnight. Water (20 mL) was added and the reaction mixture was extracted with DCM (3 x 20 mL). The combined organics were washed with brine and MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a gradient of 20% EtOAc / PE) gave N-(4-bromo-2-methoxy-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (Intermediate 5) (1.50 g, 74% yield). 1H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 8.7 Hz, 1H), 7.74 (s, 1H), 7.67-7.49 (m, 5H), 7.06 (dd, J = 8.7, 2.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 3.43 (s, 3H), 2.80 (s, 3H). m / z 387.0 / 389.0 [M+H] + .

[0539] Process 2 In a 5 mL microwave vial, add Intermediate 5 (50 mg, 0.13 mmol), 1-methyl-1H-pyrazole-4-boronic acid (24 mg, 0.19 mmol), Na 2 CO 3 (27 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol), ethylene glycol dimethyl ether (2 mL) and water (1 mL). The vial was sealed, flushed with nitrogen, degassed and then heated at 100 °C in a microwave for 45 min. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and separated. The organic layer was washed with brine (20 mL) and MgSO 4 It was dried over hexane, filtered through Celite and concentrated under reduced pressure. The residue was purified on a Shimadzu MDAP (eluting with a gradient of 30-95% MeCN / water+0.1% formic acid) to give N-[2-methoxy-4-(1-methylpyrazol-4-yl)phenyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (16 mg, 31% yield) as an off-white solid. 1 H NMR (600MHz, chloroform-d)δ 8.42(d,J=8.4Hz, 1H), 7.81(s,1H), 7.68(s,1H), 7.65(d,J=7.6Hz, 2H), 7.60-7.51(m,4H) , 7.04(d,J=8.4Hz, 1H), 6.80(d,J=1.7Hz, 1H), 3.93(s,3H), 3.49(s,3H), 2.82(s,3H).m / z 389.0[M+H] + .

[0540] Example 13 N-(2-Methoxy-4-pyrimidin-5-yl-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] In a 5 mL microwave vial, add intermediate 5 (50 mg, 0.13 mmol), pyrimidine-5-boronic acid (19 mg, 0.15 mmol), Na 2 CO 3 (27 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol), ethylene glycol dimethyl ether (2 mL) and water (1 mL). The vial was sealed, flushed with nitrogen, degassed and then heated at 90 °C in a microwave for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the phases were separated. The organic phase was washed with brine (20 mL) and MgSO 4 The mixture was dried over hexane, filtered through Celite, and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, elution with a 0-80% EtOAc / PE gradient) to give N-(2-methoxy-4-pyrimidin-5-yl-phenyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (28 mg, 53% yield) as a yellow solid. 1 H NMR (600MHz, chloroform-d)δ 9.17(s,1H), 8.89(s,2H), 8.62(d,J=8.4Hz, 1H), 7.90(s,1H), 7.67-7.63(m,2H), 7.61(t,J=7.3Hz, m / z 387.0[M+H] + .

[0541] Example 14 N-[5-(3,5-dimethylisoxazol-4-yl)-3-methoxy-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (38 mg, 0.39 mmol), 3,5-dimethylisoxazole-4-boronic acid (21.8 mg, 0.15 mmol) and intermediate 4 (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (4.2 mg, 0.01 mmol) was added quickly, the solution was degassed again for 10 min and the mixture was allowed to stir at 80 °C overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over 100 ml, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[5-(3,5-dimethylisoxazol-4-yl)-3-methoxy-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (26 mg, 47% yield) as a pale yellow solid. 1 H NMR (600MHz, chloroform-d)δ 8.01-7.91(m,2H), 7.74-7.63(m,2H), 7.55(dt,J=14.7, 7.2Hz, 3H), 6.83 (d,J=1.9Hz, 1H), 3.55(s,3H), 2.84(s,3H), 2.38(s,3H), 2.23(s,3H).m / z 405.0[M+H] + .

[0542] Example 15 N-[3-Methoxy-5-(1-methylpyrazol-4-yl)-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (38 mg, 0.39 mmol), 1-methyl-1H-pyrazole-4-boronic acid (19.4 mg, 0.15 mmol) and intermediate 4 (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (4.2 mg, 0.01 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over hexane, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[3-methoxy-5-(1-methylpyrazol-4-yl)-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (22 mg, 42% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 8.14 (s, 1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.59 (s, 1H), 7.55-7.53 (m, 2H), 7.51 (d, J = 7.4 Hz, 1H), 7.01 (s, 1H), 3.94 (s, 3H), 3.57 (s, 3H), 2.82 (s, 3H). m / z 390.4 [M+H] + .

[0543] Example 16 N-[6-[3-(dimethylamino)phenyl]-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and [3-(dimethylamino)phenyl]boronic acid (26 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction was then charged with Pd-118 (8 mg, 0.01 mmol), sealed and heated at 80 °C overnight. The reaction mixture was concentrated by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (elution with a 0-50% PE / EtOAc gradient) to give N-[6-[3-(dimethylamino)phenyl]-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (42 mg, 72% yield). 1 H NMR (600MHz, chloroform-d)δ 8.68(d,J=8.2Hz, 1H), 7.75(s,1H), 7.67-7.54(m,5H), 7.38-7.35(m,1H), 7.33(d,J=8.2 Hz, 1H), 7.31-7.27(m,2H), 6.78-6.72(m,1H), 3.71(s,3H), 3.00(s,6H), 2.83(s,3H).m / z 429.0[M+H] + .

[0544] Example 17 N-[6-(2-cyclopropylpyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and (2-cyclopropylpyrimidin-5-yl)boronic acid (25 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed and heated at 80° C. overnight. The reaction mixture was concentrated by Genevac, then DCM and water were added. The reaction mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system and further purified by mass directed preparative HPLC to give N-[6-(2-cyclopropylpyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (8 mg, 16% yield). 1 H NMR (600MHz, chloroform-d)δ 9.07(s,2H), 8.74(d,J=8.2Hz, 1H), 7.77(s,1H), 7.66-7.61(m,3H), 7.60-7.55(m,2H), 7.29(d,J=8.2Hz, 1H), 3. 68(d,J=1.3Hz, 3H), 2.84(s,3H), 2.29(tt, J=8.4, 4.7Hz, 1H), 1.17(dt,J=6.2, 3.3Hz, 2H), 1.13-1.08(m,2H).m / z 428.0[M+H] + .

[0545] Example 18 N-[3-Methoxy-5-(1H-pyrazol-4-yl)-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (25.2 mg, 0.26 mmol), 1H-pyrazole-4-boronic acid pinacol ester (30 mg, 0.15 mmol) and intermediate 4 (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (4.2 mg, 0.01 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over 100 ml, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[3-methoxy-5-(1H-pyrazol-4-yl)-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (23 mg, 45% yield) as a white solid. 1 H NMR (600MHz, chloroform-d) δ 10.65(br m / z 375.9[M+H] + .

[0546] Example 19 N-[3-Methoxy-5-(1-methylpyrazol-4-yl)pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 6-N-(5-bromo-3-methoxy-pyrazin-2-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide To a solution of 5-bromo-3-methoxypyrazin-2-amine (13.50 g, 66.17 mmol) in anhydrous THF (40 mL) at -78 °C was added a solution of lithium bis(trimethylsilyl)amide (99.25 mL, 99.25 mmol). The reaction mixture was stirred at -78 °C for 10 min, warmed to room temperature over 20 min, then cooled back to -78 °C. A solution of intermediate 2 (20.11 g, 79.4 mmol) in THF (30 mL) was added slowly and the reaction mixture was gradually warmed to room temperature and allowed to stir over the weekend. The reaction mixture was concentrated under reduced pressure to give a brown solid. The brown residue was dissolved in MeOH (250 mL) with heat / sonication and treated with water (50 mL). The precipitate formed was filtered under reduced pressure, washed with water, and air-dried. The solid was dissolved in EtOAc (200 mL) with heat / sonication, washed with water (100 mL), and diluted with MgSO 4 It was dried over, filtered and concentrated under reduced pressure to give N-(5-bromo-3-methoxy-pyrazin-2-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (Intermediate 6, 13.2 g, 49%) as a brown solid. 1 H NMR (600 MHz, chloroform-d) δ 8.00 (s, 1H), 7.78 (s, 1H), 7.62-7.57 (m, 3H), 7.57-7.52 (m, 2H), 3.68 (s, 3H), 2.82 (s, 3H). m / z 390.9 81 [M+H] for Br + .

[0547] Process 2 In a 5 mL microwave vial, add Intermediate 6 (100 mg, 0.26 mmol), Na 2 CO 3(54 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), 1-methyl-1H-pyrazole-4-boronic acid (49 mg, 0.39 mmol), ethylene glycol dimethyl ether (2 mL) and water (1 mL). The vial was sealed, flushed with nitrogen, degassed and then heated at 120 °C in a microwave for 1 h. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the phases were separated. The organic phase was washed with brine (20 mL) and MgSO 4 The mixture was dried over hexane, filtered through Celite, and concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, elution with a 0-80% EtOAc / PE gradient) to give N-[3-methoxy-5-(1-methylpyrazol-4-yl)pyrazin-2-yl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (50 mg, 48% yield) as a yellow solid. 1 H NMR (600 MHz, chloroform-d) δ 8.09 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.66-7.62 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 3.94 (s, 3H), 3.72 (s, 3H), 2.83 (s, 3H). m / z 391.0 [M+H] + .

[0548] Example 20 N-[6-(1,3-dimethylpyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (34 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-10% MeOH / DCM gradient) and further purification by flash silica column chromatography on an ISCO system (0-100% EtOAc / PE gradient) gave N-[6-(1,3-dimethylpyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (37 mg, 69% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.60 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.67-7.54 (m, 6H), 6.96 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 2.82 (s, 3H), 2.51 (s, 3H). m / z 404.0 [M+H] + .

[0549] Example 21 N-[6-(1-isopropylpyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (37 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-60% EtOAc / PE gradient) to give N-[6-(1-isopropylpyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (33 mg, 58% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.60 (d, J = 8.1 Hz, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.65-7.58 (m, 3H), 7.57-7.54 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 4.50 (heptet, J = 6.7 Hz, 1H), 3.65 (s, 3H), 2.81 (s, 3H), 1.53 (d, J = 6.7 Hz, 6H). m / z 418.0 [M+H] + .

[0550] Example 22 N-[2-Methoxy-6-(1,3,5-trimethylpyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (37 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction was then charged with Pd-118 (8 mg, 0.01 mmol), sealed and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-90% EtOAc / PE gradient) to give N-[2-methoxy-6-(1,3,5-trimethylpyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 32%). 1 H NMR (600MHz, chloroform-d)δ 8.64(d,J=8.1Hz, 1H), 7.70(s,1H), 7.66-7.59(m,3H), 7.59-7.55(m,2H), 6.86(d, J=8.1Hz, 1H), 3.75(s,3H), 3.64(s,3H), 2.83(s,3H), 2.40(s,3H), 2.37(s,3H).m / z 418.0[M+H] + .

[0551] Example 23 N-[2-Methoxy-6-(2-methylpyrazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (32 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-90% EtOAc / PE gradient) to give N-[2-methoxy-6-(2-methylpyrazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (38 mg, 72% yield). 1 H NMR (600MHz, chloroform-d)δ 8.71(d,J=8.1Hz, 1H), 7.75(s,1H), 7.66-7.61(m,3H), 7.60-7.57(m,2H), 7.45(d,J=1.9Hz, m / z 390.0[M+H] + .

[0552] Example 24 N-[2-Methoxy-6-(3-methyl-4-pyridyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and (3-methyl-4-pyridyl)boronic acid (21 mg, 0.15 mmol) in 1,4-dioxane (2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system and further purification by mass-directed preparative HPLC gave N-[2-methoxy-6-(3-methyl-4-pyridyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (5 mg, 9% yield). 1 H NMR (600MHz, chloroform-d)δ 8.75(d,J=8.0Hz, 1H), 8.57-8.41(m,2H), 7.79(s,1H), 7.67-7.61(m,3H), 7.60-7.55(m,2H) ), 7.33(d,J=5.0Hz, 1H), 7.09(d,J=8.1Hz, 1H), 3.64(s,3H), 2.84(s,3H), 2.42(s,3H).m / z 401.0[M+H] + .

[0553] Example 25 N-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A 5 mL microwave vial was charged with Intermediate 1 (50 mg, 0.13 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (34 mg, 0.15 mmol), KOAc (51 mg, 0.52 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was degassed for 10 min before adding Pd-118 (8.4 mg, 0.01 mmol) and sealing the vial and heating at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure, redissolved in DCM and passed through a hydrophobic frit. The filtrate was concentrated under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, elution with a 0-10% MeOH / EtOAc gradient) to give N-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 33% yield) as a colorless solid. 1 H NMR (600MHz, chloroform-d)δ 8.64(d,J=8.1Hz, 1H), 7.70(s,1H), 7.66-7.63(m,2H), 7.63-7.59(m,1H), 7.57(dd,J=8.1, 6. m / z 404.0[M+H] + .

[0554] Example 26 N-[2-Methoxy-6-(1H-pyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (30 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-10% MeOH / DCM gradient) and trituration of the resulting solid with ether afforded N-[2-methoxy-6-(1H-pyrazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (35 mg, 69% yield). 1 H NMR (600 MHz, chloroform-d) δ 8.63 (d, J = 8.1 Hz, 1H), 7.99 (s, 2H), 7.70 (s, 1H), 7.66-7.59 (m, 3H), 7.58-7.55 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 3.66 (s, 3H), 2.83 (s, 3H). m / z 374.0 [MH] - .

[0555] Example 27 N-[6-[6-(hydroxymethyl)-3-pyridyl]-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Step 1 - Synthesis of intermediate 7-N-[2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide To a microwave vial under an inert atmosphere was added Intermediate 1 (1.50 g, 3.86 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.28 g, 5.02 mmol) and anhydrous 1,4-dioxane (44 mL). The solution was degassed with nitrogen for 15 min and then washed with Pd(dppf)Cl. 2 (complex with DCM, 315 mg, 0.380 mmol) and KOAc (1.14 g, 11.59 mmol) were added quickly. The mixture was degassed again with nitrogen for 15 min and then heated to 80 °C using an aluminum heating block for 1 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (30 mL). The solution was washed with water (20 mL) and diluted with MgSO 4 After drying over 100° C., filtration and concentration under reduced pressure gave the crude product, which was purified by trituration with PE (60 mL). The suspension was allowed to settle, the supernatant was removed and the trituration procedure was repeated with additional PE (20 mL). The resulting solid was dried under reduced pressure to give N-[2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (Intermediate 7, 1.69 g, 95%) as a brown powder. 1 H NMR (500 MHz, chloroform-d) δ 8.60 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.64-7.57 (m, 3H), 7.57-7.50 (m, 2H), 7.45 (dd, J = 7.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.81 (s, 3H), 1.34 (s, 12H). m / z 354.0 [M+H for boronic acid] + .

[0556] Process 2 A solution of KF (76.1 mg, 1.31 mmol), (5-bromopyrid-2-yl)methanol (82.1 mg, 0.440 mmol) and intermediate 7 (200 mg, 0.459 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (28.5 mg, 0.044 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir at room temperature overnight. LCMS analysis showed the reaction was nearly complete the next morning, so the reaction mixture was heated to 45 °C for 4 h to drive the reaction to completion. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous phase was back-extracted with DCM (3 x 20 mL) and the combined organic extracts were washed with MgSO 4 Drying over, filtration and concentration under reduced pressure gave the crude product which was purified by automated column chromatography (12 g silica, gradient 0-10% MeOH / DCM) to give N-[6-[6-(hydroxymethyl)-3-pyridyl]-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide as a grey solid (102 mg, 56% yield); 1 H NMR (500MHz, chloroform-d)δ 9.13(s,1H), 8.73(d,J=8.1Hz, 1H), 8.21(dd,J=8.2, 2.2Hz, 1H), 7.77(s,1H), 7.66-7.61(m,3H), 7.61 -7.55(m,2H), 7.35(d,J=8.1Hz, 1H), 7.29(d,J=8.2Hz, 1H), 4.79(s,2H), 3.71(s,3H), 2.84(s,3H).m / z 417.1[M+H] + .

[0557] Example 28 N-[2-Methoxy-6-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (50 mg, 0.13 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (36 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction mixture was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was reduced by Genevac, then DCM and water were added. The mixture was stirred vigorously and then passed through a phase separator. The solvent was evaporated and the residue was purified by flash silica column chromatography on an ISCO system (0-10% MeOH / DCM gradient) and trituration of the resulting solid with ether afforded N-[2-methoxy-6-(1-methyl-6-oxo-3-pyridyl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (38 mg, 67%). 1 H NMR (600MHz, chloroform-d)δ 8.67(d,J=8.1Hz, 1H), 7.98(d,J=2.5Hz, 1H), 7.90(dd,J=9.5, 2.6Hz, 1H), 7.72(s,1H), 7.67-7.60(m,3H), 7.59-7.56(m, 2H), 7.06(d,J=8.2Hz, 1H), 6.63(d,J=9.5Hz, 1H), 3.67(s,3H), 3.63(s,3H), 2.83(s,3H).m / z 417.0[M+H] +

[0558] Example 29 N-(5-imidazo[1,2-a]pyridin-5-yl-3-methoxy-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] To a solution of intermediate 4 (100 mg, 0.24 mmol) in 1,4-dioxane (3 mL), 2 Pin 2(80.8 mg, 0.32 mmol) and KOAc (72 mg, 0.73 mmol) were added. The reaction mixture was degassed by bubbling nitrogen gas for 3 min and then Pd(dppf)Cl 2 (complex with DCM, 10 mg, 0.01 mmol) was added. The reaction mixture was heated at 90 °C for 1 h. The reaction mixture was concentrated and the residue was dissolved in EtOAc (10 mL) and washed with water (3 mL). The organic layer was removed and MgSO 4 The mixture was dried over 100° C., filtered, and concentrated under reduced pressure. The resulting crude material (65 mg, 0.15 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). KOAc (44 mg, 0.45 mmol) and 5-bromoimidazo[1,2-a]pyridine (35 mg, 0.18 mmol) were added and the solution was degassed with nitrogen for 15 min. Pd(dppf)Cl 2 (6.1 mg, 0.01 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C overnight. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-(5-imidazo[1,2-a]pyridin-5-yl-3-methoxy-2-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (17 mg, 25% yield) as a white solid. 1 H NMR (600MHz, chloroform-d)δ 8.29(s,1H), 8.06(s,1H), 7.70-7.62(m,4H), 7.62-7.52(m,4H), 7.25-7.23(m ,1H), 7.21-7.19(m,1H), 6.72(d,J=6.9Hz, 1H), 3.56(s,3H), 2.86(s,3H).m / z 426.11[M+H] + .

[0559] Example 30 N-(6-imidazo[1,2-a]pyridin-5-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (31.5 mg, 0.32 mmol), 5-bromoimidazo[1,2-a]pyridine (54 mg, 0.28 mmol) and intermediate 7 (105 mg, 0.24 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (8.4 mg, 0.01 mmol) was quickly added, the solution was degassed again for 10 min, and the mixture was allowed to stir at 90 °C for 40 min. Water (10 mL) was then added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-(6-imidazo[1,2-a]pyridin-5-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (28 mg, 24% yield) as a pale yellow solid. 1 H NMR (600MHz, chloroform-d)δ 8.83(d,J=8.1Hz, 1H), 8.39(s,1H), 7.85(s,1H), 7.66(d,J=6.6Hz, 5H), 7.61(d,J=7.3Hz, 2H), 7 .36(d,J=8.1Hz, 1H), 7.23(d,J=8.3Hz, 1H), 7.04(d,J=7.0Hz, 1H), 3.69(s,3H), 2.86(s,3H).m / z 426.0[M+H] + .

[0560] Example 31 N-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-3-methoxy-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] To a microwave vial was added Intermediate 4 (50 mg, 0.13 mmol), 1,4-dioxane (2.0 mL), water (0.2 mL), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34.3 mg, 0.15 mmol) and KOAc (25.3 mg, 0.26 mmol). The reaction mixture was degassed with nitrogen for 3 min before adding Pd-118 (4.2 mg, 0.010 mmol). The vial was sealed and heated at 80° C. overnight. After cooling, the mixture was concentrated under reduced pressure and the crude product was directly purified by automated column chromatography (12 g silica, elution with a 2-3% MeOH / DCM gradient) to give N-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-3-methoxy-2-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (12.0 mg, 20% yield) as a pale yellow solid. 1 H NMR (600 MHz, chloroform-d) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.58-7.54 (m, 3H), 6.89 (s, 1H), 3.55 (s, 3H), 2.83 (s, 3H), 2.26 (s, 6H). m / z 404.1 [M+H] + .

[0561] Example 32 N-[2-Methoxy-6-(4-methoxy-1H-indazol-6-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A 5 mL microwave vial was charged with intermediate 7 (70 mg, 0.16 mmol), 6-bromo-4-methoxy-1H-indazole (36 mg, 0.16 mmol), KOAc (32 mg, 0.32 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was degassed with nitrogen before adding Pd-118 (13 mg, 0.02 mmol) and sealing the vial and heating at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to give N-[2-methoxy-6-(4-methoxy-1H-indazol-6-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 23% yield) as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 13.14(s,1H), 9.45(s,1H), 8.36(d,J=7.9Hz, 1H), 8.03(s,1H), 7.79(s,1H), 7.70(dd,J=12. 2, 7.5Hz, 3H), 7.55(d,J=7.6Hz, 3H), 7.22(s,1H), 4.00(s,3H), 3.93(s,3H), 2.66(s,3H).m / z 456.0[M+H] + .

[0562] Example 33 N-[6-(3-amino-1H-indazol-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (31.5 mg, 0.32 mmol), 5-bromo-1H-indazol-3-amine (34 mg, 0.16 mmol) and intermediate 7 (70 mg, 0.16 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (11.2 mg, 0.01 mmol) was quickly added, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C for 3 h. Then water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO4 It was dried over 100 ml, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[6-(3-amino-1H-indazol-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10.8 mg, 14% yield) as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 11.47(s,1H), 9.44(s,1H), 8.55-8.13(m,1H), 7.90(s,1H), 7.72(t,J=8.4Hz, 3H), 7.6 1(d,J=12.4Hz, 2H), 7.54(d,J=7.9Hz, 3H), 5.36(s,2H), 3.92(s,3H), 2.65(s,3H).m / z 441.1[M+H] + .

[0563] Example 34 N-[6-(1H-indazol-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A 5 mL microwave vial was charged with intermediate 7 (70 mg, 0.16 mmol), 6-bromo-1H-indazole (32 mg, 0.16 mmol), KOAc (32 mg, 0.32 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was degassed with nitrogen before adding Pd-118 (13 mg, 0.02 mmol) and sealing the vial and heating at 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography to give N-[6-(1H-indazol-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (13.3 mg, 18% yield) as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6)δ 13.15(s,1H), 9.46(s,1H), 8.37(s,1H), 8.20(s,1H), 8.08(s,1H), 7.82(s,2H), 7.71(d m / z 426.0[M+H] + .

[0564] Example 35 N-[6-(3-amino-1H-indazol-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (31.5 mg, 0.32 mmol), 6-bromo-1H-indazol-3-amine (34 mg, 0.16 mmol) and intermediate 7 (70 mg, 0.16 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (11.2 mg, 0.01 mmol) was quickly added, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C for 3 h. Then water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over 100 ml, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[6-(3-amino-1H-indazol-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10.8 mg, 14% yield) as a pale yellow solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 11.47(s,1H), 9.44(s,1H), 8.55-8.13(m,1H), 7.90(s,1H), 7.72(t,J=8.4Hz, 3H), 7.6 1(d,J=12.4Hz, 2H), 7.57-7.51(m,Hz, 3H), 5.36(s,2H), 3.92(s,3H), 2.65(s,3H).m / z 441.1[M+H] + .

[0565] Example 36 N-[6-(2-chloropyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (2.00 g, 5.15 mmol) in 1,4-dioxane (5 mL) was sparged with nitrogen for 10 min. The reaction was then charged with Pd-118 (335 mg, 0.52 mmol) and KF (1.50 g, 25.76 mmol) in one portion. The reaction was sealed and sparged with nitrogen for an additional 10 min before heating at 80° C. A degassed suspension of (2-chloropyrimidin-5-yl)boronic acid (1.63 g, 10.30 mmol) in 1,4-dioxane (15 mL) was added dropwise to the hot solution over 12 h using a syringe pump. After the addition was complete, the reaction was held at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and taken up in DCM (30 mL). Water (30 mL) was added and the organics were separated using a phase separator. The organics were concentrated under reduced pressure and the residue was purified by flash silica column chromatography on an ISCO system (24 g silica, elution with a 0-50% PE / EtOAc gradient, then flushed with a 0-10% MeOH / DCM gradient) to give N-[6-(2-chloropyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (159 mg, 7% yield) as a yellow solid. 1 H NMR (600MHz, chloroform-d)δ 9.12(d,J=1.1Hz, 2H), 8.79(d,J=8.1Hz, 1H), 7.80(s,1H), 7.67-7.61(m,3 H), 7.61-7.56(m,2H), 7.35(d,J=8.2Hz, 1H), 3.69(s,3H), 2.84(s,3H).m / z 421.0[M+H] + .

[0566] Example 37 N-(6-Methoxy-[2,3'-bipyridin]-5-yl)-5-methyl-3-phenylisoxazole-4-carboxamide [ka] A 10 mL microwave vial was charged with N-(6-bromo-2-methoxypyridin-3-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (50.0 mg, 0.13 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (31.7 mg, 0.15 mmol), KOAc (50.6 mg, 0.52 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was degassed with nitrogen for 10 min. Pd-118 (8.4 mg, 0.01 mmol) was added quickly and the mixture was further degassed with nitrogen before stirring at 80 °C overnight. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2 x 10 mL). The organic layer was washed with MgSO 4 The mixture was dried over 100 ml of hexane, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (12 g, silica, 0-90% EtOAc / PE over 25 CV). The CVs containing the product were combined and evaporated under reduced pressure. The precipitate was then dried under reduced pressure at 40° C. to give N-(6-methoxy-[2,3′-bipyridin]-5-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (40.0 mg, 76%) as a pale yellow solid. 1 H NMR (600MHz, chloroform-d)δ 9.28-9.14(m,1H), 8.74(d,J=8.1Hz, 1H), 8.57(dt,J=4.8, 1.3Hz, 1H), 8.21(dq, J=8.1, 1.6Hz, 1H), 7.78(s,1 M / z 387.0[M+H] + .

[0567] Example 38 N-(6-imidazo[1,2-a]pyrazin-8-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] To a 5 mL microwave vial was added 8-chloroimidazo[1,2-a]pyrazine (21.2 mg, 0.14 mmol), intermediate 7 (60 mg, 0.14 mmol), KOAc (27.0 mg, 0.28 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The mixture was degassed with nitrogen for 3 min before adding Pd-118 (11.3 mg, 0.02 mmol). The vial was sealed and heated at 80° C. overnight. The mixture was concentrated under reduced pressure and the residue was purified by automated column chromatography to give N-(6-imidazo[1,2-a]pyrazin-8-yl-2-methoxy-3-pyridyl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (8.8 mg, 15%). 1 H NMR (600 MHz, DMSO-d 6 )δ 9.46(s,1H), 8.64(d,J=4.5Hz, 1H), 8.50(s,1H), 8.40(d,J=8.0Hz, 1H), 8.21(s,1H), 8.02(d,J =4.5Hz, 1H), 7.86(s,1H), 7.78-7.65(m,2H), 7.63-7.49(m,3H), 3.88(s,3H), 2.67(s,3H).m / z 427.1[M+H] + .

[0568] Example 39 N-[6-(5-amino-6-methoxy-pyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (27 mg, 0.28 mmol), 5-bromo-3-methoxy-pyrazin-2-amine (28 mg, 0.14 mmol) and intermediate 7 (60 mg, 0.14 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (11.2 mg, 0.01 mmol) was quickly added, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C for 3 h. Then water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over 100 ml, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[6-(5-amino-6-methoxy-pyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10 mg, 16% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 9.37(s,1H), 8.38(s,1H), 8.28(d,J=7.9Hz, 1H), 7.70(d,J=6.9Hz, 2H), 7.64(d,J=8. 1Hz, 1H), 7.58-7.50(m,3H), 6.62(s,2H), 3.99(s,3H), 3.86(s,3H), 2.65(s,3H).m / z 433.1[M+H] + .

[0569] Example 40 N-[6-(6-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KOAc (27 mg, 0.28 mmol), 5-bromopyrazin-2-amine (24 mg, 0.14 mmol) and intermediate 7 (60 mg, 0.14 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was degassed with nitrogen for 15 min. Pd-118 (11.2 mg, 0.01 mmol) was quickly added, the solution was degassed again for 10 min, and the mixture was allowed to stir at 80 °C for 3 h. Then water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine and MgSO 4 It was dried over hexane, filtered and concentrated to dryness. Purification by flash silica column chromatography afforded N-[6-(6-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 32% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 9.42(s,1H), 8.57(s,1H), 8.43(s,1H), 7.87(s,1H), 7.79(d,J=8.1Hz, 1H), 7.69 (d,J=7.1Hz, 2H), 7.62-7.49(m,3H), 6.52(s,2H), 3.88(s,3H), 2.65(s,3H).m / z 403.1[M+H] + .

[0570] Example 41 N-(2-Methoxy-6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-5-methyl-3-phenylisoxazole-4-carboxamide [ka] To a solution of intermediate 1 (190 mg, 0.49 mmol) in dimethoxyethane (3 mL), (2-methoxypyrimidin-5-yl)boronic acid (113 mg, 0.74 mmol), Na 2 CO 3 (130 mg, 1.22 mmol) and Pd(dppf)Cl 2(combined with DCM, 20 mg, 0.03 mmol) was added successively. The resulting mixture was heated at 90° C. overnight. After completion of the reaction, the volatiles were evaporated under reduced pressure. The residue was dissolved in water (3 mL) and extracted with DCM (3×1 mL). The combined organic layers were separated and washed with Na 2 SO 4 Drying over and concentration under reduced pressure gave the crude product which was further purified on a C18 HPLC (0-100% MeOH / water gradient) to give N-(2-methoxy-6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (92 mg, 45% yield). 1H NMR (600MHz, chloroform-d) δ 9.04(s,2H), 8.78-8.65(m,1H), 7.76(s,1H), 7.66-7.61(m,3H), 7.61-7.55(m,2H), 7.25(s,1H), 4.06(s,3H), 3.69(s,3H), 2.84(s,3H). m / z 418.0[M+H] + .

[0571] Example 42 N-(6-Methoxy-[2,4'-bipyridin]-5-yl)-5-methyl-3-phenylisoxazole-4-carboxamide [ka] A 10 mL microwave vial was charged with intermediate 1 (50.0 mg, 0.13 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (31.7 mg, 0.15 mmol), KOAc (50.6 mg, 0.52 mmol), 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was degassed with nitrogen for 10 min. Pd-118 (8.4 mg, 0.01 mmol) was added quickly and the mixture was further degassed with nitrogen before stirring at 80 °C overnight. The reaction mixture was then concentrated under reduced pressure. The dark residue was dissolved in DCM (20 mL) and washed with water (2 x 10 mL). The organic layer was washed with MgSO 4The residue was purified by flash column chromatography (12 g, silica, elution with 0-90% EtOAc / PE) to give N-(6-methoxy-[2,4'-bipyridin]-5-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (26.0 mg, 50%) as a brown solid. 1 H NMR (600MHz, chloroform-d)δ 8.76(d,J=8.1Hz, 1H), 8.71-8.57(m,2H), 7.90-7.74(m,3H), 7.67-7.61(m, 3H), 7.62-7.55(m,2H), 7.44(d,J=8.1Hz, 1H), 3.71(s,3H), 2.84(s,3H).m / z 387.0[M+H] + .

[0572] Example 43 N-[6-(2-aminopyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KF (76.1 mg, 1.31 mmol), 2-amino-5-bromopyrimidine (76.0 mg, 0.44 mmol) and intermediate 7 (200 mg, 0.44 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (28.5 mg, 0.04 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir overnight at room temperature. LCMS analysis showed the reaction was nearly complete the next morning, but both starting materials were still observable, so the mixture was heated at 45 °C and monitored by LCMS analysis. LCMS analysis after 4 h showed complete consumption of starting material. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous phase was back-extracted with DCM (3 x 20 mL). The combined organic extracts were washed with MgSO 4Drying over, filtration and concentration under reduced pressure gave the crude product which was purified by automated column chromatography (12 g silica, elution with a 0-10% MeOH / DCM gradient) to give N-[6-(2-aminopyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (114 mg, 64% yield) as a beige solid. 1 H NMR (500 MHz, DMSO-d 6 )δ 9.45(s,1H), 8.90(s,2H), 8.27(d,J=7.8Hz, 1H), 7.77-7.67(m,2H), 7.60-7. 52(m,3H), 7.49(d,J=8.1Hz, 1H), 6.96(s,2H), 3.89(s,3H), 2.66(s,3H).m / z 403.0[M+H] + .

[0573] Example 44 N-(5-imidazol-1-yl-3-methoxy-pyrazin-2-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of L-proline (4.5 mg, 0.04 mmol) in DMSO (1.5 mL) was added with copper(I) iodide (7.4 mg, 0.04 mmol), K 2 CO 3 (107 mg, 0.77 mmol) and Intermediate 6 (100 mg, 0.26 mmol) were added. The reaction mixture was degassed with nitrogen before imidazole (17 mg, 0.26 mmol) was added. The reaction mixture was heated at 80 °C for 16 h, then diluted with EtOAc (30 mL) and filtered through Celite. The filtrate was washed with water (30 mL), brine (30 mL) and MgSO 4The residue was dried over silica, filtered and concentrated under reduced pressure. The residue was adsorbed onto silica and purified on a Shimadzu MDAP (elution with a gradient of 10-95% MeCN / water + 0.1% formic acid) to give N-(5-imidazol-1-yl-3-methoxy-pyrazin-2-yl)-5-methyl-3-phenyl-isoxazole-4-carboxamide (38 mg, 37% yield) as a cream solid. 1 H NMR (600MHz, chloroform-d)δ 8.17(s,1H), 8.07(s,1H), 7.88(s,1H), 7.64-7.59(m,3H), 7.57(t,J=7.5Hz,2H), 7.26(d,J=1.3Hz, 2H), 3.76(s,3H), 2.85(s,3H).m / z 377.0[M+H] + .

[0574] Example 45 N-(6-(2-(dimethylamino)pyrimidin-5-yl)-2-methoxypyridin-3-yl)-5-methyl-3-phenylisoxazole-4-carboxamide [ka] A 10 mL microwave vial was charged with Example 36 (30.0 mg, 0.07 mmol), dimethylamine (71.1 μL, 0.14 mmol), DIPEA (24.8 μL, 0.14 mmol) and THF (1.5 mL). The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (4 g, silica, elution with a 0-100% EtOAc / PE gradient). The CVs containing the product were combined and evaporated under reduced pressure to give N-(6-(2-(dimethylamino)pyrimidin-5-yl)-2-methoxypyridin-3-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (14.0 mg, 41% yield) as a colorless solid. 1H NMR (600MHz, chloroform-d)δ 8.89(s,2H), 8.65(d,J=8.1Hz, 1H), 7.70(s,1H), 7.66-7.59(m,3H), 7.57(dd,J=7 m / z 431.0[M+H] + .

[0575] Example 46 N-[2-Methoxy-6-(1,2,4-triazol-1-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of intermediate 1 (100 mg, 0.25 mmol) in DMSO (2 mL) was added with L-proline (3 mg, 0.026 mmol), copper(I) iodide (5 mg, 0.026 mmol), 1,2,4-triazole (21.5 mg, 0.31 mmol) and K 2 CO 3 (107 mg, 0.77 mmol) was added. The reaction mixture was evaporated and backfilled with nitrogen three times, then heated at 120 °C overnight. The reaction mixture was diluted with EtOAc (10 mL) and filtered over Celite. The clear filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was then diluted with MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 35% EtOAc / PE gradient) afforded N-[2-methoxy-6-(1,2,4-triazol-1-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (27 mg, 26% yield) as a white solid. 1H NMR (600 MHz, chloroform-d) δ 8.93 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.66-7.62 (m, 3H), 7.61-7.56 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 3.68 (s, 3H), 2.84 (s, 3H). m / z 377.0 [M+H] + .

[0576] Example 47 N-[2-Methoxy-6-[2-(methylamino)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] To a solution of Example 36 (50 mg, 0.12 mmol) in THF (2 mL) was added a 2M solution of methylamine in THF (0.18 mL, 0.36 mmol) and DIPEA (0.06 mL, 0.36 mmol). The reaction was stirred at 70° C. overnight. Further portions of methylamine (0.18 mL, 0.36 mmol) and DIPEA (0.06 mL, 0.36 mmol) were added and the reaction continued for a further 7 h. The reaction mixture was concentrated under reduced pressure and the resulting solid was partitioned between chloroform and water. The solution was passed through a hydrophobic frit and the filtrate was evaporated under reduced pressure. The residue was then purified by flash silica column chromatography on an ISCO system (using a 0-10% MeOH / DCM gradient) to give N-[2-methoxy-6-[2-(methylamino)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (28 mg, 54% yield). 1 H NMR (600MHz, chloroform-d)δ 8.86(s,2H), 8.68(d,J=8.4Hz, 1H), 7.72(s,1H), 7.66-7.60(m,3H), 7.57(t,J=7.4Hz, 2H) , 7.16(d,J=8.2Hz, 1H), 5.22(s,1H), 3.67(s,3H), 3.05(d,J=5.0Hz, 3H), 2.83(s,3H).m / z 417.0[M+H] + .

[0577] Example 48 N-[6-(2-ethoxypyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A solution of KF (76.1 mg, 1.31 mmol), 5-bromo-2-ethoxy-pyrimidine (93.3 mg, 0.46 mmol) and intermediate 7 (200 mg, 0.46 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 15 min. Pd-118 (28.5 mg, 0.044 mmol) was added quickly, the solution was degassed again for 10 min, and the mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (3×20 mL) and brine (20 mL). The organic extract was washed with MgSO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure to give the crude product which was purified by automated column chromatography (12 g, silica, gradient of 0-10% MeOH:DCM) to give the partially purified product. Trituration in MeOH (5 mL) was performed, the solid was allowed to settle and the supernatant was removed by pipette. The solid was further dried in a vacuum oven at 40° C. for 3 hours to give N-[6-(2-ethoxypyrimidin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (95 mg, 48%) as a beige solid. 1 H NMR (500MHz, chloroform-d)δ 9.04(s,2H), 8.74(d,J=8.2Hz, 1H), 7.77(s,1H), 7.69-7.63(m,3H), 7.63-7.57(m,2H), 7.3 0-7.24(m,2H), 4.48(q, J=7.1Hz, 2H), 3.70(s,3H), 2.85(s,3H), 1.47(t,J=7.1Hz, 3H).m / z 432.1[M+H] + .

[0578] Example 49 N-[6-(1H-benzotriazol-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A microwave vial was charged with Intermediate 1 (60 mg, 0.15 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzotriazole (37.8 mg, 0.15 mmol), 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. KOAc (45 mg, 0.45 mmol) and Pd-118 (10 mg, 0.015 mmol) were added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120 °C for 30 min. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4 The mixture was dried over 100 ml and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a gradient of 3% MeOH / DCM) afforded N-[6-(1H-benzotriazol-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (10 mg, 14% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 9.47(s,1H), 8.55(s,1H), 8.39(s,1H), 8.18(d,J=8.6Hz, 1H), 7.96(s,1 H), 7.80-7.69(m,3H), 7.61-7.50(m,2H), 3.94(s,3H), 2.66(s,3H).m / z 427.0[M+H] + .

[0579] Example 50 N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A microwave vial was charged with Intermediate 7 (60 mg, 0.137 mmol), 5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (29.3 mg, 0.140 mmol), 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. 2 CO 3 (146 mg, 1.37 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4 The mixture was dried over ice and concentrated to dryness under reduced pressure. 3 Purification by flash silica column chromatography in aqueous solution containing 25% MeOH / DCM gradient elution) afforded N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (21 mg, 33% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 9.51(s,1H), 8.70(d,J=8.0Hz, 1H), 8.48(s,1H), 7.77-7.65(m,3H), 7.60-7. 49(m,4H), 7.41(d,J=8.6Hz, 1H), 6.13(s,2H), 3.89(s,3H), 2.67(s,3H).m / z 442.1[M+H] + .

[0580] Example 51 N-[2-Methoxy-6-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A microwave vial was charged with Intermediate 7 (60 mg, 0.14 mmol), 5-bromo-1-methyl-1H-1,2,4-triazole (21.2 mg, 0.13 mmol), 1,4-dioxane (2 mL) and water (1 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. 2 CO 3 (146 mg, 1.37 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4 The mixture was dried over hexane and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-[2-methoxy-6-(1-methyl-1,2,4-triazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (17 mg, 32% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 )δ 9.41(s,1H), 8.51(s,1H), 8.38(s,1H), 7.75-7.63(m,3H), 7.58-7.50(m,3H), 3.92(s,3H), 3.84(s,3H), 2.65(s,3H).m / z 391.0[M+H] + .

[0581] Example 52 N-[2-Methoxy-6-(2-methyl-1,2,4-triazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A microwave vial was charged with Intermediate 7 (60 mg, 0.14 mmol), 5-bromo-1-methyl-1H-1,2,4-triazole (21.2 mg, 0.13 mmol), 1,4-dioxane (2 mL) and water (1 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. 2 CO 3 (146 mg, 1.37 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4 The mixture was dried over 100 ml and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-[2-methoxy-6-(2-methyl-1,2,4-triazol-3-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (8 mg, 14% yield) as a white solid. 1 H NMR (600 MHz, chloroform-d) δ 8.82 (d, J = 8.2 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.67-7.63 (m, 3H), 7.62-7.56 (m, 2H), 4.30 (s, 3H), 3.67 (s, 3H), 2.84 (s, 3H). m / z 391.2 [M+H] + .

[0582] Example 53 N-[2-Methoxy-6-[2-(trifluoromethyl)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Process 1 To a solution of 5-bromo-2-(trifluoromethyl)pyrimidine (100 mg, 0.44 mmol) in 1,4-dioxane (5 mL),2 Pin 2 (145 mg, 0.57 mmol) was added. The reaction mixture was degassed with nitrogen for 10 min, and then Pd(dppf)Cl 2 (combined with DCM, 18 mg, 0.02 mmol) and KOAc (130 mg, 1.32 mmol) were added. The reaction mixture was degassed for an additional 10 min and then heated to 90 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL) and washed with water (10 mL). The organic layer was removed and MgSO 4 After drying on, it was evaporated to dryness and the resulting solid was triturated with ether and used directly in the next step without further purification.

[0583] Process 2 A solution of intermediate 1 (50 mg, 0.13 mmol) and crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyrimidine (42 mg, 0.15 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was treated with KOAc (51 mg, 0.52 mmol) and the mixture was sparged with nitrogen for 10 min. The reaction was then charged with Pd-118 (8 mg, 0.01 mmol), sealed, and heated at 80° C. overnight. The reaction mixture was concentrated under reduced pressure and taken up in DCM (10 mL). Water (10 mL) was added and the organics were separated using a phase separator. The organics were then concentrated under reduced pressure and the residue was purified by flash silica column chromatography on an ISCO system (12 g silica, elution with a 0-50% PE / EtOAc gradient) to give N-[2-methoxy-6-[2-(trifluoromethyl)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (32 mg, 52% yield). 1H NMR (600 MHz, chloroform-d) δ 9.38 (s, 2H), 8.83 (d, J = 8.1 Hz, 1H), 7.83 (s, 1H), 7.68-7.62 (m, 3H), 7.62-7.58 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H), 2.85 (s, 3H). m / z 456.0 [M+H] + .

[0584] Example 54 N-[6-(3-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Na in 1,4-dioxane (2 mL) and water (1 mL) 2 CO 3 A solution of Intermediate 7 (36 mg, 0.33 mmol), 3-bromopyrazin-2-amine (22 mg, 0.13 mmol) and Intermediate 7 (50 mg, 0.12 mmol) was degassed with nitrogen for 15 min. Pd-118 (8.4 mg, 0.013 mmol) was added quickly, the solution was degassed again for 10 min and the mixture was allowed to stir at 120 °C for 1 h. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine (10 mL) and MgSO 4 The mixture was dried over hexane, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (elution with a 2% MeOH / DCM gradient) afforded N-[6-(3-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (18 mg, 37% yield) as a yellow solid. 1H NMR (600MHz, chloroform-d)δ 8.83(d,J=8.4Hz, 1H), 8.11(d,J=8.5Hz, 1H), 7.97(d,J=2.4Hz, 1H), 7.94(d,J=2.4Hz, 1H), 7 .76(s,1H), 7.66-7.62(m,3H), 7.61-7.57(m,2H), 6.78(s,2H), 3.67(s,3H), 2.84(s,3H).m / z 403.1[M+H] + .

[0585] Example 55 N-[6-(5-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride [ka] Na in 1,4-dioxane (8 mL) and water (4 mL) 2 CO 3 A solution of Intermediate 7 (146 mg, 1.37 mmol), 5-bromopyrazin-2-amine (88 mg, 0.50 mmol) and Intermediate 7 (200 mg, 0.46 mmol) was degassed with nitrogen for 15 min. Pd-118 (33.6 mg, 0.046 mmol) was added quickly, the solution was degassed again for 10 min and the mixture was allowed to stir at 100 °C for 1 h. Water (10 mL) was added and the reaction mixture was extracted with DCM (3 x 10 mL). The combined organics were washed with brine (10 mL) and MgSO 4 The mixture was dried over ice, filtered, and concentrated to dryness. Purification by flash silica column chromatography on an ISCO system (2% MeOH / DCM gradient elution) gave the free base, which was subsequently treated with HCl (1.2 equiv.) to give N-[6-(5-aminopyrazin-2-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (23 mg, 11% yield) as a yellow solid. 1 H NMR (600 MHz, DMSO-d 6) δ 9.40(s,1H), 8.77(s,1H), 8.30(d,J=8.0Hz,1H), 7.91(d,J=1.4Hz,1H), 7.77-7.68(m,2H), 7.66(d,J=8.0Hz,1H), 7.60-7.47(m,3H), 6.73(s,2H), 3.87(s,3H), 2.64(s,3H). m / z 403.2 [M+H for free base] + .

[0586] Example 56 N-(3-Methoxy-5-(pyrimidin-5-yl)pyrazin-2-yl)-5-methyl-3-phenylisoxazole-4-carboxamide [ka] In a 5 mL microwave vial, intermediate 6 (30 mg, 0.08 mmol), pyrimidin-5-ylboronic acid (19 mg, 0.15 mmol), potassium phosphate tribasic (55 mg, 0.26 mmol) and Pd(dppf)Cl 2 (compounded with DCM, 10.6 mg, 0.01 mmol). The vial was sealed, purged with nitrogen, and then treated with 1,4-dioxane (2 mL) and water (0.2 mL). The reaction mixture was heated at 120 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (10 mL), washed with water (10 mL), brine (10 mL), and concentrated with MgSO 4 The mixture was dried over hexane, filtered and concentrated under reduced pressure. The residue was then purified by reverse-phase column chromatography (12 g, C18 cartridge, eluting with a 10-100% MeOH / water gradient) and the relevant fractions were concentrated to give an aqueous solution. The solution was extracted with EtOAc (20 mL) and the organic extract was washed with brine (10 mL) and MgSO 4 The solid was dried over ice, filtered, and the organics removed under reduced pressure. The solid was suspended in water (10 mL), filtered by vacuum filtration, and washed with water to give N-(3-methoxy-5-(pyrimidin-5-yl)pyrazin-2-yl)-5-methyl-3-phenylisoxazole-4-carboxamide (8.2 mg, 26% yield) as an off-white solid. 1H NMR (600 MHz, chloroform-d) δ 9.23 (s, 3H), 8.42 (s, 1H), 8.02 (s, 1H), 7.66-7.60 (m, 3H), 7.60-7.55 (m, 2H), 3.77 (s, 3H), 2.86 (s, 3H). m / z 389.1 [M+H] + .

[0587] Example 57 N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] A microwave vial was charged with Intermediate 7 (60 mg, 0.138 mmol), 6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (29 mg, 0.137 mmol), 1,4-dioxane (1.2 mL) and water (0.3 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. 2 CO 3 (146 mg, 1.37 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4 The mixture was dried over 100 ml and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a 3% MeOH / DCM gradient) afforded N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (20 mg, 31% yield) as a white solid. 1H NMR (600MHz, chloroform-d)δ 8.97(s,1H), 8.73(d,J=8.2Hz, 1H), 7.93(d,J=9.2Hz, 1H), 7.76(s,1H), 7.68-7.62(m,3H), 7.59 (t,J=7.6Hz, 2H), 7.41(d,J=9.2Hz, 1H), 7.27(s,1H), 4.50(s,2H), 3.70(s,3H), 2.84(s,3H).m / z 442.2[M+H] + .

[0588] Example 58 N-[2-Methoxy-6-(1,3,4-oxadiazol-2-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Process 1 A 5 mL microwave vial was charged with palladium(II) acetate (3.5 mg, 0.02 mmol) and tri-tert-butylphosphonium tetrafluoroborate (18 mg, 0.06 mmol). The vial was flushed with nitrogen and then charged with phenyl formate (126 mg, 1.03 mmol), Intermediate 1 (200 mg, 0.52 mmol) and Et 3 The vial was sealed, purged with nitrogen, and heated to 80° C. for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL) and the layers were separated. The organic layer was diluted with MgSO 4 The residue was adsorbed onto silica, filtered and concentrated under reduced pressure and purified by flash column chromatography (12 g silica, elution with a 0-90% EtOAc / PE gradient) to give phenyl 6-methoxy-5-[(5-methyl-3-phenyl-isoxazole-4-carbonyl)amino]pyridine-2-carboxylate (118 mg, 51%) as a colorless solid. 1H NMR (600MHz, chloroform-d)δ 8.82(d,J=8.1Hz, 1H), 7.93(s,1H), 7.91(d,J=8.1Hz, 1H), 7.67-7.61(m,3H), 7.61-7.55(m,2) H), 7.44-7.39(m,2H), 7.30-7.24(m,1H), 7.21(d,J=8.1Hz, 2H), 3.71(s,3H), 2.85(s,3H).m / z 430.0[M+H] + .

[0589] Process 2 A 5 mL microwave vial was charged with phenyl 6-methoxy-5-[(5-methyl-3-phenyl-isoxazole-4-carbonyl)amino]pyridine-2-carboxylate (80 mg, 0.19 mmol), hydrazine hydrate (0.01 mL, 0.22 mmol) and EtOH (2 mL). The vial was sealed and heated at 100° C. in a microwave for 30 min. The volatiles were removed under reduced pressure. The residue was adsorbed onto silica and purified by flash column chromatography (12 g silica, elution with a 0-90% EtOAc / PE gradient) to give N-[6-(hydrazinecarbonyl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (55 mg, 76%) as a colorless solid. 1 H NMR (600MHz, chloroform-d)δ 8.80(d,J=8.1Hz, 1H), 8.51(s,1H), 7.81(s,1H), 7.78(d,J=8.1Hz, 1H), 7.66- 7.60(m,3H), 7.58(t,J=7.5Hz, 2H), 4.02(s,2H), 3.61(s,3H), 2.83(s,3H).m / z 368.0[M+H] + .

[0590] Process 3 A 5 mL microwave vial was charged with N-[6-(hydrazinecarbonyl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (51 mg, 0.14 mmol) and trimethyl orthoformate (2.0 mL, 18 mmol), followed by p-toluenesulfonic acid monohydrate (2.6 mg, 0.01 mmol). The vial was sealed, purged with nitrogen, and heated in a microwave at 100° C. for 10 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with water (2 mL). The residue was adsorbed onto silica and purified by flash column chromatography (4 g silica, elution with a 0-90% EtOAc / PE gradient) to give N-[2-methoxy-6-(1,3,4-oxadiazol-2-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (42 mg, 77%) as a colorless solid. 1 H NMR (600 MHz, chloroform-d) δ 8.84 (d, J = 8.2 Hz, 1H), 8.46 (s, 1H), 7.88 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.67-7.61 (m, 3H), 7.61-7.57 (m, 2H), 3.71 (s, 3H), 2.84 (s, 3H). m / z 378.0 [M+H] + .

[0591] Example 59 N-[2-Methoxy-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] To Example 36 (30 mg, 0.07 mmol) in 2,2,2-trifluoroethanol (2 mL, 27.45 mmol) was added KOH (40 mg, 0.71 mmol) and the reaction was stirred for 2 h at 50° C. The reaction mixture was poured into water and the solid was isolated by filtration, washed with cold ether and dried in a vacuum oven to give N-[2-methoxy-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide (16 mg, 44% yield). 1 H NMR (600MHz, chloroform-d)δ 9.06(s,2H), 8.75(d,J=8.1Hz, 1H), 7.77(s,1H), 7.66-7.61(m,3H), 7.59(t,J=7.6 m / z 486.0[M+H] + .

[0592] Example 60 5-[6-Methoxy-5-[(5-methyl-3-phenyl-isoxazole-4-carbonyl)amino]-2-pyridyl]pyrimidine-2-carboxylic acid [ka] In a 25 mL microwave vial, Example 70 (187.6 mg, 0.42 mmol) was suspended in THF (9 mL) and water (3 mL). LiOH (176.7 mg, 4.21 mmol) was added and the reaction mixture was stirred at room temperature for 2.5 h. LCMS of the reaction mixture showed complete conversion of starting material to product. The organics were removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with 1 M HCl. The solid was filtered under reduced pressure and washed with water (10 mL) followed by MeOH (10 mL). The sample was further dried overnight at 40° C. in a vacuum oven to give 5-[6-methoxy-5-[(5-methyl-3-phenyl-isoxazole-4-carbonyl)amino]-2-pyridyl]pyrimidine-2-carboxylic acid (143.7 mg, 75% yield). 1H NMR (500 MHz, chloroform-d) δ 9.44 (s, 2H), 8.84 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.71-7.55 (m, 5H), 7.49 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H), 2.85 (s, 3H). m / z 432.0 [M+H] + .

[0593] Example 61 N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride [ka] A microwave vial was charged with Intermediate 7 (60 mg, 0.138 mmol), 7-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine (29 mg, 0.137 mmol), 1,4-dioxane (1.2 mL) and water (0.3 mL). The reaction mixture was evacuated and backfilled with nitrogen three times. 2 CO 3 (146 mg, 1.37 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added. The reaction mixture was then evacuated and backfilled with nitrogen three times before being irradiated in a microwave at 120° C. for 1 h. The reaction mixture was concentrated to dryness. The residue was taken up in DCM (10 mL) and the organics were washed with water (10 mL) and brine (10 mL). The collected organics were diluted with MgSO 4The solid was dried over hexane, filtered and concentrated to dryness under reduced pressure. Purification by flash silica column chromatography on an ISCO system (elution with a 40% EtOAc / PE gradient) gave the free base as an off-white solid. The solid was dissolved in DCM (1 mL) followed by addition of 1M HCl in ether (0.1 mL). Immediate formation of a solid was noted. The reaction was stirred for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the solid was further triturated with ether (3 mL). The solid was filtered, washed with ice-cold ether (2 mL) and dried under reduced pressure to give N-[6-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-2-methoxy-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide hydrochloride (27 mg, 33% yield) as a white solid. 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.52(s,1H), 8.79(d,J=7.0Hz,1H), 8.47(s,1H), 8.16(s,1H), 7.94-7.81(m,2H), 7.69(d,J=7.2Hz,2H), 7.60-7.50(m,3H), 3.92(s,3H), 2.66(s,3H). m / z 442.2 [M+H for free base] + .

[0594] Example 62 N-[2-Methoxy-6-(1,2,4-triazol-4-yl)-3-pyridyl]-5-methyl-3-phenyl-isoxazole-4-carboxamide [ka] Process 1 A microwave vial was charged with intermediate 1 (250 mg, 0.64 mmol), L-proline (14.8 mg, 0.13 mmol), ammonium bicarbonate (255 mg, 3.2 mmol) and DMSO (2 mL). The reaction mixture was evacuated and backfilled three times before copper(I) iodide (24.5 mg, 0.13 mmol)...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, Ring A is selected from A1, A2 and A3: 【Chemistry 2】 is selected from R １ is selected from phenyl and 5- or 6-membered heteroaryl; R １ Ha, Haro, C １～４ Alkyl, C １～４ Haloalkyl, -OR ａ１ , -SR ａ１ and -NR ａ１ R ｂ１ optionally substituted with one or more substituents selected from R ２ H, halo, C １～４ Alkyl, C １～４ Haloalkyl, -OR ａ２ , -SR ａ２ and -NR ａ２ R ｂ２ is selected from Said C １～４ Alkyl is halo, -OR ａ３ , -SR ａ３ and -NR ａ３ R ｂ３ optionally substituted with one or more substituents selected from R ３ is C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １～３ Alkyl-, -OR ４ , -NR ５ R ６ , -SR ５ , 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms and 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms-C １～３ alkyl-; R ４ and R ５ are independently H, C １～４ Alkyl, C １～４ Haloalkyl, C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １～３ Alkyl-, 4- to 7-membered heterocyclyl containing one or more ring oxygen atoms, and 4- to 7-membered heterocyclyl-C containing one or more ring oxygen atoms １～３ alkyl-; R ６ is H, C １～４ Alkyl and C １～４ haloalkyl; R ３ , R ４ , R ５ Or R ６ Any C in any of １～４ Alkyl, C ３～６ Cycloalkyl or C ３～６ Cycloalkyl-C １～３ Alkyl- is halo, -OR ａ４ , -SR ａ４ and -NR ａ４ R ｂ４ optionally substituted with one or more substituents selected from X １ , X ２ and X ３ are independently N and CR ７ Selected from: R ７ Each occurrence independently represents H, halo, -CN, C １～４ Alkyl, C １～４ Haloalkyl, -OR ８ , -NR ８ R ９ And -S(O) ｘ R ８ where x is 0, 1 or 2; R ８ and R ９ are each independently H, C １～４ Alkyl and C １～４ haloalkyl; R ７ , R ８ Or R ９ Any C in any of １～４ Alkyl is halo, -CN, -OR ａ５ , -S(O) ｘ R ａ５ (wherein x is 0, 1 or 2) and -NR ａ５ R ｂ５ optionally substituted with one or more substituents selected from Ring B is one or more R １０ C optionally substituted with ６～１０ selected from aryl and 5- to 12-membered heteroaryl, where when Ring B is a heteroaryl, Ring B is attached to the remainder of the compound of formula (I) by a ring atom in the aromatic ring of said heteroaryl; R １０ each occurrence independently represents halo, -CN, -NO ２ , =O, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, Q １ -L １ -, -OR １１ , -S(O) ｘ R １１ (wherein x is 0, 1 or 2); -NR １１ R ａ６ , -C(O)R １１ , -OC(O)R １１ , -C(O)OR １１ , -NR ａ６ C(O)R １１ , -NR ａ６ C(O)OR １１ , -C(O)NR １１ R ａ６ , -OC(O)NR １１ R ａ６ , -NR ａ６ SO ２ R １１ , -SO ２ N.R. １１ R ａ６ and -NR ａ６ C(O)NR １１ R ａ６ is selected from Said C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R １２ Optionally replaced by; R １１ are independently H, C １～６ Alkyl and C １～６ haloalkyl; １～６ Alkyl is one or more R １３ Optionally replaced by; Q １ Each occurrence of represents independently ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １～３ Alkyl-, 4- to 7-membered heterocyclyl, 4- to 9-membered heterocyclyl-C １～３ Alkyl-, phenyl, phenyl-C １～３ Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C １～３ alkyl-, Said C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １～３ Alkyl-, 4- to 7-membered heterocyclyl and 4- to 9-membered heterocyclyl-C １～３ Alkyl- is one or more R １４ and optionally replaced by The phenyl, phenyl-C １～３ Alkyl-, 5- or 6-membered heteroaryl and 5- or 6-membered heteroaryl-C １～３ Alkyl- is one or more R １５ Optionally replaced by; L １ is a bond, or -O-, -S(O) ｘ - (wherein x is 0, 1 or 2), -NR ａ７ -, -C(O)-, -OC(O)-, -C(O)O-, -NR ａ７ C(O)-, -C(O)NR ａ７ --, --NR ａ７ C(O)O-, -OC(O)NR ａ７ --, --NR ａ７ SO ２ -, -SO ２ N.R. ａ７ - and -NR ａ７ C(O)NR ａ７ - selected from; R １２ , R １３ and R １４ each occurrence independently represents halo, ═O, —CN, —NO ２ , C １～４ Alkyl, C １～４ Haloalkyl, -OR ａ８ , -S(O) ２ R ａ８ , -NR ａ８ R ｂ８ , -C(O)R ａ８ , -OC(O)R ａ８ , -C(O)OR ａ８ , -NR ａ８ C(O)R ｂ８ , -C(O)NR ａ８ R ｂ８ , -NR ａ８ C(O)OR ｂ８ , -OC(O)NR ａ８ R ｂ８ , -NR ａ８ SO ２ R ｂ８ and -SO ２ N.R. ａ８ R ｂ８ is selected from Said C １～４ Alkyl is halo, -CN, -OR ａ９ , -NR ａ９ R ｂ９ and -SO ２ R ａ９ optionally substituted by 1 or 2 substituents selected from R １５ each occurrence independently represents halo, ═O, —CN, —NO ２ , C １～４ Alkyl, C １～４ Haloalkyl, -OR ａ１０ , -S(O) ２ R ａ１０ , -NR ａ１０ R ｂ１０ , -C(O)R ａ１０ , -OC(O)R ａ１０ , -C(O)OR ａ１０ , -NR ａ１０ C(O)R ｂ１０ , -C(O)NR ａ１０ R ｂ１０ , -NR ａ１０ C(O)OR ｂ１０ , -OC(O)NR ａ１０ R ｂ１０ , -NR ｂ１０ SO ２ R ａ１０ and -SO ２ N.R. ａ１０ R ｂ１０ is selected from Said C １～４ Alkyl is halo, -CN, -OR ａ１１ , -NR ａ１１ R ｂ１１ and -SO ２ R ａ１１ optionally substituted by 1 or 2 substituents selected from R ａ１ , R ｂ１ , R ａ２ , R ｂ２ , R ａ３ , R ｂ３ , R ａ４ , R ｂ４ , R ａ５ , R ｂ５ , R ａ６ , R ａ７ , R ａ８ , R ｂ８ , R ａ９ , R ｂ９ , R ａ１０ , R ｂ１０ , R ａ１１ and R ｂ１１ Each occurrence of represents independently: H, C １～４ Alkyl and C １～４ haloalkyl; or Any -NR in the substituent ａ１ R ｂ１ , -NR ａ２ R ｂ２ , -NR ａ３ R ｂ３ , -NR ａ４ R ｂ４ , -NR ａ５ R ｂ５ , -NR ａ８ R ｂ８ , -NR ａ９ R ｂ９ , -NR ａ１０ R ｂ１０ , -NR ａ１１ R ｂ１１ , -NR ５ R ６ , -NR ８ R ９ Or -NR １１ R ａ６ can form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl being halo, ═O, C １～４ Alkyl and C １～４ haloalkyl) or a pharma- ceutically acceptable salt thereof, provided that (i) and (ii): (i) Ring A is A2, and R ２ is H, then R ３ is -NR ５ R ６ rather than; and (ii) The compound of formula (I) 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, which is not

2. R ２ is C １～４ alkyl, for example, R ２ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

3. R １ teeth, 【Chemistry 4】 (In the formula, X ４ is CH or N; and R １０１ is H or halo; Optionally, R １ teeth, 【Chemistry 5】 (selected from 2. The compound of claim 1, wherein:

4. Ring A is 【Chemistry 6】 2. The compound of claim 1 having a structure selected from:

5. X １ and X ２ is CH, and optionally, X ３ is N or CH, or a pharma- ceutically acceptable salt thereof.

6. X ３ is N, or a pharma- ceutically acceptable salt thereof.

7. X ２ and X ３ is N, and X １ is CR ７ and optionally, X １ or a pharma- ceutically acceptable salt thereof.

8. R ３ is -OR ４ and -NR ５ R ６ Optionally, R ４ is C ３～６ Cycloalkyl, C １～４ Alkyl and -NR ａ４ R ｂ４ C substituted by ２～４ alkyl; R ａ４ and R ｂ４ are independently H and C １～４ alkyl; and R ５ and R ６ are independently H and C １～４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is selected from the group consisting of aryl, ... and aryl;

9. (i) R ３ is -OR ４ and R ４ is C １～４ Alkyl and C ３～６ cycloalkyl; or (ii) R ３ is -OR ４ and R ４ is a 4- to 6-membered heterocyclyl containing one ring oxygen atom or a 4- to 6-membered heterocyclyl-C containing one ring oxygen atom １～３ is alkyl-; or (iii) R ３ is methoxy, 【Chemistry 7】 or (iv) R ３ teeth, 【Chemistry 8】 or (v) R ３ is methoxy, and 【Chemistry 9】 or (vi) R ３ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

10. (i) Ring B is each one or more R １０ and monocyclic or bicyclic 5- to 12-membered heteroaryl, optionally substituted with (ii) Ring B is each one or more R １０ or (iii) Ring B is one or more R １０ bicyclic 9- or 10-membered heteroaryl optionally substituted with 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein optionally, said heteroaryl in any of (i), (ii) and (iii) contains one ring nitrogen atom and optionally 1 to 3 ring heteroatoms selected from O, S and N.

11. Ring B is 【Chemistry 10】 (wherein p′ is 0 or 1; p″ is 0, 1 or 2; p''' is 0, 1, 2 or 3; and 【Chemistry 11】 indicates the point of attachment to the remainder of the compound of formula (I) 2. The compound of claim 1, selected from:

12. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring B is bonded to the remainder of the compound of formula (I) via a ring carbon atom in the aromatic ring in Ring B;

13. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring B is attached to the remainder of the compound of formula (I) via a ring nitrogen atom in the aromatic ring in Ring B.

14. (i) Ring B is 【Chemistry 12】 wherein p″ is 0, 1 or 2, and optionally p″ is 0. or (ii) Ring B is 【Chemistry 13】 (wherein p is 0, 1, 2 or 3; 【Chemistry 14】 indicates the point of attachment to the remainder of the compound of formula (I) or (iii) Ring B is 【Chemistry 15】 wherein p is 0 or 1; and 【Chemistry 16】 indicates the point of attachment to the remainder of the compound of formula (I); optionally, p is 1. or (iv) Ring B is 【Chemistry 17】 (In the formula, 【Chemistry 18】 indicates the point of attachment to the remainder of the compound of formula (I) 2. The compound of claim 1, wherein:

15. (i) R １０ Each occurrence independently represents halo, -CN, C １～４ Alkyl, C １～４ Haloalkyl, -C １～４ Alkyl-NR ａ８ R ｂ８ , —OH, —OC １～４ Alkyl, -OC １～４ Haloalkyl, -OC ２～４ Alkyl-NR ａ８ R ｂ８ , -NH ２ , -NR ａ６ C １～４ Alkyl, -NR ａ６ C ２～４ Alkyl-OR ａ８ , -NR ａ６ C ２～４ Alkyl-NR ａ８ R ｂ８ , -C(O)C １～４ Alkyl, -C(O)C １～４ Haloalkyl, —C(O)C １～４ Alkyl-NR ａ８ R ｂ８ , -COOH, -C(O)OC １～４ Alkyl, —C(O)NR ａ６ C １～４ Alkyl, —C(O)NR ａ６ C ２～４ Alkyl-OR ａ８ , -C(O)NR ａ６ C ２～４ Alkyl-NR ａ８ R ｂ８ and Q. １０２ -L １０２ - selected from; Q １０２ is selected from 4- to 6-membered heterocyclyl and 5- or 6-membered heteroaryl; The 4- to 6-membered heterocyclyl is independently halo, ═O, C １～４ Alkyl, -OR ａ８ , -NR ａ８ R ｂ８ and -C(O)R ａ８ azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted by one or more (e.g., 1 or 2) substituents selected from The 5- or 6-membered heteroaryl is independently halo, C １～４ Alkyl, -OR ａ１０ and -NR ａ１０ R ｂ１０ selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl, optionally substituted by one or more (e.g., 1 or 2) substituents selected from L １０２ is a bond or C １～３ Alkylene, —O— and —NR ａ７ - selected from; or (ii) R １０ is -NR ａ８１ R ｂ８１ , -C １～３ Alkyl-NR ａ８１ R ｂ８１ , -NR ａ８１ -C ２～３ Alkyl-NR ａ８１ R ｂ８１ , -C(O)C １～３ Alkyl-NR ａ８１ R ｂ８１ and -C(O)NR ａ８１ C ２～３ Alkyl-NR ａ８１ R ｂ８１ is selected from R ａ８１ and R ｂ８１ are independently H and C １～３ alkyl; or (iii) R １０ is -NR ａ８１ R ｂ８１ and -C １～３ Alkyl-NR ａ８１ R ｂ８１ is selected from R ａ８１ and R ｂ８１ are independently H and C １～３ alkyl; or (iv) R １０ is fluoro, chloro, cyano, nitro, oxo, hydroxy, methyl, ethyl, isopropyl, cyclopropyl, amino, -NH(Me), -N(Me) ２ , 【Chemistry 19】 【Chemistry 20】 (In the formula, 【Chemistry 21】 indicates the point of attachment to ring B.

2. The compound of claim 1, selected from:

16. Ring B is 【Chemical 22】 optionally, Ring B is selected from 【Chemistry 23】 2. The compound of claim 1, wherein:

17. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from compound list 1 herein.

18. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

19. α5-GABA Ａ A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prophylaxis or treatment of a receptor-mediated disease or medical disorder.

20. α5-GABA Ａ A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prophylaxis or treatment of cognitive impairment associated with a receptor-mediated disease or medical disorder.

21. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prophylaxis or treatment of a disease or medical disorder mediated by an α5-GABA A receptor, comprising: α5-GABA Ａ The disease or medical disorder mediated by R may be Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive impairment (e.g., cognitive impairment associated with chemotherapy, anesthetics, bacterial or viral infections (e.g., HIV)), memory impairment, age-related cognitive impairment (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, Down's syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or parasympathetic nervous system disorders). frenetic disorder), psychosis, post traumatic stress disorder, anxiety disorder, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, alcohol disorder (e.g., alcoholism), drug withdrawal, movement disorder, restless legs syndrome, cognitive impairment disorder, multi-infarct dementia, vascular dementia, mood disorder, depression, neuropsychiatric disorder, attention deficit hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive impairment associated with stroke, cognitive impairment associated with brain injury or trauma, cognitive impairment associated with brain tumor, attention disorder, and Dup15q syndrome; 19. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, optionally for use in the treatment or prevention of post-operative cognitive dysfunction, such as anaesthetic-induced cognitive dysfunction.

22. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the prophylaxis or treatment of cognitive impairment associated with a disease or medical disorder mediated by the α5-GABA A receptor, comprising: The disease or medical disorder mediated by α5-GABA A R includes Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive impairment (e.g., cognitive impairment associated with chemotherapy, anesthetics, bacterial or viral infection (e.g., HIV)), memory impairment, age-related cognitive impairment (e.g., mild cognitive impairment, MCI), bipolar disorder, autism, Down's syndrome, neurofibromatosis type I, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis (ALS), psychotic disorders (e.g., schizophrenia, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or parasympathetic nervous system disorders). frenetic disorder), psychosis, post traumatic stress disorder, anxiety disorder, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug addiction, alcohol disorder (e.g., alcoholism), drug withdrawal, movement disorder, restless legs syndrome, cognitive impairment disorder, multi-infarct dementia, vascular dementia, mood disorder, depression, neuropsychiatric disorder, attention deficit hyperactivity disorder, neuropathic pain, chronic neuroinflammation, cognitive impairment associated with stroke, cognitive impairment associated with brain injury or trauma, cognitive impairment associated with brain tumor, attention disorder, and Dup15q syndrome; 19. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, optionally for use in the treatment or prevention of post-operative cognitive dysfunction, such as anaesthetic-induced cognitive dysfunction.

23. α5-GABA Ａ for use in the prevention or treatment of a neurological or neuropsychiatric disorder mediated by R (e.g., for the treatment or prevention of cognitive impairment associated with a neurological or neuropsychiatric disorder); Optionally, the neurological disease is a neurodevelopmental disorder (e.g., Attention Deficit Disorder (ADHD), Down's Syndrome, a learning disability, cerebral palsy, autism, or a speech disorder); Optionally, the neurological disease is a neurodegenerative disease (e.g., Alzheimer's disease, dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or Creutzfeldt-Jakob disease (CJD)); for example, the neurodegenerative disease is Huntington's disease. The compound of any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof or the pharmaceutical composition of claim 18.

24. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the treatment or prevention of psychiatric and / or neurological symptoms (in particular cognitive dysfunction) caused by or associated with a viral or bacterial infection.

25. A compound according to any one of claims 1 to 17 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, for use in the treatment or prevention of depression.

26. For use in the treatment or prevention of cognitive impairment associated with a psychotic disorder; Optionally, the compound or composition according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, is for use in the treatment or prevention of cognitive impairment associated with schizophrenia.

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